key: cord-321997-3dkl6iha authors: hussain, abdulzahra; vasas, peter; el-hasani, shamsi title: obesity as a risk factor for greater severity of covid-19 in patients with metabolic associated fatty liver disease date: 2020-04-29 journal: metabolism doi: 10.1016/j.metabol.2020.154256 sha: doc_id: 321997 cord_uid: 3dkl6iha nan j o u r n a l p r e -p r o o f disease progression. not only, nash and nafld are important predictive factors for the outcomes in acute and chronic disease processes but also the obesity surgery and its complications [7] . we think that the authors had reached the correct conclusion indirectly, as obesity is the primary aetiology for the liver disease [nash, nafled] and rarely considered as independent conditions. when they coexist, they do so because of obesity. several other studies have reported obesity as a significant factor for mortality in covid-19 patients [8-10].this subject is more important in the current covid-19 crisis knowing the pandemic of obesity. in addition to the known defective immune system in the obesity, the virulence of covid-19 and the differences in the incidence of obesity across the world, it is not clear what is the magnitude /severity of liver disease could add to production of critical illness like severe pneumonia. we believe more powerful studies are needed to confirm why obesity is a risk factor for critical illness and or mortality in covid-19. this will help to reduce mortality in this vulnerable group of patients. declaration: authors confirm no conflict of interest and no funding for this paper obesity as a risk factor for greater severity of covid-19 in patients with metabolic associated fatty liver disease nonalcoholic steatohepatitis: a review effect of body mass index, metabolic health and adipose tissue inflammation on the severity of non-alcoholic fatty liver disease in bariatric surgical patients: a prospective study applying non-invasive fibrosis measurements in nafld/nash: progress to date effects of laparoscopic sleeve gastrectomy on non-alcoholic steatohepatitis and liver fibrosis in japanese patients with severe obesity anand u 3 .non-alcoholic fatty liver disease: growing burden, adverse outcomes and associations nonalcoholic steatohepatitis is associated with increased mortality in obese patients undergoing bariatric surgery obesity is associated with severe forms of covid-19.obesity (silver spring) risk of covid-19 for patients with obesity lille intensive care covid-19 and obesity study group. high prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (sars-cov-2) requiring invasive mechanical ventilation.obesity (silver spring) key: cord-266380-lu6hj3a2 authors: alfaris, nasreen title: management of obesity in saudi arabia during the era of covid‐19: a clash of two pandemics date: 2020-10-01 journal: obesity (silver spring) doi: 10.1002/oby.23055 sha: doc_id: 266380 cord_uid: lu6hj3a2 obesity remains one of the world’s most challenging pandemics. the kingdom of saudi arabia carries one of the highest burdens of obesity with a prevalence of 35 %. unfortunately, . covid‐19 has arisen as an added challenge shifting focus and valuable resources to managing this emerging threat. in saudi arabia, 58% of the population are under the age of 35 years, and only 3.2% are over the age of 65 years, but unfortunately, the burden of obesity in the kingdom poses a risk of developing a more severe complicated infection. this article is protected by copyright. all rights reserved in saudi arabia, 58% of the population are under the age of 35 years, and only 3.2% are over the age of 65 years, 2 but unfortunately, the burden of obesity in the kingdom poses a risk of developing a more severe complicated infection. 3 on february 27,2020 the first response to the pandemic by the kingdom was with the swift suspension of all pilgrimage to makkah and madinah .the first case of covid-19 was confirmed on march 2 nd , 2020, and as of september 21,2020 , there were 6,093,601 tests performed with 330,246 confirmed cases and 4,512 deaths. 4 the country's ministry of health (moh) created a mobile phone application and website inquiring about symptoms and history of contacts, and a royal decree with a directive that all foreigners are entitled to free testing and treatment regardless of their visa status resulted in an active testing campaign for all migrant workers in their neighborhoods and residences. but these measures taken to contain the infection were not without consequences. key challenges that were specific for obesity care, included reduced access to healthcare resources, isolating patients, limiting their physical activity, and causing disruptions in eating habits with irregular mealtimes, frequent snacking, more processed meals, and increased anxiety and depression. to tackle these challenges the moh in saudi arabia utilized all resources to establish obesity telemedicine clinics and as a result, physicians were able to ensure that outpatient visits for obesity were not cancelled or postponed and free-of-charge home delivery for pharmacotherapy for obesity was enabled. after the lockdowns were lifted on may 31,2020, individuals with a bmi ≥ 40 kg/m 2 were instructed to continue working remotely. despite these measures, the pandemic resulted in the magnification of obesity stigma. jokes and memes about weight gain during lockdown, the reemergence of stigmatizing images of individuals with obesity, and the pressure to utilize the time during lockdown to lose weight, are this article is protected by copyright. all rights reserved some of the day-to-day struggles that our patients are being subjected to. this is particularly destructive in a culture where bmi is a measure of social acceptance and blame is laid on individuals with obesity. furthermore, individuals with obesity were being pressured to utilize the time of lockdown to lose weight. failure to do that, may have resulted in further isolation after the lockdowns and curfews were lifted resulting in devastating consequences including adapting unhealthy eating behaviors, anxiety, depression and worsening of their disease. 5 at a time when the focus is only the immediate covid-19 pandemic, our patients with obesity should not be lost, nor forgotten. it is important to understand the unique risks our patients with obesity are facing during these challenging times and to establish a strategy for caring for patients with obesity during epidemics. obesity in patients younger than 60 years is a risk factor for covid-19 hospital admission obesity stigma as a barrier to healthy eating behavior key: cord-354805-5wnp02wd authors: concepción‐zavaleta, marcio josé; gutiérrez‐ortiz, claudia; coronado‐arroyo, julia cristina; zavaleta‐gutiérrez, francisca elena; concepción‐urteaga, luis alberto title: covid‐19 and obesity: the intersection between a pandemic and an epidemic in a developing country date: 2020-09-21 journal: obesity (silver spring) doi: 10.1002/oby.23027 sha: doc_id: 354805 cord_uid: 5wnp02wd we have read with great interest the prospective cohort study published by czernichow et al (1), wherein they found that obesity doubles mortality in patients hospitalized with coronavirus disease (covid‐19), using as an indicator anthropometric, the body mass index (bmi). despite bmi being recognized as an anthropometric index of obesity and various studies confirming that it predicts cardiovascular events, the lack of information it provides on the distribution of body fat is considered its main limitation. the use of abdominal circumference and waist‐height ratio are better measures of visceral fat distribution, which is more closely associated with cardiometabolic risk;(2) however, those measures demand greater contact with covid‐19 patients. disclosure: the authors declared no conflict of interest dear editor, we have read with great interest the prospective cohort study published by czernichow et al 1 , wherein they found that obesity doubles mortality in patients hospitalized with coronavirus disease (covid-19), using as an indicator anthropometric, the body mass index (bmi). despite bmi being recognized as an anthropometric index of obesity and various studies confirming that it predicts cardiovascular events, the lack of information it provides on the distribution of body fat is considered its main limitation. the use of abdominal circumference and waist-height ratio are better measures of visceral fat distribution, which is more closely associated with cardiometabolic risk; 2 however, those measures demand greater contact with covid-19 patients. excess mortality and severity of the covid-19 disease in people with obesity is also prevalent in developing countries with constrained resources such as peru, in which preliminary findings reported by the ministry of health show that among people with obesity died from covid-19, 85.5% had obesity as assessed by bmi. excess weight continues to be a major public health problem in our country. at present, 22.7% of peruvians have obesity, representing an increase of 1.7% compared with data from 2017. moreover, obesity is more prevalent in peruvian women (26%) than in peruvian men (19.3%). the population of individuals with excess weight, including overweight and obesity, reached 60%, a value that has increased by 2.1% compared with data from 2017. 3 these two conditions are this article is protected by copyright. all rights reserved strongly associated with pre-diabetes and diabetes, which exhibit a prevalence of 22.4% and 7%, respectively, in the peruvian population 4 there are multiple mechanisms that might explain why people with obesity have more mortality and a severe course of covid-19 infection. 1 severe acute respiratory syndrome coronavirus 2 (sars-cov-2) penetrates human cells through direct binding with angiotensin converting enzyme 2 (ace2) receptors on the cell surface. the ace2 expression in adipose tissue is higher than that in the lung, a major target organ affected by covid-19. the population with obesity has more adipose tissue and adipose tissue might serve as a viral reservoir. furthermore, obesity is associated with a state of chronic low-grade inflammation and increased levels of circulating proinflammatory cytokines, such as leptin, tumor necrosis factor α, and interleukin 6, which may impair immune response and affect the lung parenchyma, thus contributing to increased morbidity associated with obesity in covid-19 infection. 5 additionally, obesity is associated with insulin resistance, overactivity of the renin angiotensin-aldosterone system, impaired pulmonary function, and hypercoagulability, which are associated with worse outcomes in covid-19 infection. 1 to date, despite recognition of the many conditions associated with obesity, peru has not developed an effective public health program for the prevention and control of obesity. additionally, obesity it is not considered a chronic disease, and thus does not have insurance coverage. 6 as studies have highlighted the association between this disease and its mortality and severity of sars-cov-2 infection, peru and other countries are recognizing the importance of considering obesity as a disease and developing effective health system strategies and public health approaches. obesity doubles mortality in patients hospitalized for sars-cov-2 in paris hospitals, france: a cohort study on 5795 patients association between anthropometric indicators of obesity and cardiovascular risk factors among adults in prediabetes in peru: consensus of experts prevalence of diabetes and impaired fasting glucose in peru: report from perudiab, a national urban population-based longitudinal study the impact of obesity on severe disease and mortality in people with sars-cov-2: a systematic review and meta-analysis obesity and outcomes in covid-19: when an epidemic and pandemic collide overweight and obesity in peru: urgent need to have a public health policy for their control this article is protected by copyright. all rights reserved key: cord-277074-1emlkii0 authors: ekiz, timur; pazarlı, ahmet cemal title: relationship between covid-19 and obesity date: 2020-06-02 journal: diabetes metab syndr doi: 10.1016/j.dsx.2020.05.047 sha: doc_id: 277074 cord_uid: 1emlkii0 n/a. as the high prevalence of obesity in covid-19 has been shown, the possible interactions between obesity and covid-19 need to be further deciphered. from this point of view, we determined the obesity prevalence of the top 20 ranked countries by total deaths due to covid-19. the data regarding the obesity prevalence of countries were obtained from global health services data of the world health organization [1, 2] . interestingly, the united states of america ranked first in terms of obesity prevalence (36.2%), overweight prevalence (31.7%), and also the number of total deaths. overall, most of the countries had a prevalence between 20% and 30% (e.g., uk, canada, iran, mexico, chile). the obesity prevalence was less than 10% in two countries (india and china) only ( figure 1 ). when we look at the correlation analysis between the obesity prevalence and the number of total deaths de to covid-19, the number of total deaths significantly correlated with the obesity prevalence (p=0.039, r=0.464) (figure 2) . in other words, as the obesity prevalence increased, the number of total deaths increased. it can be said that obesity-related conditions seem to worsen the effect of covid-19. herein, we believe that cardiovascular and metabolic effects, sleep apnea, vitamin d deficiency, dysregulation of the renin-angiotensin-aldosterone system (raas) as well as sarcopenia should be taken into account as obesity-related confounders to covid-19. therefore, highlighting the possible associations of the aforementioned conditions would be reasonable for the fight against covid-19. the angiotensin-converting enzyme 2 (ace2) is shown to be the entry point of severe acute respiratory syndrome coronavirus 2 (sars-cov-2). this makes sense in patients with obesity because dysregulation/increase of the raas has deleterious influences on several systems, has been shown in patients with obesity. for instance, the dysregulation of the raas causes vasoconstriction, increased blood pressure, oxidative stress, inflammation, endothelial dysfunction, maladaptive immune modulation as well as fibrosis [3] . as such, obesity is a significant risk factor of diabetes mellitus, increased blood pressure, cardiovascular diseases, and respiratory diseases. further, myeloid and lymphoid responses within the raas receptor signaling are associated with abnormal cytokine profiles. the adipose tissue can manifest as a reservoir for a wider viral spread with increased shedding, immune activation, and cytokine amplification in relevant patients as well [4, 5] . on the other hand, obstructive sleep apnea (osa) is a sleep-related breathing disorder, which is characterized by hypoxia and apnea/hypopnea due to the intermittent collapse of the upper airways during sleep. first of all, obesity is a predominant risk factor for osa (obesity hypoventilation syndrome), and osa patients may be vulnerable to covid-19. obesity hypoventilation syndrome contributes to respiratory failure in patients with acute respiratory distress syndrome. [6] . this fact is vital for patients, particularly with respiratory distress and followed-up in intensive care units [7] . sleep efficacy has multisystemic effects and is accepted as a very important factor for the regulation and maintenance of the immune system. worse sleep efficacy is associated with decreased immune system activity [4] . the dysregulation/increase of the raas has been shown in osa patients, likewise in obesity [6] . vitamin d deficiency, very common in people with obesity, is accepted as another pandemic and has unfavorable impacts on several systems. immunomodulant, antiinflammatory and protective effects against infections have been shown. additionally, it should be kept in mind that vitamin d deficiency worsens obesity by enhancing lipogenesis [8] . on the other hand, sarcopenia, the age-related loss of muscle mass and function, with obesity (sarcopenic obesity) is seen in approximately one-fifth of older populations. sarcopenia is a physical determinant of frailty, and sarcopenic obesity is highly in association with increased risk of disability, institutionalization, and even mortality [9] . global health services data, obesity and overweight: world health organization coronavirus disease (covid-2019) situation reports. geneva: world health organization covid and the renin-angiotensin system: are hypertension or its treatments deleterious? front cardiovasc med is adipose tissue a reservoir for viral spread, immune activation and cytokine amplification in covid-19. obesity (silver spring) targeting the adipose tissue in covid-19.obesity (silver spring) coronavirus disease 2019 and obstructive sleep apnea syndrome obesity and the lung: 3. obesity, respiration and intensive care pereira-santos m obesity and overweight decreases the effect of vitamin d supplementation in adults: systematic review and meta-analysis of randomized controlled trials sarcopenic obesity: how do we treat it? timur ekiz reports no conflict of interest ahmet cemal pazarlı reports no conflict of interest key: cord-351223-nnuoadh6 authors: pettit, natasha n.; mackenzie, erica l.; ridgway, jessica; pursell, kenneth; ash, daniel; patel, bhakti; pho, mai t. title: obesity is associated with increased risk for mortality among hospitalized patients with covid‐19 date: 2020-06-26 journal: obesity (silver spring) doi: 10.1002/oby.22941 sha: doc_id: 351223 cord_uid: nnuoadh6 objective: obesity has been identified as a risk factor for severe covid‐19 caused by the sars‐cov2 virus, however a direct association with mortality has not been reported. we sought to determine whether obesity is a risk factor for mortality among covid‐19 patients. methods: the study was a retrospective cohort, including patients with covid‐19 between march 1 and april 18, 2020. the primary objective was to determine if obesity is a predictor of mortality. results: a total of 238 patients were included, 218 patients (91.6%) were african american, 113 (47.5%) were male, and the mean age was 58.5 years. of the included patients, 146 (61.3%) were obese (bmi >30kg/m(2)), with 63 (26.5%), 29 (12.2%), and 54 (22.7%) with class 1, 2, and 3 obesity, respectively. obesity was identified as a predictor for mortality (or 1.7(1.1‐2.8),p=0.016), as was male gender (or 5.2(1.6‐16.5),p=0.01) and older age (or 3.6(2.0‐6.3),p<0.0005). obesity (or 1.7(1.3‐2.1),p<0.0005) and older age (or 1.3(1.0‐1.6),p=0.03) were also risk factors for hypoxemia. conclusions: obesity was found to be a significant predictor for mortality among inpatients with covid‐19 after adjusting for age, gender, and other comorbidities. patients with obesity were also more likely to present with hypoxemia. conclusions: obesity was found to be a significant predictor for mortality among inpatients with covid-19 after adjusting for age, gender, and other comorbidities. patients with obesity were also more likely to present with hypoxemia. several risk factors for severe disease and poor outcomes in coronavirus disease 2019 (covid-19) have been identified. [1] [2] [3] [4] [5] [6] [7] early reports from chinese series identified hypertension, diabetes, chronic pulmonary disease, and cardiovascular disease as the comorbidities most consistently associated with hospitalization, respiratory support, intensive care unit (icu) admission, and death in covid-19 patients. subsequent reports from the united states and europe suggested that patients with a higher body mass index (bmi) are at greater risk for hospital admission and severe disease requiring respiratory support. 8, 9 based on these reports that many patients hospitalized for covid-19 had a bmi >30kg/m 2 , we sought to evaluate whether obesity was associated with all-cause mortality in hospitalized patients with confirmed covid-19 at a single academic medical center. we also examined the association between obesity and secondary outcomes including hypoxemia upon hospital admission, icu admission at any point, mechanical ventilation at any point, and hospital length of stay. this article is protected by copyright. all rights reserved. all sars-cov2 positive patients admitted to the university of chicago medical center, an 811bed academic medical center on the south side of chicago, between march 1, 2020 and april 18, 2020 who had completed their hospital course (including deceased patients) were included in the analysis. a diagnosis of covid-19 required a positive sars-cov2 test using the roche cobas® sars-cov-2 rt-pcr high-throughput assay or xpert xpress® sars-cov-2 assay. 10 11 information was recorded on patient age, race/ethnicity, bmi, comorbidities, covid-19directed therapies (antivirals, il-6 cytokine inhibitor therapy), admission oxygen requirement, and survival-to-discharge. admission to the icu, need for mechanical ventilation, and hospital length of stay were also documented. the primary analysis was the relationship between the primary endpoint of all-cause mortality and bmi group after multivariable adjustment for demographics and comorbidities. secondary analyses included assessing the association of bmi group with oxygen requirement upon hospital admission, length of stay, icu admission at any point, and mechanical ventilation at any point. data are reported as median (interquartile range) or mean (standard deviation) for continuous variables and as frequency (percentage) for categorical variables. tests of significance for differences between obesity groups were done using the kruskal-wallis test for continuous variables, and the fisher's exact test for categorical variables. effects of obesity on mortality and admission hypoxemia were assessed using a multivariable logistic regression with an additive effects model to adjust for comorbid. a p-value < 0.05 was considered significant for this article is protected by copyright. all rights reserved. covariates in the multivariable analysis, and bivariate analyses were also done for all covariates in the multivariable model. bonferroni correction was applied to all univariate and bivariate pvalues to control the family-wise error rate at 0.05. all statistical analyses were performed with stata version 15.0. this project received a formal determination of quality improvement status according to university of chicago medicine institutional policy. as such, this initiative was deemed not human subjects research and was therefore not reviewed by the institutional review board. a total of 238 patients with covid-19 were included. baseline characteristics, length of stay, and mortality rates for each of the 5 bmi categories are shown in after bonferroni correction). the majority of patients were african american (91.6%). the most common comorbidities were hypertension (52.9%), diabetes (28.6%), pulmonary disease (26.5%), and cardiovascular disease (21.4%). more patients in the higher obesity groups had diabetes. on hospital admission, 98 (41.2%) of patients were on room air, 120 (50.4%) required 1-5l supplemental oxygen via nasal cannula, and 12 (5%) required oxygen supplementation of 6l via nasal cannula or more. four patients (1.7%) required high-flow nasal cannula and an additional this article is protected by copyright. all rights reserved. 4 patients (1.7%) were intubated on presentation. patients with obesity were more likely to require supplemental oxygen on presentation compared to normal weight patients (32.6% of normal weight patients requiring supplemental oxygen vs 58.7% in class 1 obesity, 62.1% in class 2 obesity, and 77.8% in class 3 obesity, fisher's exact test p < 0.001). approximately 70% of patients received covid-19 directed therapy (antivirals and/or immunemodulators). about one-quarter of patients (27.3%) eventually required icu admission and 14.7% were intubated during their hospital course. the overall median length of stay was 5 (iqr 3-8) days and the overall mortality rate was 10.1%. there were no significant differences between groups with respect to these outcomes. table 3 summarizes the results of the regression analyses for mortality and hypoxemia on admission. obesity, male gender, and older age were associated with increased mortality. significant predictors for hypoxemia on admission included obesity and age as well. older age was the only variable associated with icu admission after multivariable adjustment for other covariates (or 1.4, 95% ci 1.1-1.8, p=0.01, data not shown). older age (or 1.6, 95% ci 1.2-2.2, p=0.01) was associated with requirement for mechanical ventilation (data not shown). none of the variables assessed were significantly associated with length of stay after multivariable adjustment (data not shown). this article is protected by copyright. all rights reserved. our study shows that amongst hospitalized patients with covid-19 infection, obesity was significantly associated with mortality after adjusting for age, gender, and other comorbidities. for every increase from one bmi category to the next, there was a 70% increased odds of mortality in the multivariable model. this finding provides further evidence that obesity is a key comorbidity in covid-19 that may not only predict severe disease requiring hospital admission, oxygen supplementation, or mechanical ventilation, but may also predict increased mortality. 8, 9 we also found that older age and male gender was significantly associated with mortality, as has elsewhere been reported. [1] [2] [3] [4] [5] [6] [7] although patients with obesity in our study were more likely to require supplemental oxygen on admission, there was no significant association between obesity and the need for icu admission or mechanical ventilation throughout the hospital stay. this may reflect our small sample size or our institution's practice of using high-flow nasal cannula or helmet ventilation rather than intubation for respiratory support, when possible. our finding of an association between obesity and severe covid-19 with poor clinical outcomes is congruent with what has been observed with other severe viral infections, including h1n1. obesity was found to be associated with an increased risk of severe disease, hospitalization, and death during the 2009 h1n1 influenza pandemic. 12, 13 there is evidence that impaired lung mechanics and higher concentrations of pro-inflammatory molecules may both contribute to the propensity in patients with obesity to develop more severe complications from respiratory viral infections. abdominal obesity restricts the movement of the diaphragm and chest wall, this article is protected by copyright. all rights reserved. resulting in a reduction in functional residual capacity and making mechanical ventilation more challenging. 14, 15 patients with obesity are also known to have higher concentrations of proinflammatory cytokines and adipokines (e.g. leptin, alpha-tnf, mcp-1, and il-6) and lower antiinflammatory adipokine concentrations (e.g. adiponectin) which can result in a dysregulated immune response. 16 our study has several limitations, including small sample size and use of retrospective observational analysis. additionally, >90% of the patients in our study population were african american, potentially limiting applicability of our results to other populations and limiting our ability to examine the relationship between race, obesity, and severe illness. as we did not evaluate cause of death, we were unable to assess whether there is a common pathway to mortality in covid-19 patients with obesity. our findings add further weight to the evidence that patients with obesity are at greater risk for severe disease and mortality in covid-19. future studies reporting on the covid-19 patient population should include obesity as a comorbidity to validate and account for these findings. additional studies are also needed to further explore the relationship between race and obesity in severe disease. (7) 2 (4.1) 0 (0) 0 (0) 5 (9.3) 0.08 * significant after bonferroni correction for multiple comparisons (p < 0.0038) †asthma, chronic obstructive pulmonary disease, bronchitis, sarcoidosis, obstructive sleep apnea ‡ coronary artery disease, heart failure, valvular heart disease, arrhythmia abbreviations: bmi: body mass index; sd: standard deviation; vte: venous thromboembolism this article is protected by copyright. all rights reserved. this article is protected by copyright. all rights reserved. clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study clinical features of patients infected with 2019 novel coronavirus in wuhan, china clinical course and outcomes of critically ill patients with sars-cov2 pneumonia in wuhan, china: a single-centered, retrospective, observational study epidemiologic features and clinical course of patients infected with sars-cov2 in singapore baseline characteristics and outcomes of 1591 patients infected with sars-cov2 admitted to icus of the lombardy region, italy characteristics and outcomes of 21 critically ill patients with covid-19 in washington state covid-19 in critically ill patients in the seattle region -case series obesity in patients younger than 60 years is a risk factor for covid-19 hospital admission high prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (sars-cov2) requiring invasive mechanical ventilation the detection of sars-cov2 using the cepheid xpert xpress sars-cov2 and roche cobas sars-cov2 assays morbid obesity as a risk factor for hospitalization and death due to 2009 pandemic influenza a (h1n1) disease risk factors for severe outcomes following 2009 influenza a (h1n1) infection: a global pooled analysis the effect of obesity on lung function ards in obese patients: specificities and management influenza and obesity: its odd relationship and the lessons for covid-19 pandemic key: cord-267505-4tw7kfek authors: frühbeck, gema; baker, jennifer lyn; busetto, luca; dicker, dror; goossens, gijs h.; halford, jason c.g.; handjieva-darlenska, teodora; hassapidou, maria; holm, jens-christian; lehtinen-jacks, susanna; mullerova, dana; o'malley, grace; sagen, jørn v.; rutter, harry; salas, ximena ramos; woodward, euan; yumuk, volkan; farpour-lambert, nathalie j. title: european association for the study of obesity position statement on the global covid-19 pandemic date: 2020-04-27 journal: obes facts doi: 10.1159/000508082 sha: doc_id: 267505 cord_uid: 4tw7kfek nan of health and well-being, is greatly concerned about this global health challenge and its significant impacts on individuals, families, communities, health systems, nations, and wider society. it may seem counterintuitive that covid-19, a communicable disease, has such contiguity with non-communicable diseases such as obesity. however, people with obesity have an elevated risk of hospitalization, serious illness, and mortality, likely due to chronic lowgrade inflammation [1] , an altered immune response to infection, as well as related cardiometabolic comorbidities [2] , and the covid-19 pandemic is likely to have a significant impact on people with obesity. the lockdowns imposed by many countries, combined with extensive efforts to isolate both vulnerable populations and people with diagnosed or suspected covid-19 and to quarantine potential contacts, have many consequences for health behaviours and well-being. in the face of this crisis, we will also witness how psychosocial determinants of health, including geographic location, and access to care affect global health in general and people living with obesity in particular. given that obesity is a prevalent, persistent, serious, complex, chronic, and relapsing disease among the general population [3] , it is important that we pay special attention to these challenges especially during the covid-19 pandemic and when planning management of the aftermath to avoid placing an even greater burden on individuals, health systems, and society over the short, medium, and long term. as a complement to the immediate and urgent healthcare response it is also imperative to consider potential future health consequences. pandemics can influence thinking and drive maladaptive behaviours among individuals through cognitive distortion. quarantine and isolation may increase psychosocial distress in many ways, influenced by duration, the provision of information, fear of infection, social and familial isolation, the availability of supplies, financial hardship, and stigmatization. several strategies can help reduce the impact of these stressors. in this context, providing detailed and credible information, optimizing remote clinical support, virtual connections to family and friends to increase/support/retain emotional closeness, facilitating entertainment and activities (e.g., books, games, indoor hobbies and physical activity, phones, internet access), and appealing to altruism to validate the efforts of individuals in isolation and quarantine are helpful strategies [4] . trust is an essential element of taking a rational approach to this crisis. scientific societies can play a key role in facilitating dissemination of credible, timely information. to respond to urgent covid-19 healthcare needs, much health service delivery has been restructured, and elective, non-essential medical and surgical procedures have been postponed. this restructuring of health services can preserve personal protective equipment, beds, ventilators, and other material for reallocation in response to the crisis. bariatric medical and surgical procedures have been among those cancelled, and regular appointments of other non-acute patients have been scaled down, leaving many people with chronic diseases without the appropriate care they need. the role of easo is crucial in (1) identifying the particular needs of healthcare providers and persons living with obesity during the covid-19 pandemic, (2) disseminating sciencebased information, and (3) sharing knowledge, evidence-based recommendations, and guidance toward the clinical, patient, and policy communities using social and other media, which allow us to reach millions of people across europe. fortunately, easo has many communication channels and can be creative in engaging with our wide constituency and stakeholder communities. in collaboration with the easo european coalition for people living with obesity (ecpo), easo is committed to activating channels to identify the information and support needs of people with obesity, and to respond to those needs in an evidence-based and patient-centred way. easo and ecpo have actively confronted this challenging situation by sharing best practices, recommendations, and useful tips on how to cope with quarantine measures. to create these resources, easo focuses on the four pillars of health promotion individuals can act upon, namely (1) energy intake (including hydration), (2) energy expenditure, (3) sleep, and (4) mental health and resilience. during quarantine, it is particularly important for all of us to maintain psychological well-being (see specific resource on "practical advice on how to maintain healthy lifestyle habits amidst the covid-19 pandemic" on the easo website) [5] . the covid-19 pandemic will pass, but the challenge to nurture our health in meaningful and feasible ways and to avoid potential collateral effects will remain. for this reason, it is particularly important to work together, supporting communities to prevent and manage obesity, particularly during periods of prolonged lockdown. there are, for example, ways to prevent obesity progression through reduced energy intake if we are moving less; fun and creative ways to increase energy expenditure at home; and psychological strategies to reduce stress, avoid emotional eating, and optimize sleep. obesity management strategies such as behavioural and medical interventions can also be implemented while in lockdown. we recognize that people with obesity face many challenges in their communities, including pervasive weight bias and stigma [6] . we have seen an increasing frequency of fat shaming memes on social media, which perpetuate misconceptions about obesity and about people with obesity. easo challenges weight bias and obesity stigma. stigmatizing healthcare experiences may cause people with obesity to avoid or delay contacting healthcare providers during this pandemic, which may result in more severe covid-19 outcomes [7] . like all people living with chronic disease, persons living with obesity may need continued support to manage their disease during the covid-19 pandemic. in the absence of physical consultations with healthcare professionals, obesity care may be delivered using telemedicine. easo can facilitate the delivery of quality care by sharing information and providing recommendations for the development and implementation of virtual telemedical clinical consultations. easo experts are developing protocols for virtual consultations for patients with obesity during the covid-19 pandemic, which will be shared on the easo website. there is emerging evidence that obesity is associated with significantly higher intensive care unit resource utilization [8, 9] and that critically ill patients with obesity who also have malnutrition experience worse outcomes than patients with obesity without malnutrition [10] . emerging data demonstrate that people with obesity may also experience more severe covid-19 symptoms and may be more likely to need complex intensive care treatment. a retrospective cohort study conducted in france found that patients with severe obesity (body mass index [bmi] > 40 kg/m 2 ) who contracted covid-19 were more likely to need invasive mechanical ventilation, independent of age, hypertension, and diabetes [11] . from chinese data, we have learned that persons with underlying type 2 diabetes, cardiovascular conditions, and hypertension appear to face a greater risk of complications from a covid-19 diagnosis [12, 13] . thus, people with obesity who also have diabetes should ensure that they maintain good glycaemic control, as it can help reduce infection risk and severity [14] . people living with both obesity and type 2 diabetes may also need more frequent blood glucose monitoring (through the use of self-monitoring blood glucose devices, for example) and medication adjustment to maintain normoglycaemia to adapt to the new energy requirements of decreased activity and energy intake. in addition, according to a chinese study, elderly persons (> 65 years) with type 2 diabetes were also more likely to be affected by covid-19 [15] . the most recent data from new york city show that the factors most associated with hospitalization risk were age and obesity (bmi > 40 kg/m 2 ), followed by heart failure and chronic kidney disease [16] . this study also found that severe obesity was the strongest risk factor for developing acute respiratory distress syndrome and requiring intubation. more research is needed to understand the relationships between obesity and covid-19. in order to conduct appropriate studies, national authorities and others will need to develop accurate surveillance protocols, collecting data on weight, height, bmi, and obesity-related complications. easo will continue to advocate for the importance of research and surveillance during and after the covid-19 pandemic. healthcare professionals, national health systems, and policymakers need access to evidence-based information and guidance to meet the healthcare needs of patients with obesity who have been affected by covid-19. whether this means having access to the right size equipment for patients with obesity or understanding the medication and nutritional needs of patients who have undergone bariatric surgery, easo experts will use the emerging data about obesity and covid-19 to develop relevant resources and guidance. although at this point, data describing the health effects and impacts of covid-19 on obesity during lockdown, quarantine, and self-isolation during the short, medium, and long term are scarce, easo will mobilize its expert membership to contribute to novel and high-impact research and support tools related to covid-19 and obesity. the issues discussed in this position statement have important implications for health systems, people living with obesity, and society. our global ability to adapt to the demands of the pandemic will be determined by our willingness to develop resilient systems that are particularly protective of high-risk individuals and vulnerable populations. easo is a trusted society well positioned to help and with the capacity to assist. health equity is embodied in all easo activities. together with our task forces, scientists, persons living with obesity, and the clinical care community, we are all working toward the same goal -improving population health. easo will leverage and mobilize its resources in efficient ways to empower persons living with obesity and to support governments in promoting behaviours, practices, and policies which support health and well-being for all during the present lockdown and beyond. as a catalyst for change and a convener, easo will continue to work with our many partners to research, educate, and advise the general population, people living with obesity, healthcare professionals, and policymakers on how to take achievable action during these challenging times. frühbeck et obesity and inflammation: the linking mechanism and the complications obesity altered t cell metabolism and the response to infection the abcd of obesity: an easo position statement on a diagnostic term with clinical and scientific implications the psychological impact of quarantine and how to reduce it: rapid review of the evidence european association for the study of obesity. covid-19 and obesity joint international consensus statement for ending stigma of obesity weight bias and health care utilization: a scoping review impact of obesity on intensive care unit resource utilization after cardiac operations prevalence of obesity and the effect on length of mechanical ventilation and length of stay in intensive care patients: a single site observational study the relationship among obesity, nutritional status, and mortality in the critically ill lille intensive care covid-19 and obesity study group. high prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (sars-cov-2) requiring invasive mechanical ventilation clinical features of patients infected with 2019 novel coronavirus in wuhan epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive study clinical considerations for patients with diabetes in times of covid-19 epidemic clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study factors associated with hospitalization and critical illness among 4,103 patients with covid-19 disease in new york city all authors declare no conflict of interest in the development of this position statement, which was authored under the auspices of easo. all authors are members of the executive committee of easo and receive no funding for that role. key: cord-354928-brliql4d authors: wang, jian; zhu, li; liu, longgen; zhao, xiang‐an; zhang, zhaoping; xue, leyang; yan, xuebing; huang, songping; li, yang; cheng, juan; zhang, biao; xu, tianmin; li, chunyang; ji, fang; ming, fang; zhao, yun; shao, huaping; sang, dawen; zhao, haiyan; guan, xinying; chen, xiaobing; chen, yuxin; issa, rahma; wei, jie; huang, rui; zhu, chuanwu; wu, chao title: overweight and obesity are risks factors of severe illness in patients with covid‐19 date: 2020-07-31 journal: obesity (silver spring) doi: 10.1002/oby.22979 sha: doc_id: 354928 cord_uid: brliql4d objective: we aimed to observe the clinical characteristics of coronavirus disease 2019 (covid‐19) patients with overweight and obesity. methods: consecutive covid‐19 patients from 10 hospitals of jiangsu province, china were enrolled. results: 297 covid‐19 patients were included. 39.39% and 13.47% of patients were overweight and obese, respectively. the proportions of bilateral pneumonia (92.50% vs. 73.57%, p=0.033) and type 2 diabetes (17.50% vs. 3.57%, p=0.006) were higher in patients with obesity than lean patients. the proportions of severe illness in patients with overweight (12.82% vs. 2.86%, p=0.006) and obesity (25.00% vs. 2.86%, p<0.001) were significantly higher than lean patients. more patients with obesity developed respiratory failure (20.00% vs. 2.86%, p<0.001) and acute respiratory distress syndrome (5.00% vs. 0%, p=0.024) than lean patients. the median days of hospitalization were longer in patients with obesity than lean patients (17.00 days vs. 14.00 days, p=0.029). overweight (or 4.222, 95%ci 1.322‐13.476, p=0.015) and obesity (or 9.216, 95% ci 2.581‐32.903, p=0.001) were independent risk factors of severe illness. obesity (hr 6.607, 95% ci 1.955‐22.329, p=0.002) was an independent risk factor of respiratory failure. conclusion: overweight and obesity were independent risk factors of severe illness in covid‐19 patients. more attention should be paid to these patients. coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (sars-cov-2) was declared as pandemic by the world health organization (1) . although most of the sars-cov-2 infection typically leads to relatively mild symptoms, 287,399 patients still died globally up to may 13, 2020 (2) . old age and comorbidities, such as hypertension, diabetes, and chronic respiratory disease, were identified as risk factors of poor outcomes for covid-19 patients according previous studies (3, 4) . obesity was regarded as a common risk factor to aggravate the severity of respiratory diseases, which was associated with poor prognosis in influenza a (h1n1) pulmonary infection (5, 6) . animal experiments have found that obesity alters inflammatory and pathological responses in the lung during influenza (7) (8) (9) . excessive adipose accumulation could result in insulin resistance, oxidative stress, chronic inflammation, and circulating nutrients abnormality (10, 11) . however, few studies have focused on the impacts of obesity on covid-19. a retrospective study enrolled 124 covid-19 patients who were admitted to intensive care unit (icu) showed more patients required invasive mechanical ventilation (imv) therapy with increased body mass index (bmi) (12) . another study found that covid-19 patients who were aged <60 years with a bmi between 30-34 kg/m 2 had 2.0 and 1.8 times risk of admission to acute and critical care as compared with individuals with a bmi <30 kg/m 2 , respectively (13) . these studies suggested that obesity may be associated with the severity of covid-19. however, several confounders such as age, the presence of comorbidities were not adjusted which might have impacted the results. whether overweight and obesity are independent risk factors of severe covid-19 requires further research. in addition, the sample sizes are relatively small in the previous studies (12, 13) . this study aimed to investigate the clinical features of covid-19 patients with overweight and obesity in a multi-center cohort of covid-19 in jiangsu province, china. between january 18, 2020 and february 26, 2020, three hundred and forty-two consecutive covid-19 patients from 10 medical centers in 10 cities of jiangsu, china were enrolled. all covid-19 patients were diagnosed by clinical manifestations, chest this article is protected by copyright. all rights reserved ct, and real-time polymerase chain reaction (rt-pcr) according to world health organization interim guidance and the guidelines for the diagnosis and treatment of novel coronavirus (2019-ncov) infection by the national health commission (trial version 5) (14, 15) . all covid-19 patients were tested positive for sars-cov-2 by rt-pcr in throat swab specimens. the last followed-up date was february 29, 2020. the study was approved by the ethics review boards of these medical centers. we retrospectively recorded the clinical characteristics, complications, and outcomes of patients by electronic medical record system. the computational formula of body mass index (bmi) was weight (kg) divided by height (m) squared. according to criterion of guidelines for prevention and control of overweight and obesity in chinese adults, 24 kg/m 2 ≤ bmi <28 kg/m 2 and bmi ≥ 28 kg/m 2 was defined as overweight and obesity, respectively (16, 17) . severe covid-19 was defined according to the current guideline as follows: (1) respiratory frequency ≥30/min; (2) pulse oximeter oxygen saturation ≤93% at rest; (3) oxygenation index ≤300 mmhg (15) . acute respiratory distress syndrome (ards) was defined according to the berlin definition (18) . continuous variables were described as medians (interquartile range (iqr)) and categorical variables were presented as the counts and percentages. the independent group t tests (normal distribution) and mann-whitney u (non-normal distribution) were used to compared continuous variables between groups. chi-square or fisher exact test was used to compare the categorical variables. multivariate logistic and cox regression analysis was used to adjust for confounding factors, including age, gender and comorbidities. p<0.05 was considered to be statistical significant. spss version 22.0 software (spss inc., chicago, il, united states) was used for the analysis. thirty-four patients were excluded due to the lack of bmi data and 11 patients under 12 years old were also excluded. eventually, two hundred and ninety-seven patients were enrolled in this study. the clinical characteristics were presented in table 1 . of the 297 covid-19 patients, 117 (39.39%) and 40 (13.47%) patients were overweight (24 kg/m 2 ≤ accepted article bmi < 28 kg/m 2 ) and obesity (bmi ≥ 28 kg/m 2 ), respectively. the median age was 38.00 the proportions of patients use of atomized inhalation of interferon α-2b (60.00%, 56.41%, and 57.50%, p=0.84), lopinavir-ritonavir (70.01%, 75.21%, and 80.00%, p=0.383), and arbidol (52.86%, 47.86%, and 52.50%, p=0.709) were comparable among three groups ( table 2 logistic regression analysis was performed to identify the association between obesity and severe illness ( this article is protected by copyright. all rights reserved the associated factors of respiratory failure in covid-19 patients were analyzed by cox regression analysis ( overweight and obesity are serious global health problems (19, 20) . the global prevalence ratios of overweight and obesity are 38.5%-39.4% and 10.1%-14.8% respectively in the general population (21) . in our study, 39.39% and 13.47% of the covid-19 patients were overweight and obese, respectively, suggesting that overweight and obesity may be not susceptible factors of covid-19. in our study, the most common symptoms were fever and cough, which were similar with previous studies (22, 23) . however, there were no significant differences in clinical symptoms among patients with different bmi. patients with obesity had higher fbg levels and higher proportion of type 2 diabetes indicating that obesity was associated with an increased risk of type 2 diabetes. several studies have demonstrated that the presence of type 2 diabetes was a significant risk factor of severe illness and fatal outcome of covid-19 (24) (25) (26) . thus, the association between the obesity-related comorbidities and severe covid-19 deserves further investigation. in our study, more patients with obesity had bilateral pneumonia compared to lean patients. in the report by cai et al, among 383 covid-19 patients from shenzhen, china, obesity was also associated with a higher risk of severe pneumonia compared with lean patients (27) . more patients with overweight and obesity received oxygen therapy and non-imv in the present study. our results revealed that overweight and obesity were risk factors of severe illness and more likely to developed complications such as respiratory failure and ards. after adjusting the confounding factors such as age and sex, overweight and obesity were still independent risk factors of severe illness of covid-19. taken together, these results suggested that overweight and obesity were independently associated with the severity of covid-19. however, the mechanisms of overweight and obesity contributing to severe covid-19 this article is protected by copyright. all rights reserved are not yet defined. obesity was regarded as a risk factor of severe illness and poor prognosis in many infectious diseases (28) . obesity induces systematically chronic inflammation by increasing the secretion of cytokines such as interleukin 6, interleukin 8 and tnf-α, which may aggravate the injury of lung parenchyma and bronchi (29) (30) (31) . previous study also found that obesity might impair adaptive immune responses in influenza virus infection (32) . a similar mechanism might exist in covid-19 patients. in addition, obesity causes a decrease in protective cardiorespiratory reserve and immune dysfunction (33) . sattar et al also reported obesity could increase the risk of thrombosis, which is an unignorable risk factor of severe covid-19 (33) . with regards to lung function, obesity reduce expiratory volume and forced vital capacity (33) (34) (35) . in addition, animal models demonstrated that obesity leads to decreased natural killer cell cytotoxicity and increased mortality in influenza infection (36) . however, the mechanisms of overweight and obesity in the severity of covid-19 deserve further investigation. there were several limitations in our study. firstly, the outcomes of the covid-19 patients had relative favorable outcomes with no death patients. thus, we could not analyze the association of overweight/obesity and fatal outcome in covid-19 patients. secondly, the associations of overweight/obesity with imv could not be analyzed either. however, kalligeros et al reported the potential association of obesity with severe outcomes in 102 patients hospitalized with covid-19 (37) . they found that obesity was independently associated with the use of imv (37) . thirdly, many of the treatments and outcomes (oxygen therapy, non-imv, admission to icu, days of hospitalization) are subject to bias from clinicians who were in charge for the management of patients. fourthly, our study was conducted later in the pandemic and by this point people had suspicions and some studies were already conducted on the topic that overweight and obesity were risk factors for more severe covid-19 outcomes. thus, the clinicians in charge of care might have just been overly cautious which might have biased our results. furthermore, we could not include all the patients in our province. thus, there is a potential selection bias in our study. however, nearly half of the confirmed cases in our province were included in our present study. we consider that our study is representative. finally, the impacts of overweight and obesity on the long-term outcomes of covid-19 patients remain unclear. in conclusion, covid-19 patients with overweight and obesity had higher risks of severe this article is protected by copyright. all rights reserved illness. therefore, more attention should be paid to covid-19 patients with overweight or obesity. however, more studies are needed to confirm our findings and to reveal the underlying mechanisms of overweight and obesity associated with higher risks of severe illness in covid-19. this article is protected by copyright. all rights reserved this article is protected by copyright. all rights reserved this article is protected by copyright. all rights reserved world health organization. who characterizes covid-19 as a pandemic world health organization. novel coronavirus (covid-19) situation clinical characteristics of coronavirus disease 2019 in china clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study obesity increases mortality and modulates the lung metabolome during pandemic h1n1 influenza virus infection in mice metabolic syndrome as an independent risk factor of hypoxaemia in influenza a (h1n1) 2009 pandemic impaired wound healing predisposes obese mice to severe influenza virus infection diet-induced obesity impairs the t cell memory response to influenza virus infection accepted article this article is protected by copyright. all rights reserved dietinduced obese mice exhibit altered heterologous immunity during a secondary 2009 pandemic h1n1 infection the impact of obesity on the immune response to infection the inflammation highway: metabolism accelerates inflammatory traffic in obesity high prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (sars-cov-2) requiring invasive mechanical ventilation obesity in patients younger than 60 years is a risk factor for covid-19 hospital admission clinical management of severe acute respiratory infection when novel coronavirus (ncov) infection is suspected: interim guidance national health commission. guidelines for the diagnosis and treatment of coronavirus disease 2019 (covid-19) by the national health commission (trial version 6) association of obesity with the clinicopathological features of thyroid cancer in a large, operative population: a retrospective case-control study body mass index and all-accepted article this article is protected by copyright. all rights reserved cause mortality in patients with atrial fibrillation: insights from the china atrial fibrillation registry study acute respiratory distress syndrome: the berlin definition childhood obesity, prevalence and prevention obesity and diabetes in the developing world--a growing challenge the epidemiology of obesity epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive study clinical features of patients infected with 2019 novel coronavirus in wuhan clinical characteristics and outcomes of patients with severe covid-19 with diabetes clinical characteristics of 145 patients with corona virus disease 2019 (covid-19 diabetes mellitus is associated with increased mortality and severity of disease in covid-19 pneumonia -a systematic review, metaanalysis, and meta-regression obesity and covid-19 severity accepted article this article is protected by copyright. all rights reserved in a designated hospital in shenzhen obesity and the risk and outcome of infection systemic inflammation mediates the detrimental effects of obesity on asthma control body mass index and acute kidney injury in the acute respiratory distress syndrome th1 and th17 hypercytokinemia as early host response signature in severe pandemic influenza obesity impairs the adaptive immune response to influenza virus obesity a risk factor for severe covid-19 infection: multiple potential mechanisms reduction of total lung capacity in obese men: comparison of total intrathoracic and gas volumes the effects of body mass index on lung volumes diet-induced obese mice have increased mortality and altered immune responses when infected with influenza virus association of obesity with disease severity among patients with covid-19 online ahead of print this article is protected by copyright. all rights reserved this article is protected by copyright. all rights reserved this article is protected by copyright. all rights reserved key: cord-318391-2s0rjfn8 authors: akirov, amit; cahn, avivit; del prato, stefano; home, philip; van gaal, luc; chan, juliana; ning, guang; raz, itamar title: tackling obesity during the covid‐19 pandemic date: 2020-08-14 journal: diabetes metab res rev doi: 10.1002/dmrr.3393 sha: doc_id: 318391 cord_uid: 2s0rjfn8 nan most people contracting coronavirus disease 2019 (covid-19) develop a non-serious disease with some remaining entirely asymptomatic. however, the disease may manifest severely and lead to mortality secondary to the development of respiratory failure and disseminated organ failure [1] . potential risk factors for severe illness include advanced age and underlying medical conditions, such as diabetes mellitus and cardiovascular disease [1, 2] . furthermore, studies have consistently shown that obesity is an important risk factor for severe covid-19 [3] [4] [5] [6] [7] [8] [9] [10] . the prevalence of obesity has been rising steadily, globally, with a recent report in the united states revealing that 42% of adults are obese, while 9% fulfil the criteria for severe obesity [11] . the current covid-19 pandemic mandated lockdown in many countries with closure of schools and non-essential businesses. while clearly effective in curbing the epidemic spread, a further increase in the prevalence of obesity is a predictable untoward outcome [12] , as people eat more and exercise less [13] . a study to assess the effects of lockdown during covid-19 epidemic on lifestyle in patients with type 2 diabetes in north india reported carbohydrate consumption and frequency of snacking increased in 21% and 23% of study participants, respectively, while exercise duration decreased in 42% and weight gain was documented in 23% of patients [14] . a survey in china showed that during semilockdown, normal weight individuals had less awareness of weight gain, the average steps per day and the average moderate or vigorous-intensity exercise declined significantly for both genders [15] . increased caloric consumption during the lockdown, as well as poor food choices, increased intake of fast-foods and preordered meals which are frequently high in salt, saturated fat and sugar are possible contributors to weight gain. moreover, the reduced availability of indoor gyms or outdoor physical activities markedly reduced the opportunity for regular exercise. these restrictions, combined with the sedentary lifestyle imposed by the lockdown, will inevitably lead to further weight gain. this article is protected by copyright. all rights reserved. an early report based on uk biobank data suggested a dose-response association between body mass index (bmi), waist circumference and positive testing for covid-19 [16] . obesity was associated with an approximately 3-fold increased risk for severe covid-19 (33.3% vs. 14.7%, respectively), and longer hospital stay (median 23 vs. 18 days, respectively) was noted in obese vs. non-obese patients [4] . obesity has also been associated with a significantly higher rate of icu admission or death [8] . furthermore, obesity class i (bmi>30 kg/m2) and obesity class ii (bmi>35 kg/m2) have been associated with an increased risk for need of invasive mechanical ventilation in patients hospitalized for covid-19, independent of age, sex, diabetes mellitus and hypertension [9, 13] . lighter et al. reported that among those under 60 years of age, obesity (bmi > 30 kg/m2) was twice as likely to result in hospitalization for covid-19 and in the need for critical care [17] . a study from france also supported the association between obesity and severe covid-19, including increased risk for icu admission in obese individuals [5] . kass and colleagues investigated the association of bmi and age in patients admitted to icus in the united states due to covid-19. their study demonstrated a shift in the age threshold of developing severe covid-19 disease in obese patients, such that severe obesity places young patients in their 30s at a similar risk category as elderly normal weight patients [18] . similarly, busetto et al. from italy reported that overweight or obese patients hospitalized due to covid-19 were more than 10 years younger compared to those with normal weight, yet despite their younger age, these patients required invasive mechanical ventilation and icu admission more frequently [6] . a study from china reported similar findings, noting the association of obesity with high mortality risk in young patients with covid-19 [3] . this article is protected by copyright. all rights reserved. included 1317 patients with diabetes and confirmed covid-19, and revealed a significant and positive association between bmi and death or mechanical ventilation within a week of admission [19] . data from england reported that patients with type 1 or type 2 diabetes were at increased risk for covid-19 associated mortality, and there was a u-shaped relationship with bmi. in patients with type 1 diabetes and bmi ≥40 kg/m 2 mortality was more than double that of those with bmi 25-29.9 kg/m 2 , and in those with type 2 diabetes and bmi of ≥40 kg/m 2 mortality risk was almost 1.5-fold higher [20] . the opensafely collaborative reviewed electronic medical records from over 17 million uk adults, aiming to identify risk factors for mortality from covid-19. the study noted that both diabetes and obesity were associated with increased risk for death from covid-19. the fully adjusted model showed a dose-response association between bmi and mortality, with an increase of 27%, 56%, and 127% in mortality risk for those with bmi 30-34.9, 35-39.9, and ≥40 kg/m 2 , respectively [21] . obesity has been observed to be associated with severe covid-19 disease, independent of diabetes, hypertension and cardiovascular disease -concomitant disorders also known to contribute to severe disease [18] .several potential underlying mechanisms have been proposed. disruption of lung function in patients with obesity secondary to excess pressure on the diaphragm while lying supine was suggested to limit ventilation and reduce mucous and probably viral clearance [18] . obesity is associated with an increase in pro-inflammatory cytokines, and it has been proposed that the pro-inflammatory state, hypoxia, immobilization and diffuse intravascular coagulation triggered by sars-cov-2 infection increase the risk for thromboembolism in these more susceptible individuals [22] . poyiadji et al. reported that in patients with covid-19 bmi > 30 kg/m 2 was associated with a 2.7-fold this article is protected by copyright. all rights reserved. increased risk for pulmonary embolism. interestingly, the researchers also reported that statin therapy prior to admission may reduce the risk for thromboembolism in both obese and non-obese patients [23] . endothelial dysfunction which is a known characteristic of obesity, hypertension and diabetes mellitus may also contribute to the excess morbidity. the acute endothelial damage induced by sars-cov-2 may promote lung microvascular dysfunction, vascular leakage, alveolar oedema and hypoxia with those having pre-existing alterations at greater risk [24] . varga et al identified the presence of sars-cov-2 infectious components within endothelial cells, resulting in endothelial inflammation, apoptosis and pyroptosis in patients with covid-19 [25] . higher levels of angiotensin-converting enzyme-2 (ace-2), the receptor enabling the penetration of sars-cov-2, have been noted in obese patients, due to higher volume of adipose tissue. this increased number of ace-2 expressing cells potentially promote increased viral shedding, immune activation and cytokine disturbances [26] . visceral adipose tissue may play an important role in the predisposition to worse covid-19 outcomes. interleukin-6, which can be secreted from visceral adipose tissue, was found to be increased in patients who died of covid-19. furthermore, ectopic visceral fat is also important, as studies have shown that patients with obesity present accumulation of adipose tissue within the lung parenchyma, which correlated with inflammatory infiltrate and pulmonary injury [27] . visceral deposition of fat within the abdomen was also reported to be independently associated with worse clinical outcomes in patients with covid-19 and visceral adipose tissue accumulation was strongly associated with the need of intensive care and intubation [28] . this article is protected by copyright. all rights reserved. as it has been suggested that vitamin d may inhibit viral replication and had important effects on the immune system and inflammatory response [30] . however, the association between vitamin d deficiency and severe covid-19 disease is still debated. the prognostic role of diabetes independently from obesity and vice-versa have not always been addressed appropriately in all the studies reported. the covid-19 pandemic has resurfaced human vulnerability to communicable diseases, yet, non-communicable disorders have emerged as no less important at these times as well. obesity is clearly a pivotal risk factor associated with severe disease -including greater rate of hospital admission, icu admission, need for ventilation and excess mortality. in fact, obesity has been the underlying cause of the severe form of the disease seen in many young patients. thus, greater attention to protective measures against contracting the disease and heightened vigilance to complications in this population is mandated. it is yet unclear how to prevent risk of complications in the obese patient contacting covid-19, yet, close follow up, early use of anti-coagulants, statins, in appropriate cases, and maintenance of a balanced nutrition alongside vitamin and mineral supplementations or repletion as needed are sound recommendations. control of additional comorbidities if present including hyperglycemia and blood pressure cannot be overstated. while limited data are available to support the use of aspirin for the treatment of sars-cov-2, it is frequently used off-label to treat viral infections as previous studies have supported its antiviral effects, including inhibition of viral replication and reduction of lung injury secondary to neutrophil and platelet aggregation [31] . furthermore, periods of quarantine and lockdown lead to further exacerbation of the obesity pandemic, one for which no 'vaccine' is available for in the foreseeable future. thus, special care should be taken to mitigate progression of obesity this article is protected by copyright. all rights reserved. secondary to quarantine, including increasing availability of healthy food choices aiming to maintain adequate supply of fruits, vegetables and low caloric nutrients, while limiting advertisement of fast-foods and emphasizing the importance of wise food choices in the media. consideration should be taken to encouraging physical activity either outdoor activity (such as jogging, biking, power-walking, or hiking), or indoor activity (such as indoor gyms, online fitness classes, home exercise) when possible while maintaining social distancing. while the present data support the increased tendency of obese people to develop severe covid-19 disease once contracted, an increased risk of infection with increasing bmi has not been clearly demonstrated. there is need for additional studies to explore the benefits of various interventions in reducing the morbidity and mortality of obese patients, and a holistic approach addressing the infected individuals as well as the overall obese population must be adopted. this article is protected by copyright. all rights reserved. obesity shifts the prevalence of severe covid-19 disease to a younger age [18] . encourage obese individuals, at any age, to pay special care to social distancing recommendations. increase awareness of health care teams to the risks associated with obesity. in infected young obese patients provide care and monitoring similar to that provided to elderly patients [18] . obesity is associated with increased risk of venous thromboembolism in patients with covid-19 [22, 23] . have a low threshold of initiating anticoagulants to obese patients with covid-19, as a correlation between heparin use and lower mortality rates has been observed [32] . initiate statins in obese patients with dyslipidemia poorly controlled by diet alone, as this has been noted to be associated with lower risk for pulmonary embolism [23] . vitamin d deficiency, more prevalent in the obese, may increase the risk for complications of covid-19 [30] . vitamin d supplementation may protect against acute respiratory infections [33] , however, this is still under discussion. concomitant hypertension and hyperglycemia increase the risk for severe covid-19 disease [34] [35] [36] . strive for better control of blood pressure [36] and glucose during the pandemic [34, 35] . maintain telehealth contact with primary care to ensure continuous supply of medications and access to medical advice where needed. periods of quarantine and lockdown lead to further exacerbation of the obesity pandemic [12] . telehealth services may prevent marked weight gain during lockdown periods [37] . utilize the media to deliver healthpromoting messages encouraging physical activity and balanced diet. this article is protected by copyright. all rights reserved. exercise facilities when possible. maintain outdoor activity (such as jogging, biking, power-walking, or hiking), or indoor activity (such as indoor gyms, online fitness classes, home exercise), when possible, and while maintaining social distancing and using a face mask. characteristics of and important lessons from the coronavirus disease 2019 ( covid-19 ) outbreak in china summary of a report of 72 314 cases from the chinese center for disease control and prevention clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study accepted article this article is protected by copyright. all rights reserved. patients prevalence of obesity among adult inpatients with covid-19 in france obesity and covid-19 : an italian snapshot. obes obesity as a predictor for a poor prognosis of covid-19 : a systematic review analysis of early data from high prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (sars-cov-2) requiring invasive mechanical ventilation. obes coronavirus infections and type 2 diabetes-shared pathways with therapeutic implications prevalence of obesity and severe obesity among adults: united states covid-19-related school closings and risk of weight gain among children dq&a impact of covid-19 on the diabetes community in the united states available online effects of nationwide lockdown during covid-19 epidemic on lifestyle and other medical issues of patients with type 2 diabetes in north india changes in body weight, physical activity and lifestyle during the semi-lockdown period after the outbreak of covid-19 in china: an online survey obesity and risk of covid-19: analysis of uk biobank obesity in patients younger than 60 years is a risk factor for covid-19 hospital admission obesity could shift severe covid-19 disease to younger ages phenotypic characteristics and prognosis of inpatients with covid-19 and diabetes : the coronado study type 1 and type 2 diabetes and covid-19 related mortality in england: a cohort study in people with diabetes opensafely: factors associated with covid-19-related hospital death in the linked electronic health records of 17 million adult nhs patients incidence of thrombotic complications in critically ill icu patients with covid-19 acute pulmonary embolism and covid-19 increased severity of covid-19 in people with obesity: are we overlooking plausible biological mechanisms? obes endothelial cell infection and endotheliitis in covid-19 risk of covid-19 for patients with obesity obesity and sars-cov-2 -a population to safeguard visceral fat shows the strongest association with the need of intensive care in patients with covid-19 the role of adipocytes and adipocyte-like cells in the severity of covid-19 infections the interplay between vitamin d and viral infections should aspirin be used for prophylaxis of covid-19-induced coagulopathy? med. hypotheses accepted article this article is protected by copyright the association between treatment with heparin and survival in patients with covid-19 vitamin d supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data association of blood glucose control and outcomes in patients with covid-19 and pre-existing type 2 diabetes glycosylated hemoglobin is associated with systemic inflammation, hypercoagulability, and prognosis of covid-19 patients association of hypertension and antihypertensive treatment with covid-19 mortality: a retrospective observational study zooming towards a telehealth solution for vulnerable children with obesity during covid-. obes key: cord-290551-a02tueuu authors: singh, shailendra; bilal, mohammad; pakhchanian, haig; raiker, rahul; kochhar, gursimran s.; thompson, christopher c. title: impact of obesity on outcomes of patients with covid-19 in united states: a multicenter electronic health records network study. date: 2020-08-21 journal: gastroenterology doi: 10.1053/j.gastro.2020.08.028 sha: doc_id: 290551 cord_uid: a02tueuu nan during the 2009 h1n1 influenza a virus pandemic, obesity was significantly associated with increased risk for hospitalization and mortality 1 . in 2020, the covid-19 pandemic has a higher estimated case fatality rate 2 . it has hit the united states (u.s) at a time when obesity has also reached epidemic status, with the prevalence of obesity increased from 30.5% to 42.4%, and severe obesity increased from 4.7% to 9.2%, over the past decade 3 . comorbidities associated with obesity are widely recognized risk factors for poor covid-19 outcomes 4 ; however, larger population-based data evaluating obesity as an independent risk factor continues to be sparse. we performed a retrospective cohort study using trinetx (cambridge, ma, usa), a global federated health research network that provided access to electronic medical records of patients from multiple large member healthcare organizations (hcos) in united states. details of the data source are described in the supplementary. a search query was performed to identify all adult patients (> 18 years) with a diagnosis of covid-19 between january 20, 2020, and may 31, 2020. the search criteria to identify potential covid-19 patients were based on specific covid-19 diagnosis codes or positive laboratory confirmation of covid-19. identified covid-19 patients were stratified based on a body-mass index (bmi) or a diagnosis code for obesity. patients with a documented bmi > 30 or a diagnosis of obesity within 1 year before the diagnosis of covid-19 were included in the obesity group. patients with a documented bmi <30 or with no documented diagnosis of obesity within the last one year were included in the control group. we excluded all patients where bmi varied between > 30 and <30 in the preceding year before the diagnosis of covid-19 or diagnosis of obesity was present, but bmi was reported as <30 in the preceding year. details of patient selection are outlined in supplementary figure 1. obesity group and control groups were compared after 1:1 propensity score matching (psm). the primary outcome was a composite of intubation or death up to 30 days after diagnosis of covid-19. sensitivity analysis and subgroup analysis based on the obesity class were also performed. details of the statistical analysis, sensitivity analysis, and limitations are also provided in the supplementary. a total of 41,513 covid-19 adult patients from 26 hcos in the united states were identified. out of these covid-19 patients, 8,641 patients with documented bmi >30 (n=5879) or diagnosis of obesity (n=2762) were included in the obesity group, and 31,273 patients with bmi<30 (n=6437) or without any reported diagnosis of obesity were all included in the control group (supplementary figure 1) . gender, racial and ethnic differences were seen between the groups, and patients in the obesity group had a significantly higher proportion of comorbidities compared to the control group (table 1 ). in the crude, unadjusted analysis, patients in the obesity group were more likely to have a 30-day composite outcome of death or mechanical ventilation compared to the control group (rr 1.99, 95% ci 1.84-2.15). after psm, a relatively balanced cohort of obese and non-obese patients were obtained (n=8112 patients in each group) ( table 1 ). the risk of composite outcome was higher in the obesity group compared to the control group (rr 1.56, 95% ci 1.41-1.73). kaplan meier survival analysis showed that the cumulative probability of being composite event-free up to 30-days remained significantly lower in the obesity group than the control group (87.7% vs. 90.5%, p-log rank <0.0001) (supplementary figure 2) . the risk of mortality, intubation, and hospitalization was higher in obesity group compared to the control group in the matched cohort (table 1 ). in a propensity-matched sub-group analysis based on obesity class, the risk of composite outcome, and other poor outcomes was highest in patients with obesity class 3 (table 1 ). the results of the sensitivity analysis confirmed the robustness of our main findings (supplementary). our study using a large nationally representative database showed that covid-19 patients with any degree of obesity had a significantly higher risk of hospitalization and intubation or death compared to patients without obesity. a substantial incremental risk of intubation or death in the obesity cohort persisted even after meticulous psm to adjust for confounding comorbidities. patients with severe obesity were at highest risk of these poor outcomes. the covid-19 pandemic has exposed the delivery of healthcare in the u.s and has provoked a reckoning regarding our healthcare model moving forward. the u.s. obesity epidemic has continued to grow for decades without any signs of abating. obesity and its associated comorbidities are now a significant determinant of covid-19 outcomes 5 in a population where over 90 million adults have obesity and are highly susceptible. disproportionate prevalence of obesity and associated comorbidities probably also have played a significant role in the racial and ethnic disparities seen during the covid-19 pandemic. the obesity cohort derived from our data source showed a higher proportion of african americans and hispanics in the obesity group. obesity increases the risk of poor outcomes in this vulnerable population with limited access to health care. advanced age and male gender are major risk factors for worse prognosis and higher mortality in covid-19 patients 6 . however, a larger proportion of patients with obesity in our cohort were females, and the impact of this can be dramatic enough to shift severe covid-19 outcomes towards females. similarly, a large number of younger patients with obesity are also affected by severe covid-19 with poor outcomes. in the u.s., where obesity is an epidemic, its impact is not only limited to clinical outcomes. along with the psychosocial impact of social distancing and quarantining that is applicable to the entire society, persons with obesity must contend with "weight stigma." derogation of persons with obesity is not uncommon and, unfortunately, more socially acceptable than other marginalized groups 7 . these biases and behaviors are not limited to the general public, j o u r n a l p r e -p r o o f and studies have shown that many healthcare workers can also have negative attitudes and stereotypes about persons with obesity 8 . our findings highlight the need for a vast improvement in the care of patients with obesity during this pandemic and moving forward. physicians should manage covid-19 patients with obesity aggressively as outcomes can be significantly worse than in the general population. in the long-term, preparing for future pandemics or if covid-19 becomes seasonal, there is also a serious need to develop and implement weightloss strategies. there is a necessity for more healthcare professionals, including gastroenterologists, to play a central role in caring for patients with obesity. j o u r n a l p r e -p r o o f trinetx (cambridge, ma, usa) is a global federated health research network providing access to electronic health records (ehr) of patients from 34 large member healthcare organizations (hcos) in united states. covid-19 data was incorporated in trinetx using specific diagnosis and terminology following the world health organization (who) and centers for disease control (cdc) covid-19 criteria. real-time access to hippa compliant de-identified longitudinal clinical data to member hcos is provided on a cloud-based platform. a typical hco is a large academic health center with data coming from the majority of its affiliates. in addition to ehr data available in a structured fashion (e.g., demographics, diagnoses, procedures, medications, lab test results, vital signs), trinetx can also extract facts of interest from the narrative text of clinical documents using natural language processing. data is mapped to a standard and controlled set of clinical terminologies and transformed into a proprietary data schema. this transformation process includes an extensive data quality assessment to reject records that do not meet quality standards. trinetx data has been granted a waiver from the western irb because it is a federated network and only aggregate counts and statistical summaries of the de-identified information without any protected health information received from participating hco's. both the patients and hco's as data sources remain anonymous. the software checks the basic formatting to ensure, for example, that dates are appropriately represented. it enforces a list of fields that are required (e.g., patient identifier) and rejects those records where the required information is missing. referential integrity checking is done to ensure that data spanning multiple database tables can be successfully joined together. as the data is refreshed, the software monitors changes in volumes of data over time to ensure data validity. trinetx requires at least one non-demographic fact for a patient to be counted in our dataset. patient records with only demographics information are not included in datasets. demographics are coded to hl7 version 3 administrative standards. diagnoses are represented by icd-10-cm codes. if an hco provides data in icd-9-cm, the data source uses a 9-to-10-cm mapping based on gems plus custom algorithms & curation to transform data from icd-9-cm to icd-10-cm. diagnoses data are enriched with the chronic condition indicator (cci). depending on the coding system used by an hco, procedure data coded in icd-10-pcs or cpt. for many procedures, both icd-10-pcs and cpt codes are added to a query to define a cohort. medications are represented at the level of ingredients, coded to rxnorm, and organized by ndf-rt therapeutic classes. lab results, vitals, and findings are coded to loinc. to ease finding and using common labs, loinc codes are combined up to clinically significant levels for most frequent labs and coded as tnx: lab. the search was conducted following the cdc covid-19 coding guidance. these codes included 2) were excluded to reduce any false positive covid-19 patients because this icd-9 code can still be used occasionally as "catch-all' code for more than 50 viral infections. in addition to the icd codes, following loinc codes with positive laboratory results were also used to identify covid trinetx has the capability of analyzing data based on a temporal relationship to the index event. the index event in our study was defined as the diagnosis of covid-19. baseline characteristics were estimated from any time before the index event. presenting laboratory values, and medications were recorded from the time of index event up to two weeks before the index event. outcomes were assessed from the index event up to 30 days after the index event. the risk for intubation (mechanical ventilation), hospitalization, and mortality after diagnosis of covid-19 was recorded. the primary outcome was a composite of intubation or death. regression was performed in python 3.6.5 using standard libraries numpy and sklearn. the same analyses were also performed in r 3.4.4 software to ensure the matching of outputs. after the calculation of propensity scores, matching was performed using a greedy nearest-neighbor matching algorithm with a caliper of 0.1 pooled standard deviations. the order of the rows in the covariate matrix can impact the nearest neighbor matching; therefore, the order of the rows in the matrix was randomized to eliminate this bias. for each outcome, the risk ratio with a 95% confidence interval was calculated to compare the association of obesity with the outcome. kaplan-meier survival analyses were used to estimate the survival probability of composite outcome at the end of 30 days following the index event. patients were censored when the time window ended or on the day after the last fact in their record. hypothesis testing for kaplan-meier survival curves was conducted using the log-rank test. a-priori defined two-sided alpha of less than <0.05 was used for statistical significance. selection bias in the obesity group and the control group was possible. therefore, we performed a sensitivity analysis by varying the inclusion criteria. we first included all patients with a diagnosis of obesity in their health records at any time before covid-19 diagnosis and compared them to a cohort of patients with no record of obesity. secondly, we compared patients with a diagnosis of obesity in the last three months and one month to a cohort of patients with no reported obesity. additional sensitivity analyses included the same set of main analyses but also adjusting for medications (angiotensin-converting enzyme inhibitors (acei) or angiotensin receptor blockers (arb)) and presenting laboratory values (ferritin, crp and ldh). finally, given the possibility that poor outcomes in patients with obesity might be higher at presentation or related to late presentation and access to health care, we performed an analysis excluding the composite outcomes in the first two days after diagnosis. an analysis of a larger group of selected patients using diagnostic criteria of obesity as any time before the index event (after psm n=9769) showed a higher risk for composite outcomes in the obesity group ( j o u r n a l p r e -p r o o f we acknowledge the limitations due to the retrospective nature of the study. the data derived from ehr based database is susceptible to errors in coding when patient information is translated into codes. however, extensive data quality assessment that includes data cleaning and quality checks minimizes the risk of data collection errors at the investigator's end. adjustments for missing data is not currently possible on trinetx platform. cases of covid-19 could have been misdiagnosed as other cases of pneumonia or viral infections due to diagnosis or coding errors, especially early in the pandemic. we likely missed patients who were asymptomatic or had mild disease and did not seek medical attention; therefore, our cohort may represent the more severe spectrum of the covid-19 disease. data on exposure history, incubation time, and dynamic changes in patients' clinical condition could not be estimated from the ehr database. socioeconomic and structural determinants, psychological elements, geographical factors, and health care delivery during covid-19 could have impacted the care of patients with obesity but were beyond the scope of our study. despite these limitations, our study uses a large national database to evaluate the impact of obesity in covid-19 patients. given our study population is representative of multiple centers across the u.s., the results are more generalizable than singlecenter or regional experiences. in addition, even though our study was not randomized, we performed a robust statistical analysis using propensity score matching. morbid obesity as a risk factor for hospitalization and death due to 2009 pandemic influenza a(h1n1) disease. plos one assessment of deaths from covid-19 and from seasonal influenza prevalence of obesity and severe obesity among adults: united states clinical course and risk factors for mortality of adult inpatients with covid-19 china: a retrospective cohort study obesity is associated with worse outcomes in covid-19: analysis of early data from new york city clinical features of patients infected with 2019 novel coronavirus in wuhan cpt: intubation, endotracheal, emergency procedure) or "1015098" (cpt: ventilator management) or "5a1935z" (icd10: respiratory ventilation, less than 24 consecutive hours) or "5a1945z" (icd10: respiratory ventilation, 24-96 consecutive hours) or "5a1955z" (icd10: respiratory ventilation, greater than 96 consecutive hours) or "0bh17ez" (icd10: insertion of endotracheal airway into trachea, via natural or artificial opening) or 0bh18ez (icd10: insertion of endotracheal airway into trachea, via natural or artificial opening endoscopic) or 0bh13ez (icd10: insertion of endotracheal airway into trachea statistical analysis all statistical analyses were performed in real-time using trinetx. the means, standard deviations, and proportions were used to describe and compare patient characteristics. categorical variables were compared using the pearson chi-square test and continuous variables using an independent-samples t-test. we performed a 1:1 propensity score matching (psm) to reduce the effects of confounding. covariates included in the propensity score model included age, race, ethnicity, dyslipidemia, diabetes mellitus, chronic lower respiratory diseases (chronic obstructive pulmonary disease (copd) and asthma), ischemic heart diseases, heart failure, pulmonary heart diseases, cerebrovascular diseases, chronic kidney disease, fatty liver, cirrhosis of liver, malignant neoplasm, and nicotine use (table 1) j o u r n a l p r e -p r o o f codes used for patient characteristics included in the propensity score matching. coding system and codes key: cord-261891-yiiz9s53 authors: czernichow, sébastien; beeker, nathanael; rives‐lange, claire; guerot, emmanuel; diehl, jean‐luc; katsahian, sandrine; hulot, jean‐sébastien; poghosyan, tigran; carette, claire; sophie jannot, anne title: obesity doubles mortality in patients hospitalized for sars‐cov‐2 in paris hospitals, france: a cohort study on 5795 patients date: 2020-08-20 journal: obesity (silver spring) doi: 10.1002/oby.23014 sha: doc_id: 261891 cord_uid: yiiz9s53 background: preliminary data from different cohorts of small sample size or with short follow‐up indicate poorer prognosis in people with obesity compared to other patients. this study aims to precisely describe the strength of association between obesity in patients hospitalised with covid‐19 and mortality and clarify the risk according to usual cardiometabolic risk factors in a large cohort. methods: this is a prospective cohort study including 5795 patients aged 18‐79 years hospitalized from 1(st) february 2020 to 30 april 2020 in paris area, with confirmed infection by sars‐cov‐2. adjusted regression models were used to estimate the odds ratios (or) and 95% confidence intervals (95% ci) for mortality rate at 30 days across bmi classes, without and with imputation for missing bmi. results: 891 deaths occurred at 30 days. mortality was significantly raised in people with obesity with the following or in bmi 30‐35, 35‐40 and >40 kg/m(2): 1.89 (95%ci 1.45‐2.47), 2.79 (1.95‐3.97) and 2.55 (1.62‐3.95), respectively (18.5‐25 kg/m(2), as the reference class). this increase holds for all age classes. conclusion: obesity doubles mortality in patients hospitalized with covid‐19. since the end of 2019 and its emergence from china, the pandemic of covid-19 has become the main worldwide public health threat responsible of lockdown measures for million people. covid-19 symptoms range from a wide variety of clinical presentation: from none to severe respiratory symptoms leading to death. 1 this article is protected by copyright. all rights reserved obesity, and especially its most extreme forms, is a source of stigma 2 , high emergency care utilization 3 , higher morbidity and increased mortality. 4 in the context of infectious disease, high body mass index (bmi) has been recognized as a risk factor for nosocomial, skin, as well as, respiratory disease infections. 5 about ten years ago, against the backdrop of the h1n1 influenza epidemic, it was clearly pointed out in a meta-analysis on more than 3000 individuals, that people with severe obesity had a two-fold increased risk for intensive care unit (icu) admission and mortality, compared to counterparts without obesity. 6 in two single-center studies, the risk for need of invasive mechanical ventilation in patients with covid-19 related severe acute respiratory syndrome was higher in patients with severe obesity, compared to normal weight patients, 7 but not for those with class i obesity (bmi 30 to 35 kg/m²). 8 preliminary data from different cohorts of patients infected by covid-19 of small sample size (lower than 400 patients), with short follow-up or with poorly described bmi indicate poorer prognosis in people with obesity compared to other patients. for instance one study shows higher mortality frequency in people with severe obesity admitted to icu compared to people with less severe obesity 9 . however, it is not possible to conclude from these results that obesity is an independent factor of mortality for patients infected with covid-19 due to the small sample sizes of these studies, neither to have a precise estimate of obesity size effect due to the absence of bmi categories and incomplete follow-up. these results need therefore to be confirmed in a large cohort, with available bmi and adequate follow-up. to further investigate the topic, we conducted an analysis of the association between bmi and risk for mortality at 30 days after hospitalization for covid-19 in all paris area-based public university hospitals. this article is protected by copyright. all rights reserved the assistance publique -hôpitaux de paris (ap-hp) is the largest hospital entity in europe with 39 hospitals (22,474 beds) mainly located in the greater paris area with 1.5 m hospitalizations per year (10% of all hospitalizations in france). since 2014, ap-hp is building an analytics platform based on a clinical data repository (cdr), aggregating day-to-day clinical data from 8.8 million patients captured by clinical databases. 10 the cdr has received the authorization of the french data protection authority (commission nationale de l'informatique et des libertés, cnil, n°1980120). from the beginning of covid-19 epidemics, the eds-covid database stemmed from this initiative. the later database retrieved electronic health records from all ap-hp facilities and aggregates them into a clinical data warehouse following omop common data model. 11 our analysis follows recommendations provided by the reporting of studies conducted using observational routinely-collected health data (record) statement. 12 this study was approved by the institutional review board (authorization number irb 00011591) from the scientific and ethical committee from the ap-hp. all subjects included in this study were informed about the reuse of their data for research and subjects that objected to the reuse of their data were excluded from this study, in accordance to french legislation. this article is protected by copyright. all rights reserved smoking status was defined as being current smoker or having an history of smoking using the formerly mentioned "covid19-aphp-nlp pipeline". comorbidities were extracted from icd-10 codes of previous and current hospitalization, i10 for hypertension, n18 for chronic kidney disease, g473 for sleep apnea, e78 for dyslipidemia, c00 to d48 for malignancies. heart failure was defined as having an i50 icd-10 code in a previous hospitalization. diabetes was defined as having a e11 icd-10 codes of diabetes or having a hba1c greater than 6.5% in any previous hospitalization. indirect information concerning bmi value was also retrieved for bmi imputation in patients with missing bmi. using 4-digits e66 icd-10 codes, the following variables were created: this article is protected by copyright. all rights reserved class, e6606, e6616, e6626, e6686, e6696 as icd-10 [40; 50] bmi class, e6607, e6617, e6627, e6687, e6697 as icd-10 >50 bmi class. malnutrition was extracted using e43 to e46 icd-10 codes. mentions of obesity in free-text reports were also retrieved using the formerly mentioned "covid19-aphp-nlp pipeline". age at admission, sex, icu admission and death during hospitalisation were extracted from hospital administrative data. considered outcome was death during hospitalisation at 30 days after positive covid pcr. outcome was retrieved through administrative hospital data. patients' characteristics were defined according to bmi classes and sex using median and interquartile range for continuous variables and proportion for binary variables both before and after missing bmi imputation. we imputed missing bmi category using predictive mean matching considering as the following as explaining variables: comorbidities (hypertension, diabetes, sleep apnea, dyslipidemia, chronic kidney disease, heart failure, cancer), smoking status, sex, age and indirect information regarding bmi value (obesity from free-text reports, variables extracted from 4-digits e66 icd-10 codes and malnutrition icd-10 codes). to assess the predictive ability of these variables, we performed a regression analysis on bmi using the same this article is protected by copyright. all rights reserved explaining variables on the complete dataset. to account for imputation variability, we generated five imputed samples. multivariate or (95% ci) were estimated according to bmi classes, with adjustment for comorbidities, smoking status, age and sex using logistic regressions, both including and excluding patients with missing bmi and with stratification on age class. for analysis including patients with imputed bmi, variation across imputed datasets was taken into account by incorporating samples variability in the estimated confidence intervals. all analyses were performed using r 4.0.2 software and mice package was used for multiple imputations process. during the period of february 1 st through april 30, 2020, a total of 8671 patients with a pcrconfirmed covid-19 infection were hospitalised in one of the thirty nine hospitals (fig. 1 ). among them, 5795 patients were between 18 and 80 years old and had available bioclinical data of whom 4056 had available bmi (2597 extracted from free-text reports and 1459 extracted from clinical signs). mean (sd) age was 58.9 y (14.7) in women (n=2004) and 60.3 y (13.0) in men (n=3791) ( table 1) . mean bmi was 29.3 (7.5) and 27.2 (6) kg/m² in women and men, respectively. comorbidities were frequent and increased with bmi classes. people with class iii obesity aggregated the most risk factors. admission in intensive care unit (icu) increased with bmi classes. use of mechanical ventilation did not follow an obvious trend across bmi classes. bmi was imputed for 1739 patients and main bmi predictor in the imputation model were variables derived from indirect information on bmi from this article is protected by copyright. all rights reserved hospitalization reports and icd-10 codes (see regression coefficients and significance on supplementary table 2) . correlation coefficient for the regression model used to assess the ability to predict bmi was 63%, therefore the available indirect information on bmi were relevant to predict bmi. mortality was significantly higher in people with obesity taking into account age groups, sex, figure s1 ). this large study investigates the role of obesity on mortality risk at 30 days in patients hospitalized with covid-19 infection in any of the 39 university public hospitals in paris region (france). we have shown that obesity was a major prognostic factor, independently of known chronic comorbidities. several hypotheses can be made to explain a worst survival rate in people with obesity compared to people without obesity. first, obesity is characterized by an increased lowthis article is protected by copyright. all rights reserved grade inflammatory state that relates to a dysfunctional adipose microenvironment. 13 the adipose cells are responsible for the secretion of pro-inflammatory adipokines, such as alpha-tnf, interleukine-6, lower adiponectin and increased leptin. the dysregulated cytokinic environment may be the early biological step that mediates multiple organ failure. 14 second, obesity accumulates several respiratory disorders such as obstructive sleep apnea syndrome, asthma, restrictive respiratory syndrome and obesity hypoventilation syndrome. 15 people with obesity are at particular risk of acute respiratory distress syndrome (ards), whatever the aetiology of the syndrome. 16 one explanation for the high prevalence of ards in people with obesity may be the very specific pulmonary mechanics of such patients, characterized mainly by excessively high pleural pressures with generally preserved chest wall compliance. such a pattern leads to the frequent occurrence of negative transpulmonary pressures favouring a greater incidence of atelectasis. 17 one suggested mean to counteract such phenomenon is to use high positive end-expiratory pressure (peep) settings, ideally based on oesophageal monitoring. 18 an important result of the study is the poorer vital prognosis observed in people with obesity and with covid-19. such a result is contrasting with the general findings of similar or even better prognosis than in the ards population without obesity. 19 however, one should keep in mind the worse vital prognosis previously observed in people with obesity with h1n1 infection. 6 a specific detrimental influence of the viral insult in people with obesity is therefore conceivable. in addition, the design of the study didn't allow to precisely assessing the ventilator settings used in people with obesity with covid-19, compared to those without this article is protected by copyright. all rights reserved obesity. bmi data was missing in about a third of included patients and was therefore imputed when missing. of note, we benefitted from a large number of indirect information regarding bmi missing values using free-text reports and icd-10 codes, but it was not sufficient to accurately predict bmi. however, odds ratios before and after imputation were similar values. this study was considerably facilitated by the eds-covid database, which retrieved electronic health records from all ap-hp facilities and aggregates them into a clinical data warehouse. this clinical data warehouse allowed retrieving in real time a large set of data to deeply characterize our study population. this approach was secured by a data quality program ensuring high standard of quality for this database. 10 furthermore, even if we were able to collect a large sample size, bmi does not capture body composition or even variations in weight. indeed, our data indicate poorer prognosis with aging, both for undernutrition and severe obesity, which strongly relates to muscle mass loss and sarcopenia in the context of an hypercatabolic state related to covid-19 infection. 23 it has been previously shown that sarcopenic obesity is associated with a longer hospital stay and a worst recovery after icu. 24 our results might be limited by the fact that only mortality during hospitalization was considered. however, it is unlikely that patients hospitalized for covid-19 died from their infection after being discharged from hospital. therefore, the subsequent underestimation of mortality due to this potential bias is likely to be limited. this article is protected by copyright. all rights reserved in summary, our data show for the first time in a large multicentre setting that obesity is related to mortality in patients hospitalized with covid-19. the presence or absence of cardiometabolic risk factors did not modify the increased mortality risk. in the context of a global covid-19 pandemic lockdown, the detrimental effect of accumulating sedentary lifestyle and increased food intake will worsen quality of life, depression risk, 25 and global mortality in fragile patients with severe obesity. thus, people with obesity in covid-19 pandemic context require a personalized management. clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study joint international consensus statement for ending stigma of obesity obesity and emergency care in the french constances cohort body-mass index and mortality among adults with incident type 2 diabetes obesity and site-specific nosocomial infection risk in the intensive care unit obesity is associated with higher risk of intensive care unit admission and death in influenza a (h1n1) patients: a systematic review and metaanalysis obesity is associated with severe forms of covid-19 high prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (sars-cov-2) requiring invasive mechanical ventilation covid-19 in critically ill patients in the seattle region -case series initializing a hospital-wide data quality program. the ap-hp experience observational health data sciences and informatics (ohdsi): opportunities for observational researchers the reporting of studies conducted using observational routinely-collected health data (record) statement inflammatory processes in obesity: focus on endothelial dysfunction and the role of adipokines as inflammatory mediators obesity a risk factor for severe covid-19 infection: multiple potential mechanisms obesity in the critically ill: a narrative review body mass index is associated with the development of acute respiratory distress syndrome obesity and ards: opportunity for highly personalized mechanical ventilation? a lung rescue team improves survival in obesity with acute respiratory distress syndrome ards in people with obesity: specificities and management sarcopenic obesity in the icu effect of obesity on intensive care morbidity and mortality: a meta-analysis we would like to acknowledge the authors thank the eds aphp covid consortium integrating the aphp health data warehouse team as well as all the aphp staff and volunteers who contributed to the implementation of the eds-covid database and operating solutions for this database (list in the supplementary table 1) . s. czernichow reports honorarium from novonordisk for board participation and conferences, as well as participation to mygoodlife. all other authors declared no conflict of interest this article is protected by copyright. all rights reserved sc and asj designed the study and had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. sc drafted the paper with the help of asj, crl, tp, eg, jsh, jld, sk, nb and cc. asj and nb did the analyses. data were collected from all assistance publique -hôpitaux de paris. all authors critically revised the manuscript for important intellectual content and gave final approval for the version to be published. the study was funded by assistance publique hôpitaux de paris. the study sponsor had no role in study design, data collection, data analysis, data interpretation, or writing of this report. the corresponding author (sc) had full access to all the data in the study and had final responsibility for the decision to submit for publication. this article is protected by copyright. all rights reserved this article is protected by copyright. all rights reserved ccepted article this article is protected by copyright. all rights reserved key: cord-311535-ppkwd1kp authors: korakas, emmanouil; ikonomidis, ignatios; kousathana, foteini; balampanis, konstantinos; kountouri, aikaterini; raptis, athanasios; palaiodimou, lina; kokkinos, alexander; lambadiari, vaia title: obesity and covid-19: immune and metabolic derangement as a possible link to adverse clinical outcomes date: 2020-07-01 journal: am j physiol endocrinol metab doi: 10.1152/ajpendo.00198.2020 sha: doc_id: 311535 cord_uid: ppkwd1kp recent reports have shown a strong association between obesity and the severity of covid-19 infection, even in the absence of other comorbidities. after infecting the host cells, severe acute respiratory syndrome coronavirus 2 (sars-cov-2) may cause a hyperinflammatory reaction through the excessive release of cytokines, a condition known as “cytokine storm,” while inducing lymphopenia and a disrupted immune response. obesity is associated with chronic low-grade inflammation and immune dysregulation, but the exact mechanisms through which it exacerbates covid-19 infection are not fully clarified. the production of increased amounts of cytokines such as tnfα, il-1, il-6, and monocyte chemoattractant protein (mcp-1) lead to oxidative stress and defective function of innate and adaptive immunity, whereas the activation of nod-like receptor family pyrin domain containing 3 (nlrp3) inflammasome seems to play a crucial role in the pathogenesis of the infection. endothelial dysfunction and arterial stiffness could favor the recently discovered infection of the endothelium by sars-cov-2, whereas alterations in cardiac structure and function and the prothrombotic microenvironment in obesity could provide a link for the increased cardiovascular events in these patients. the successful use of anti-inflammatory agents such as il-1 and il-6 blockers in similar hyperinflammatory settings, like that of rheumatoid arthritis, has triggered the discussion of whether such agents could be administrated in selected patients with covid-19 disease. obesity has long been associated with worse prognosis of viral infections (30) . higher mortality rates and a prolonged, more severe clinical course was observed in obese people in the 1957-1960 "asian" and the 1968 "hong kong" influenzas (22, 39) , whereas more recently obesity was recognized as a predisposing factor for worse clinical outcomes and death in the 2009 h1n1 pandemic. in accordance with these previous results, recent reports have demonstrated a strong association of worse clinical outcomes in covid-19 disease with obesity, even in the absence of any other comorbidity. in a study in a single french center, obesity [body mass index (bmi) ͼ 30 kg/m 2 ] and severe obesity (bmi ͼ 35 kg/m 2 ) were present in 47.6% and 28.2% of severe cases, respectively, whereas the need for interventional mechanical ventilation (imv) increased with bmi categories independently of age, diabetes, and hypertension (31) . petrilli et al. (25) showed that among other factors, bmi ͼ 40 kg/m 2 was a strong hospitalization risk factor, with an odds ratio (or) of 6.2 in an academic health system in new york city. in a retrospective study by lighter et al. (17) , patients aged under 60 yr with a bmi of 30 -34 kg/m 2 were two and 1.8 times more likely to be admitted to acute and critical care, respectively, compared with individuals with bmi ͻ30 kg/m 2 , with the risk escalating for bmi ͼ35 kg/m 2 (2.2 and 3.6 times, respectively). the unfavorable effects of obesity in the course of viral infections have been attributed to the metabolic derangement and chronic inflammation of the adipose tissue depots leading to blunted macrophage activation and impaired t and b lymphocyte responses. however, whether these mechanisms apply to the novel coronavirus infection remains unclear. in this review, we briefly present the pathophysiology of the severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection. we then discuss the possible mechanisms through which the metabolic and immune derangement in obesity can lead to more severe clinical outcomes, with their understanding being necessary in the search for novel treatment targets in the future. sars-cov-2 consists of four different types of structural proteins: spike (s), nucleocapsid (n), membrane (m), and envelope (e) proteins. the entry into host cells is mediated by the s protein, which comprises two separate subunits: s1 subunit, responsible for binding to the host cell receptor, and s2 subunit, responsible for the fusion between viral and cellular membranes. the cellular receptor for the virus is the angiotensin-converting enzyme 2 (ace2), which is expressed in type i and type ii alveolar epithelial cells in the lungs as well as in many other tissues such as the heart, the endothelium, the kidneys, and the pancreas (23) . after binding, serine proteases such as tmprss2 mediate the cleavage of the spike, and then proteases such as furin release the spike fusion peptide and facilitate viral entry into the cells through endosomes. the infection results in increased cell apoptosis, which triggers the activation of proinflammatory cytokines and chemokines and the recruitment of inflammatory cells. on the other hand, the virus itself causes increased apoptosis of lymphocytes (cd3, cd4, and cd8 t cells), and the subsequent lymphocytopenia and impaired function of lymphocytes ends up in a fulminant hypercytokinemia known as "cytokine storm" (40) . this condition resembles secondary hemophagocytic lymphohistiocytosis (shlh) or macrophage activation syndrome (mas), a common finding in severe viral infections and sepsis, which is characterized by excessive circulating levels of il-6, il-2, il-7, tnf␣, cxc-chemokine ligand 10 (cxcl10), monocyte chemoattractant protein-1 (mcp-1), macrophage inflammatory protein-1␣ (mip1␣), and other proinflammatory molecules, and is associated with progression to acute respiratory distress syndrome (ards) and multiorgan failure (21) . as we mentioned above, the association of obesity with prolonged recovery and worse clinical outcomes in viral infections has long been known. in recent years, as the role of adipose tissue as a distinct endocrine organ is being elucidated, obesity has been considered an independent risk factor for increased susceptibility to infections, sepsis, and higher mortality (9) . this increased risk has been attributed to the state of chronic, low-grade inflammation that characterizes obesity, which results in metabolic and immune derangement. as the pathophysiology of sars-cov-2 infection is being unraveled, the links between the severity of clinical presentation and the dysmetabolic background are revealed ( fig. 1) . the dysfunctional hypertrophic adipocytes in obesity produce an excessive amount of cytokines such as il-6, il-8, monocyte chemoattractant protein-1 (mcp-1/ccl2), leptin, and plasminogen activator inhibitor-1 (pai-1), among others, which leads to the increased recruitment of macrophages, especially polarized m1 macrophages (12, 19) . these cells, in turn, produce high amounts of proinflammatory molecules like il-1␤, il-6, il-8, tnf␣, and mcp-1 (18) , an effect that is enhanced also by the action of the increased circulating levels of free fatty acids (ffas) through the nf-b pathway (35) . the cumulative effect of these actions is a state of chronic inflammation and hypercytokinemia, which leads to defective innate immunity and creates a conducive ground for the hyperinflammatory response mediated through mas in severe covid-19 cases (10). the adaptive immunity is also adversely affected in obesity, with several studies showing a decline in naïve cd4ϩ t cells, as well as an imbalance of cd4ϩ t helper cells toward th17 and th22 proinflammatory subsets (9, 20) . similarly, in patients with covid-19, peripheral counts of cd4ϩ and cd8ϩ t cells are low, but with a higher ratio of proinflammatory th17 cells (10) . even more interestingly, the presence of increased levels of il-1␤ in patients with covid-19 infection suggests that cell pyroptosis, mediated through the activation of the nod-like receptor family pyrin domain-containing 3 (nlrp3) inflammasome, might be strongly involved in the pathogenesis of the infection (13) . the role of inflammasome activation has already been pointed out in studies on other coronavirus infections, where it was demonstrated that viroporin 3a activated the nlrp3 inflammasome during the sars-cov infection (8) , whereas another study on mers-cov infection revealed increased amounts of pyroptotic markers (caspase-1 and il-1␤) in the patient group (15) . even more importantly, in a study by grailer et al. (11) in mice, the presence of acute lung injury (ali) after airway instillation of lipopolysaccharide (lps) was dependent on availability of nlrp3 and caspase-1, which are known features of the nlrp3 inflammasome. as numerous increased macrophage recruitment inflammasome activation impaired adaptive immunity macrophage activation syndrome-mas ("cytokine storm") increased arterial stiffness impaired no function chronic oxidative stress studies both in humans and animal models have shown, nlrp3 expression is increased in obesity, rendering it a pivotal factor in recruitment of macrophages and immune activation (16, 27) . therefore, agents that inhibit its action, such as colchicine, seem promising in the treatment of specific covid-19 patients. in addition, agents such as anakinra, an il-1 blocker, and tocilizumab, an il-6 blocker, which have proven beneficial in the treatment of rheumatoid arthritis, which is accompanied as well by an excessive cytokine release, have been tested in randomized controlled trials (rcts) in severe cases of covid-19, with favorable results and unremarkable adverse events so far (29, 37) . a recent report by varga et al. (34) pointed out for the first time the role of the endothelium in the pathogenesis of co-vid-19. more specifically, postmortem histology of three patients with severe infection revealed viral inclusion structures in endothelial cells, accumulation of inflammatory cells associated with the endothelium, congestion of the small lung vessels, and endothelitis of the submucosal vessels of the small intestine, implying that the virus uses the ace2 receptors expressed on endothelial cells in a pattern similar to that of alveolar infection, and therefore, the clinical presentation might be worse in vulnerable patients with preexisting endothelial dysfunction. obesity is such a typical example, and the mechanisms that lead to vascular abnormalities are various. the hyperinsulinemia and insulin resistance that is a common feature of obesity leads to reduction in the insulin-stimulated phosphoinositide 3-kinase (pi3k) endothelial nitric oxidase synthase (enos) signaling pathway, reducing the vasculoprotective effects of nitric oxide (no) and its anti-inflammatory actions (4). increased oxidative stress due to raas-induced activation of nadph oxidase, xanthine oxidase, and mitochondrial oxidative stress results in increased destruction of no, and its decreased bioavailability further induces macrophage activation (3). the chronic exposure of endothelial cells to the increased circulating levels of leptin observed in obesity leads to a decreased no production and increased mcp-1 expression, which further enhances leukocyte infiltration into vascular cells (5, 32) . perivascular adipose tissue (pvat), exerting anticontractile effects on the endothelium in lean individuals, contributes to vasoconstriction and endothelial malfunction in obesity via increased secretion of tnf␣, il-6, reactive oxygen species (ros), and chemerin while downregulating no production (26) . consistent with the favorable results in hypercytokinemia and acute hyperinflammatory state, the administration of tocilizumab to rheumatoid arthritis patients has been shown to improve pulse wave velocity and brachial blood pressure, which were used as indices of vascular function, and a similar benefit in covid-19 patients could thus be presumed (14) . another serious consideration in sars-cov-2 infection is its cardiovascular manifestations. acute cardiac injury is highly prevalent in patients with covid-19 and is associated with worse clinical outcomes (13, 41) . although the relatively high rate of heart failure (23%) that was observed in patients with covid-19 could not be explicitly attributed to exacerba-tion of a preexisting condition or a new cardiomyopathy (7, 41) , the presence of acute myocarditis was the definite cause of death in 7% of patients in a case series of 150 patients with covid-19, whereas in other studies, postmortem histology revealed fulminant myocarditis with the presence of inflammatory mononuclear infiltrates in myocardial tissue (28, 38) . the risk of venous thromboembolism also seems important, as in a significant percentage of patients with severe infection, elevated levels of d-dimers have been observed, whereas ϳ71% of patients met clinical criteria for disseminated intravascular coagulation (dic) (33, 41) . obesity is a well-established risk factor for cardiovascular disease (cvd) both per se and through its common comorbidities, such as insulin resistance (ir), diabetes mellitus (dm), and hypertension. the most common alteration in cardiac morphology in obesity is left ventricular (lv) hypertrophy, with hypertension and ir being important determinants of the lv mass (1, 2) . in addition, obesity is associated with activation of the renin-angiotensinaldosterone system (raas), which leads to increased levels of angiotensin ii, with direct effects on the myocardium (36) . apart from structural changes, obesity is associated with lv diastolic dysfunction and heart failure (1, 2, 24) . chronic inflammation by the proinflammatory cytokines mentioned above leads to upregulation of procoagulant factors (like the tissue factor) and adhesion molecules (like p-selectin), downregulation of anticoagulant regulatory proteins (such as tissue factor pathway inhibitor, antithrombin, and the protein c anticoagulation system), increased thrombin generation, and enhanced platelet activation, thus increasing the risk for thrombosis (6) . again, in patients with rheumatoid arthritis, the administration of anakinra (mainly) and tocilizumab resulted in a simultaneous improvement in oxidative stress and myocardial deformation, rendering these agents a potential treatment option for patients with covid-19 and cardiovascular manifestations (14) . obesity has emerged as a major risk factor for worse covid-19 outcomes. chronic inflammation and oxidative stress, hypercytokinemia, immune dysregulation, endothelial dysfunction, and cardiovascular abnormalities are all possible mechanisms through which the excess in adipose tissue could lead to the acute hyperinflammatory state that characterizes severe sars-cov-2 infections and is responsible for its complications. the lessons learned from other diseases with a similar inflammatory profile, such as rheumatoid arthritis, provide useful insights into the better understanding of these mechanisms and, above all, propose that patients with obesity could be appropriate candidates for the use of agents such as colchicine and anti-il-1 and anti-il-6 compounds early in the course of the disease, benefiting from the amelioration of their preexisting, proinflammatory state. of course, large rcts are necessary to further clarify the pathways through which metabolic derangement leads to worse covid-19 outcomes and establish the ideal treatment regimen for each individual patient. obesity and heart failure: epidemiology, pathophysiology, clinical manifestations, and management obesity cardiomyopathy: pathophysiology and evolution of the clinical syndrome cellular mechanisms underlying 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patients with co-vid-19 disease in new york city assessment of vascular and endothelial dysfunction in nutritional studies current role of the nlrp3 inflammasome on obesity and insulin resistance: a systematic review clinical predictors of mortality due to covid-19 based on an analysis of data of 150 patients from wuhan, china interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome back to the future: lessons learned from the 1918 influenza pandemic lille intensive care covid-19 and obesity study group. high prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (sars-cov-2) requiring invasive mechanical ventilation inflammatory cytokines in vascular dysfunction and vascular disease abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia endothelial cell infection and endotheliitis in covid-19 correlation of tlr4 and klf7 in inflammation induced by obesity obesity cardiomyopathy: pathogenesis and pathophysiology effective treatment of severe covid-19 patients with tocilizumab pathological findings of covid-19 associated with acute respiratory distress syndrome obesity and influenza associated mortality: evidence from an elderly cohort in hong kong clinical characteristics of 140 patients infected with sars-cov-2 in wuhan clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study key: cord-301423-stod75j2 authors: parekh, niyati; deierlein, andrea l title: health behaviours during the coronavirus disease 2019 pandemic: implications for obesity date: 2020-08-04 journal: public health nutrition doi: 10.1017/s1368980020003031 sha: doc_id: 301423 cord_uid: stod75j2 objective: obesity is a risk factor for severe complications and death from the coronavirus disease 2019 (covid-19). public health efforts to control the pandemic may alter health behaviors related to weight gain, inflammation, and poor cardiometabolic health, exacerbating the prevalence of obesity, poor immune health, and chronic diseases. design: we reviewed how the pandemic adversely influences many of these behaviors, specifically physical activity, sedentary behaviors, sleep, and dietary intakes, and provided individual level strategies that may be used to mitigate them. results: at the community level and higher, public health and health care professionals need to advocate for intervention strategies and policy changes that address these behaviors, such as increasing nutrition assistance programs and creating designated areas for recreation and active transportation, to reduce disparities among vulnerable populations. conclusions: the long-lasting impact of the pandemic on health behaviors, and the possibility of a second covid-19 wave, emphasize the need for creative and evolving, multi-level approaches to assist individuals in adapting their health behaviors to prevent both chronic and infectious diseases. obesity is a major public health concern in the usa. there are approximately 42 % of americans with obesity (defined as a bmi > 30 kg/m 2 ), of which 9 % suffer from severe obesity (bmi > 40 kg/m 2 ) (1) . emerging evidence suggests that obesity is a strong risk factor for severe complications, hospitalisation and death from the coronavirus disease 2019 (covid-19) (2) . in new york city, compared with adults (aged < 60 years) with a bmi < 30 kg/m 2 , those with a bmi 30-34 kg/m 2 and those with a bmi > 35 kg/m 2 were 1·8 (95 % ci 1·2, 2·7) times and 3·6 (95 % ci 2·5, 5·3) times more likely to be admitted to acute and critical care, respectively (3) . although the specific biological mechanisms continue to be elucidated, inflammation and immune dysregulation are central to the aetiology of covid-19, attacking the lungs and vasculature system and progressing to the heart, kidneys and other organs throughout the body (2, 4) . individuals with obesity may be particularly susceptible to covid-19 infection due to the range of comorbidities associated with excess adiposity, including hyperglycaemia, hypertension, inflammation and impaired respiratory function (5) . while social distancing measures are necessary to control the pandemic, they will also have unintentional consequences that may worsen the obesity epidemic and its related comorbidities in the usa. sheltering-in-place has significantly altered health behaviours and the food environment by limiting opportunities for daily physical activities, encouraging screen time and sedentary behaviours, disturbing sleep and promoting consumption of ultraprocessed foods and alcohol. all of these behaviours may contribute to weight gain and the development of cardiometabolic diseases, such as diabetes, hypertension and cvd. during this time, public health professionals are faced with the dual challenge of continuing to promote obesity prevention strategies, while supporting covid-19 containment efforts. herein, we discuss modifiable behavioural risk factors for weight gain that have been affected by the pandemic: physical activity, sedentary behaviours, sleep and diet (fig. 1) . we provide strategies to improve them, which can be incorporated into public health messaging, interventions and tele-medicine during this period. the majority of american adults do not meet the national recommendations of at least 150 min of moderate physical activity or 75 min of vigorous physical activity (or an equivalent combination) per week (6) . physical activity is associated with a wide range of meaningful health benefits. individuals who engage in regular physical activity are more likely to have a healthy weight status; reduced risks of cardiometabolic diseases, some cancers and osteoporosis; improved cognition; and shorter periods of depression and anxiety (7) . physical activity is also critical for improving quality of life among individuals with chronic conditions and disabilities. social distancing and lockdown measures have diminished opportunities to participate in several domains of physical activity, particularly those related to recreation, transportation and work. recreational sources of activity, such as health clubs, gyms, pools, and indoor and outdoor sports facilities (e.g., tennis and basketball courts), have limited access and even after re-opening many individuals may be reluctant to use them. daily activities associated with transportation and work, for example, walking a child to the bus stop, running errands or climbing a flight of stairs at the office, have also been drastically reduced. these short bouts of activity throughout the day are important contributors to daily energy expenditure and weight gain prevention and allow for breaks in sedentary behaviours. during this time, efforts should be made to schedule movement throughout the day, particularly for individuals who do not have a regular exercise routine. walking is an excellent low-impact exercise that can improve cardiovascular fitness and increase energy expenditure, even in short 10-min increments (8) . caregiving and household activities, such as playing with children, cleaning and gardening, may also be used to off-set lost daily activities from other domains. additionally, at-home exercise classes and programmes are available for free or low cost on many social media platforms (e.g., instagram, youtube and facebook) for various types of exercises and skill levels. information on these resources and other physical activity strategies can be tailored and distributed to target populations. the average american adult spends 7·2-9·5 h/d engaged in sedentary behaviours, such as sitting while working, higher alcohol intake fig. 1 (colour online) interrelationships of behavioural risk factors for weight gain that have been affected by the covid pandemic; the confluence of these behavioural changes is hypothesised to exacerbate the national prevalence of obesity that is a threat for disease severity and mortality reading, watching television and using computers, smartphones or other devices (9) . although the overall evidence for an association between sedentary behaviours and obesity in adults is inconsistent, sitting for extended time periods is associated with greater waist circumference and higher blood levels of tag, glucose and insulin, which are biomarkers of poor cardiometabolic health (10) . the types of sedentary behaviours that individuals engage in are also important. among all of the sedentary behaviours, television watching likely has the greatest influence on weight gain due to the obesogenic behaviours that accompany it (9) . television watching is an environmental stimulus that increases food intakes, independent of hunger-satiety signals or food palatability; therefore, consumption of meals and energy-dense snack foods in front of the television may result in excess energy, fat and sugar intakes (11) . television watching also exposes individuals to advertisements for unhealthy foods and beverages, which may further encourage their consumption (12) . for the majority of individuals, stay-at-home measures have increased sedentary time, especially among apartment dwellers. physical activity breaks throughout sedentary time can reduce sitting-related health risks and are associated with lower bmi and improved cardiometabolic health biomarkers (13) . individuals can also keep meals and snacking separate from all work-, school-and leisure-related sedentary behaviours to reduce opportunities for overeating and junk food consumption. modern society has resulted in an increased prevalence of deficient sleep health, which encompasses inadequate sleep duration, poor sleep quality and sleep disorders. the average american adult suffers from deficient sleep due to sleeping less than the recommended 7-8 h/night, having a job that requires shift work and/or having a sleep disorder (e.g., insomnia, sleep apnoea) (14) . deficient sleep is associated with increased risks of diabetes, hypertension, cvd and obesity (14) . experimental studies demonstrate that restricted or impaired sleep reduces glucose tolerance and insulin sensitivity and alters appetite-regulating hormones, resulting in decreased satiety and increased feelings of reward and pleasure in response to food stimuli (15) . individuals with short or disrupted sleep report greater energy intakes, which may be attributed to more frequent meal occasions, larger portion sizes and preference for energy-dense foods that are high in fat and carbohydrates (16) . moreover, energy expenditure from physical activities is often reduced among people with inadequate sleep (16) . the pandemic may disrupt and shorten sleep in several ways, including altering usual bed times (e.g., going to bed later), increasing screen time and intensifying anxiety and stress levels. individuals may be able to overcome some of this disruption by maintaining good sleep hygiene practices, such as setting a consistent sleep/wake routine, extending sleep duration to meet recommended amounts and avoiding or reducing blue light exposure from screen use (using blue light blocking glasses or software) around bedtime, since blue light may interfere with melatonin levels and stimulate brain activity (17) . limiting late-night snacking and alcohol consumption and achieving recommended amounts of daily physical activity also help to regulate sleep. the external and household food environments are strongly correlated with individual diet quality and health. greater access to and purchases of fruits, vegetables and whole grains are associated with higher nutrient intakes, improved immune function and reduced chronic illness, while greater access to and purchases of ultra-processed foods are associated with nutrient deficiencies and chronic disease development (18) . ultra-processed foods are defined as industrially manufactured, ready-to-eat or ready-to-heat formulations, which contain little to no whole, fresh foods. prior to the pandemic, ultra-processed foods constituted the majority of energies purchased by us households and were the main source of total and added sugars, na and fats. although some ultra-processed foods may provide vitamins and other essential nutrients (e.g., vitamin c, n-3 fatty acids and folic acid), the majority of these foods contain preservatives and additives (e.g., na, trans fats, high fructose maize syrup, artificial colourings, nitrites and sulphites), as well as neo-formed contaminants and chemicals (19, 20) . these ingredients are hypothesised to influence cardiometabolic disease development through several mechanisms, including dysregulating blood lipid, glucose and hormone concentrations; altering gut microbiota; increasing body fat stores; and generating oxidative stress and inflammation (18, 21) . additionally, ultra-processed foods are hypothesised to promote poor dietary habits, such as snacking and overeating, due to their convenience, omnipresence, low cost and large portion sizes (18) . the pandemic has drastically changed the food environment. record high unemployment rates compounded by interruptions in the food supply chain due to worker shortages, heightened safety inspections and delays in the transportation and delivery of fresh foods have left consumers with no choice but to consume what they can afford and access at their local food stores. lockdown measures have also reduced the frequency of grocery shopping, further decreasing the ability to purchase perishable fresh foods, particularly produce. rates of household food insecurity are mounting and early reports from grocery retail stores demonstrate historically high sales of shelf-stable and ultra-processed foods, such as boxed macaroni and cheese and snack foods, as well as alcohol (22, 23) . aside from issues surrounding substance abuse and mental health, alcohol consumption is associated with stimulating appetite, overeating and weight gain. although achieving optimal dietary quality is challenging during this time, individuals can make several efforts to increase their intakes of nutrient-dense foods. grocery store purchases should focus on frozen, canned (low na varieties) or dried plant-based items, like whole grains (e.g., brown rice, whole grain maize meal, whole wheat pasta and oats), pulses (legumes and beans), vegetables and fruits, as well as fresh produce that does not quickly perish, such as apples, pears, cabbage, carrots, squashes, sweet potatoes and beets. gardening, even in window sills and balconies, may further help to encourage consumption of vegetables, fruits and fresh herbs. stay-at-home measures have also increased reliance on cooking and baking, which provides the opportunity to make more healthful versions of storebought processed foods. for example, soups and stews, pizza, breads and cookies may all be home made with whole grains, vegetables and low sugar and salt content. beverage consumption should focus on varieties of water (e.g., plain, seltzer and fruit infused), while avoiding all sugar-sweetened beverages. the us dietary guidelines recommend that if alcohol is consumed then it should be done in moderation, defined as up to one drink for women and two drinks for men per day (24) . for individuals who consume alcohol, daily drinking should be limited and should not be higher than pre-pandemic intakes, which may suggest that alcohol is being used as a coping mechanism for social isolation, boredom and other stressors. historically, obesity has been of public health concern due to its strong associations with chronic disease morbidity and mortality. the covid-19 pandemic has highlighted that obesity greatly increases susceptibility to complications and mortality from infectious diseases as well. public health measures to control the pandemic may alter health behaviours related to weight gain, inflammation and poor cardiometabolic health, exacerbating the prevalence of obesity, poor immune health and chronic diseases in the usa and other countries with developed economies. however, for many of these behaviours, specifically physical activity, sedentary behaviours, sleep and dietary intakes, the influence of the pandemic can be mitigated. table 1 summarises individual-level practices related to each behaviour that may be promoted during this time. at the community level and higher, public health and health care professionals need to advocate for intervention strategies and policy changes that address these behaviours. for example, expanding community nutrition services and government food assistance programmes to reduce disparities among vulnerable populations or increasing designated areas for recreation and active transportation, such as green spaces, street traffic closures and protected bike lanes to provide safe spaces for individuals to exercise, walk, run and bike while maintaining social distance, particularly in urban areas. the long-lasting impact of the pandemic on health behaviours and the possibility of a second covid-19 wave emphasise the need for creative and evolving, multi-level approaches to assist individuals in adapting their health behaviours to improve immune function and prevent both chronic and infectious diseases. during extended periods of screen time • limit late-night snacking and avoid eating in the absence of hunger • limit consumption of packaged salty and sweet foods and sugarsweetened beverages • consume more plant-based foods, specifically whole grains, vegetables, fruits, lean proteins and dairy. substitute with lowsugar, low-salt frozen or canned items if fresh produce is unavailable • cook healthy meals at home • maintain good sleep hygiene practices; aim for at least 7 h of sleep every night, avoid screens, bright lights, and caffeinated and alcoholic drinks before bed • consume alcohol in moderation or do not drink at all • cope 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environmental stimuli induce increased meal intake in healthy women: comparison of television viewing versus listening to a recorded story in laboratory settings priming effects of television food advertising on eating behavior meta-analysis of the relationship between breaks in sedentary behavior and cardiometabolic health the epidemiology of sleep and obesity short sleep duration and dietary intake: epidemiologic evidence, mechanisms, and health implications the role of sleep duration in the regulation of energy balance: effects on energy intakes and expenditure dealing with sleep problems during home confinement due to the covid-19 outbreak: practical recommendations from a task force of the european cbt-i academy characterization of the degree of food processing in relation with its health potential and effects ultraprocessed products are becoming dominant in the global food system the un decade of nutrition, the nova food classification and the trouble with ultra-processing ultra-processed diets cause excess calorie intake and weight gain: an inpatient randomized controlled trial of ad libitum food intake americans drop kale and quinoa to lock down with chips and oreos pandemic drives alcohol sales -and raises concerns about substance abuse dietary guidelines for americans 8th edition acknowledgements: none. financial support: none. conflict of interest: none. authorship: a.d. and n.p. wrote this work. ethics of human subject participants: not applicable. key: cord-325138-riu4jdc2 authors: hassink, sandra g.; fairbrother, gerry title: obesity and hunger threaten the foundations of child health date: 2020-08-13 journal: acad pediatr doi: 10.1016/j.acap.2020.08.010 sha: doc_id: 325138 cord_uid: riu4jdc2 nan on the face of it, childhood obesity and child hunger seem like very different problems. however a deeper look reveals that the root causes of each are intertwined and overlapping. both are conditions of poverty, both result from lack of nutritious food, and both lead to disease and affect large numbers of children. childhood obesity and food insecurity can co-occur, and in some children food insecurity is associated with an increased risk of obesity. 1, 2 further, and especially important now: both obesity and food insecurity confer increased risk from covid-19 and are potentially exacerbated by the stress of food scarcity during the pandemic. food insecurity and obesity in children co-exist with childhood poverty and both are most prevalent in the poorest regions. 3,4,5, in 2017, nearly 35% of households with children and incomes below 185% of the federal poverty level, were food insecure compared to <6% among more affluent households. 4 a study of 68 school districts in massachusetts found an independent relationship between community income status and rates of childhood overweight/obesity indicating that the economic status of a family may be more important than race and ethnicity in childhood obesity prevalence. 6 common systemic factors that may lead to both obesity and food insecurity in economically disadvantaged populations include, poorer access to and higher cost of nutritious foods and a shared food system that advantages lower-cost, high energy dense foods. 7 not surprisingly given the connection with poverty, food insecurity rates vary with economic conditions, with greater food insecurity in economic downturns. in the great recession, food insecurity in households with children jumped from 15.8% in december 2007 to a high of 21.3% in june of 2009. by 2018, pre covid-19, the overall rate dropped to13.9%. 8 with the sharply enhanced and continuing rise in unemployment due to covid-19 restrictions, food insecurity has increased and may even exceed levels seen in the great recession. 9 both obesity and food insecurity result from lack of nutritious food childhood obesity and food insecurity coexist but their relationship is complex. no consistent theories have yet emerged to explain these relationships. however, we know that availability of nutritious food is key to reducing both obesity and food insecurity in children. the underlying causes of food insecurity and obesity have to do with our inability to ensure that all children have a daily food intake that "contains an appropriate density of nutrients, is sufficiently diverse that it supplies adequate but not excessive amounts of nutrition, is palatable and culturally acceptable, affordable and available year round and overall supports normal growth and development". 10 food insecurity may compromise nutritional quality with the purchase of cheaper, more energy dense foods. 11 findings suggest prices of fruits and vegetables and fast food may have some influence on consumption in certain subgroups, such as children and low income families. 12, 13 in a longitudinal study, children's weight was positively related to fruit and vegetable prices with children in poverty and children at risk for overweight the most price sensitive. 14 affordable food pricing for nutritious foods should be considered when policy makers look at economic strategies to drive purchasing. 13 both obesity and food insecurity lead to disease. both obesity and food insecurity negatively affect child and later adult health and wellbeing. children in food-insecure households have worse general health and are more likely to have asthma, chronic skin conditions and depressive symptoms, colds, stomach problems, 15 and stress. 16, 17 compromise in immune functioning associated with food insecurity may also compromise overall child health status. 18 in addition, children who are food insecure have a greater risk of hospitalization, and food-insecure households have higher mean health care expenditures than food-secure households. 19 childhood obesity is a multisystem chronic disease and children with obesity are more likely to have high blood pressure, non-alcoholic fatty liver disease, asthma, 20 type 2 diabetes mellitus, polycystic ovary syndrome, sleep apnea, musculoskeletal disorders, and psychological problems. 21 these underlying disease states make children more vulnerable to adverse outcomes if they do contract covid-19. cardiovascular disease and type 2 diabetes in adulthood are linked to obesity in childhood. 22, 23 childhood obesity results in increased healthcare costs from prescription drugs, emergency room visits and outpatient expenditures. 24 it is important to appreciate that access to healthy food is not only crucial to prevention of childhood obesity and hunger, it also constitutes treatment for childhood obesity 25 and the health effects of hunger. 26 withholding healthy food from children with obesity and obesity-related comorbidities is essentially withholding treatment for their disease. both obesity and food insecurity affect large numbers of children. in the united states in 2015-2016 the prevalence rates for childhood obesity were 13.9% in children 2-5 yr., 18.4% in children [6] [7] [8] [9] [10] [11] yr., and 20.6% in adolescents 12-19 yrs. with an overall prevalence of 18.5 %. 27 in 2018, 13.9% of households with children under 18 years were food insecure. if these households were headed by a single man or woman, rates of food insecurity increased to 15.9% and 27.8% respectively. 28 childhood obesity rates have progressed steadily upward from 5-6% in the 1970s to 18.5% in 2016. 27 in contrast, food insecurity rates vary with economic conditions as described earlier. not surprisingly, given the level of food insecurity among low-income households, there are a number of federal programs that provide food for low-income children and families-15 in the us department of agriculture alone. 29 specific federal programs which "serve as critical supports for the physical and mental health and academic competence of children " are snap, wic, child and adult care food program, school breakfast and lunch program, and the summer food service program 26 food programs like these are opportunities to provide healthy food for children most at risk for food insecurity and obesity. these programs serve a critical role, but they are lacking in important ways, primarily in having inadequate levels of funding and in having requirements that make it difficult for families to access the benefit. both snap and wic are important sources of nutrition for children and infants. snap is the largest federal nutrition assistance program. it provides benefits to eligible low-income individuals and families via an electronic benefits transfer card. this card can be used like a debit card to purchase eligible food in authorized retail food stores. wic provides federal grants to states for supplemental foods, health care referrals, and nutrition education for low-income pregnant, breastfeeding, and nonbreastfeeding postpartum women, and to infants and children up to age five who are found to be at nutritional risk. 29, 30 in fiscal year 2017, snap served an average of 8.6 million households with children each month, representing 42 % of all snap households. 31 since the 2008 recession snap caseloads have declined with 45 states having fewer snap recipients in 2018 than in 2013. in 10 states by 2018 snap participation had fallen to pre-recession levels and was expected drop even further because of the improving economy 32 instead, in response to widespread unemployment, school and child care closures due to covid-19 snap enrollment is expected to increase for the foreseeable future. 33 snap is even more crucial in the economic downturn because increased access to and participation in snap reduces the rise in food insecurity for children 34 and risk of obesity in children under 3. 35 households that experience reduction of snap benefits have increased household food insecurity, child food insecurity, housing instability and energy insecurity. 36 in contrast, wic participation initially dropped with the onset of the covid pandemic due to in person visit requirements, closure of wic offices and enrollment timing limitations. 37 these added to known barriers to wic participation which include 1) eligible families not knowing they can apply 2) at risk families not perceiving a need for the program 38 3) fears that wic participation may threaten immigration status 39 4) fear of stigma from receiving government aid 40 5) difficulty with transportation 6) need to miss work 7) stress and 8) language concerns. 41 . making wic widely accessible to families hit hard by covid-19 is crucial because wic has been shown to both reduce the prevalence of food insecurity 42, 43 and obesity 44 and is an important contributor to early childhood health. . in contrast to snap and wic, which provide funds to households so that they might buy food, other programs provide food directly to recipients in specific sites. both types of programs lessen the burden of food costs on families. the child and adult care food program (cacfp), one of the latter types of program, provides cash reimbursement to family day care, child care centers, homeless shelters, and after-school programs for meals and snacks served to children. 45 attending a cacfp-participating center has been associated with reduction of underweight and overweight with a possible reduction in food insecurity. 46 there have been successful multicomponent intervention trials in child care centers which have prevented excess weight gain especially for children higher weight categories and children with lower socioeconomic status. 47 both center and home-based child care are subject to state and sometimes local or federal regulatory control, representing an opportunity to influence nutrition and feeding practices in a systematic way. 48 participation in school meal programs decreases food insecurity of low-income students during the school year. 49, 50 and decreases risk of overweight for girls who have food-insecurity 51 school closures due to the covid-19 pandemic have exacerbated food insecurity by reducing children's access to school meals. summer food assistance via electronic benefit cards, reduced the prevalence of very low food security among school aged children by one third and improved children's dietary quality. 52 food insecurity and obesity are damaging to child health and negatively impact their health as adults. focusing on policies and programs that take aim at the double burden of food insecurity and obesity is a population health priority. this is especially urgent in light of the effects of covid-19 on availability and access to healthy food. poor diet is now the leading cause of poor health in the us, causing more than half a million deaths per year. 53 the country needs to correct this. the covid-19 pandemic is laying bare the inequalities in availability of and access to nutritious food. federal nutrition assistance programs should provide access to the healthiest possible nutrition for children and should ensure that all eligible children and families have healthy nutrition year round. overall funding for both snap and wic need to be increased, and specific benefits to families need to rise as well. snap benefits to families were derived from the most meager of usda's four food plans, and even before the pandemic, were inadequate and needed to be increased. 54, 55 the flexibility of snap-ed to assist in food distribution and enrollment in snap and the pandemic electronic benefit transfer should be increased through and beyond the pandemic. 56 to maximize the health impact of this program particularly in light of the covid-19 pandemic, barriers to enrollment and participation should be aggressively addressed by state and federal agencies as well as health care systems. studies have shown that adults receiving snap benefits improved their diet quality with an increase of fruit and vegetable intake when they received incentives such as; for every dollar of snap benefits the household spent on fruits and vegetables in participating retailers, 30 cents in snap benefits was added back to their ebt card. 57, 58, 59 incentives for healthy food are supported by both adult snap participants and eligible non participants. 60 snap is an ideal vehicle for incentivizing healthy eating both within program requirements and in snap education. states should view increasing participation and lowering barriers to participation part of their public health strategy. healthcare systems should consider snap enrollment part of chronic disease treatment. school meals and snacks may fulfill up to 2/3 of a child's daily nutritional 61 however the nutritional content of these meals can be highly variable. 62 policies need to assure that all children will receive a healthy high quality school meal and snack in their school setting. emergency relief during covid-19 should include requiring fema in conjunction with the usda to coordinate meal distribution through the course of the pandemic, similar to natural disaster relief, extend the expanded electronic benefits transfer through and beyond the pandemic , provide funding relief for school nutrition programs to cover losses incurred during school closures and allow free meals to all children to allow time for processing of new school meal applications in the transition back to school. 56 compared to non-immigrant families, immigrant families are more likely to experience food insecurity. 63 . one quarter of children under 5, (5,577,000 children in 2018), have at least one parent who is an immigrant with 93.6% of children in these families born in the us. 64 adults who are documented immigrants who are not part of specific exempt groups i.e. refugees, lawful permanent residents, and have been in the us fewer than 5 years cannot receive snap benefits. 65 however, these families have the right to apply for snap their u.s. citizen children. 66 . nevertheless, studies have shown that eligible children of parents who are immigrants are less likely to participate in snap when their parents are ineligible. 67 a recent study documented a decrease in snap participation among immigrant families and the authors and others suggest that fear among immigrant families related to participation in snap due to public charge rulings, lack of education about enrollment of citizen children, need for assurances of data confidentiality of applicant families, and need to reduce anti-immigrant rhetoric are all important strategies to address food insecurity in this population. 68, 69 conclusion food insecurity and obesity are damaging to child and adult health. childhood, a time when optimal nutrition essential for healthy growth and development, is being compromised by systemic factors that we can change. understanding the impact and overlap of obesity and food insecurity on child health can help us focus on policies that address the overall state of nutrition related illness that compromise the health and well-being of our population. household food insecurity 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metropolitan area food prices and food outlet density. public health food prices and weight gain during elementary school: 5-year update food insecurity and child health maternal depression, changing public assistance, food security, and child health status poverty, material hardship, and depression psychological stress in children may alter the immune response impact of food insecurity and snap participation on a systematic review and meta-analysis estimating the population prevalence of comorbidities in children and adolescents aged 5 to 18 years health consequences of obesity the impact of childhood and adolescent obesity on cardiovascular risk in adulthood: a systematic review investigating the role of childhood adiposity in the development of adult type 2 diabetes in a 64-year follow-up cohort: an application of the parametric gformula within an agent-based simulation study the impact of obesity on health service utilization and costs in childhood expert committee recommendations regarding the prevention, assessment, and treatment of child and adolescent overweight and obesity: summary report sarah e. barlow pediatrics prevalence of obesity among adults and youth: united states usda nutrition assistance programs characteristics of supplemental nutrition assistance program households: fiscal year caseload and spending declines have accelerated in recent years june snap data tables loss of snap is associated with food insecurity and poor health in working families with snap, young children's health, and family food security and healthcare access associations of food stamp participation with dietary quality and obesity in children special supplemental nutrition program for women, infants, and children participation and infants' growth and health: a multisite surveillance study immigration legal status and use of public programs and prenatal care sources of stigma for means-tested government programs concerns and structural barriers associated with wic participation among wic-eligible women a longitudinal study of wic participation on household food insecurity identifying the effects of wic on food insecurity among infants and children state-specific prevalence of obesity among children aged 2-4 years enrolled in the special supplemental nutrition program for women, infants, and children -united states the child and adult care food program and food insecurity the child and adult care food program and the nutrition of preschoolers obesity prevention and obesogenic behavior interventions in child care: a systematic review early child care and education: a key component of obesity prevention in infancy children receiving free or reduced-price school lunch. have higher food insufficiency rates in summer the school breakfast program strengthens household food security among low-income households with elementary school children lower risk of overweight in school-aged food insecure girls who participate in food assistance: results from the panel study of income dynamics child 46development supplement a summer nutrition benefit pilot program and low-income children's food security us burden of disease collaborators. the state of us health, 1990-2016: burden of diseases, injuries, and risk factors among us states more adequate snap benefit would help millions of participants better afford food report of the 50th anniversary of the white house conference on food, nutrition, and health: honoring the past, taking actions for the future early childhood program participation, from the national household education surveys program of 2016 effects of subsidies and prohibitions on nutrition in a food benefit program: a randomized clinical trial evaluation of the healthy incentives pilot (hip): final report: prepared by abt associates for the us department of agriculture, food and nutrition service improving the nutritional impact of the supplemental nutrition assistance program: perspectives from the participants feeding low income children during the covid-19 pandemic nejm 2020 a historical review of changes in nutrition standards of usda child meal programs relative to research findings on the nutritional adequacy of program meals and the diet and nutritional health of participants: implications for future research and the summer food service program children in immigrant families: essential to america's future; the foundation for child development the health and well-being of young children of immigrants trends in food insecurity and snap participation among immigrant families u.s.-born young children approaches to protect children's access to health and human services in an era of harsh immigration policy key: cord-344614-5zcylf6k authors: moriconi, diego; masi, stefano; rebelos, eleni; virdis, agostino; manca, maria laura; de marco, salvatore; taddei, stefano; nannipieri, monica title: obesity prolongs the hospital stay in patients affected by covid-19, and may impact on sars-cov-2 shedding date: 2020-06-04 journal: obes res clin pract doi: 10.1016/j.orcp.2020.05.009 sha: doc_id: 344614 cord_uid: 5zcylf6k introduction: on the last three months the new sars-cov-2 coronavirus has created a pandemic, rapidly spreading all around the world. the aim of the study is to investigate whether obesity impacts on covid-19 morbidity. methods: one hundred consecutive patients with covid-19 pneumonia admitted in our medical unit were evaluated. anthropometric parameters and past medical history were registered. nasopharyngeal swab samples and biochemical analysis were obtained at admission and during hospital stay. results: patients with (ob, 29) and without obesity (n-ob, 71) were similar in age, gender and comorbidities, with the exception of hypertension that was more frequent in ob group. at admission, inflammatory markers were higher in ob than n-ob group. ob group showed a worse pulmonary clinical picture, with lower pao2 (57 ± 15 vs. 68 ± 14 mmhg, p = 0.042), and sao2 (88 ± 6 vs. 92 ± 5 %, p = 0.049) at admission consequently requiring higher volumes of oxygen (fi02: 38 ± 15 vs. 29 ± 19%, p = 0.047) and a longer period to achieve oxygen weaning (10 ± 6 vs. 15 ± 7 days, p = 0.03). ob group also had positive swabs for longer time (19 ± 8 vs. 13 ± 7, days, p = 0.002), and required longer hospital stay (21 ± 8 vs. 13 ± 8, days, p = 0.0008). partial least square regression analysis showed that bmi, age and crp at admission were related to longer length of hospital stay, and time for negative swab. on the contrary, in this cohort, obesity did not predict higher mortality. conclusions: subjects with obesity affected by covid-19 require longer hospitalization, more intensive and longer oxygen treatment, and they may have longer sars-cov-2 shedding. obesity is an increasingly important mortality risk factor, partially because it increase the risk of several non-communicable diseases [1, 2, 3, 4] . pathogenetic mechanisms underlying these diseases appear to be related, at least in part, to a chronic, low-level inflammatory exposure which often accompanies adipose tissue accumulation and promotes the development of metabolic and cardiovascular complications. furthermore, the thromboembolic risk is known to be higher in patients with obesity than in the general population [5] . although increased body mass index (bmi) has been associated with a higher susceptibility to and more severe presentation of infections [6] (such as h1n1 influenza virus), data remain conflicting. indeed, several reports have suggested that patients with obesity might have a lower mortality rate during severe sepsis than normal-weight patients [7, 8, 9, 10, 11, 12] . this phenomenon seems to be in line with some studies reporting a paradoxical association between overweight and class i obesity and reduced mortality in patients with chronic heart failure [13, 14] . on the last three months, the new sars-cov-2 infection has rapidly spread around the world. even though the outbreak started in china, the pandemic quickly moved to europe and america, leading to a crisis of several national health systems. compared to china, in these westernized societies the population is older, and there is a much higher prevalence of obesity. these features might aggravate the severity of the disease, given the greater frailty of the population and the well-established mechanical restrictive pattern imposed by high body weight to the respiratory system dynamic. furthermore, in obese patients there is an increased prevalence of respiratory diseases, including chronic obstructive pulmonary disease (copd) and sleep apnea. these factors might explain the greater severity, hospitalization and mortality from h1n1 virus infection observed in obese compared to non-obese patients [15] . recent studies have suggested that bmi represents a risk factor for severe complications in patients with covid-19 [16, 17] . in the present study, we wished to investigate whether in our cohort of covid-19 subjects, obesity was predicting a worse outcome, in terms of mortality, or of other factors that could be related to a worse clinical picture. consecutive patients admitted to the covid-19 unit of cisanello hospital, at the "azienda ospedaliero universitaria pisana-aoup (pisa, italy), between march 16 th and april 15 th , 2020 were enrolled in this single-centre, retrospective, observational cohort study. this retrospective observational study was based on medical records, in strict agreement with local ethical statement of aoup. patient confidentiality was protected by assigning an anonymous identification code, and the electronic data were stored in a locked, password-protected computer. all patients were diagnosed with covid-19 pneumonia according to world health organization interim guidance [20] with sars symptoms characterized by dyspnea, increased respiratory frequency, decreased j o u r n a l p r e -p r o o f blood oxygen saturation, and need for oxygen support therapy. two nose and pharyngeal swab samples were obtained from all patients at admission and, at different times depending on the clinical evolution of the disease, during the hospital stay. the presence of the sars-cov-2 genome was detected using real-time reverse transcriptase-polymerase chain reaction assays [21] . demographic, anthropometric and clinical parameters, including sex, age, body mass index (bmi), blood pressure, heart and respiratory rate, oxygen saturation, body temperature, oxygen requirements were recorded at the admission. vital signs were regularly collected during hospitalization to monitor clinical conditions. arterial blood gasses and venous blood samples (for standard biochemistry and circulating levels of inflammatory markers) were collected at the admission and, depending on the patient clinical conditions, during the hospital stay. cytokines were measured by quantikine elisa assay kits (r&d system). detailed medical history was recorded from all patients, with a specific focus on the following diseases: hypertension, cardiovascular disease, diabetes, dyslipidemia, chronic respiratory disease, chronic obstructive pulmonary disease (copd). quantitative data were expressed as mean sd or median [interquartile range], for variables with normal or skewed distribution, respectively. continuous variables with a normal distribution were compared by the student t test, while the variables with a skewed distribution by the mann whitney u test. categorical data, expressed as percentage, were analysed with x 2 test. in order to identify the variables, at admission, maximally contributing to the duration for obtaining a negative oropharyngeal or nasal swab, and the length of hospital stay, respectively, two partial least square (pls) regressions [22] were generated. variables with variable importance in projection (vip, expressing a measure of a variable's relevance in the model) greater than 1,50 were considered significant for association with the dependent variable (duration for a negative swab, or length of hospital stay). the same method has been used in order to identify the variables maximally contributing to group separation of subjects between survisors and dead. a p value <0.05 was considered to be significant; when necessary correction for multiple testing was applied. statistical analysis was performed by r and ibm-spss packages for mac os x. a total of 100 consecutive patients admitted in our covid-medical unit were enrolled in the present study. patients were grouped by bmi ( ≥30 kg/m^2 or < 30 kg/m2) as patients with obesity (ob, 29) and patients without obesity (n-ob, 71). the ob group was mainly constituted by class i obesity subjects, with only 4 patients with bmi ranging between 35 and 40 kg/m 2 . the anthropometric and biochemical characteristics of the study participants at admission are shown in table 1 . age and sex distribution were similar between the two groups, as well as the main comorbidities, except for hypertension that was more frequent in the ob group (ob vs. nthere were no differences in total blood count, fasting plasma glucose, indexes of cytolysis, renal and liver function between the two groups. among inflammatory markers, ferritin, c-reactive protein (crp) and tumor necrosis factor alpha (tnf-α) levels were higher in the ob group than n-ob subjects ( table 2) . no differences were found in any other cytokine parameters. ob patients tended to have a worse blood gas analysis compared to the n-ob subjects, with a lower value of arterial oxygen pressure (57±15 vs. 68±14 mmhg, p= 0.042) and worse oxygen saturation (88±6 vs. 92±5, %, p= 0.049), consequently requiring higher oxygen support (fi02 via venturi mask 38±15 vs. 29±19%, p= 0.047). pls detected the following variables strictly related (vip > 1,50) to length of hospital stay: age, bmi, lymphocytes, hemoglobin and crp at admission. regarding the dependent variable "length of hospital stay", the method identify: age, bmi and crp at admission. according to these results, patients with obesity showed a longer duration for obtaining a negative oropharyngeal or nasal swab (19±8 vs. 13±7, days, p= 0.002), required a longer period to achieve oxygen weaning 13±8, days, p= 0.0008) (figure 1 a-b) . in any case, at discharge, no difference was found in crp levels (0. the crp at admission was associated with a longer length of hospital stay and time for negative swab (figure 2) . in this relatively small sample size, we did not find any difference in the mortality rates between the two groups (16% vs. 19%, ob vs n-ob, respectively, p=ns). moreover, pls regression aimed to detect the variables at admission related to "survivor/dead" provided the following results: age j o u r n a l p r e -p r o o f (67±17 vs. 80±7 yrs), lymphocytes (1304±1034 vs. 784±412, mm 3 ) and creatinine (1.0±0.4 vs. our study shows that obesity is associated with a severer respiratory presentation of covid-19 and severer elevation of inflammatory markers, likely leading to higher oxygen demands at admission, prolonged oxygen requirement during hospitalization, delayed viral clearance and extended hospital stay. these characteristics, however, did not translate into a higher risk of mortality in subjects with obesity compared to the patients without obesity. in a retrospective study on 112 covid-19 patients with cardiovascular disease admitted to the intensive care unit (icu) in wuhan, bmi has been reported to be associated with higher mortality [17, 23] . furthermore, lighter et al. [16] found that in patients aged <60 years, class ii obesity was associated with a doubled risk of icu access, whereas in patients aged 60 years, body weight did not appear to be a predictive factor for hospital admission or access to icu. in another recent paper [24] it has also been described that of 124 patients admitted to icu for covid-19, almost half of them were affected by obesity, and a higher bmi was associated with an increased risk of mechanical ventilation. nearly 90% subjects requiring invasive mechanical ventilation had class ii or iii obesity. in our cohort of patients, the prevalence of obesity (28%) in covid-19 patients is higher compared to that (11%) reported by italian health institute (epicentro) [18] . this difference could have multiple explanations; first of all, our cohort is relatively small; moreover, out patients were older and represented a selected population, with greater clinical impairment and need for hospitalization compared to the total sars-cov-2 confirmed cases in italy. in a preliminary report of 52 subjects, we have previously reported that obesity was associated with a longer length of hospital stay [25] . we now confirm this finding, expanding the population included in our cohort and providing potential explanations for these results. we now did not find any significant difference concerning previous comorbidities between ob and n-ob group. furthermore, in lps regression analysis, age, bmi and crp at admission were related to the duration of the hospitalization. even though the prevalence of copd was not higher in the ob compared to the n-ob group, obesity in itself might impair the respiratory system dynamic, reducing lung compliance and increasing respiratory muscle reactivity, ultimately leading to an impaired gas exchange also in apparently healthy individuals [26] . it is know that subjects with obesity per se have an increased pro-inflammarory pattern [27] . for this reason, beyond the potential impact on the lung mechanics, obesity might influence the clinical presentation and evolution of sars-cov-2 infection through j o u r n a l p r e -p r o o f exacerbation of the immune-inflammatory response related to the disease, as confirmed by the increased levels of several inflammatory markers detected in the peripheral blood of patients with obesity in our population. particularly, the abnormal secretion of adipokines and cytokines like tnf-alpha by the adipose tissue can sustain and amplify the inflammatory response to the sars-cov-2 infection, with potential consequences not only on the lung but also on the cardiovascular system [7] [8] . of note, yende et al. have already documented that elevated pre-infection levels of systemic inflammatory markers predict a higher risk of hospitalization in patients with community-acquired pneumonia [28] . collectively, these considerations might explain the later recovery, delayed weaning from o2 therapy and prolonged relapse from viral clearance of patients with obesity compared to the n-ob group observed in our study. this hypothesis is in keeping with previous results showing a higher risk of invasive mechanical ventilation in subjects with higher bmi, independently of other comorbidities [19] , as well as the prolonged viral shedding observed in people with >30 kg/m 2 bmi during influenza a infection [29] . it should be highlighted, however, that the estimated duration of the viral shedding calculated in our report might be inaccurate. indeed, the days of viral shedding were counted starting from the date of the first positive swab performed upon admission to the emergency department. information regarding the exact onset of the clinical symptoms was not systematically recorded. another limitation of the present study is represented by the small number of patients included in our cohort, associated with a lack of a better characterization of adiposity. while in a routine clinical setting the most commonly used definition of obesity is based on the presence of a bmi >30 kg/m 2 , it is well established that other measures such as waist-to-hip ratio might provide better information on the amount of visceral vs. subcutaneous adipose tissue; thus they might better reflect the presence of a pro-inflammatory environment related to fat accumulation. however, in the setting of an acute medical ward, with the huge burden of patients faced during phase 1 of the pandemic, collection of these measures was practically impossible. finally, we did not have information on the severity of insulin resistance associated with obesity, which is known to have an impact on the risk of cardiac dysfunction and cvd-related mortality [30] . phase 2 of the pandemic might represent an excellent opportunity for deepening our knowledge and acquiring further information regarding the potential influence of waist-to-hip ratio and the levels of insulin resistance on the association between obesity and severity of the sars-cov-2 infection. in conclusion, our data show that subjects with obesity affected by covid-19 required extended hospitalization and more intensive and prolonged oxygen treatment. still, they did not have an increased risk of mortality as compared to the subjects without obesity. our data also suggest that people affected by obesity might require more time to clear from sars-cov-2 shedding. if future studies will confirm this finding, clinical guidelines for the isolation period upon infection from j o u r n a l p r e -p r o o f sars-cov-2 should be personalized in case of individuals with obesity. finally, subjects with obesity affected by covid-19 have higher crp and tnf-α levels, and future studies should clarify whether the pro-inflammatory state that is commonly observed in obesity could provide a mechanistic background for their severer clinical presentation and evolution in course of sars-cov-2 infection. diego moriconi has made substantial contributions to conception, collection and interpretation of data and he has been involved in drafting the manuscript. stefano masi, eleni rebelos, salvatore de marco have made substantial contributions to data collection and they have been involved in drafting the manuscript. maria laura manca, has been involved in statistical analysis. agostino virdis, stefano taddei have been involved in revising it critically for important intellectual content. monica nannipieri has made substantial contributions to conception and design of the study, data interpretation, and she has been involved in writing of the manuscript. all the authors have declared that no conflict of interest exists. this work has not been published before and it is not under consideration for publication anywhere else. the authors received no funding and declare no conflict of interest all retrospective data involving human participants were in accordance with the ethical standards and with the 1964 helsinki declaration and its later amendments or comparable ethical standards. 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is suspected [www document clinical features of patients infected with 2019 novel coronavirus in wuhan partial least squares methods: partial least squares correlation and partial least square regression early antiviral treatment contributes to alleviate the severity and improve the prognosis of patientswith novel coronavirus disease (covid-19) high prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (sars-cov-2) requiring invasive mechanical ventilation importance of metabolic health in the era of covid-19 obesity and respiratory diseases differential impact of weight loss and glycemic control on inflammasome signaling preinfection systemic inflammatory markers and risk of hospitalization due to pneumonia obesity increased the duration of influenza a virus shedding in adults causes, characteristics, and consequences of metabolically unhealthy normal weight in humans j o u r n a l p r e -p r o o f j o u r n a l p r e -p r o o f key: cord-325055-todb1d4x authors: rychter, anna maria; zawada, agnieszka; ratajczak, alicja ewa; dobrowolska, agnieszka; krela‐kaźmierczak, iwona title: should patients with obesity be more afraid of covid‐19? date: 2020-06-24 journal: obes rev doi: 10.1111/obr.13083 sha: doc_id: 325055 cord_uid: todb1d4x covid‐19 crisis has lasted since the late 2019 to the present day. the severity of the disease is positively correlated with several factors, such as age and coexisting diseases. furthermore, obesity is increasingly considered as a yet another risk factor, particularly, because it has been observed that people suffering from excessive body weight may experience a more severe course of covid‐19 infection. on the basis of current research, in our nonsystematic review, we have investigated the extent to which obesity can affect the sars‐cov‐2 course and identify the potential mechanisms of the disease. we have also described the role of proper nutrition, physical activity and other aspects relevant to the management of obesity. the crisis caused by coronavirus disease 2019 , also known as severe acute respiratory syndrome coronavirus 2 (sars-cov-2), began in late 2019 in wuhan (capital of hubei, china) and has spread worldwide in early 2020. 1, 2 according to world health organization (who) report of may 16, since the beginning of the outbreak over 4 million cases have been confirmed, more than 300 000 of which have been fatal. 3 however, we are also facing another pandemic-the global prevalence of obesity almost tripled between 1975 and 2016, and it is currently estimated that over 2 billion people suffer from excessive body weight. 4, 5 the current estimates indicate that obesity rates will continue to rise until at least 2030. 6 it is generally accepted that obesity is associated with an increased overall mortality, where the life expectancy of an individual suffering from severe obesity is reduced by 5-20 years. 7 moreover, it also increases the risk of developing several co-morbidities, also associated with the severity of the covid-19 infection, such as cardiovascular disease (cvd), type 2 diabetes (t2dm), kidney disease or numerous types of cancer. 8, 9 additionally, obesity also increases the risk of developing pneumonia and other viral respiratory tract infections. 10, 11 due to the fact that excessive body weight constitutes a serious global issue, it requires even more attention because it is presumably associated with the severity of the current covid-19 pandemic. although the current data are scarce, in our nonsystematic review, we have tried to investigate how many of sars-cov-2 patients suffer from obesity and to identify the potential mechanisms which would further explain the association between obesity and sars-cov-2 severity. moreover, we have also described both nutritional and behavioural aspects which could provide a basis for the potential guidelines. although the data regarding the impact of sars-cov-2 in individuals with obesity are limited and their association has not been fully defined yet, it has been observed that people suffering from excessive body weight may experience a more serious covid-19 infection. 12, 13 it is particularly evident in individuals who are affected by other risk factors mentioned earlier, which associated with a more severe course of the disease. this association was also observed during influenza a pandemic in 2009, where obesity was recognized as an independent risk factor of complications. in fact, patients with obesity, following a high-fat diet, suffered over 40% longer than those without excessive body weight. 14,15 therefore, it seems that obesity during covid-19 outbreak requires more attention, especially in the western countries where the prevalence of obesity is high. 16 according to the covid-19-associated hospitalization surveillance network in the united states at the turn of march 2020, 48% of hospitalized patients presented obesity (range across age groups = 41-59%). 17 the receptor for covid-19, similarly to other coronaviruses, has a high affinity for human angiotensin-converting enzyme-2 (ace-2), expressed in type 1 and 2 alveolar epithelial cell and endothelium, but also in such organs as the heart, endothelium, pancreas and the intestinal epithelium. 27 in fact, ace-2 is considered to be the receptor allowing the entry of covid-19 into the host cells by means of the activation of the renin-angiotensin-system (ras). 28 sars-cov-2 affinity for the ace-2 receptor is higher than in the case of sars-cov. 29 it is vital to point out that the adipose tissue might be prone to sars-cov-2 because the expression of ace-2 is higher in adipose tissue than in the lung tissue. 15 nevertheless, there is no current evidence for direct covid-19 infection of adipose tissue. 26, 30, 31 at this point, it should be emphasized that the existing recommendations do not advise a discontinuation of ace inhibitors and angiotensin receptor blockers, used nowadays as a treatment for hypertension unless the physician recommends otherwise. 32, 33 'cytokine storm' , that is, one of the mechanisms responsible for the severity of covid-19, is the hyperactivation of the immune system and is associated with an increased level of interleukin (il)-6, interferon γ and other proinflammatory cytokines. 34 38, 39 leptin is involved in the surfactant production and the development of lungs in the neonatal period, but it also participates in the ventilatory drive regulation. 40 another adipokine-omentin may play a role in the pathogenesis of asthma; however, it can also have a protective effect on the pulmonary endothelial function and decrease pulmonary permeability and inflammation. 41 reduced omentin, ghrelin and adiponectin levels were observed in individuals suffering from obstructive sleep apnea (osa). 41, 42 obesity can also predispose to a greater viral shedding, leading to a greater viral exposure. 37 because obesity-related co-morbidities are commonly identified among covid-19 individuals, they can also account for additional risk factors regarding the severity of covid-19 complications in obesity. 34, 43, 44 obesity predisposes to several comorbidities and mechanisms which lead to a more severe course of covid 19. 10 although, these co-morbidities were mentioned before, it is crucial to stress that metabolic disorders, such as hypertension, insulin resistance, dyslipidemia or prediabetes, which frequently occur in patients suffering from obesity, also predispose to a poorer covid-19 outcome. 8, 9, 43 furthermore, research studies indicate that individuals suffering from obesity present lower vitamin d levels. 45 the characteristics of patients with obesity regarding possible factors affecting a more severe covid-19 course are shown in table 2 . most of the covid-19 patients present symptoms of a respiratory disease. 51, 52 hospitalization rates and the number of respiratory infections are higher in individuals with obesity than in normal-weight patients. 40 the likely mechanisms which emphasize these effects are poorly understood, but it is suggested that obesity-induced imbalances in adipokine levels could impair pulmonary vascular endothelial function and cause lung damage. 61 furthermore, not only has leptin been the characteristic of patients with obesity-associated with high risk and worse outcome of covid-19 pulmonary function pulmonary oedema, lung damage, increased pulmonary vascular permeability, impaired gas exchange, reduced oxygen saturation of blood, decreased erv and frc, lower muscle strength, lower lung volume involved in the physiological but also in the pathological conditions of the respiratory system, such as copd, osa and asthma. 62 in fact, due to high leptin levels among patients with obesity, leptin resistance can be the result of upregulation of socs-3, which also negatively regulates antiviral interferons (infs) signalling. 63 furthermore, ifn deficiency might constitute the link between the risk factors, such as obesity, and the severity of pulmonary disorders. 62 several studies demonstrated that individuals with excessive body weight had improved survival rates, or a chronic disease prognosis, for example, of cvd when compared with healthy body weight individuals. [64] [65] [66] [67] this phenomenon was called 'the obesity paradox' and, according to cvd disease, it may relate to even 30% of patients with obesity. 68 whether the obesity paradox will be present among covid-19 patients remains to be seen, nevertheless, the phenomenon was reported among other respiratory diseases, such as copd or ards. 53, 69 its pathophysiological basis remains unknown; however, an increased bmi seems to be associated with a better survival and a slower decline in the lung function in patients with a mild course of chronic obstructive pulmonary disease. 70 it may be partially explained by the fact that a severe form of copd can lead to weight loss and later to cachexia-it would seem that obesity would prevent this. 71 moreover, the obesity paradox in copd could also be explained by adipokines, because certain individuals can have a more 'favourable' adipokine profile. 71 regardless of the obesity paradox in copd, a low-energy diet which leads to weight loss, combined with physical activity, is still recommended among patients with obesity and respiratory disorders. 72 it alleviates the symptoms and improves the functional capacity and strength, as well as helps to maintain a freefat mass. to the best of our knowledge, there are no specific guidelines concerning the nutritional treatment of covid-19 patients with obesity. however, such organizations as who, or the european association for the study of obesity (easo) have prepared nutritional guidelines and tips regarding nutrition during quarantine. 73-76 it seems obvious that because obesity possibly is associated with the severity of covid-19, it is recommended to apply a hypocaloric diet to reduce body weight. 31 what is more, weight loss is also beneficial in terms of lung function. 77 several behavioural and nutritional aspects could be essential among patients with obesity, and they should be considered when preparing future guidelines. on the basis of the existing knowledge, an adequate intake of vitamins a, e, b3, b6, b12, d, and folate, as well as zinc, copper, selenium, iron, and omega-3 polyunsaturated fatty acids is essential for the maintenance of proper immune function. 36, 75, [78] [79] [80] although micronutrient insufficiency and nutritional status increase the risk of covid-19 infection and could worsen its outcome, the use of supraphysiologic amounts to improve the course of covid-19 is not currently recommended. 81, 82 however, studies have demonstrated that the intake of several vitamins and micronutrients, such as vitamin a, c, b1, potassium, magnesium, calcium, or iron is usually insufficient in patients suffering from obesity and therefore should be taken into account. 83 whether vitamin d supplementation should be increased in covid-19 period remains unclear and is not currently recommended. in fact, more randomized-controlled trials should be performed to confirm these suggestions. 84 it has been shown that a high consumption of saturated fatty acids (sfas) can induce lipotoxic state, cause adipose tissue inflammation and promote the activation of the innate immune system due to the activation of toll-like receptor 4 (trl-4). 85, 86 in the animal model, a high-fat diet induced mcp-1 for macrophage infiltration into the lung tissue and an increased lipopolysaccharide induced interleukin-1β and tumour necrosis factor α (tnfα) production. 87 a high intake of both protein and fat may be associated with higher levels of plasma interleukin-6 and tnfα. 88 however, the interaction between nutrition and immunology is extensive and very complex; thus, more randomized-controlled trials should be conducted in this area. 89 psychosocial burdens, for example, stress or depression, have been associated with obesity, and a psychological support is an essential approach to managing obesity. 90 during covid-19 pandemic, increased psychological distress was observed both in infected individuals and in the general population. 91 additionally, social isolation was found to be a predictor of an increased mortality, as well as a possible cause of depression and anxiety in the youth. 92, 93 it is worth noticing that individuals suffering from obesity are usually more vulnerable to distress and psychological impact of covid-19 quarantine can influence the proper obesity management. 94 psychological distress can also lead to a binge and emotional eating among bariatric surgery patients (in time before or after the surgery), which can be associated with poorer long-term results. 94 however, the association between psychological aspects and obesity during the current epidemiological situation needs to be further investigated; psychological support should definitely constitute one of the elements of the proper obesity management during covid-19 pandemic. although the recent statistics are limited, it could be assumed that during the prolonged sars-cov-2 quarantine the level of physical activity is lower than usual. in fact, physical inactivity not only predisposes to weight gain but can also lead to the loss of strength, skeletal muscle mass and immune competence. 82 it is vital to bear in mind that quarantine reduced the physical activity level not only for habitually, physically active individuals but also for those whose activity was associated with work, or school, as well as those who mainly work physically. 93 ventilation-acquired dysphagia in sars-cov-2 survivors could be a challenge and will require a special nutritional support. we would like to thank the translationlab, a biomedical translation company, for linguistic proofreading. the authors declare no conflict of interest. severe acute respiratory syndrome-related coronavirus: the species and its viruses -a statement of the coronavirus study group severe acute respiratory syndrome coronavirus 2 (sars-cov-2) and coronavirus disease-2019 (covid-19): the epidemic and the challenges world health organization. coronavirus disease (covid-19). 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(a mini review of some indirect evidence related to obesity) krela-kaźmierczak i. should patients with obesity be more afraid of covid-19? key: cord-301833-q8jiep32 authors: peres, karina colombera; riera, rachel; martimbianco, ana luiza cabrera; ward, laura sterian; cunha, lucas leite title: body mass index and prognosis of covid-19 infection. a systematic review date: 2020-08-14 journal: front endocrinol (lausanne) doi: 10.3389/fendo.2020.00562 sha: doc_id: 301833 cord_uid: q8jiep32 a better understanding of the sars-cov-2 virus behavior and possible risk factors implicated in poor outcome has become an urgent need. we performed a systematic review in order to investigate a possible association between body weight and prognosis among patients diagnosed with covid-19. we searched in cochrane library, embase, medline, who-global literature on coronavirus disease, opengrey, and medrxiv. we used the robins-i tool or cross-sectional/prevalence study quality tool from ahrq, to evaluate the methodological quality of included studies. nine studies (two prospective cohorts, four retrospective cohorts and three cross-sectional) were included and assessed the relationship between obesity and covid-19 prognosis. risk of bias of the included studies ranged from moderate to critical. clinical and methodological heterogeneity among them precluded meta-analyses. most of the included studies showed some degree of association to: (a) higher bmi and worse clinical presentation and (b) obesity and need of hospitalization. the results were inconsistent about the impact of obesity on mortality. based on limited methodological quality studies, obesity seems to predict poor clinical evolution in patients with covid-19. further studies with appropriate prospective design are needed to reduce the uncertainty on this evidence. a better understanding of the sars-cov-2 virus behavior has become an urgent need as the pandemic caused continues to plague the world adding more and more victims. a series of reports have looked for risk factors in order to provide means of prevention and treatment to the population. the first chinese publications made clear that age may impact prognosis (1) (2) (3) , but with the advance of covid-19 to western european and north american countries, some novel factors have emerged as determinants of risk and poor outcome. in contrast to china, there is a high prevalence of obesity in these countries (4) that may help explain, at least in part, the reason why obesity has just emerged as a marker of unfavorable clinical evolution. the prevalence of obesity has rapidly increased over the years (5) , especially among elderly (6) . obesity is a multifactorial disorder characterized by excessive fat accumulation and an increment of proinflammatory cytokines, which entails a constant state of immune deregulation (7) . this chronic deregulation may interfere with immune homeostasis and impair the effectiveness of the immune response. it is not without reason that obesity has been implicated in poor outcomes among many clinical conditions and high all-cause mortality (8) . however, although it accumulates rapidly, data on the role of obesity on covid-19 risk and prognosis are still confusing and hard to interpret. scrambling to learn more about the virus, doctors and scientists try to rapidly share their findings generating a large flood of publications that has put new strain on a scientific process accustomed to vetting and publishing new results much more slowly. herein, we perform a systematic review in order to evaluate if overweight and obesity may predict poor outcome in patients with covid-19. to investigate a possible association between body weight and prognosis among patients diagnosed with covid19 . the clinical question is, as structured through the peco acronym: ( this was a systematic review carried out in the universidade federal de são paulo (unifesp) through a collaboration with the university of campinas (unicamp), brazil. the study was conducted in accordance with the amstar-2 (assessing the methodological quality of systematic reviews) (9) . the protocol was prospectively registered at the prospero database (registration number cdr42020182189, https://www.crd.york. ac.uk/prospero/display_record.php?recordid=182189). this reporting was written following the prisma statement (10). we considered any study design using a comparative group as follows: controlled trials (randomized, quasi-randomized, or non-randomized) that conducted subgroup analyses according to body weight, cohort and case-control studies, and analytic cross-sectional studies with a control group. adults or children with confirmed diagnosis of covid-19, in accordance with world health organization criteria (11) . we considered any definition of overweight or obesity, as assumed by the authors of primary studies. however, only similar definitions were evaluated together into quantitative or qualitative synthesis. we considered all clinical, laboratory and image outcomes as presented by the authors of primary studies. however, we prioritized the outcomes below: primary outcomes: • all-cause mortality; • serious adverse events: assessed by the rate of participants who experienced at least one serious adverse event, as per defined as those that are life-threatening; which may lead to death, requirement of a treatment in an emergency room, hospitalization (initial or prolonged), disability or permanent damage, or congenital anomaly/birth defect (12) . • sars-cov-2 acute respiratory syndrome: assessed by the rate of participants who progressed to acute respiratory syndrome. • clinical status, assessed by the ordinal scale for clinical improvement-world health organization (scale from 0 to 7, the higher the score, the worse the clinical condition), as defined by the world health organization (who) (13) . secondary outcomes: • mortality related to sars-cov-2 infection (covid-19); • any adverse event: assessed by the rate of participants who experienced at least one adverse event. • time to clinical improvement, defined as a reduction of at least two points in the score of the ordinal scale for clinical improvement-world health organization (scale from 0 to 7, the higher the score, the worse the clinical condition), as defined by the world health organization (who) (13) . • hospitalization in an intensive care unit; • need for invasive mechanical ventilation; • length of hospitalization. • length of hospitalization in intensive care unit; • length of invasive mechanical ventilation; • rate of negative pcr viral load (any specimen). we assessed all dichotomous outcomes listed above at any time point. however, we only pooled similar time points together: short term (up to 1 month, inclusive) or long term (more than 1 month). when a study reported an outcome more than once in the same period, we considered the last measurement. a comprehensive search of the literature was carried out using an electronic search with no restriction regarding date, language or status of publication. sensitive search strategies (supplementary file 1) were developed for the following databases: the selection process was conducted in a two-stage process aided by the rayyan platform (14) . in the first phase, two review authors independently assessed all titles and abstracts retrieved by the search strategies. studies marked as "potentially eligible" were then screened at the second phase, which consisted in the reading of the full text to confirm its eligibility. any divergence was solved by a third reviewer. studies excluded in the second phase were presented in the "excluded studies table" and the reasons for exclusion as well. the procedures for data extraction were performed by two independent reviewers and a pre-established data extraction form was used. disagreements in this process were solved by a third reviewer. the methodological quality of the included studies was evaluated by two independent reviewers by the use of validated tools for each study design, as following: • randomized controlled trial: cochrane risk of bias table (15); • non-randomized, quasi-randomized trial: robins-i (16); • cohort or case-control: robins-i (16). robins-i was used as there are, as yet, no draft versions of robins-e available. the domains "classification of interventions" and "deviations from intended interventions" were adapted to consider "exposures" instead of "interventions." • cross-sectional: cross-sectional/prevalence study quality, agency for healthcare research and quality (17) . the unit of analysis was the individual. considering the context requiring a rapid answer, the authors from primary studies were not contacted for missing data. depending on data availability and homogeneity of studies, we planned to pool results from similar studies by randomeffects meta-analyses (software review manager 5.3). risk ratios (or odds ratios) and mean differences would be calculated for dichotomous and continuous data, respectively. a 95% confidence interval would be considered for the analyses. when meta-analysis was not possible the results were presented as qualitative synthesis (descriptive presentation). methodological and clinical diversity of included studies would be considered for conducting or not meta-analyses. the existence of statistical heterogeneity would be evaluated by chi 2 test and its extension by the i 2 test (i 2 ≥ 50% indicates high heterogeneity among studies). we planned to conduct the following subgroup analyses: (a) presence of diabetes and/or hypertension and (b) age of participants (<65 vs. ≥65). we planned to conduct the following subgroup analyses: (a) fixed effects vs. random effects model meta-analysis. when the results of fixed effect meta-analysis provide a different result, both would be reported; (b) excluding from analysis studies at high risk of bias; and (c) excluding from analysis unpublished studies or those available exclusively in a pre-print version and not peer reviewed. investigation of publication bias assessment was planned by visual inspection of funnel plots for meta-analysis with at least 10 studies. however, due to heterogeneity between included studies it was not possible to conduct meta-analyses nor additional analyses. the search retrieved 937 records. after excluding 88 duplicates, we screened the titles and abstracts of 849 references, excluded 836 that did not comprise inclusion criteria, and selected 13 for full text reading. we excluded four studies (detailed below). therefore, the review included nine observational studies. the flow diagram of the process of study identification and selection is presented in figure 1 . this systematic review included nine studies: two prospective cohort studies (18, 19) , four retrospective cohort studies (20-23), and three cross-sectional studies (24) (25) (26) . table 1 presents the main characteristics of the included studies. table 2 summarizes the studies excluded after selection. bmi was the only measure used as a criteria for classifying body weight, considered as a continuous or ordinal scale variable. the included studies had different study designs and considered different outcomes of interest. due to these clinical and methodological heterogeneity among included studies it was not appropriate to conduct meta-analyses. risk of bias assessment of the included studies and reasons for judgement are presented in tables 3, 4 . overall, cohort studies were classified as critical to moderate risk of bias, and crosssectional studies varied between 36 and 63% of agreement with bias domains. we reviewed data from 17,568 patients with sars-cov-2 infection, included in nine studies. most of these studies highlighted some level of association between obesity and disease severity, encompassing hospitalization rate, admission to icu, invasive ventilation need and mortality. according to validated tools, these studies presented moderate to critical risk of bias, which limits the reliability in the results. garg et al. (29) only data of obesity prevalence, with no outcome association analysis. richardson et al. (30) only data of obesity prevalence, with no outcome association analysis. according to covidview database of centers for disease control and prevention (cdc) in the usa, until may 2, 2020 the overall rate for covid-19-associated hospitalization were 162.2 per 100,00 in individuals 65 years and older, decreasing to 79.0-26.2 for individuals <65 years. furthermore, preliminary data showed that about 91.5% of hospitalized patients present at least one underlying medical condition. besides obesity, the most common critical comorbidities observed in the hospitalized covid-19 patients were hypertension, metabolic disease, cardiovascular and pulmonary diseases (31) . three of 4 north american studies showed increased bmi among patients who required hospitalization. argenziano et al. (24) also described that patients who require in-hospital admission had more chronic diseases, such as hypertension, diabetes, and obesity. to date, icu patients presented significantly higher bmi compared to those admitted in the emergency or inpatient floors. lighter and colleagues (20) analyzed retrospectively a cohort of 3,615 patients positive for covid-19 stratified by age. thirty-eight percent (38%) of these patients presented bmi >30 kg/m 2 . an increased risk of hospitalization in acute care or icu was demonstrated for patients <60 years older with obesity (bmi 30-34 kg/m 2 ) and severe obesity (bmi ≥35 kg/m 2 ) compared to patients bmi <30 kg/m 2 . once younger patients generally do not represent higher risk for a severe presentation of covid-19, authors suggest that obesity may be an unrecognized risk factor for hospital care. in a cross-sectional study, petrilli et al. (26) showed that hospitalized patients were more likely to be male and present cardiovascular diseases, diabetes and obesity. in fact, as confirmed by a multivariate analysis, obesity (bmi > 40 kg/m 2 ), older age (≥65 years) and history of heart failure were independent predictors of unfavorable outcome. cummings et al. (18) observed similar prevalence of obesity among hospitalized patients. however, authors failed to demonstrate that obesity is a predictor of mortality. two cohort studies evaluate the severity of covid-19 disease in chinese patients. the retrospective study by liu et al. (21) evaluated 30 medical staff infected with novel coronavirus in january, 2020. most of them presented a common type of the disease (n = 26) and four patients a more severe condition defined as pulmonary insufficiency. until the end of the study, 80% of the patients were discharged, none of them needed critical hospital care or died. in relation to obesity the authors reported higher bmi in patients with severe compared to the mild presentation. zheng et al. (19) prospectively evaluated 66 patients with metabolic associated fatty liver disease (mafld) stratified by obesity status dividing patients according to severe and non-severe covid-19 based on the national health commission & state administration of traditional chinese medicine. frequency of obesity was higher between severe disease patients compared to non-severe, furthermore mafld patients with concurrent obesity had more severe presentation of the disease. indeed, obesity in patients with mafld increased the risk of severe illness in almost 6-fold (unadjusted or 5.77, 95% ci 1.19-27.91, p = 0.029). after adjustment for age, sex, smoking, diabetes, hypertension, and dyslipidemia, association with obesity and covid-19 remained significant and confirmed obesity as an independent marker of critical illness. however, as commented by hussain et al. (32) , mafld and obesity are rarely considered as independent conditions, in the cases of concurrent diseases they coexist due to obesity. a third chinese study (22) demonstrated that mean bmi of the 16 patients who needed icu care (25.5 kg/m 2 ) were higher than the general group (22.0 kg/m 2 ). between the 17 deaths reported, 88% had bmi >25 kg/m 2 . most of the deceased patients also presented hypertension, coronary heart disease and heart insufficiency. in a mexican study (25) , obese patients, as expected, had higher proportions of other comorbidities as hypertension, diabetes, cardiovascular disease, asthma, and chronic obstructive pulmonary disease (copd). increased lethality of covid-19 was reported specially in patients with diabetes, early onset diabetes (<40 years), concurrent obesity or several concurrent comorbidities (p < 0.001). as presented in table 1 , obese patients had higher risks of hospitalization, pneumonia, icu admission, invasive ventilation and 7-fold increased risk of mortality. simonnet et al. (23) described that the distribution of bmi categories in covid-19 patients admitted to icu care in france differed from the control patients with non-sars-cov-2 respiratory disease. the frequency of obesity (bmi > 30 kg/m 2 , 47.6%) and severe obesity (bmi > 35 kg/m 2 , 28.2%) were higher among patients with covid-19 infection compared to control patients (25.2 and 10.8%, respectively). besides, the median of bmi (31.1 kg/m 2 ) of the 85 patients who required invasive ventilation was higher than the patients who did not (27.0 kg/m 2 , n = 39). an univariate logistic regression analysis showed that bmi ≥35 kg/m 2 (vs. bmi <25 kg/m 2 ) was a risk for need of invasive ventilation (or 6.75, 95%ci 1.76-25.85, p = 0.015), remaining significant after adjustment for age, diabetes and hypertension in a multivariate analysis (or 7.36 95% ci 1.63-33.14, p = 0.021). this systematic review presents some strengths including the use of stringent methods of cochrane reviews, reproduced in a short term due to the need of rapid responses to guide clinical decisions during the pandemic. the search for studies was highly sensitive and it was conducted in formal databases, preprint, and gray literature repositories and specific sources for covid-19 as well. the present study has some limitations. the included studies adopted different methods to assess obesity as a predictor of poor outcome precluding a meta-analysis. once covid-19 is a public health emergency, a considerable amount of in summary, our systematic review suggests that obesity is likely to be a predictor of poor outcome in patients with covid-19, in all continents. obesity is associated with several clinical conditions (e.g., diabetes and hypertension). it is associated with restrictive lung ventilatory defect, which may worsen the severe respiratory failure syndrome. in obesity, the dysfunctional adipocytes produce massive amounts of pro-inflammatory cytokines, which entails a chronic inflammation, harming innate and adaptative immune responses (33) (34) (35) . the increase in pro-inflammatory cytokines observed among obese patients may add to the inflammatory response triggered by the sars-cov-2, and both contribute to poor outcome and high all-cause mortality (7, 8) . likewise, obesity is a well-established risk factor for cardiovascular disease, which triggers diverse physiologic alterations that include activation of renin-angiotensin-aldosterone system, reduction of vasculo-protective effects, upregulation of procoagulant factors, downregulation of anticoagulant factors and chronic oxidative stress and inflammation (36) (37) (38) . hence, obese patients with covid-19 may benefit from an aggressive approach, including eager evaluation and early hospitalization. in addition, health politics may assure obese patients prompt access to the health care system. the investigation of the mechanisms that may be underlying the association between obesity and poor outcome in patients with covid-19 will certainly help the understanding of this subject. therefore, further studies with appropriate prospective design are needed to reduce the uncertainty on this evidence. all datasets presented in this study are included in the article/supplementary material. kp contributed to the design, critical review of the literature and data, composition of the manuscript, and final approval. rr and am contributed to the design, critical review of the literature and data, risk of bias, composition of the manuscript, and final approval. lw contributed to the design, selection of the notable articles for review, critical review of the literature and data, composition of the manuscript, clinical and translational orientation, and final approval. lc contributed to the conception and design, selection of the notable articles for review, critical review of the literature and data, composition of the manuscript, and final approval. all authors contributed to the article and approved the submitted version. 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or both preferred reporting items for systematic reviews and meta-analyses: the prisma statement global surveillance for covid-19 caused by human infection with covid-19 virus what is a serious advers event? content curr as novel coronavirus. covid-19 therapeutic trial synopsis rayyana web and mobile app for systematic reviews cochrane handbook for systematic reviews of interventions version 6.0 (updated robins-i: a tool for assessing risk of bias in non-randomised studies of interventions appendix d: quality assessment forms epidemiology, clinical course, and outcomes of critically ill adults with covid-19 in new york city: a prospective cohort study. medrxiv obesity as a risk factor for greater severity of covid-19 in patients with metabolic associated fatty liver disease obesity in patients younger than 60 years is a risk factor for covid-19 hospital admission clinical characteristics of 30 medical workers infected with new coronavirus pneumonia clinical characteristics and outcomes of 112 cardiovascular disease patients infected by 2019-ncov high prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (sars-cov-2) requiring invasive mechanical ventilation characterization and clinical course of 1000 patients with covid-19 in new york: retrospective case series predicting mortality due to sars-cov-2: a mechanistic score relating obesity and diabetes to covid-19 outcomes in mexico. medrxiv factors associated with hospitalization and critical illness among 4,103 patients with covid-19 disease in new york city. medrxiv targeting the adipose tissue in covid-19 is adipose tissue a reservoir for viral spread, immune activation, and cytokine amplification in coronavirus disease hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease 2019-covid-net, 14 states presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with covid-19 in the new york city area obesity as a risk factor for greater severity of covid-19 in patients with metabolic associated fatty liver disease obesity and type 2 diabetes mellitus drive immune dysfunction, infection development, and sepsis mortality complex immune dysregulation in covid-19 patients with severe respiratory failure role of innate and adaptive immunity in obesity-associated metabolic disease obesity cardiomyopathy: pathogenesis and pathophysiology oxidative stress and vascular disease in diabetes: is the dichotomization of insulin signaling still valid? mechanisms of thrombosis in obesity the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 peres, riera, martimbianco, ward and cunha. this is an openaccess article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-319580-awtp0mpg authors: mccartney, stephen a.; kachikis, alisa; huebner, emily m.; walker, christie l.; chandrasekaran, suchi; adams waldorf, kristina m. title: obesity as a contributor to immunopathology in pregnant and non‐pregnant adults with covid‐19 date: 2020-08-11 journal: am j reprod immunol doi: 10.1111/aji.13320 sha: doc_id: 319580 cord_uid: awtp0mpg the ongoing coronavirus disease 2019 (covid‐19) pandemic has led to a global public health emergency with the need to identify vulnerable populations who may benefit from increased screening and healthcare resources. initial data suggests that overall, pregnancy is not a significant risk factor for severe coronavirus disease 2019 (covid‐19). however, case series have suggested that maternal obesity is one of the most important co‐morbidities associated with more severe disease. in obese individuals, suppressors of cytokine signaling are upregulated and type i and iii interferon responses are delayed and blunted leading to ineffective viral clearance. obesity is also associated with changes in systemic immunity involving a wide range of immune cells and mechanisms that lead to low‐grade chronic inflammation, which can compromise antiviral immunity. macrophage activation in adipose tissue can produce low levels of pro‐inflammatory cytokines (tnf‐α, il‐1β, il‐6). further, adipocyte secretion of leptin is pro‐inflammatory and high circulating levels of leptin have been associated with mortality in patients with acute respiratory distress syndrome. the synergistic effects of obesity‐associated delays in immune control of covid‐19 with mechanical stress of increased adipose tissue may contribute to a greater risk of pulmonary compromise in obese pregnant women. in this review, we bring together data regarding obesity as a key co‐morbidity for covid‐19 in pregnancy with known changes in the antiviral immune response associated with obesity. we also describe how the global burden of obesity among reproductive age women has serious public health implications for covid‐19. the emerging coronavirus disease 2019 (covid-19) pandemic caused by infection with the novel betacoronavirus sars-cov-2 continues to challenge public health systems globally. although the majority of patients with covid-19 have self-limited disease consisting predominantly of mild respiratory symptoms, approximately 20-30% develop acute respiratory distress syndrome (ards) [1] [2] [3] [4] . the centers for disease control have recently refined their risk categories for covid-19 to state that obesity was a major risk factor 5 . in pregnant women, severe covid-19 disease is also associated with obesity 6, 7 . over the last decade, non-communicable metabolic diseases such as hypertension, diabetes and obesity have increased in prevalence globally 8 . in the united states, more than one-third of reproductive age women are considered to be obese [body mass index (bmi) ≥ 30 kg/m 2 ) 9 . at the same time, the immunology and pathophysiology associated with covid-19 in pregnancy and especially in the setting of other comorbidities such as obesity is poorly understood. this review is directed towards summarizing how obesity affects the severity of covid-19 clinical disease and negatively impacts the antiviral immune response. in non-pregnant populations, obesity has been associated with severe covid-19 disease. a retrospective review of 770 patients with covid-19 from the two medical centers in new york found that obese patients were more likely to present with symptoms; obese patients also had a significantly increased risk of icu admission or death (rr 1.58) even after adjusting for race, age and troponin levels 10 . another retrospective study from a third medical center in new york including 200 patients with covid-19 found that a bmi ≥ 35 kg/m 2 was independently associated with higher in hospital mortality compared to a bmi of 25-34 kg/m 2 (adjusted odds ratio 3.78; 95% ci: 1.45-9.83). similarly, bmi ≥ 35 kg/m 2 was a significant predictor for increasing oxygenation requirements and intubation 11 . an italian retrospective study demonstrated similar findings with overweight or obese patients more often requiring ventilation and a higher level of care despite younger age than older patients with normal bmi 12 . obese pregnant women are at increased risk for complications of viral infection from influenza, cytomegalovirus, and sars-cov-1 and related complications such as ards 13-17 . the increased risk of severe respiratory viral disease due to obesity and pregnancy was most strikingly noticed with the accepted article h1n1 pandemic in 2009 17 . in a study of hospitalized patients with a confirmed h1n1 influenza a viral infection in the united states, class iii obesity was associated with hospitalization regardless of whether the patient had chronic medical conditions 18 . immune changes in obesity have also been associated with increased susceptibility of viral infection including increased peak viral loads and delayed clearance in influenza 19 . several case series and cohort studies have reported an increased severity of covid-19 in pregnancies complicated by elevated bmi and obesity (table 1 ). an early report of two pregnant women with severe covid-19 necessitating icu admission in the postpartum period was notable for a bmi of 38 and 47 kg/m 2 in these cases 20 . in a cohort study of 46 pregnant women with covid-19 in washington state, obesity emerged as a key co-morbidity in women with severe covid-19 6 ; of five pregnant women with severe disease in which information to calculate the body mass index was available, four were overweight or obese prior to pregnancy 6 . in a study of pregnant women in italy, it was reported that of 14 women with severe disease, the median bmi was 30 kg/m 2 , which was significantly elevated compared to women with mild disease (p=0.02) 21 . another cohort study from 12 medical centers in the united states included 64 pregnant women hospitalized due to covid-19; of 64 women with severe or critical covid-19 disease, the average bmi was 33.5 kg/m 2 22 . this study also demonstrated that critically ill pregnant women with covid-19 had a lower bmi than severely ill women, suggesting that while obesity may be a risk factor for severe disease, obese women may have lower mortality than lean women. interestingly, the idea that obese women may have a greater disease severity, but lower mortality than lean women mirrors other studies from the critical care literature, which have coined this finding as the "obesity paradox" 23 . maternal deaths have been linked with obesity, however. a case series from iran including nine pregnant women with severe covid-19 disease of which seven died, three women had a bmi > 30 kg/m 2 24 . a case series of 124 maternal deaths from brazil found that obesity (undefined) was significantly associated with mortality 25 . further, several case reports or series from the united states and the united kingdom have reported maternal deaths or severe maternal morbidity in women with obesity 26-32 . finally, the largest series of pregnant women with covid-19 to date including 427 cases in the united kingdom demonstrated that 34% of cases were obese compared to 23% of controls 7 . this article is protected by copyright. all rights reserved understanding the immunopathology of infection with this novel virus is rapidly evolving. sars-cov-2 shares 80% rna sequence homology with sars-cov-1, allowing extrapolation of likely shared pathophysiology and immune response [33] [34] [35] . both viruses enter the cell via angiotensinconverting enzyme-related carboxypeptidase 2 (ace2) receptor, though the sars-cov-2 spike protein binds ace2 with significantly higher affinity than sars-cov-1 36 . healthy individuals have higher concentrations of ace2 in lung tissues, specifically bronchial smooth muscle cells, alveolar epithelium, type ii pneumocytes and alveolar macrophages 37,38 . extrapulmonary expression of ace2 occurs in myocardial cells 38 , enterocytes in the ileum and jejunum 39 , proximal tubular cells in the kidney 38 , oral mucosa 40 , and arterial and venous endothelium 41 . in contrast, the strongest evidence suggests negligible placental expression of ace2 and tmprss2, a serine protease that acts as a canonical mediator of cell entry for sars-cov-2 in conjunction with ace2 42 . multiple cells, predominantly within the lung, but also within other target organs (e.g. heart, kidney) express the canonical receptor for sars-cov-2 entry. during the initial stage of most viral infections, the type i and type iii interferon (ifn) response is the primary mechanism leading to viral clearance. immune cells detect viral nucleic acids through pattern this article is protected by copyright. all rights reserved inflammatory response by producing pro-inflammatory cytokines (tnf-, il-1, il-6), which, in turn, lead to additional lung injury and immune cell recruitment 51,52 . cytokines and chemokines result in activation of adaptive immune t and b cells as well as recruitment of neutrophils and monocytes. viral-specific cd8 t cells are cytotoxic primarily to infected cells and serve to limit the release of additional viral particles, while neutrophils non-specifically release reactive oxygen species and leukotrienes, which are directly toxic to pneumocytes and endothelial cells. additionally, high levels of ifn and pro-inflammatory cytokines also lead to cell death directly with and without viral infection through induction of apoptosis. patients with severe covid-19 typically have high levels of systemic pro-inflammatory cytokines, lymphopenia, and inflammatory lung infiltrates, which is consistent with a maladaptive patterns of cytokine production and inflammatory misfiring 53-56 . elevated cytokines are also associated with multiple pathologic effects in the lung including endothelial apoptosis and vascular leaking, an ineffective antiviral response, diffuse alveolar damage, inflammatory cellular infiltrates and intravascular thrombosis [57] [58] [59] . adipose tissue is an active endocrine and immune organ consisting primarily of adipocytes, but also multiple immune cell types, which represent the second most frequent type of cells in this tissue 60, 61 . macrophages are the most common immune cell type in adipose tissue and, in lean individuals, produce type 2 cytokines (il-4, il-10) and anti-inflammatory molecules 62, 63 . however, in obese individuals, activated macrophages in adipose tissue produce pro-inflammatory cytokines tnf-, il-1 and il-6, which results in recruitment and activation of additional monocytes, as well as nkt cells and mast cells. adaptive immune cells also play a role in obesity-associated inflammation. adipose tissue from lean individuals is composed primarily of cd4+ th2 cells and regulatory t cells (treg), which promote an anti-inflammatory environment, while obese adipose tissue is enriched for cd4+ th1 and th17 cells as well as cytotoxic cd8+ t cells [64] [65] [66] . changes in t cell polarization may be due to altered metabolite availability in obesity, which contributes to t cell differentiation and response to pulmonary infection 67, 68 . in addition to changes in t-helper cell phenotype, obesity is also associated with t cell dysfunction. obesity results in increased production of memory t cells, and in a mouse model of viral infection, the memory t cell response to viral infection in obese animals resulted in increased pathogenesis rather than a protective response 69 this article is protected by copyright. all rights reserved also been associated with t cell exhaustion, which may be responsive to treatment with biologic therapies 70, 71 . adipose tissue and cytokine-like hormone released from adipocytes, called adipokines, may directly and indirectly impair the pulmonary immune response. the adipocyte overflow hypothesis suggests that when an adipocyte can no longer hypertrophy to accommodate storage of new lipids, an "overflow" of fatty acids occurs into the body 72, 73 ; lipids may then be recognized by innate immune pathogen recognition receptors at ectopic sites to stimulate a low-grade inflammatory response 74 . adipose tissues also release adipokines that can act as powerful regulators of the immune response. leptin is a key adipokine and can regulate both innate and adaptive immunity to mediate a proinflammatory immune response 75 . an inflammatory microenvironment can also downregulate production of adiponectin by adipocytes, which impairs the anti-inflammatory response. interestingly, high-levels of leptin that are typical in obese individuals increase the risk of the severity of respiratory infections in both humans and mouse models 76 . high circulating leptin levels were associated with mortality in non-pregnant adults hospitalized for acute respiratory distress syndrome due to pneumonia, even after adjusting for bmi 76 . the placental trophoblast and amnion also secrete leptin, which may further impair the pulmonary immune response in pregnant women 77 . finally, adipose tissue is present in subcutaneous, visceral, and omental locations; the cellular and metabolic properties of each type of tissue are unique. alterations in visceral adiposity have been associated more closely with adverse metabolic and health outcomes and immunologic dysfunction 78, 79 . in addition to inducing immunologic dysfunction, excess adipose tissue also changes the mechanics and physiology of respiration. the increased metabolic requirements in obesity results in higher oxygen consumption and increased work of breathing 80 . obesity also results in greater production of carbon dioxide, which leads to decreased respiratory drive. mechanically, increased fat deposits within the abdominal cavity reduce the compliance of the respiratory system 81 . increased abdominal adipose tissue mass leads to elevated abdominal pressure and lower lung volume by reducing expiratory reserve and functional residual capacity 82 . obesity is also associated with airway narrowing which can lead to gas trapping 83 . the combination of decreased lung volumes, increased abdominal pressure and narrowing of the airway leads to increased work of breathing with early fatigue of respiratory muscles. this article is protected by copyright. all rights reserved pregnancy provides both a physiologic and immunologic challenge for the maternal host during which it must balance providing access to nutrition, protection from infection, and tolerance of a genetically foreign fetus. to accommodate these functions, there is dynamic regulation of the maternal immune system, both systemically and at the maternal-fetal interface during pregnancy. pregnancy requires both pro-inflammatory and tolerogenic immune responses at specific times during gestation [84] [85] [86] . during the early first trimester, a localized inflammatory response is necessary for embryonic implantation into the uterine decidua 87, 88 . at the time of human parturition, a functional progesterone withdrawal in humans coupled with an inflammatory response direct the cascade of biological events that culminate in birth [89] [90] [91] [92] accepted article levels are one of the strongest clinical correlates for severe covid-19 disease 104, 105 . in addition, a change in cd4+ t cell polarization from th2 and treg cytokines (il-4, il-10, il-13) to a proinflammatory th1 and th17 response observed in obese individuals is associated with production of pro-inflammatory cytokines, such as tnf-, il-1, il-6, and il-17, which provides a potential mechanism for an earlier initiation of cytokine release and inflammatory misfiring in obese patients. the expression of ace2 by adipocytes and immune cells also suggests the possibility that adipose tissue may represent a potential reservoir for viral infection and may lead to increased viral burden or persistence; however, no studies to date have demonstrated that adipocytes can be directly infected with sars-cov-2. these obesity-driven alterations in the immune response likely contribute to the severity of covid-19 in obese pregnant women. maternal obesity has emerged as a key risk factor increasing susceptibility of pregnant women to severe covid-19 disease. this is likely the result of complex immunologic, metabolic, endocrine and physiologic changes associated with obesity, which affect the immune response to viral infection. the increasing global burden of obesity may lead to more severe pregnancy morbidity and has the potential to regress decades of progress in global health and, by extension, to improvements in reproductive and pregnancy care worldwide. analyses comparing obesity rates in over the last three decades show that obesity among pregnant women has increased drastically worldwide 106 . in 2017-2018, obesity among women 20 years and over was 41.9% in the united states 9 . currently the us also has the highest number of covid-19 infections worldwide 107 . in light of the global covid-19 pandemic, there has been a call for renewed prioritization of non-communicable diseases such as obesity that increase susceptibility of women with sars-cov-2 infection to severe disease or mortality 108 . carefully designed epidemiologic studies are required to assess the linkage between covid-19 disease severity, obesity and associated socioeconomic factors. there is also an urgent need to focus research on how risk factors, like obesity, alter the immune response to sars-cov-2 and influence disease pathogenesis of covid-19 (box 1). finally, given global trends in the rise of obesity over the last 3 decades, urgent action is needed 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clock of human pregnancy the influence of pregnancy on systemic immunity th1/th2/th17 and regulatory t-cell paradigm in pregnancy influenza, immune system, and pregnancy. reproductive sciences (thousand oaks, calif) plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome influenza virus-related critical illness: pathophysiology and epidemiology viral infections and interferons in the development of obesity and inflammation: the linking mechanism and the complications inflammation in maternal obesity and gestational diabetes mellitus dysregulation of immune response in patients with covid-19 in wuhan, china. clinical infectious diseases : an official publication of the infectious diseases society of america covid-19) situation report -153. world health organization maternal health and non-communicable disease prevention: an investment case for the post covid-19 world and need for better health economic data symptoms and critical illness among obstetric patients with coronavirus disease 2019 (covid-19) infection 34%) 3 maternal deaths 50/243 iatrogenic ptb, 29 (46%) due to covid-19. 3 iufd, 2 nnd lokken et al. 6 usa (wa) 46 15 (35.7%) 6 (15%) severe covid-19 box 1. research questions 1. what is the mechanism of increased risk for severe covid-19 disease in obese nonpregnant and pregnant women? does the second and third trimester of pregnancy represent a time of increased risk for severe covid-19? if yes, how does gestational age modify the effect of obesity on covid-19 disease severity? is preterm birth more common in obese pregnant women with covid-19 due to concern for respiratory compromise? are certain therapies more effective for treatment of severe covid-19 in obese pregnant women compared to lean or non-pregnant women? does increased surveillance for covid-19 in obese pregnant women improve health outcomes? can adipose tissue serve as a reservoir for sars-cov-2 viral infection through adipocyte ace2 expression? are viral loads higher of sars-cov-2 in obese versus lean pregnant women? are the kinetics of viral clearance different in obese versus lean pregnant women? can we design epidemiologic studies to further assess whether the risk of severe covid-19 infection in obese pregnancy is directly related to obesity itself or to associated socioeconomic factors? accepted article key: cord-011333-yyhwtnza authors: faienza, maria felicia; chiarito, mariangela; molina-molina, emilio; shanmugam, harshitha; lammert, frank; krawczyk, marcin; d’amato, gabriele; portincasa, piero title: childhood obesity, cardiovascular and liver health: a growing epidemic with age date: 2020-02-04 journal: world j pediatr doi: 10.1007/s12519-020-00341-9 sha: doc_id: 11333 cord_uid: yyhwtnza background: the frequency of childhood obesity has increased over the last 3 decades, and the trend constitutes a worrisome epidemic worldwide. with the raising obesity risk, key aspects to consider are accurate body mass index classification, as well as metabolic and cardiovascular, and hepatic consequences. data sources: the authors performed a systematic literature search in pubmed and embase, using selected key words (obesity, childhood, cardiovascular, liver health). in particular, they focused their search on papers evaluating the impact of obesity on cardiovascular and liver health. results: we evaluated the current literature dealing with the impact of excessive body fat accumulation in childhood and across adulthood, as a predisposing factor to cardiovascular and hepatic alterations. we also evaluated the impact of physical and dietary behaviors starting from childhood on cardio-metabolic consequences. conclusions: the epidemic of obesity and obesity-related comorbidities worldwide raises concerns about the impact of early abnormalities during childhood and adolescence. two key abnormalities in this context include cardiovascular diseases, and nonalcoholic fatty liver disease. appropriate metabolic screenings and associated comorbidities should start as early as possible in obese children and adolescents. nevertheless, improving dietary intake and increasing physical activity performance are to date the best therapeutic tools in children to weaken the onset of obesity, cardiovascular diseases, and diabetes risk during adulthood. obesity in children and adolescents has emerged as one of the most serious health problems, condition which threatens future health and longevity. over the past 30 years, childhood obesity rate has doubled and, in some cases, even tripled in developed countries [1] . according to the global health observatory data 2017 by world health organization (who), there are over 340 million obese children and adolescents aged [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] . the aim of this thematic review is to provide current data about the impact of excessive body fat accumulation in infancy across adulthood, as a sound predisposing factor of cardiovascular and hepatic consequences. we also discuss the impact of physical and dietary behaviors starting from childhood on obesity-related comorbidities. the rate of increase in obesity is faster in children than in adults [2] . countries with a rapid development, as china, are displaying a remarkable increase in childhood obesity, with the number of overweight and obese chinese children aged 7-18 years increasing by 28 times from 1985 to 2000 [3] . in the united states, the prevalence of obesity in the pediatric population reaches 18.5%, affecting almost 14 million of children and adolescents [4] . in italy, about 21% of children are overweight and 10% are obese, with obesity trends expected to increase further [5] . a similar trend emerged in a previous ultrasonographic study in children and adolescents in southern italy [6] . obese children have a fivefold increased risk to stay obese during adulthood, as compared to normal-weight children [7, 8] . infancy and childhood are critical moments in which key metabolic changes occur with health effects later in life. both the children born large for gestational age or small for gestational age have the risk to develop obesity and metabolic consequences (fig. 1) . genetic factors play only a minor role whilst social, economic, and environmental factors drive the increase of the obesity prevalence. the role of epigenetic factors at an early age is also important in determining adulthood metabolic abnormalities [9] [10] [11] [12] [13] . table 1 depicts the potential weight-related comorbidities in obese children. obese children are more susceptible to cardiovascular diseases (cvd) [14] [15] [16] [17] , metabolic alterations [18, 19] , orthopedic complications, and psychosocial disorders, such as low self-esteem, anxiety, social isolation, and poor academic performance [20] . in addition, obese children may show abnormalities in the liver, reproductive system, brain, as well as increased blood pressure, impaired gluco-lipid metabolism, and sleep apnea. thus, the priority is to design preventive measures to halt the number of obese children becoming unhealthy during adulthood [21] . obesity results from excessive fat accumulation in the body, usually assessed by body mass index (bmi), i.e., body weight (kg) divided by the square of height (m 2 ). according to the international classification by the who, adults are considered overweight when bmi ≥ 25 kg/m 2 and obese if bmi ≥ 30 kg/m 2 . incorrect evaluation of bmi as indicator of body adiposity can occur when muscle in children up to 2 years, the diagnosis of overweight and obesity relies on the weight/length ratio using the who 2006 reference curves. for children over 2 years, the diagnosis is based on the use of bmi using the who 2006 reference curves up to 5 years, and the who 2007 reference curves thereafter. the diagnosis of overweight is made for bmi values ≥ 85th percentile and < 95th percentile, while obesity is defined by bmi values ≥ 95th percentile [22, 23] . the 99th percentile is the cut-off used to define severe obesity since this value corresponds to a higher prevalence of cardio-metabolic risk factors and persistence of obesity later in life, as compared with lower percentiles [14] . however, the who terminology used to define severe obesity differs from younger (up to 5 years of age) compared to older children and adolescents. indeed, the 99th percentile identifies obesity in the former group, and severe obesity in the latter. the different cut-off used to define these conditions is justified by the differences in growth process at different ages [24, 25] . the recommendation to use the who reference curves relies on their higher sensibility in identifying overweight and obese children. indeed, the italian bmi thresholds [26] underestimated the prevalence, likely due to the curves based on dates collected in a time when the increase in obesity had already occurred [27] . body composition can change among different ethnicities. for example, within the same bmi, non-hispanic black children and adolescents show lower percentages of fat mass than non-hispanic white or mexican americans. this condition explains why they are less prone to become obese [28] . singapore chinese adolescents, on the other hand, tend to have higher fat mass than dutch caucasian adolescents [29] , and they are more predisposed to develop obesity-related consequences; hence, the cut-off to define overweight and obesity in asian children and adolescents is lower [30] . notably, in a recent meta-analysis, the number of genomic loci associated with height and bmi was disproportionately increased compared to previously published genome-wideassociated studies [31] . the authors suggest that the discovery of new loci will increase prediction accuracy and provide further data to explain complex trait biology. cvds are the most frequent cause of morbidity and mortality globally. atherosclerosis is one of the main contributing factors for cvd. this process begins already during childhood mostly under the influence of environmental factors. some studies suggest that maternal weight gain in early pregnancy may be a critical period for an adverse childhood cardiovascular risk profile [32] . other studies found an association between bmi in childhood and increased risk of adulthood cvd and mortality. twig et al. examined bmi in a cohort of 2,300,000 israeli aged 16 and 19 years, in the search for a correlation between death and cvd later in life. in the 40-year follow-up, a correlation existed between increased risk of cardiovascular events and all-cause mortality in adults whose bmi increased during adolescence [33] . baker et al. found similar results in a cohort of 276,853 danish children. in particular, the increase of 1 unit in bmi z score in 13-year-old children almost doubled the risk of adulthood cvd [34] . bjorge et al. found a correlation of obesity with premature death, even if the critical age range associated with such increased risk remained uncertain [35] . concerning the critical bmi threshold, aune et al. conducted a meta-analysis of the available studies investigating the correlations of bmi with all-cause mortality. the nadir existed at bmi 23-24 kg/m 2 among non-smokers, 22-23 kg/m 2 among healthy non-smokers, and 20-22 kg/m 2 when the analysis was limited to studies with longer durations of follow-up [36] . due to the strong correlation between childhood obesity and the cvd risk during adulthood, several studies aimed to identify early markers of cvd. mcgill et al. demonstrated the presence of early atherosclerotic lesions [37] , which appear first in the distal aorta and then in the carotid arteries. carotid intima-media thickness (cimt) is considered a valid marker of pre-clinical atherosclerosis, and several studies support its role as independent predictor of cvd even in asymptomatic subjects [38] . in addition, cimt may be a good marker of cardiovascular alterations in children, although studies show some discrepancies [39] . freedman et al. analyzed a cohort of 513 subjects and detected a positive correlation between bmi measured throughout life and cimt at age of 35 years. these associations, however, were restricted to adults who continued to be obese. in particular, they found the bmi-cvd correlation to be weak before the age of 11 years, but it progressively increased with age, reaching the strongest correlation among adolescents aged 15-18 years [40] . juonala et al. found no significant association between bmi measured at 3, 6, 9 or 15 years and cimt 21 years later, even though a positive correlation existed with bmi at ages 12 and 18 [41] . in a longer followup, wright et al. did not find any significant correlations between childhood bmi and cimt at the age of 50 [42] . the raising prevalence of obesity, metabolic syndrome together with insulin resistance [43] , worldwide is associated with liver abnormalities encompassing the clinical spectrum of nonalcoholic fatty liver disease (nafld). nafld occurs in the absence of other triggering factors such as hepatitis c, alcohol consumption, parenteral nutrition, or steatogenic drugs. whereas nonalcoholic fatty liver (nafl)-a relatively benign condition [44] -implies more than 5% of fatty hepatocytes without hepatocellular injury, the term nonalcoholic steatohepatitis (nash) is associated with fatty liver and hepatocellular injury revealed by the histological findings of hepatocyte ballooning, with or without fibrosis [45] . a third category is nash cirrhosis, showing current or previous evidence of histologic nash or nafl. ethnicity, age, metabolic syndrome, insulin resistance [46, 47] , dyslipidemia [48] , high intake of dietary fructose [49] [50] [51] , all influence the development of nafld [52] , with males showing higher risk than females [53] . in children, nafld is now the most common cause of liver disease [54] [55] [56] , and this trend is somewhat worrisome because even in children nash may evolve to fibrosis, cirrhosis (as early as 8 years) [57, 58] , and even liver failure [59] [60] [61] . this correlation nafld/nash, however, seems weaker in children than adults, suggesting a milder phenotype of nafld [62] . since adults with nafld have high risk to die from cardiovascular disease, clinicians and the public should be aware that children with nafld must receive a full evaluation to detect or prevent important comorbidities listed in table 1 , and including type 2 diabetes mellitus, and cardiovascular disease. based on elevated serum aminotransferases, imaging or liver biopsy, the prevalence of nafld in children and adolescents and in obese children ranges between 6 and 38%, depending on the context, the population studied, and the ethnicity ( table 2) . as reported in adults, also children with nafld remain mostly asymptomatic [8] or describe mild symptoms such as pain in the right upper quadrant or nonspecific symptoms, including fatigue and abdominal discomfort [63, 64] , or symptoms due to obesity-associated comorbidities (i.e., gallstones, gastroesophageal reflux disease, etc.) [65] . thus, physical examination should look for comorbidities, splenomegaly, and end-stage liver disease (cirrhosis). serum abnormalities include elevated liver transaminases, alkaline phosphatase, and gamma-glutamyl transpeptidase [8, 56, 58, 66, 67] which tend to improve upon adoption of healthy lifestyles (see below) [66, 68] . notably, even in children with nash the levels of aminotransferases may remain normal [69] , and this possibility is intrinsic to the limited sensitivity and specificity of serum aminotransferase levels for clinically significant nafld. due to the high and further raising prevalence of obesity and metabolic syndrome in children, recent guidelines recommend the screening of obese children as the primary screening for nafld. steps vary according to the existence of concomitant comorbidities and levels of serum transaminases (i.e., normal, moderate, and > 2 upper normal limit persistent elevation) [15] . at least in children, imaging techniques for the screening diagnosis of nafld are not routinely recommended [15, 70] , due to poor sensitivity and specificity (ultrasonography) [71, 72] , poor correlation with steatohepatitis, fibrosis (magnetic resonance) [73] [74] [75] , or detection of only advanced fibrosis, costs, lack of definitive cut-off values and need validation (magnetic resonance elastography) [76] . the role of liver biopsy (which ultimately confirms the diagnosis of nafld and determines the severity of the fatty liver disease with the presence and extent of inflammation and fibrosis [15, 56] ) needs to be discussed on a case-by-case basis. cases should include forms of more progressive nafld, possibility of table 2 studies relating diagnosis of nonalcoholic fatty liver disease with prevalence of nonalcoholic fatty liver disease in children/adolescents nhanes national health and nutrition examination surveys, nash nonalcoholic steatohepatitis, nafld nonalcoholic fatty liver disease a limited sensitivity and specificity for clinically significant nafld [71, 72] other liver diseases, and morbidly obese scheduled for bariatric surgery. in spite of the emerging epidemics of pediatric nafld worldwide, there is no established treatment so far, even when considering metformin (for improving insulin sensitivity), vitamin e (for reducing inflammatory changes in the liver), cysteamine bitartrate (as antioxidant agent), and ursodeoxycholic acid (for reducing the bile acid hepatotoxic effect) [15] . as a matter of fact, aggressive treatment of comorbidities and lifestyle intervention (diet, exercise, weight management, counseling) remain the mainstay of treatment even in pediatric nafld [77, 78] . physical inactivity affects a vast majority of children and adolescents who become prone to high obesity rates and related diseases, including cvd and nafld. promotion of programs involving physical activity has, therefore, become a relevant topic in health policy. messing et al. conclude that "multi-component interventions in childcare facilities and schools stand out prominently" [79] . molina-molina et al. have recently discussed several mechanisms for which physical inactivity might affect cvd [80] . between ages 5-6 and 8-9, there are similar increases in physical inactivity for both boys and girls, as reflected in a british cohort of 57 primary schools [81] . already during adolescence, physical activity starts to decrease, contrarily to body weight [82] . a series of factors such as dietary intake and sedentary behaviors contribute to childhood obesity [83] . the phenotype of obesity could differ depending on the children's age, gender, and family characteristics. studies on television viewing and total recreational screen time in youth might be associated with adverse cvd risk factors, such as adiposity, increased triglycerides, and metabolic syndrome [84] . other authors have linked sedentary time with diabetes and high blood pressure in obese and overweight adolescents [85, 86] . several hours of television viewing by adolescents doubles the odds for metabolic syndrome later in adulthood, as observed in a study by wennberg et al. [87] . not only sedentary behaviors, but above 10 hours of night time sleep in primary school children from germany was also associated with obesity [88] . poor dietary habits in children also increase the risk of obesity. among children, parents and caretakers have the greatest influence on their eating habits [89] . according to a study by lipowska et al., children's eating patterns are influenced by the parent-child interaction, shaping the nutritional status, which ultimately contributes to their health [90] . nutritional status of children can also have direct effect on growth, development, and nutrition related-health problems [91] . the portion size of food consumed each day depends on age, sex, stage of growth, body weight and size, and level of physical activity [92] . children who consume large portion sizes, hyper-caloric and high-energy-dense foods gain excess weight and body fat, while cvd risk increases [93] . reduced consumption of fats, carbohydrates, and added sugars and more intakes of vegetables and fruits could decrease obesity in children and risk to cvd [94] . both an optimal nutrition and regular physical activity increase the chances of healthy maturation during childhood [95] . according to elmaogullari et al., age and bmi are the most important factors to be considered in childhood obesity [96] . overall, changing dietary patterns seems the best treatment against obesity, cvd, diabetes, and nafld. the epidemic of obesity and obesity-related comorbidities worldwide raises concerns about the impact of early abnormalities during childhood and adolescence. exact evaluation of body composition parameters is required at an early age, to classify correctly the metabolic abnormalities, and to decrease the chances of further dysmetabolic changes at a later age. two key abnormalities in this context include cardiovascular diseases, and nonalcoholic fatty liver disease, a wide spectrum of conditions ranging from simple liver steatosis, steatohepatitis, and (metabolic) cirrhosis. notably, nonalcoholic fatty liver is associated with increased risk of mortality in the adults. this means that appropriate metabolic screenings and associated comorbidities should start as early as possible in obese children and adolescents. nevertheless, improving dietary intake and increasing physical activity performance are to date the best therapeutic tools in children to weaken the onset of obesity, cvd, and diabetes risk during adulthood. or national research committee and with the 1964 helsinki declaration and its later amendments or comparable ethical standards. no financial or nonfinancial benefits have been received or will be received from any party related directly or indirectly to the subject of this article. global prevalence and trends of overweight and obesity among preschool children global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the 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youth: approaches to the prevention and management of childhood obesity: a scientific statement from the video game playing is independently associated with blood pressure and lipids in overweight and obese adolescents screen viewing and diabetes risk factors in overweight and obese adolescents hammarstrom a. television viewing and low leisure-time physical activity in adolescence independently predict the metabolic syndrome in mid-adulthood crosssectional associations of objectively assessed sleep duration with physical activity, bmi and television viewing in german primary school children dietary behaviors and caregiver perceptions of overweight and obesity among chinese preschool children gender and body-fat status as predictors of parental feeding styles and children's nutritional knowledge, eating habits and behaviours prevalence of obesity in the united states development of food intake patterns for the mypyramid food guidance system reduction of risk for cardiovascular disease in children and adolescents dietary and policy priorities for cardiovascular disease, diabetes, and obesity: a comprehensive review physical activity and obesity in children risk factors that affect metabolic health status in obese children key: cord-291627-5dqwyd9r authors: yadav, rakhee; aggarwal, sandeep; singh, archna title: sars-cov-2-host dynamics: increased risk of adverse outcomes of covid-19 in obesity date: 2020-07-21 journal: diabetes metab syndr doi: 10.1016/j.dsx.2020.07.030 sha: doc_id: 291627 cord_uid: 5dqwyd9r background and aim: the pandemic of covid-19 has put forward the public health system across countries to prepare themselves for the unprecedented outbreak of the present time. recognition of the associated risks of morbidity and mortality becomes not only imperative but also fundamental to determine the prevention strategies as well as targeting the high-risk populations for appropriate therapies. methods: we reviewed, collated and analysed the online database i.e. pubmed, google scholar, researchgate to highlight the demographic and mechanistic link between obesity and associated risks of severity in covid-19. results: we observed a changing dynamic in the reporting from the time of initial pandemic in china to currently reported research. while, initially body mass index (bmi) did not find a mention in the data, it is now clearly emerging that obesity is one of the profound risk factors for complications of covid-19. conclusion: our review will help clinicians and health policy makers in considering the importance of obesity in making the prevention and therapeutic strategies of covid-19. an extra attention and precaution for patients with obesity in covid-19 pandemic is recommended. background: on december 31, 2019 several cases of pneumonia with an unidentified origin emerged from wuhan, china which were reported to world health organisation (who). 1 the cause of these cases was confirmed to be severe acute respiratory syndrome coronavirus 2 (sars-cov-2) after a week. 2 considering its spread; the outbreak was declared a public health emergency of international concern on january 30 2020 and later who announced a name for the new coronavirus disease as covid19. 3 as of july 14, 2020 there have been 1,29,64,809cases and 45,70,288 deaths globally due to covid-19 spanning across all countries with usa, brazil and europe reporting the maximum load. 4 while most people with covid-19 develop no symptoms or have only mild illnesses, the evidence from china indicate that approximately 14% develop severe disease that requires hospitalisation and oxygen support, while 5% require admission to an intensive care unit (icu). 5 due to the mounting public health concerns about covid 19 worldwide, scientists have been poring over data about the spectrum of clinical manifestations of covid-19. certain factors such as age and co-morbidities like hypertension, diabetes and cardiovascular disorders have mostly been found to be associated with severe illnesses requiring robust measures and support from health care system. 6 such an association with obesity and high bmi has been insufficiently reported and considering it as the forerunner of many of these co-morbidities, it becomes inevitable to investigate an association of obesity with severe outcomes of covid-19. nonetheless, the exact mortality rate varies greatly between regions and countries which can partly be due to the varying extent of testing and also possibly be due to differing trajectories based on population demographics and quality of health care availability. keeping in mind that there is lack of herd immunity and absence of an effective vaccine and antiviral therapy, countries are bound to take stringent measures to flatten the transmission curve in order to cope with the demands of health care systems. thus, taking into account evidence and lessons from the ongoing situation of covid-19 from different parts of the world, it becomes imperative to identify which patients are most at risk for hospitalisation. it can assist emergency care providers in making triage decisions. further, it can help inform policymakers about highest risk populations, who may need particular protection through policy decisions. finally, it can help epidemiologists to improve the accuracy of projections about the likely need for hospital beds and staffing in a region by knowing its demographic characteristics. hence, we put forth the detailed evidence and changing clinical demographics related to obesity being an important risk factor for complicated outcomes in covid-19, thereby also ascertaining the putative reasons behind it. after a scrutiny of published literature, we found a paucity of information about the bmi of cases of covid-19 because majority of the studies from china 7 which have reported comorbidities, did not provide any data on bmi of such patients. however, the findings from a retrospective analysis on 112 patients with covid-19 infection admitted in a hospital in wuhan, between 20 january 2020 to 15 february 2020 are noteworthy. in this study, the bmi of the critical group was significantly higher than that of the general group. patients were further divided into two groups, survivors (84.8%) and non-survivors (15.18%). among the non-survivors, 88.2% of patients had a bmi > 25 kg/m 2 , which was in a significantly higher proportion (p < 0.001) than in survivors (18.8%). 8 the authors concluded that a higher bmi was more often seen in critical cases and non-survivors. in another study from wenzhou, china; it was found that the presence of obesity in metabolic associated fatty liver disease (mafld) patients was associated with a ~6 -fold increased risk of severe covid-19 illness (unadjusted -or 5.77, 95% ci 1. 19 -27.91, p=0.029 ). this association with obesity and covid-19 severity remained significant (adjusted -or 6.32, 95% ci 1. 16 -34.54, p=0 .033) even after adjusting for age, sex, smoking, diabetes, hypertension, and dyslipidaemia. 9 moreover, qingxian cai et al examined an association between obesity and severity of covid-19 using data from only the referral hospitals in shenzhen, china. 10 they found that overweight group showed 86% of higher odds, and obesity group showed 2·42-fold higher odds of developing severe pneumonia. as the covid-19 continues to spread worldwide, such an evidence from china is sufficient to provide an insight to clinicians to maintain a high level of attention for obese patients. persons with severe obesity who become ill and require intensive care (5% of infections) present challenges in patient management like difficult intubations, difficulty in obtaining an imaging diagnosis (there are weight limits on imaging machines) and a requirement of special beds and positioning/transport equipment which might not be widely available in a majority of hospital set ups. a close survey of the available data on co-morbidity and mortality for covid-19 across the world (later march and april 2020); points towards the emergence of obesity as one of the major risks for complications apart from older age. [12] [13] [14] [15] [16] [17] [18] a descriptive study of a small sample of 24 critically ill patients diagnosed with covid-19 in the seattle region (usa) was among the first to report bmi data (3 patients with a bmi in the normal category, 7 with overweight, 13 with obesity and 1 with missing data). although the numbers were too small for meaningful statistical analyses but 85% of the patients with obesity required mechanical ventilation and 62% of the patients with obesity died was a noteworthy finding. these proportions were greater than those in the patients without obesity, in which 64% required mechanical ventilation and 36% died. 11 many recent studies are now reporting obesity as one of the risk factors for severity of covid-19 in usa, brazil, uk, italy, spain and france [12] [13] [14] [15] [16] [17] [18] 67 (summarised in the in the current scenario, since usa has become the epi-centre of the covid-19 pandemic; the dynamics of patient characteristics in terms of associated complications is showing a difference from the initial data put out by china. this might be attributed, on one hand, to the paucity of reported bmi related information of the positive and critical cases from the data of china during the initial stages, and on the other hand, to the higher incidence and prevalence of obesity in usa as compared to other nations in the world. the prevalence of obesity in us has been 42.4% in 2017-2018 with a high burden of class iii obesity i.e. 9.2% of the population with bmi>40kg/m 2 . 20 in fact, it is also listed as a risk factor for covid-19 by the usa centres for disease control and prevention. 21 in india, the prevalence of obesity varies due to age, gender, geographical environment and socio-economic status. according to icmr-indiab study 2015, prevalence rate of obesity and central obesity varies from 11.8% to 31.3% and 16.9% to 36.3% respectively. 22 infact more than 135 million individuals are affected by obesity 22 and the prevalence is rising fast amounting to a huge burden on healthcare infrastructure in our country, particularly, abdominal obesity which is considered to be one of the leading causes of cardiovascular diseases. moreover, asians often display lower cardiorespiratory fitness and carry proportionally more fat percentage for any bmi as compared to their counterparts from the western world. 23 the influenza of 1956-1960 (asian) and of 1968 (honk kong) have confirmed that obesity and diabetes had led to a higher mortality and a prolonged duration of illness even in the absence of other chronic conditions which increased the risk of influenza-related complications. 24 during the 2009 h1n1 pandemic, obesity was recognized as an independent risk factor for complications from influenza. 25 moreover, it had been well established that obesity increased the duration of viral shedding in h1n1 pandemic by 42% as compared to adults who did not have obesity. 25 worldwide, diabetes and obesity were the most frequently identified underlying conditions in fatal cases who were older than 20 years of age. however, anecdotal observations of high prevalence of obesity in severe and fatal cases were also reported from chile, manitoba and mexico. 25 several reports from around the world identified obesity and severe obesity as risk factors for hospitalization and mechanical ventilation. 26 the distribution of obesity among hospitalized patients in california and new mexico exceeded the 35% prevalence of obesity in us adults in 2009 to 2010. 25, 27 moreover, it's a matter of concern knowing the fact that persons with obesity have diminished protection from influenza immunization with a study showing that adult recipients of influenza vaccine (iiv3) with obesity had two times greater incidence of influenza and/or influenza like illness despite being vaccinated. 28 thus, prior experience of the impact of obesity on morbidity and mortality from previous influenza pandemics should definitely sensitise the clinicians in caring for patients with obesity and covid-19 towards a need for their aggressive management. moreover, strict precautionary measures must be advised to this group of individuals in the present pandemic. these include mandatory social distancing and home quarantine considerations with a close watch on the quality and quantity of food being consumed. obesity potentiates multiple cardiovascular risk factors with premature development of cardiovascular disease and adverse cardiorenal outcomes. in individuals with diabetes, obesity and excess ectopic fat leads to impairment of insulin sensitivity and a reduced betacell function. both limit the ability to evoke an appropriate metabolic response upon immunologic challenge. overall, there is a loss of integrated regulation of metabolism required for the complex cellular interactions and for an effective host defence, further leading to the functional immunologic deficit. there is a significant worsening of the clinical profile and influenza disease severity whenever there is presence of multiple co-morbidities associated with obesity. 23 furthermore, obesity enhances thrombosis, which is evident by the association between severe covid-19 and pro-thrombotic disseminated intravascular coagulation and high rates of venous thromboembolism. beyond cardiometabolic and thrombotic consequences, obesity has detrimental effects on lung function, diminishing forced expiratory volume and forced vital capacity. 23 obesity has a well-known impact on pulmonary functions. it is associated with decreased expiratory reserve volume, functional capacity, and respiratory system compliance. pulmonary function is further compromised by decreased diaphragmatic excursion, making ventilation even more difficult. 29 all these are possible determinants of worst clinical outcomes in covid-19 with obesity and associated metabolic co-morbidities. during the present pandemic, till now, it has been well established that cardiovascular diseases and diabetes are the major risk factors for poor outcomes but considering a higher bmi to be a forerunner for both these co-morbidities, the inclusion of obesity and overweight individuals as candidates for poor covid-19 outcomes becomes very important. however due to paucity of reported anthropometric characteristics from the initial outbreak in china, it is difficult to comment on obesity being independent risk factor for complicated covid-19. but changing demographic dynamics has now pointed towards importance of noting the important anthropometric data for all the affected individuals. obesity is considered as a chronic inflammatory state. such individuals have a higher concentration of several pro-inflammatory cytokines like tnf-α, mcp-1 and il-6, mainly produced by visceral and subcutaneous adipose tissue leading to a defect in the innate immunity. 30 when an antigen is presented in such an environment, a reduced macrophage activation and a blunted pro-inflammatory cytokine production occurs. 31 this microenvironment explains the emergence of antiviral-resistant and vaccine escape variants in the obese population. 32, 33 studies of cytokine dynamics in human "cytokine storm" models shows that il6 sustains activation of multiple cytokine pathways for many days post initial immune insult. 34 interestingly, in early covid-19 studies il6 was a strong independent predictor of mortality. 35 human adipose tissue is a major source of il6 and its receptor il6r 36 and, thus, adipose tissue may provide a reservoir for il6 activation and cascade signalling in viral infection. viral spread from affected organs to adjacent adipose tissue may take days, with subsequent prolonged viral shedding contributing to the delayed cytokine storm and consequences for tissue injury in patients with covid-19. in line with this, il6 inhibition has already been proposed as a treatment in covid-19 and the results of trials of tocilizumab are awaited. 37 b and t cell responses are impaired in obese patients, and this causes an increased susceptibility and a delay of resolution of the viral infection. 38, 39 the hormonal milieu is such that in obesity; that there is an adipokine dysregulation with higher leptin (pro-inflammatory adipokine) and lower adiponectin (anti-inflammatory adipokine) levels. leptin resistance was also found to be an important factor associated with severe lung injury in 2009 h1h1 pandemic. 38 not only this, studies in obese mouse models have suggested that both innate and adaptive immune responses to influenza a virus and its vaccine antigens like type i interferon response, natural killer cell functions, antigen presentation by dendritic cells and antigen specific memory of cd8 + lymphocytes were defective. 38 additionally, a diminished interferon response and an increased influenza virus replication were found in normal bronchial epithelial cells derived from obese subjects. [40] [41] [42] shared viral tropism for lung epithelium and adipose tissue has already been shown for h5n1 virus infection. 44 gralinski and collaborators identified the complement system as an important host mediator of sarscov-induced disease. 43 notably, eculizumab, an antibody with complement system modulatory activity, is now being studied in an fda expanded type of trial (clinicaltrials.gov identifier: nct04288713) to assess its effect on covid-19 infected patients relative to duration of intensive care treatment and mechanical ventilation, together with mortality outcomes. 45 currently there is no evidence for direct sars-cov-2 infection of adipose tissue, although ace2 receptor expression represents a basis for viral tropism in several cells within this tissue 46 including adipocytes, smooth muscle cells and endothelial cells. 47 if we look into the past influenza pandemics also, it has been found that many adipose tissue resident cells are proven targets for multiple viruses like adipocytes (h1n1, type a influenza and adenovirus 36), 48 severe acute respiratory syndrome coronavirus (sars-cov) binds with the angiotensin converting enzyme 2 (ace2) receptor for intracellular invasion, and the mechanism for acute lung injury during infection has been postulated to be mediated through the activation of the renin-angiotensin-system (ras). 55 ras blockade has been proposed as a potential treatment for covid-19. 56 remarkably, ace2 is expressed in the human adipose tissue. individuals with obesity have more adipose tissue and therefore an increased number of ace2 expressing cells.the overall angiotensin converting enzyme (ace)/ angiotensin ii (ang ii)/type 1 angiotensin 2 receptor (at1r) ras axis activation plays an important role in the pathophysiology of obesity and visceral adiposity-related cardiac risk. 58 thus, the interaction between ace2-ras system, adipose tissue and the sars-cov-2 could, at least partially, explain the higher morbidity and mortality risk of covid-19 in obese patients. additionally, it can be stated that treatment with specific anti-hypertensive medications (ace inhibitors and angiotensin receptor blockers, arbs) will increase expression of ace2 and increase patient susceptibility to viral host cell entry and propagation. 59 thus a layer of complexity is added while managing covid-19 infected persons who have more than one co-morbidity. secondly, human dipeptidyl peptidase 4 (dpp4) was also identified as a functional receptor for the spike protein of the middle east coronavirus (mers-co-v). 60 mers-cov binds to the receptor-binding domain and interacts with t cells and nuclear factors such as nf-kβ, involved in the pathogenesis of inflammatory disorders. dpp4 a transmembrane protein, has been found to be highly expressed in human visceral adipose tissue and is associated with insulin resistance and adipocyte inflammation.. dpp-4 inhibition increases glucagon like peptide -1 (glp-1) secretion leading to an improved insulin sensitivity and glucose metabolism within the adipocyte. 61 dpp4 inhibitors are commonly prescribed in type 2 diabetes with obesity.considering the immune modulatory effects of dpp4 inhibitors like suppression of t-cell proliferation and the secretion of pro inflammatory cytokines, such as il-6 and 10, 62 it becomes logical to translate such findings in context to covid-19 in obesity. thus dpp4 may represent a potential target for preventing and reducing the risk and progression of the acute respiratory complications that type 2 diabetes may add to covid-19 in obesity. progressive consolidation of the lung leading to severe acute respiratory syndrome is recognised as the most common complication of sars-cov virus. 63 this virus shares a high degree of genetic homology with sars-cov-2. one of the main reasons for this pulmonary consolidation is an extensive pulmonary fibrosis which was evident from ct scan and autopsy findings in sars-cov infections. 63, 11 the pathophysiology of pulmonary fibrosis is not fully elucidated but role of myofibroblasts in modifying the lung structure and functions have been established in such conditions. 64 such cells have also been found to be connected with adipocyte -myofibroblasts trans-differentiation in certain fibrotic lesions of skin. 65 moreover, pathophysiological pathways have been linked with adipogenic-myogenic transition in lungs in pulmonary fibrosis where pulmonary lipofibroblasts have been proposed to be playing a central role. this population of cells carry characteristic lipid droplets and express high levels of perilipin-2 and are found adjacent to the ace2 expressing alveolar epithelial cells. 66 thus its logical to explore whether sars-cov/cov-2 can directly influence these cells and thereby promote enhanced lipofibroblast-myofibroblast transition. 66 it has also been postulated that adipose tissue can serve as a viral reservoir, whereas transdifferentiation of pulmonary lipofibroblasts into myofibroblasts can contribute to the development of pulmonary fibrosis and thus is likely to influence the clinical severity of covid-19. 66 further, this population of cell has been proposed to increase the severity of the local response to covid-19 in the lung. 66 this could be explored to avert the pulmonary complications of covid-19 in obesity. the pandemic of covid-19 has put the public health system under immense strain to tackle the load of its high transmission and critical complications with the available limitations of the present health-care infrastructure. putting together, our data has brought up some important insights towards considering bmi and obesity as one of the risk factors for severity and critical admissions for covid-19 (as summarised in figure 1) . however, whether obesity, over and above its cardio-metabolic co-morbidities might independently contribute to covid-19 risk; needs more robust and detailed prospective survey. coronavirus disease 2019 (covid-19): a systematic review of imaging findings in 919 patients world health organization. who director-general's remarks at the media briefing on 2019-ncov on 11 coronavirus disease (covid-19) situation report -103 the epidemiological characteristics of an outbreak of 2019 novel coronavirus disease (covid-19) in china the 2019 novel coronavirus disease (covid-19) pandemic: a review of the current evidence characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72,314 cases from the chinese center for disease control and prevention clinical characteristics and outcomes of 112 cardiovascular disease patients infected by 2019-ncov obesity as a risk factor for greater severity of covid-19 in patients with metabolic associated fatty liver disease obesity and covid-19 severity in a designated hospital covid-19 in critically ill patients in the seattle region-case series clinical characteristics of covid-19 in new york city factors associated with hospitalization and critical illness among 4,103 patients with covid-19 disease in presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with covid-19 in the new york city area obesity in patients younger than 60 years is a risk factor for covid-19 hospital admission hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease 2019 -covid-net, 14 states high prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (sars-cov-2) requiring invasive mechanical ventilation icnarc report on covid-19 in critical care. 2020. www.icnarc.og predicting mortality due to sars-cov-2: a mechanistic score relating obesity and diabetes to covid-19 outcomes in mexico centres for disease control and prevention. overweight and obesity covid-19 and obesity-lack of clarity, guidance, and implications for care prevalence of obesity in india: a systematic review obesity a risk factor for 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infuenza across multiple spatiotemporal scales dynamics of a cytokine storm clinical predictors of mortality due to covid-19 based on an analysis of data of 150 patients from wuhan, china obesity is a positive modulator of il-6r and il-6 expression in the subcutaneous adipose tissue: significance for metabolic inflammation chictr2000029765 -a multicentre, randomized controlled trial for the efficacy and safety of tocilizumab in the treatment of new coronavirus pneumonia (covid-19) 2020 leptin mediates the pathogenesis of severe 2009 pandemic infuenza a (h1n1) infection associated with cytokine dysregulation in mice with diet-induced obesity role of the pyruvate dehydrogenase complex in metabolic remodeling: diferential pyruvate dehydrogenase complex functions in metabolism impaired wound healing predisposes obese mice to severe infuenza virus infection inf-lambda prevents infuenza virus spread from the upper airways to the lungs and limits virus transmission obesity related microenvironment promotes emergence of virulent infuenza virus strains complement activation contributes to severe acute respiratory syndrome coronavirus pathogenesis obesity and sars-cov-2: a population to safeguard characterization of human influenza a (h5n1) virus infection in mice: neuro-, pneumo-and adipotropic infection towards a knowledge-based human protein atlas angiotensin converting enzyme 2 contributes to sex differences in the development of obesity hypertension in c57bl/6 mice association between h1n1 infection severity and obesity-adiponectin as a potential etiologic factor obesity increases the duration of influenza a virus shedding in adults infection-induced inflammatory response of adipocytes in vitro adenovirus 36 dna in human adipose tissue human cytomegalovirus infection of human adipose-derived stromal/stem cells restricts differentiation along the adipogenic lineage pathology and pathogenesis of severe acute respiratory syndrome intracellular infections enhance interleukin-6 and plasminogen activator inhibitor 1 production by cocultivated human adipocytes and thp-1 monocytes angiotensin-converting enzyme 2 is a functional receptor for the sars coronavirus angiotensin receptor blockers as tentative sars-cov-2 therapeutics two things about covid-10 might need attention renin angiotensin-aldosterone system inhibitors in patients with covid-19 covid-19 and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: what is the evidence? dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-emc covid-19 and diabetes: can dpp4 inhibition play a role? dpp4-directed therapeutic strategies for mers-cov sars coronavirus and lung fibrosis heterogeniety of fibroblasts and myofibroblasts in pulmonary fibrosis myofibroblast in murine cutaneous fibrosis originate from adiponectin-positive intradermal progenitors the role of adipocytes and adipocyte like cells in the severity of covid-19 infections clinical characteristics and morbidity associated with coronavirus disease 2019 in a series of patients in metropolitan detroit all the three contributors have been working on the obesity research and have collaborative projects with dbt, icmr and at aiims. dr sandeep aggarwal is a bariatric surgeon at aiims and has more than 100 publications over the past two decades. the concept and designing with expert guidance have come from him for the present manuscript. he has also contributed in literature search, manuscript editing and review.dr archna singh has been working on adipocyte biology with special focus on cholesterol efflux in obese. apart from this, she has publications in the field of public health and nutrition with collaborative projects under dbt wellcome trust india alliance. in the present manuscript she has contributed with her intellectual content, data acquisition and analysis, alongwith manuscript editing and expert review.dr rakhee yadav has been working on adipocyte biology, extracellular matrix remodeling and insulin resistance in obese. for this manuscript, she is the guarantor, designed and conceptualized the idea with expert opinion from other contributors. she has prepared the manuscript with rigorous relevant data search and acquisition. manuscript editing and review is also done by her.we hereby declare that we have no conflict of interest related to this article sandeep aggarwal rakhee yadav key: cord-329308-ipui7lo6 authors: lim, soo; shin, soo myoung; nam, ga eun; jung, chang hee; koo, bo kyung title: proper management of people with obesity during the covid-19 pandemic date: 2020-06-30 journal: j obes metab syndr doi: 10.7570/jomes20056 sha: doc_id: 329308 cord_uid: ipui7lo6 since december 2019, countries around the world have been struggling with a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (sars-cov-2). case series have reported that people with obesity experience more severe coronavirus disease 2019 (covid-19). during the covid-19 pandemic, people have tended to gain weight because of environmental factors imposed by quarantine policies, such as decreased physical activity and increased consumption of unhealthy food. mechanisms have been postulated to explain the association between covid-19 and obesity. covid-19 aggravates inflammation and hypoxia in people with obesity, which can lead to severe illness and the need for intensive care. the immune system is compromised in people with obesity and covid-19 affects the immune system, which can lead to complications. interleukin-6 and other cytokines play an important role in the progression of covid-19. the inflammatory response, critical illness, and underlying risk factors may all predispose to complications of obesity such as diabetes mellitus and cardiovascular diseases. the common medications used to treat people with obesity, such as glucagon-like peptide-1 analogues, statins, and antiplatelets agents, should be continued because these agents have anti-inflammatory properties and play protective roles against cardiovascular and all-cause mortality. it is also recommended that renin–angiotensin system blockers are not stopped during the covid-19 pandemic because no definitive data about the harm or benefits of these agents have been reported. during the covid-19 pandemic, social activities have been discouraged and exercise facilities have been closed. under these restrictions, tailored lifestyle modifications such as home exercise training and cooking of healthy food are encouraged. ported that obesity is associated with the severity of covid-19. [6] [7] [8] however, the features of covid-19 in people with obesity have not been elucidated and it has not been determined whether obesity is an independent risk factor for susceptibility to infection with sars-cov-2 or the severity of covid-19 or both. we obtained data from a retrospective multicenter study in which all 28 of the first confirmed patients with covid-19 in the republic of korea were enrolled. five of these patients had a body mass index (bmi) >30 kg/m 2 (18%). 9 zheng et al. 10 table 1 . during the covid-19 pandemic, dietary patterns have changed to include increased reliance on delivered foods, and access to healthy food options has diminished. 11 delivered foods are mostly fast foods, such as pizza, hamburgers, fried chicken, and sugar-sweetened beverages or carbonated soda. 12 these items are probably more obesogenic than home-cooked foods. 13 increased consumption of these foods is associated with increased risk of obesity and dm. 14, 15 people with obesity or who are overweight are reported to be less active. 16, 17 in addition, during the covid-19 pandemic, community health centers, gyms, swimming pools, and parks have been closed by law in many countries as part of their quarantine strategy. these changes in the food and social environments may have contributed to an increase in body weight in people with obesity as well as in the general population. in addition to old age, smoking, and underlying cvd and dm, obesity is considered to be a risk factor for covid-19 ( fig. 1) . several factors may affect the relationship between covid-19 and obesity. studies have reported that the immune system is frequently compromised in people with obesity and that covid-19 affects the immune system, and these links may also worsen the complications of obesity. 55, 56 of note, an excess production of interleukin 6 (il-6) and other cytokines released in response to covid-19 can induce a "cytokine storm" (hypercytokinemia), which is believed to increase the fatality of covid-19. 57 covid-19 can also progress to severe respiratory illness and hypoxia, which may predispose people to being immobile and to gaining weight. obesity represents a state of chronic low-grade inflammation. hyperplastic or hypertrophied adipose tissues directly secret various inflammatory products ( fig. 1) , such as inflammatory cytokines, transforming growth factor-β, adipokines, monocyte chemoattractant protein 1 (mcp1), c-x-c motif chemokine ligand 5, hemostatic proteins, proteins affecting blood pressure, and angiogenic molecules. 58, 59 the main inflammatory cytokines derived from adipose tissues are tumor necrosis factor α (tnf-α), il-6, and il-1. increased tnf-α level in people with obesity reflects a . *possibly related to the closing of public and private facilities such as community health centers, gyms, swimming pools, parks, and schools on the basis of quarantine strategies during the covid-19 pandemic; † possibly related to the quarantine policies and financial effects during the covid-19 pandemic. socioeconomic factors: ↓physical activity, 40 ↓opportunities for exercise, 41 ↑unhealthy food consumption. 11 systemic factors: ↑inflammatory cytokine production, 42-44 compromised immune system, 45 ↑insulin resistance, 46 impaired glucose regulation, 46 ↓cardiac function, 47 ↓tissue perfusion, 48 activation of renin-angiotensin system. 49, 50 biomechanical factors: ↓lung compliance, 51 ↓functional residual capacity, 51 ↑airway hyperresponsiveness, 52 ↑small airway collapse, 52 ↑esophageal and gastric pressure, 53 ↑obstructive sleep apnea, 54 ↑hypoxemia. 54 a cumulative effect of chronic inflammation and hypercytokinemia seems to bring about a hyperinflammatory response through macrophage active syndrome, especially in patients with severe covid-19 (fig. 2) . 44 inflammation subsequently leads to hypoxia and ischemia, which results in an oxidative stress state involving release of inflammatory proteins and reactive oxygen species that impair mitochondrial function. as a result, protein synthesis by hypertrophic and hypoxic white adipocytes is altered toward the production of cytokines and other inflammatory proteins, which may lead to metabolic disease. 61, 62 a vicious cycle between elevated release of cytokines and a state of increased metabolic inflammation, which leads to cytokine storm, occurs in patients infected with sars-cov-2 (fig. 2 ). in patients with covid-19, cytokine storm has been proposed to be the cause of the multiorgan failure in patients with severe disease. 63, 64 for example, hyperglycemia was reported in 51% of patients with sars-cov-2 infection. 65 hyperglycemia or type 2 dm, which is closely associated with obesity, has been suggested as an independent predictor of poor prognosis in patients with sars-cov-2. 66 several mechanisms have been proposed to explain how sarscov-2 infection induces inflammation and promotes insulin resistance (fig. 2 ). 46 patients with covid-19 exhibit increased production and secretion of inflammatory markers, such as c-reactive protein (crp), d-dimer, ferritin, and il-6. 67 in general, virus infection increases il-6 levels and this increase is associated with increased risk of diabetic complications. 75 given its proinflammatory role in innate immunity, il-6 level may correlate with disease severity and a procoagulant profile. 76 by increasing oxidative stress, il-6 can damage proteins, lipids, and dna, and this damage may alter the organism's structure and function. viral-induced production of ifn-γ by natural killer cells causes insulin resistance in myocytes by downregulating insulin receptor transcription, thus causing insulin resistance. 46 the mechanisms linking the poor prognosis of covid-19 with obesity overlap with the pathways that regulate immune function hyperinsulinemia increases antiviral immunity through direct stimulation of cd8 + effector t-cell function. in prediabetic mice with hepatic insulin resistance caused by diet-induced obesity, infection resulted in loss of glycemic control. 46 therefore, upon encountering pathogens, the immune system transiently reduces insulin sensitivity of skeletal muscle to promote antiviral immunity and induce hyperinsulinemia, which result in glucose intolerance. taken together, these findings suggest that obesity is associated with accelerated immune system aging and/or dysregulation and that these changes may relate indirectly to the covid-19 prognosis. the immune modulation induced by obesity may be important to the susceptibility and severity of covid-19 (fig. 2) . the renin-angiotensin system (ras) appears to be activated in people with obesity. 49, 50 normally, when blood flow decreases to the kidneys, the juxtaglomerular cells of the kidneys release renin, which activates the ras. 82 in obesity, there is inappropriate activation of the ras in the context of increased sodium intake, sodium/ water retention, central blood volume, and blood pressure (fig. 1) . 49 this metabolic dysregulation is associated with the expansion in visceral adipose tissue content, which leads to increased production of angiotensinogen (up to 30% of circulating angiotensinogen) and possibly elevated plasma renin activity. 49, 50 massiera et al. 83 showed that angiotensinogen-deficient mice exhibit impaired weight gain, which supports the association between obesity and the ras. a large amount of visceral adipose tissue induces release of insulin, which activates angiotensin type 1 receptors and influences the release of tnf-α and il-6 from adipocytes, resulting in activation of the ras pathway. 84 of note, the organ involvement of sars correlates with the organ expression of ace2. in addition, the localization of ace2 expression in the endocrine pancreas suggests that coronavirus enters islets using ace2 as its receptor and damages islets, which leads to hyperglycemia. 38 these data suggest that the ras may be involved in the association between obesity and covid-19. 86 the facial features of people with obesity may differ from those without, 87, 88 and it may be more difficult to find the right mask size for people with obesity. social distancing is recommended as the most effective way of slowing the spread of covid-19. in a physically identical space, larger objects will be placed closer to each other. for this reason, it may be difficult for people with obesity to maintain social distance from other people, which may increase the risk of exposure to the virus. people with obesity tend to spend less time in work, recreation, and rest activities, and more time in activities of daily living than do those without obesity (fig. 1) . 41 glucagon-like peptide-1 (glp1) analogues have an anti-inflammatory effect. for example, the mrna levels of glp1 receptors are downregulated in monocytes that have differentiated into macrophages. 89 treatment with exendin-4 decreases monocyte/macrophage accumulation and mrna expression of inflammatory markers such as tnf-α and mcp1 in the arterial wall of apoe -/mice. 90 overexpression of glp1 in balloon-injured vessels reduces monocyte infiltration and improves reendothelialization, which contribute to reduced neointimal formation. 91 in mice fed a high-fat diet, treatment with liraglutide (30 μg/kg twice daily) decreases tnf-α expression and translocation of its downstream signal nf-κb-p65 92 and adhesion of human monocytes to tnf-α-activated human endothelial cells. 92 in vitro mcp1 expression and nf-κb-p65 translocation also decrease significantly after glp1 treatment. 91 glp1 analogues can shift the polarization profile of macrophages from m1 toward m2, 93 supporting the anti-inflammatory properties of glp1 analogues. liraglutide therapy has an anti-inflammatory effect by increasing nitric oxide production in endothelial cells. 93 liraglutide and semaglutide treatment reduce the development of atherosclerosis through mechanisms involving inflammatory pathways in apoe -/and ldl receptor -/mice. 94 in humans, glp1 and glp1 analogues have been shown to be beneficial for the treatment of chronic inflammatory diseases such as nonalcoholic fatty liver disease, 95 atherosclerosis, 91 and neurodegenerative disorders. 96 taken together, these findings suggest that glp1 analogues have a protective role against atherosclerosis that is mediated by a dampening of the inflammatory pathways. 97 therefore, alleviation of inflammatory processes in the vascular system by these agents is a rationale for the recommendation to prescribe glp1 analogues during the co-vid-19 pandemic. 102 in one in vitro study, sitagliptin, vildagliptin, and saxagliptin could not block the entry of coronaviruses into cells. 103 although ace2 is the main receptor for sars-cov-2, a recent modeling study did not rule out its interaction with cd26 or dpp4. 103 at present, there is insufficient evidence either for or against the use of dpp4 inhibitors in patients with dm and covid-19. 104 the physiological role of ace2 counter-regulates the renin-angiotensin-aldosterone system (raas). 105 independent of the raas, ace2 also regulates intestinal amino acid homeostasis and the gut microbiome. 106 in coivd-19, ace2 on the respiratory epithelium serve as a main entry of sars-cov-2. 107 interaction of sars-cov with ace2 is initiated via trimers of the sars spike protein, which extends into a hydrophobic pocket of the ace2 catalytic domain that is independent of its peptidase activity. 108 ace2 is highly expressed in the lung as well as in the heart, endothelium, kidney, and gastrointestinal tract, and the tissue distribution of ace2 overlaps with the tissue tropisms of sars-cov-2. 109 this means that ace2 expression may be implicated in the severe illness caused by covid-19. higher expression of ace2 in patients with hypertension and cvd has been postulated as a factor that increases the susceptibility to sars-cov-2. 108 by contrast, there is evidence that ace2 may have a beneficial role in covid-19. both sars-cov infection and challenge with recombinant sars spike protein trigger marked downregulation of ace2 expression in the lung. 110 downregulation of ace2 results in susceptibility of lung injury 111 and unopposed raas activation. 112 in animal models, elimination of ace2 was associated with severe lung injury, which could be recovered by recombinant ace2 protein. 111 in addition, ace2-knockout mice exhibited cardiac dysfunction, which could be reversed by concomitant deletion of ace. 113 reduced ace2 expression in cardiac injury has been confirmed in sars infection 114 and myocardial infarction. 111 given that the involvement of the cardiopulmonary system is a key factor for the severity of covid-19, ace2 may play a role in the prognosis of covid-19. people with obesity often also develop hypertension or heart failure. 112 a large multicenter study has confirmed that hypertension can increase the risk of severe covid-19 by as much as 1.7 times. 19 raas inhibitors are the mainstay for treatment of hypertension and heart failure. because raas inhibitors can increase the tissue expression of ace2 in animal models, 115 raas inhibitors may increase the susceptibility to covid-19 and its severity after exposure to sars-cov-2. 108 however, all classes of antihypertensive medication including raas inhibitors are not associated with a substantial increase in the risk of severe illness in covid19. 116 the effect of raas inhibitors on ace2 level or activity in human studies is controversial. generally, ace inhibition does not affect ace2-directed angiotensin ii metabolism, 117, 118 and only specific raas inhibitors appear to increase the ace2 level. 119 hydroxymethylglutaryl-coa reductase inhibitors or statins have anti-inflammatory properties. in the justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin trial, rosuvastatin reduced the relative risk of major cardiovascular events by 44% in people without hyperlipidemia but with elevated high-sensitivity crp level. 126 in a viral pneumonia mouse model, simvastatin directly modulated antiviral inflammatory responses in lung tissues. 127 in that study, simvastatin treatment attenuated airway inflammation, such as rantes (regulated on activation, normal t-cell expressed and secreted) expression and neutrophil recruitments. 127 rosuvastatin therapy also has additional benefits including anti-inflammatory effects beyond the lipid-lowering property, which suggests that this drug has pleiotropic effects. 128 these data support the favorable effects of statins on respiratory diseases. 129 statin therapy should be continued during the covid-19 pandemic if there is no definite contraindication. during the covid-19 pandemic, people with obesity should maintain a heathy lifestyle. regular exercise is essential to maintaining immunity. 130 healthy eating is also crucial for strengthening the immune system and reducing inflammation. 130 people with obesity who experience symptoms such as cough, sputum, fever, or a sudden increase in blood glucose level should consult their physician immediately. the clinical guidelines for the management of obesity-related disorders should be followed closely. health-care providers should make sure that their patients with obesity do not stop taking antiobesity agents, particularly glp1 analogues, or medications for obesity-related disorders such as statin and ace inhibitors or angiotensin receptor blockers, provided there is no contraindication to these patients taking these agents. in conclusion, covid-19 is a global pandemic and may pose considerable health hazard, especially for people with obesity. obesity is a risk factor for poor outcomes of viral infection because of the deleterious effects of obesity on the immune system, which can lead to mortality in people with obesity with covid-19. during the covid-19 pandemic, it is important for people with obesity to maintain a healthy lifestyle, and their medications should be adjusted properly. close monitoring of patients with obesity is required because of the restrictions imposed by the quarantine policies on physical activity and healthy eating. the optimal management strategy for these people warrants further investigation. the authors declare no conflict of interest. study concept and design: sl; acquisition of data: sl and sms; analysis and interpretation of data: sl; drafting of the manuscript: all authors; critical revision of the manuscript: all authors; administrative, technical, or material support: sl and sms; and study supervision: sl. veesler d. structure, function, and antigenicity of the sars-cov-2 spike glycoprotein angiotensin-converting enzyme 2 (ace2) as a sars-cov-2 receptor: molecular mechanisms and potential therapeutic target clinical features of patients infected with 2019 novel coronavirus in wuhan, china characteristics of and important lessons from the coronavirus disease 2019 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a growing body of evidence indicates that obesity is strongly and independently associated with adverse outcomes of covid-19 including death. by combining emerging knowledge of the pathological processes involved in covid-19 with insights into the mechanisms underlying the adverse health consequences of obesity, we present some hypotheses regarding the deleterious impact of obesity on the course of covid-19. these hypotheses are testable and could guide therapeutic and preventive interventions. as obesity is now almost ubiquitous and no vaccine for covid-19 is currently available, even a modest reduction in the impact of obesity on mortality and morbidity from this viral infection could have profound consequences for public health. emerging evidence suggests that people with obesity are at increased risk of mortality from 67 coronavirus disease 2019 (covid-19) but the mechanisms underlying this are poorly understood. an 68 improved understanding of the pathophysiological intersection of covid-19 and obesity should help 69 guide preventive and therapeutic strategies for this vulnerable group. here we summarise existing 70 knowledge regarding the pathophysiology of covid-19 and consider how its various components 71 might be exacerbated by the presence of obesity. we end by suggesting some experiments which 72 could inform public health interventions and/or approaches to therapy. 73 the strong association of obesity with adverse outcomes in covid-19 is real and relatively specific 74 to a subset of viral pneumonias. 75 soon after the emergence of covid-19 there was a flurry of reports from hospitals around the world 76 drawing attention to an apparent excess of obese patients among those ventilated 5, 10, 12, 45, 62 . 77 more recently, preprints have appeared which report much larger and more rigorous 78 epidemiological investigations. opensafely examined 5683 covid-19 deaths in the uk and related 79 these to pre-existing potential risk factors documented in over 17 million electronic health records 80 72 . as in all studies to date, age was the most important pre-existing risk factor, but the effect of 81 obesity was highly significant and graded according to the severity of the obesity. the hazard ratio 82 (adjusted for ethnicity) for death for those with class iii obesity (body mass index (bmi) >40kg/m2) 83 was as high as 2.28 (1.96-2.65). the isaric study of 16,749 covid-19 related admissions to 84 intensive care units in the uk reported a lower hazard ratio of 1.37 (1.16-1.63) associated with 85 clinician-reported obesity 19 . it should be noted, however, that bmi was not reported in this study 86 and reliance on clinical diagnosis is known to seriously underdiagnose obesity 53 . 87 in an analysis of covid-19 mortality in over 300,000 patients with diabetes, obesity was associated 88 with mortality in both type 1 (t1d) and type 2 diabetes (t2d) 36 . taken together with myriad smaller 89 studies it seems increasingly clear that obesity does indeed increase the risk of mortality and of 90 requiring admission to intensive care in people infected with sars-cov-2. in contrast to worse 91 outcomes once an obese person is infected, there is currently no evidence that obesity has a 92 significant impact on the risk of becoming infected by the virus in the first place. 93 is there something about infection with the sars-cov-2 virus that interacts so adversely with the 94 obese state, or does being obese have a similar impact on other forms of viral pneumonia? although 95 obesity has been associated with an increased risk of hospitalisation in seasonal influenza, a study of 96 almost 10,000 cases of seasonal influenza in the usa did not find any evidence of obesity as a risk 97 factor for requiring mechanical ventilation or death 6 . in contrast, it seems clear that during the 2009 98 h1n1 influenza pandemic, which largely spared the partly immune elderly, obesity was a strong risk 99 factor for adverse outcomes 51 . the role of obesity in severity of sars-cov-1 and mers-cov, other 100 pandemic coronavirus infections with poor outcomes, has not been thoroughly examined. the acute 101 respiratory distress syndrome (ards) has some pathophysiological similarities to covid-19 102 pneumonia. while obesity has been reported to increase the risk of developing ards of a variety of 103 aetiologies 32 , it has been reported to be associated with increased survival rates, something that has 104 come to be known as the ards obesity paradox 67 . thus, the association of obesity with worse 105 outcomes in acute lung infection or widespread alveolar damage of other types, appears to be 106 strongest and most consistent with covid-19 and pandemic h1n1 influenza. 107 108 what are obese patients with covid-19 dying from? 109 the majority of covid-19 patients die having required artificial ventilation for hypoxemic respiratory 110 failure due to covid-19 pneumonia 59 . emerging post-mortem histopathology of the covid 19 lung 111 offers insights into the underlying pathophysiology. briefly, there is evidence of diffuse alveolar 112 damage, as in other forms of viral pneumonia, but sometimes this is patchy 2, 48 . what is striking, and 113 shared to a degree with the pathology of pandemic h1n1 influenza 2 , is the extent of pulmonary 114 capillary microangiopathy which is considerable and near universal, at least in some series 9 . 115 complement deposition has also been observed in the endothelium in association with the 116 formation of microthrombi 44 . this suggests that covid-19 may lead to a state of alveolar 117 hypoperfusion due to a microthrombotic pulmonary angiopathy. the frequent finding of elevated 118 levels of fibrin d-dimers in a large proportion of hospitalised patients is consistent with a thrombotic 119 process, as is the frequent occurrence of venous thrombosis and pulmonary emboli during the 120 course of the illness 16, 35 . the clinical characteristics of covid-19 pneumonia are still being defined 121 but in early reports from european centres a substantial proportion of ventilated patients were 122 reported to have preserved pulmonary compliance with well aerated lungs, suggesting that hypoxia 123 is being driven by microvascular dysfunction 29, 30 . reports of ct based lung perfusion imaging 124 supports this 40 . however, a subsequent larger study from the usa described a cohort of patients 125 with respiratory mechanics more in keeping with classical ards [24] . finally, patients who are 126 seriously ill with covid-19 have evidence of high levels of inflammation with high crp and 127 circulating pro-inflammatory cytokines 11 . indeed, it has been suggested that a hyperinflammatory 128 response, occurring downstream of a vigorous activation of either adaptive or innate immunity, or 129 both, may drive the underlying pathophysiological process 47 and il-6 antagonists are being trialled 130 in severely ill patients 65 . 131 obesity is associated with a wide range of adverse health outcomes with diverse underlying 133 pathogenic processes. for some, e.g. sleep apnoea and reflux oesophagitis, the expanded mass of 134 adipose tissue itself is directly and mechanically contributing to the disease. t2d is one of the 135 commonest sequelae of obesity. an increase in circulating insulin levels in both fasting and post-136 prandial state is one of the earliest metabolic disturbances associated with obesity and it is due to 137 impaired insulin action, principally in liver and skeletal muscle 57 . this "insulin resistance" clearly 138 predisposes to developing t2d, which ensues when beta cell compensation fails. 139 the mechanism whereby chronic over-nutrition leads to insulin resistance appears to primarily 140 involve not the expanded adipose tissue itself, but the additional excess nutrient that is stored 141 ectopically in the major insulin responsive tissues, muscle and fat 41 . an alternative hypothesis 142 suggests that adipose tissue inflammation contributes directly to insulin resistance in obesity. 143 inflammation undoubtedly occurs in obesity however it has less compelling underpinning support 144 from human genetics or human pharmacology 52 . 145 146 how might the metabolic state of obesity intersect with and exacerbate pathological mechanisms 147 in covid-19? 148 enhanced production of cytokines. a corollary of storing excess fat in non-adipose tissue is that the 149 adipose tissue has reached or is reaching the limits of its ability to store fat safely. thus, in adipose 150 tissue biopsies from obese, insulin resistant people, one frequently sees an excess of dead and dying 151 adipocytes, often accompanied by an excess of infiltrating macrophages, usually arranged in crown-152 like structures 13 . these macrophages are activated and contribute to the production of a systemic 153 pro-inflammatory state, characterised by increases in circulating levels of cytokines such as tnfα, il6 154 and il1β 46, 66 . lipotoxic damage to other cells such as hepatocytes can also contribute to the 155 enhanced inflammatory state. if increased inflammation contributes to alveolar damage, then this 156 provides an obvious potential route whereby the metabolic risk factors could drive increased 157 mortality. 158 altered adipose tissue hormones adipose tissue expansion not only results in elaboration of 159 inflammatory cytokines, but also changes the profile of secreted hormones. a key signature of 160 insulin resistance is an increase in the ratio of circulating leptin and adiponectin 24 . obesity is 161 associated with higher circulating leptin and lower circulating adiponectin. there is some literature 162 associating high leptin levels with pulmonary inflammation but this is not, as yet, compelling (24, 163 25). there is, however, a growing body of evidence more securely implicating adiponectin as an 164 anti-inflammatory agent 61 . notably, adiponectin-deficient mice develop inflammation of the 165 pulmonary vasculature 63 and are predisposed to experimental acute lung injury 39 suggesting that 166 the hypoadiponectinemia frequently seen in obesity could facilitate an exaggerated inflammatory 167 response directed to pulmonary capillaries. in addition to being lower in obesity and most insulin 168 resistant states it is worth noting that adiponectin levels have been reported to be significantly 169 lower in many of the covid-19 "at risk" groups e.g. male < females 20 and south asians < white 170 europeans 1, 20 . perhaps most interesting is the finding that, at equivalent levels of body fat, black 171 people also tend to have lower levels of adiponectin than white people despite having no more 172 insulin resistance and a lower propensity to store fat ectopically 8 . however, it should be noted 173 adiponectin levels tend to rise after the age of 70 3, 14 , and old age is by far the biggest risk factor for 174 covid-19 mortality. however, it is possible that different causal pathways may mediate the risk of 175 age vs obesity on covid-19 severity. is secreted from adipose tissue, associated with insulin resistance and likely contributes to 197 thrombotic risk in obesity by impairing fibrinolysis 23 . in addition, obesity is associated with increased 198 thromboxane metabolites and mean platelet volume (both validated indices of platelet activation) 199 that normalise with weight loss 15, 18 . notably, obesity is a robust risk factor for the development of 200 thrombocytopenic thrombogenic purpura 69 with one group suggesting increased circulating 201 antibodies to adamts13 in the obese 42, 76 . 202 vasculature the role of the vasculature, particularly the endothelium, in the pathogenesis of 19 has recently been highlighted 34, 64 . in a comprehensive analysis of ace2 (the sars-cov-2 204 receptor) expression in the human vasculature the highest expression was found in the pericytes of 205 heart and brain (but not the lung) with little in endothelial cells 34 . it was proposed that 206 microvascular dysfunction associated with obesity or type 2 diabetes could permit viral passage 207 across the endothelium to infect pericytes, with their dysfunction promoting subsequent endothelial 208 activation and microthrombosis 34 . the effects of diabetes on endothelial barrier function is well 209 established 56 and there is evidence from studies of large animals that endothelial permeability is 210 increased in obesity 27 . 211 dysfunction of the systemic microcirculation is well described in obesity and the metabolic 212 syndrome 68 . while the effects of obesity on the pulmonary circulation are less studied, there is 213 emerging evidence of a pulmonary vascular dysfunction associated with obesity. in a rodent model 214 of obesity pulmonary resistance vessels were resistant to agonist and hypoxia induced 215 vasoconstriction ex vivo compared to lean controls 50 . if the vasoconstrictive response to hypoxia is 216 impaired in the human pulmonary vasculature then this could potentially exacerbate shunting in 217 covid19 pneumonia, thus contributing to hypoxia. 218 the key functional unit of the lung is the alveolar-capillary unit. key cells include type 1 219 pneumocytes (at1) separated from capillary endothelial cells by a fused basement membrane and 220 the less numerous type 2 pneumocytes (at2) that produce surfactant and serve as alveolar 221 progenitors. ace2 is the proposed receptor for sars-cov-2 and in the alveolus it is expressed 222 predominantly (if not solely) by at2 34 . critical to gas exchange and pulmonary function, the alveolar 223 capillary unit is the primary site of injury in covid-19. understanding how obesity interacts with pre-224 morbid alveolar function and injury may guide pre-emptive therapeutic intervention. 225 circulating surfactant proteins a and d have been shown to be increased in patients with obesity 226 and type 2 diabetes 21, 43 , assuming these proteins are expressed only in the lung and secreted to 227 the apical membrane, and this suggests that obesity may affect the integrity of the alveolus. the 228 science of ectopic fat has largely focused on the liver, muscle and heart, where a large body of 229 evidence clearly describes the adverse consequences to these tissues of a chronic excess of 230 intracellular lipid. more recently, however, work is emerging suggesting that, in states of over-231 nutrition, ectopic lipid can appear in cells of the pulmonary alveolus resulting in ultrastructural 232 abnormalities and altered surfactant production 25 . genetic enhancement of endogenous lipid 233 synthesis specifically in mouse at2 cells results in alveolar inflammation 54 . remarkably, at2 cells of 234 aged mice were noted to demonstrate similar gene expression changes to these mice and also 235 exhibited increased lipid content 4 suggesting that "fatty lung" could potentially be a common causal 236 pathway whereby both obesity and age worsen covid-19 pathology. similarly, genetic deletion of 237 the lipid sensor liver x receptor (lxr) resulted in accumulation of lipid in type 2 pneumocytes and, 238 subsequently, pulmonary inflammation and foam cell accumulation 17 . 239 insulin resistance, not fat mass, is key to the link between obesity and poor covid outcomes 241 if true, this is important, as even short-term low calorie diets can improve insulin sensitivity within 242 days 38 . human genetics should ultimately come to our aid here as meta-analysis of genome wide 243 snp data from covid victims throughout the world can be undertaken to examine whether the 244 genetic risk scores for insulin resistance are better predictors of outcome than those for obesity per 245 se. in the meantime, animal models of sars infection might be able to provide some early 246 information through the examination of effects of insulin-lowering and insulin-sensitising 247 medications. some commentators have argued that as it is difficult for obese patients to attain 248 normal weight then there is not much that can be done given the rapid spread of the covid-19 249 pandemic. however, if improving insulin sensitivity reduces risk then even a modest amount of 250 caloric restriction, combined with physical activity and perhaps an insulin sensitising/lowering drug 251 such as metformin, may provide a way of reducing risk of death for the large number of at risk obese 252 people 253 sars-cov-2 causes pneumonia by first entering the at2 through ace2 which is abundantly 263 expressed on their surface. these cells are lipid rich, storing polar lipids in lamellar bodies, and their 264 structure, and possibly function, are influenced by diet and obesity, at least in animal models 25, 55, 75 . 265 experiments should be undertaken to examine the effects of lipid content of cells on ace2 266 expression, viral uptake, replication and release. some viruses e.g. hepatitis c seems entirely reliant 267 on intracellular fat droplets to facilitate its movement around a cell 49 . viral infections of cells 268 frequently lead to a rapid switch from oxidative phosphorylation to aerobic glycolysis, the so called 269 warburg effect 60 . ectopic lipid in cells elsewhere is known to be associated with metabolic 270 inflexibility 26 , the inability to shift rapidly between fat and carbohydrate metabolism. might at2 271 cells that have excess lipid be less able to switch to aerobic glycolysis and thus be more prone to cell 272 death during viral infection? indeed, in mice, diet-induced obesity is associated with downregulation 273 of fatty acid synthase (fasn) in lung and genetic deletion of fasn in at2 cells impairs induction of 274 glycolysis in response to hyperoxic stress in vitro and predisposes to acute lung injury in mice 55 . 275 though unproven, it is likely that ectopic lipid in lung will start to reduce quickly after people go into 276 negative energy balance, so that modest changes in diet and exercise may be have benefit. 277 in summary, we have applied insights into the pathophysiology of the adverse consequences of 279 obesity and emerging evidence regarding the pathological mechanisms in covid-19 to suggest 280 possible routes whereby obesity can exacerbate the tissue damage associated with infection by the 281 sars-cov-2 virus. these hypotheses suggest several tractable experiments in cells, animals and 282 humans, some of which we are undertaking and which we encourage others to pursue. obesity is a 283 notoriously difficult condition to "cure" and this may explain why widespread public health 284 messaging about weight loss in the obese as a preventive measure to reduce covid-19 mortality has 285 not been vigorously pursued. if obesity is exerting its effects on covid-19 outcome through its 286 metabolic sequelae, such as insulin resistance, then those abnormalities start to improve very 287 rapidly when energy intake drops below energy expenditure. in addition to its effects on energy 288 expenditure, regular physical activity, even of moderate intensity and duration can also improve 289 insulin sensitivity and lower circulating insulin levels 37 . the potential implications for unintended 290 adverse consequences of intense covid-19 "lockdown" strategies that limit opportunities for 291 exercise are obvious. 292 given how rapidly large trials of a wide variety of pharmacological agents in covid-19 are currently 293 being undertaken (some with a rather tenuous rationale 22 ) it should be possible to consider 294 undertaking trials of simple interventions in people with obesity either before or immediately after 295 the onset of covid-19 symptoms. these could involve diet and exercise intentions that do not aim 296 for unrealistic amounts of weight loss but would be designed to ameliorate insulin resistance. these 297 interventions could be supplemented by drugs that assist in modest weight loss and lower 298 circulating insulin, such as metformin or sglt2 inhibitors, or agents that improve insulin sensitivity, 299 reduce ectopic lipid and increase circulating adiponectin, such as pioglitazone. such approaches 300 would also be applicable to t2d, another condition which predisposes to increased mortality from 301 36, 72 . in the majority of t2d cases, obesity precedes and contributes to the 302 development of diabetes through inducing compensatory hyperinsulinemia, necessitated by insulin 303 resistance, which eventually exhausts the ability of genetically vulnerable pancreatic beta cells to 304 maintain insulin production. there is evidence that, in both t1d and t2d, the level of glycaemia is 305 related to covid-19 outcomes 36, 77 . we urgently need to know if the intensification of glycaemic 306 control using an approach which sensitises patients to insulin would provide benefits to the covid-307 19 infected t2d patient that are greater than those achieve by approaches that increase levels of 308 circulating insulin, either through exogenous injection or the stimulation of endogenous secretion. 309 obesity affects a very large proportion of the population of most developed and developing 310 countries. understanding the nature of the link between chronic positive caloric imbalance and 311 covid-19 pathology could provide novel avenues to reduce the death toll produced by this 312 dangerous new viral infection. funding agencies will need to foster the interdisciplinary approaches 313 that will be required to respond to this new biomedical challenge which lies at the intersection 314 between traditional disciplines. 315 obesity is a disorder of energy balance that ensues when energy intake exceeds expenditure. 552 adipose tissue expansion occurs to safely store excess energy safely in triglyceride rich lipid droplets. 553 this process is associated with adipose tissue inflammation and elaboration of pro-inflammatory 554 cytokines, increased components of the complement system and altered adipose tissue hormones. 555 1) increased inflammatory cytokines are secreted into the systemic circulation and can act on the 556 alveolar capillary unit to potentiate the inflammatory response to sars-cov-2 infection. 2) adipose 557 tissue expansion is associated with a reduction in adiponectin secretion from the adipose tissue that 558 is that at least partly driven by systemic insulin resistance. mouse studies suggest adiponectin is 559 abundant in the pulmonary endothelium in the healthy lung and adiponectin deficiency results in 560 pulmonary vascular inflammation and pre-disposes to experimental lung injury. 3) increases in 561 circulating complement components elaborated from adipose tissue occur in expanded adipose and 562 in association with insulin resistance and could pre-dispose to complement activation and 563 subsequent thrombotic microangiopathy. when the capacity for adipose tissue to expand is 564 exceeded lipid is deposited in other organs. lipid deposition in skeletal muscle and liver likely plays a 565 causal role in the development of insulin resistance and hyperinsulinemia. 4) systemic insulin 566 resistance is associated with endothelial dysfunction that may pre-dispose to thrombosis and 567 contribute to lung injury via vascular inflammation and enhanced endothelial permeability. 5) insulin 568 resistance is robustly associated with increased plasminogen activator inhibitor-1 (pai-1) which 569 impairs fibrinolysis and may contribute to risk of thrombosis in covid-19. 6). finally, ectopic lipid 570 may actually be directly deposited in type 2 pneumocytes pre-disposing to lung injury in sars-cov-2 571 infection. 572 obesity is associated with increased covid-19 related mortality. lockhart and o'rahilly review the pathophysiological mechanisms that may underlie this link and converge on a set of testable hypotheses to guide investigation of the effects of obesity on covid-19. adipose tissue metabolites 326 and insulin resistance in nondiabetic asian indian men vanstapel pulmonary vascular endothelialitis, 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complement system in adipose tissue-related inflammation opensafely: factors associated with covid-19-531 related hospital death in the linked electronic health records of 17 million adult nhs patients. 532 medrxiv complement factor 3 is associated with 535 insulin resistance and with incident type 2 diabetes over a 7-year follow-up period: the codam 536 study longitudinal associations of the alternative and terminal pathways of 539 complement activation with adiposity: the codam study alveolar-541 capillary adaptation to chronic hypoxia in the fatty lung weight loss reduces anti-adamts13 autoantibodies 544 and improves inflammatory and coagulative parameters in obese patients association of blood glucose control and outcomes in patients with covid-19 and pre lerman, l. o., and lerman, a. (2007) . early experimental obesity is associated with coronary 400 endothelial dysfunction and oxidative stress. am j physiol heart circ physiol 292, h904-911. 401 28. gao, t., hu, m., zhang, x., li, h., zhu, l., liu, h., dong, q., zhang, z., wang, z., hu, y., et al. 402 (2020). highly pathogenic coronavirus n protein aggravates lung injury by masp-2-mediated 403 complement over-activation. medrxiv, 2020 over-activation. medrxiv, .2003 over-activation. medrxiv, .2029 29. gattinoni, l., chiumello, d., caironi, p., busana, m., romitti, f., brazzi, l., and camporota, l. key: cord-333368-kjrk8nn9 authors: huizinga, gabrielle p; singer, benjamin h; singer, kanakadurga title: the collision of meta-inflammation and sars-cov-2 pandemic infection date: 2020-09-03 journal: endocrinology doi: 10.1210/endocr/bqaa154 sha: doc_id: 333368 cord_uid: kjrk8nn9 the covid-19 pandemic has forced us to consider the physiologic role of obesity in the response to infectious disease. there are significant disparities in morbidity and mortality by sex, weight and diabetes status. numerous endocrine changes might drive these varied responses to sars-cov-2 infection including hormone and immune mediators, hyperglycemia, leukocyte responses, cytokine secretion, and tissue dysfunction. studies of patients with severe covid-19 disease have revealed the importance of innate immune responses in driving immunopathology and tissue injury. in this review we will describe the impact of the metabolically induced inflammation (meta-inflammation) that characterizes obesity on innate immunity. we consider that obesity-driven dysregulation of innate immune responses may drive organ injury in development of severe covid-19 and impair viral clearance. the chronic obesity-induced inflammation characterized by increased tissue and circulating myeloid cells has been termed metabolic inflammation or meta-inflammation. the coronavirus disease 2019 pandemic has highlighted the endocrine manifestations of obesity and impact of diabetes and obesity on immune responses to infectious disease. obesity and metabolic syndrome have been identified as risk factors for severe manifestations of sars-cov-2 infection 1, 2 . prior studies of the epidemiology of sepsis, the acute respiratory distress syndrome (ards), and other acute illnesses have raised the question of whether obesity is associated with lower mortality in critical illness -the "obesity paradox" 3, 4 . however, the covid-19 pandemic has forced reconsideration of the impact of obesity and diabetes on disease outcomes. while obesity and diabetes may complicate the delivery of supportive care in critical illness regardless of the underlying disease, lessons learned from the interaction of obesity with other systemic inflammatory syndromes suggest that obesity modifies biologic factors related to sars-cov-2 infection and the covid-19 syndrome. covid-19 was first reported in wuhan, china in december 2019 and first made its appearance in the united states in washington state on january 31, 2020. outbreaks quickly spread throughout washington and california before spreading to the rest of the us. obesity was not studied in the early sars-cov-2 studies coming from wuhan, china, likely because so little of the population is obese. however, pre-existing type 2 diabetes was demonstrated to be a risk factor for illness severity 5 . in the us, obesity, hypertension, and diabetes are commonly reported among the most common comorbidities for patients hospitalized with covid-19 across several metropolitan disease outbreaks 2,6-8 . when considering the obesity epidemic in the us, this is not surprising, as approximately 35% of men and 40% of women in the united states are obese by body mass index (bmi > 30 kg/m2) 9, 10 . however, obesity is independently associated with odds of hospital or intensive care admission among patients presenting for medical care 1, 2 . several studies suggest that a c c e p t e d m a n u s c r i p t 4 obesity is an independent predictor of hypoxic respiratory failure 11, 12 and death 13,14 among hospitalized patients, even among young patients with fewer comorbidities 15, 16 . decisions about hospital admission, and thus the characteristics of hospitalized patients, may be confounded by the expectation that obese patients require closer monitoring. population-based estimates of covid-19 mortality, however, also show a 2.6-fold increase in risk for patients with bmi > 40 17 . prior meta-analyses of both ards and sepsis have found either no harm or reduction in mortality among obese adults 18, 19 . however, severity of illness and organ damage has been demonstrated to increase based on obesity in pediatric patients [20] [21] [22] [23] . while changes in critical care practice during a pandemic could explain differences in mortality or icu admission, the association of obesity with physiologically defined hypoxic respiratory failure suggests a biologic interaction of obesity with sars-cov-2 infection. obesity as a risk factor for severe infectious disease is not a new concept and is not limited to coronavirus infections. during the 2009 influenza a/h1n1 pandemic, it was noted that obese patients were more likely to experience more severe disease requiring hospitalization than normal weight patients 24 . additionally, even when both groups were vaccinated, obese individuals were more likely to become infected with the influenza virus 25 . along with viral infections, obesity alters the course of bacterial infections 26 . all of this clinical evidence emphasizes the importance of further understanding the mechanisms by which obesity influences immune responses. the current sars-cov-2 pandemic has highlighted the increased need for research to understand the mechanisms behind severity of pandemic infection in different risk groups. a c c e p t e d m a n u s c r i p t 5 with the prevalence of obesity rising without an end in sight, it is important to understand the endocrine, metabolic, and inflammatory shifts that occur in obesity may drive increased pathogendriven morbidity and mortality. a c c e p t e d m a n u s c r i p t 6 pro-inflammatory circulating monocyte and macrophage populations are associated with a number of chronic diseases, including obesity 32 . a striking feature of obesity in both clinical and animal studies is the chronic low-grade inflammation tied with metabolic diseases, meta-inflammation 33 . increased bmi correlates with an increase of several cytokines including il-6, il-8, il-1, and tnf- and obesity also correlates with an increase in chemokines such as ccl14 34, 35 and mcp-1 36 furthering the overall inflammatory tone. hyperglycemia alone may lead to significant changes in macrophage function and inflammation. in patients with diabetes, increased glucose levels and glycolysis promoted sars-cov-2 replication in monocytes via ros/hif pathway activation leading to secondary t-cell dysfunction 37 . patients with well controlled blood glucose levels were less likely to experience serious complications and death from covid-19 compared to diabetic patients with poorly controlled blood glucose levels. the wellcontrolled patients had lower il-6, c reactive protein, and ldh levels, as well as only a 1.1% mortality rate, which is significantly lower than the 11% mortality rate seen in the poorly controlled group 5 . this association of diabetes diagnosis with covid-19 mortality is also observed on the population level as well 17 . while one cannot directly say the hyperglycemia causes this enhanced mortality, there is abundant evidence that obesity leads to long-term reprogramming of the innate immune system. macrophages from obese animals and humans have been described as metabolically active, m1 polarized, and pro-inflammatory with both regulatory and detrimental activity [38] [39] [40] . these macrophages produce cytokines, chemokines, reactive oxygen species, and factors regulating fibrosis and metabolism. overall, our understanding is that these metabolic macrophages have a similar profile to those stimulated with lipopolysaccharide (lps), an abundant bacterial derived a c c e p t e d m a n u s c r i p t 7 molecular pattern molecule and ligand of the toll-like receptor 4 (tlr4). more recently it has become clear that while the inflammatory phenotype of these macrophages is closest to what is seen with lps stimulation, traditional m1 macrophages, the added activation by fatty acids creates a unique phenotype that has characterized these obesity myeloid cells as metabolically active macrophages 41 . while changes to macrophage phenotype in obesity were originally characterized in the adipose tissue 36, 42 , it is now evident that obesity has significant effects on hematopoiesis, circulating monocytes, and macrophages in multiple organs. elevated bmi and obesity has been shown to enhance hematopoiesis and expand myeloid cell production 43,44 but it has also been shown to impair immune responses in a tlr4 dependent manner 45 . high fat diet increases the number of monocytes in circulation and expands bone marrow macrophages, neutrophils and their progenitors 43 . expansion of these progenitors leads to increased macrophage production, but also skews the resulting macrophage population to a pro-inflammatory phenotype 43, 44, 46 . during obesity there is an overall increase in chemokines, which play a role in metabolic inflammation by recruiting monocytes into adipose tissue. additionally, during obesity and type 2 diabetes (t2d), there is an increase in circulation of free fatty acids (ffas), including palmitate (pa). pa induces ccl4 release from monocytes and macrophages by interacting with tlr4 47 . obese individuals, regardless of diabetes status, also have higher circulating levels of lps 48,49 which binds to tlr4. this binding increases the production of the chemokine ccl2 in monocytes and macrophages 50 . this further leads to enhanced tissue macrophages that have the potential to lead to dysfunctional cytokine production and tissue damage if triggered. a c c e p t e d m a n u s c r i p t 8 while the phenotype of these macrophages in driving impaired metabolism is well described there are several other implications of these metabolically activated macrophages 51 . in pulmonary viral infections such as influenza, macrophages from obese mice exhibit enhanced and likely injurious pro-inflammatory cytokine production but impaired production of antiviral type-i interferons 52, 53 . obese mice suffer increased interstitial inflammation, alveolar permeability, and lung injury even in the absence of increased viral load 54 . chronic systemic inflammation is accompanied by impaired induction of pathogen-induced and lung-specific responses to influenza across a variety of obesity models 55 . pro-inflammatory activation of macrophages in obesity impairs their function in other domains, as well. for example, in obese diabetic mice, macrophages recruited to diabetic wounds as a result of epigenetic alterations have a pro-inflammatory phenotype and have elevated levels of prostaglandin e 2 (pge 2 ) production [56] [57] [58] [59] [60] . pge 2 signaling can impair macrophage innate immune functions as well as alter production of pro-inflammatory cytokines 61 . this activated state causes delayed wound healing but may also have further implications in responses to infection, which is a major physiologic function of macrophages. pge 2 signaling instructs macrophages to secrete il-10 and influences naïve t cells to shift from a th1 to a th2 phenotype. this th2 phenotype causes a decreased ability to clear intracellular pathogens, such as viruses 62 . immune system activation in obesity is not confined to adipose tissue or organ dysfunction related to metabolic disease, such as the liver or vasculature, but also has a negative effect on the immune system on the whole, leading to an increase risk of infection 63 . it is well recognized clinically that diabetes negatively impacts the body's response to infection. hyperglycemia stemming from t2d caused by obesity has proven to reduce control of invading pathogens 64 even more broadly in sepsis models, obese animals have been seen to have more severe organ damage and worsened survival 76,77 . a c c e p t e d m a n u s c r i p t 10 even a short-term high fat diet can impact the reaction to a bacterial infection. mice fed a high fat diet for 16 days and then orally challenged with listeria monocytogenes had reduced inflammatory responses, and as a result increased bacterial load and increased numbers of goblet cells 78 . obese individuals are not only susceptible to severe bacterial infections, but also severe viral infections . obesity has been shown to be a risk factor for human papilloma virus incident infection, however obesity was not associated with how long the infection persisted 79 . additionally, in the 2009 h1n1 influenza pandemic, obesity was a major risk factor for severe infection and death 24 . adults aged 20 years or older who died from h1n1 infection were more likely to be obese or morbidly obese 80 . when lean and obese mice are infected with h1n1, although the lungs exhibit the same viral titer, the obese mice lost more weight and experienced more pulmonary pathology than lean mice. additionally, the virus spread to the alveolar epithelial cells in the obese mice. the increased spreading of the virus in obese mice combined with the reduction in local production of several pro-inflammatory cytokines (while still increased in circulation) likely contributed to the increased murine morbidity and mortality due to infection 81 . the same illness severity and poor responsiveness to treatment with obesity has been demonstrated in seasonal influenza infections 82 . it has been widely speculated that higher ace-2 expression in adipose tissue may result in higher total body sars-cov-2 viral load in obese individuals. early reports have not demonstrated a correlation among viral load and obesity or initial viral load and disease severity 83 . in seasonal and pandemic influenza, however, obese individuals may be more susceptible to severe viral respiratory disease even if they mount a serologic response to vaccination 25 a c c e p t e d m a n u s c r i p t 11 along with possible impairments in pathogen clearance, obese hosts are more likely to experience the breakdown of respiratory epithelium during a pulmonary infection, which leads to increased fluid in the airway space. this allows the pathogen to have the opportunity to more easily spread throughout the body and leaves the host with reduced lung function 63 . the sars-cov-2 virus, like other members of the betacoronavirus subfamily 85 , enters mammalian cells through the interaction of the viral envelope spike glycoprotein and angiotensin converting enzyme 2 (ace-2) on host cells 86 . ace-2 is expressed in many human tissues, including not only the lungs but also kidney, brain, adipose tissue and small intestine, raising the question of which symptoms of covid-19 are due to direct viral effects versus systemic immune responses, especially in severe disease 87 . tropism of sars-cov-2 for extrapulmonary tissues is confirmed by detection of viral rna from samples outside the respiratory tract 88 . ace-2 is upregulated in adipocytes in obese and diabetic patients, which allows the virus to target and replicate in adipose tissue and has led to speculation that adipose tissue can serve as a reservoir of sars-cov-2, potentially worsening disease severity in obese individuals [89] [90] [91] . a correlation between respiratory tract viral load and obesity, however, has not been confirmed 83 . intestinal involvement in sars-cov-2 infection may interact with obesity associated metainflammation. while meta-inflammation in obesity is a systemic, multifactorial process 92 , the gut microbiome is known to have a bidirectional relationship to meta-inflammation 93 influencing intestinal inflammation 94 . sars-cov-2 infection has been associated with shifts in gut microbiota to more pathogenic taxa, as have other states of critical illness 95 . these shifts may encourage a state of a c c e p t e d m a n u s c r i p t 12 systemic inflammation. both dysbiosis and the direct enteropathic effect of sars-cov-2 infection may promote gut barrier permeability and increase metabolic endotoxemia, a potential mediator of metabolic disease and meta-inflammation in obesity 96 . establishing a connection between gut dysfunction and meta-inflammation in covid-19 survivors will require long-term studies. while considerable speculation has focused on how ace-2 levels are driven by either polymorphisms, comorbidity, or environmental factors, other genetic factors may also play a role in susceptibility to severe covid-19 disease, as well 97 . the first genome-wide association study of covid-19 severity identified two loci -one containing the abo blood group locus and another at 3p21.31 98 . the latter locus contains several chemokine genes, the expression of which may plausibly be altered in meta-inflammation. an ongoing multinational effort continues to examine how host genetics may inform susceptibility to severe covid19 and may reveal factors that interact with gene expression obesity 99 . while genetic factors explain a small part of the risk for developing diabetes, diabetes risk genes typically do not include those related to antiviral immunity 100 , emphasizing that susceptibility to sars-cov-2 infection or development of severe covid19 disease is likely due to environmental exposure and pathophysiology that develops through the life course, rather than a common predisposing genotype. in addition to obesity and comorbidity, male sex confers a significantly increased risk of severe covid-19 disease and death 14 . differences in myeloid inflammation among males and females may play a protective role in the immunopathology of covid-19, especially in the setting of obesity. a c c e p t e d m a n u s c r i p t 13 not all obese individuals are at risk for metabolic and cardiovascular disease 102 and not all obese develop obesity induced inflammation to the same degree 103 . increased androgen concentration in males is also thought to lead to increased il-10 production when peripheral blood mononuclear cells are stimulated by viral antigens, leading to a delayed and diminished pro-inflammatory response which may also explain disease severity 104 . additionally, males tend to have increased levels of proinflammatory cytokines and chemokines after stimulation with lps intraperitoneally in vivo and in in vitro assays 105, 106 . hence, this difference by sex and due to sex hormones could lead to a possible increased cytokine storm in males with obesity 107 , and explain the pathologic response and enhanced morbidity described clinically. pre-menopausal females are relatively protected from obesity induced inflammation, macrophage activation, and expansion of myeloid progenitors and are relatively protected from metabolic and cardiovascular disease 108 . in pre-clinical models, females are protected from meta-inflammation [108] [109] [110] [111] . one explanation for this is that females generally handle the expansion of adipocytes with resident macrophage proliferation without recruitment of pro-inflammatory macrophages 109 . this finding that all macrophages are not the same in responsiveness to obesity but that the overall trend is pro-inflammatory in nature requires further investigation into the overall macrophage phenotype with obesity. in the context of infection though, those with pro-inflammatory macrophages can produce an enhanced cytokine environment leading to severity of illness in obese individuals via both systemic and local lung effects 112, 113 . while the interaction of sex and diet induced obesity has been most elucidated in the setting of innate immune cell populations, sex hormone receptors are present on cells of the adaptive immune system as well, and sexual dimorphism in autoimmunity and humoral responses has been noted for a c c e p t e d m a n u s c r i p t 14 decades 114 . these differences may also be critical in favoring antiviral immunity in females. of particular note, female mice expand the population of regulatory t-cells significantly compared to male mice in obesity 115 . this cell population is noted to be deficient in obese male mice during influenza infection 54 and may play a role in limiting lung injury in the setting of viral infection. individuals of all ages are at risk for obesity, but it is not clear if weight status influences what has been seen with age related risk for covid severity. of patients aged 19-64 years admitted to the hospital, those with co-morbidities caused by high bmi were more likely to be admitted to the icu 63 and this is true regardless of sex 10 . as humans age, the immune system changes 116 , with a decreased number of lymphocytes, which are important cells for fighting viruses. this has proved to be a significant disadvantage during past epidemics, such as sars 117 . while elderly individuals are at increased risk for severe covid-19, the obesity epidemic is shifting to the most targeted demographic to a younger age group. younger covid patients are likely to have a higher bmi then older patients while this same trend did not exist in non-covid admissions 118 . age related changes in metabolic inflammation are still being understood regardless of infection 119 and the impact of this on covid-19 needs to be further examined. on the other extreme, young children have fared better than adults during this pandemic. many viruses, including respiratory syncytial virus and influenza virus, infect children at particularly high rates compared to adults aged 30-65. however, children appear to be less susceptible to sars, mers, and sars-cov-2 infection 120 . additionally, few children present with common co-morbidities seen in adults, such as hypertension, t2d, cancers, and pulmonary diseases. the absence of these diseases may allow children to only have a mild case of the virus 122 . more recently some children a c c e p t e d m a n u s c r i p t 15 who have recovered from sars-cov-2 infection are presenting with post-infectious cytokine release syndrome, indicative by a fever, gi symptoms, and a rash. consistent with early life metainflammation with obesity it appears that obese children are at higher risk for severe disease 123 . does hyperglycemia worsen covid-19 or does covid-19 lead to immune pancreatic damage leading to hyperglycemia? covid-19 patients have been found to have elevated blood sugars during hospitalization and those with uncontrolled diabetes had a higher mortality 124 . however, sars-cov-2 virus can also damage the pancreas by infecting the  and  cells, which function to regulate blood sugar levels. in severe covid-19 cases, 17% of patients were diagnosed with pancreatic injury, compared to only 1-2% in non-severe cases 125 . one possible explanation is that the virus can also increase pro-inflammatory cytokines that destroy these cells. this could possibly lead to an autoimmune disease and development of type 1 diabetes (t1d) 126 . prior studies have demonstrated that sars coronavirus itself can directly damage islets 127 , further research will be needed to see if t1d or beta cell failures were caused by covid-19 and if this has happened to other individuals 128 . given ace-2 expression in the pancreas it has been hypothesized that this may be a mechanism for pancreatic damage specifically in sars-cov2 infection 127 . obesity is a significant risk factor for severe covid-19 illness. patients with obesity and metabolic disease frequently experience a state of low-grade chronic meta-inflammation. prior studies of vaccine efficacy and response to viral and bacterial infection show that 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systematic review and meta-analysis clinical features, and disease severity in patients with coronavirus disease 2019 (covid-19) in a children's hospital in glycemic characteristics and clinical outcomes of covid-19 patients hospitalized in the united states ace2 expression in pancreas may cause pancreatic damage after sars-cov-2 infection diabetic ketoacidosis precipitated by covid-19 in a patient with newly diagnosed diabetes mellitus binding of sars coronavirus to its receptor damages islets and causes acute diabetes new-onset diabetes in covid-19 remdesivir for the treatment of covid-19 -preliminary report remdesivir in adults with severe covid-19: a randomised, doubleblind, placebo-controlled, multicentre trial a c c e p t e d m a n u s c r i p t 22 a c c e p t e d m a n u s c r i p t a c c e p t e d m a n u s c r i p t 25 key: cord-300991-ipy24zxp authors: khan, amira sayed; hichami, aziz; khan, naim akhtar title: obesity and covid-19: oro-naso-sensory perception date: 2020-07-08 journal: j clin med doi: 10.3390/jcm9072158 sha: doc_id: 300991 cord_uid: ipy24zxp through a recent upsurge of severe acute respiratory syndrome coronavirus-2 (sars-cov-2) pandemic, the clinical assessment of most of the coronavirus disease 19 (covid-19) patients clearly presents a health condition with the loss of oro-naso-sensory (ons) perception, responsible for the detection of flavor and savor. these changes include anosmia and dysgeusia. in some cases, these clinical manifestations appear even before the general flu-like symptoms, e.g., sore throat, thoracic oppression and fever. there is no direct report available on the loss of these chemical senses in obese covid-19 patients. interestingly, obesity has been shown to be associated with low ons cues. these alterations in obese subjects are due to obesity-induced altered expression of olfacto-taste receptors. besides, obesity may further aggravate the sars-cov-2 infection, as this pathology is associated with a high degree of inflammation/immunosuppression and reduced protection against viral infections. hence, obesity represents a great risk factor for sars-cov-2 infection, as it may hide the viral-associated altered ons symptoms, thus leading to a high mortality rate in these subjects. in the month of december 2019, there was an uprising of pneumonia, marked with respiratory distress, among the residents of wuhan district, located in the north-east of china [1] . the virus responsible for this health disaster was identified as severe acute respiratory syndrome coronavirus-2 (sars-cov-2) which belonged to the single-stranded enveloped rna viruses, and the disease was termed as coronavirus disease 2019 (covid-19) [2] . it is surprising that in the beginning of the pandemic, most of the covid-19 patients in wuhan (china) had some primary health problems, including obesity [1] . a recent cohort, conducted in 12 hospitals of the new york state on covid-19 patients, has proposed that there were 41% obese patients, admitted between march 1, 2020 and april 4, 2020 [3] . the incidence of obesity is increasing steadily in all the corners of the world, with 650 million clinically ill subjects requiring either a surgical or medical treatment [4] . the management of obesity has become a challenging task because this pathology is a favorable ground for several chronic diseases, including cardiovascular complications, type-2 diabetes mellitus, cancer, atherosclerosis, arthrosis and renal dysfunction, and respiratory tract infections (rti) in virus-affected patients [5] [6] [7] . the rti are the main physiological targets in covid-19 illness [1] . we would like to recall that during 2009 influenza pandemic, obesity was associated with reduced pulmonary immune defenses against the virus [8] . indeed, obese subjects were not only more prone to infection with the influenza (h1n1) the virus [8] . indeed, obese subjects were not only more prone to infection with the influenza (h1n1) virus, but also developed post-infection severity of illness [9] . an increase in adiposity has been shown to alter the integrity of respiratory epithelium, which might lead to dysfunctional airway fluxes [10] . due to high weight load with excessive pressure on belly and thorax, obesity will contribute to reduced pulmonary gas exchange capacities, such as forced expiratory volume (fev) and forced vital capacity (fvc) . the experiments conducted on mice have suggested that obesity is associated with high lung permeability [11] . epidemiological data confirm that there is an increased rate of pneumonia and rti in covid-19 obese patients [12] . in fact, the first report on rti in obese subjects was published by a french team wherein 47% of covid-19 patients were found to be obese with a high degree (nearly 90%) of artificial ventilation [13] . the marked inflammation leading to immunosuppression in obesity seems to favor viral infections [14] [15] [16] . sheridan et al. [17] observed that high body mass index (bmi) was associated with a high decline in influenza antibody titers and decreased cd8 + t-cell activation after 12 months postvaccination. as far as sars-cov-2 infection is concerned, tan et al. [18] assessed immunological alterations in covid-19 patients, wherein they noted an overall decline in cd4 + t-cells, cd8 + t-cells, b cells and natural killer (nk) cells. moreover, the number of immunosuppressive t-regulatory, treg (cd4 + cd25 + foxp3 + ) cells and concentrations of il-6, il-10, and c-reactive protein (crp) were upregulated in patients with severe covid-19 [18] , suggesting that sars-cov-2 infection may lead to "over-immunosuppression" in the case of obesity ( figure 1 ). the figure shows the immunosuppression in obese subjects. the adipose tissue of the obese is highly inflamed and, consequently, releases a number of cytokines, particularly il-6 and tnf-α. whose secretion is further potentiated by leptin. the lipopolysaccharide (lps)-triggered endotoxemia further aggravates inflammatory condition by inducing the release of il-6 and tnf-α from macrophages via tlr4 activation. obesity is also marked with high production of il-10, which decreases the function of dendritic cells. the prolonged inflammation will lead to immunosuppression that may favor the viral infection. severe acute respiratory syndrome coronavirus-2 (sars-cov-2) has also been shown to induce immunosuppression. once installed, sars-cov-2 will aggravate the obesity-induced lung dysfunctions. (+) and (−) show, respectively, stimulatory and inhibitory actions. since dendritic cells (dcs) are the key players in the regulation of th1/th2 dichotomy and t-cell tolerance, their importance to trigger an anti-viral response has been considered primordial [19] . o'shea et al. [20] have demonstrated that obesity impacts the functions of these cells to trigger appropriate t-cell responses. this interesting report further showed that not only the number of circulating dcs were significantly lower in obese participants than lean subjects, but also in vitro activated-dcs from obese participants expressed less cd83 (a dcs maturation marker) and also produced, in high quantities, the il-10, an immunosuppressive cytokine [21] . the il-10, in turn, has the adipose tissue of the obese is highly inflamed and, consequently, releases a number of cytokines, particularly il-6 and tnf-α. whose secretion is further potentiated by leptin. the lipopolysaccharide (lps)-triggered endotoxemia further aggravates inflammatory condition by inducing the release of il-6 and tnf-α from macrophages via tlr4 activation. obesity is also marked with high production of il-10, which decreases the function of dendritic cells. the prolonged inflammation will lead to immunosuppression that may favor the viral infection. severe acute respiratory syndrome coronavirus-2 (sars-cov-2) has also been shown to induce immunosuppression. once installed, sars-cov-2 will aggravate the obesity-induced lung dysfunctions. (+) and (−) show, respectively, stimulatory and inhibitory actions. since dendritic cells (dcs) are the key players in the regulation of th1/th2 dichotomy and t-cell tolerance, their importance to trigger an anti-viral response has been considered primordial [19] . o'shea et al. [20] have demonstrated that obesity impacts the functions of these cells to trigger appropriate t-cell responses. this interesting report further showed that not only the number of circulating dcs were significantly lower in obese participants than lean subjects, but also in vitro activated-dcs from obese participants expressed less cd83 (a dcs maturation marker) and also produced, in high quantities, the il-10, an immunosuppressive cytokine [21] . the il-10, in turn, has been shown to inhibit the ability of dcs to stimulate cd4 + t-cells and to downregulate mhc-ii, cd86 (a co-stimulatory signal protein), and antigen presentation to cd4 + t-cells [21] . obesity is also marked with high concentrations of leptin, which is also known to trigger the production of il-6 and tnf-α from adipose tissues ( figure 1 ) and to increase the risk for viral infection. indeed, tnf-α administration in mice favors the induction of an experimental autoimmune disease [22] . the adipose tissue is the main source of circulating tnf-α in obesity, as its synthesis is increased by adipocytes in obese subjects and a weight-loss results in its low concentrations [23] . in obesity, leptin further decreases the secretion of adiponectin, an anti-inflammatory adipokine. in fact, the adipose tissue of obese subjects is an inflammatory "hot spot" that is also infiltrated by macrophages [24] . besides, obesity is also marked with a change in gut microbiota that leaks the entry of lipopolysaccharide (lps) into blood circulation. the lps is directly responsible for endotoxemia, so-called, "low grade inflammation", via toll-like receptor-4 (tlr-4), by inducing the production of il-1β, tnf-α and il-6 from macrophages and, at the same time, some of the adipocytes are also differentiated into "macrophage-like" cells [25] . finally, we can state that il-6 and tnf-α are the main players of inflammation in obesity ( figure 1 ). these two cytokines, along with il-1β via the nf-kb pathway, have been proposed to be the major cause of immunosuppression [26] as they induce accumulation and activation of myeloid-derived suppressor cells (mdscs) whose expansion interrupts the maturation of macrophages, dcs and granulocytes [27] . obesity is also associated with other immunosuppressive landmarks, such as low lymphocyte subset counts and their decreased polyclonal proliferation and oxidative burst activity of monocytes, increased thymic aging, and reduced t-cell repertoire diversity, which lead to increased risk for viral infections and rti both in experimental models and clinical studies [28] . luzi and radaelli [29] have proposed that there would be high viral shedding in obese subjects, thus increasing the probabilities of spreading the viral infection. it is also noteworthy that obesity, complicated by diabetes, may further aggravate the patient's health status. indeed, bello-chavolla et al. [30] have tried to establish a link between obesity and diabetic condition in sars-cov-2 infection. these investigators concluded that obesity might increase the lethality of covid-19 in diabetic subjects. diabetes, due to the deleterious role of hyperglycemia on immune responses, represents a risk factor for covid-19 infection in obesity [31, 32] . a french nationwide study, coronado (coronavirus sars-cov-2 and diabetes outcomes), has clearly shown the deleterious role of obesity in life-threatening outcomes in a large diabetic population with covid-19 [33, 34] . a perusal of above-mentioned studies clearly demonstrates that chronic inflammation, leading to immunosuppression, may contribute to decreased protection against viral infections in obese subjects [35] . it has been recently reported that a significant number of covid-19 patients suffer from a sudden loss of their senses of smell and taste, even in clinical conditions that are not marked with common viral symptoms such as fever, dry cough or thoracic oppression [36, 37] . a large number of covid-19 patients (from 60% to 80%) from iran have complained of a complete loss of their sense of smell or taste [38] . a multicentric european study conducted on covid-19 patients demonstrated that nearly 87% of patients reported olfacto-gustatory dysfunctions [39] . a recent meta-analysis on covid-19 patients, incorporating 10 research articles from 7 countries, has reported that nearly 52% and 43% of them had, respectively, gustatory and olfactory dysfunctions [40] . in france, gautier and ravussin [41] reported that there was a sudden appearance of anosmia and/or ageusia in a small number of covid-19 patients. similarly, almost two-thirds of covid-19 patients from germany also complained of anosmia [42] . in the usa, a survey was performed in the month of april 2020 on covid-19 patients, and 37.7% of participants complained of altered smell and taste perception [43] . interestingly, the changes in gusto-olfactory perception in covid-19 patients were more prevalent in home-quarantined subjects, independently of age and gender [44] . it is important to mention that sars-cov-2 does not generate clinically significant nasal congestion or rhinorrhea as seen in general nasal infections [45] [46] [47] [48] . does sars-cov-2 infect taste buds or nasal mucosal epithelia? a recent report, conducted in mice, has demonstrated that mouse sustentacular cells, involved in the transfer of odorant messages to olfactory neurons, express angiotensin converting enzyme 2 (ace2), which is a port of entry of sars-cov-2 ( figure 2 ) [49] . j. clin. med. 2020, 9, x for peer review 4 of 12 buds or nasal mucosal epithelia? a recent report, conducted in mice, has demonstrated that mouse sustentacular cells, involved in the transfer of odorant messages to olfactory neurons, express angiotensin converting enzyme 2 (ace2), which is a port of entry of sars-cov-2 ( figure 2 ) [49] . the duration and intensity of sars-cov-2-induced inflammation will also depend on pre-existing inflammation (like in obesity) and genetic or epigenetic backgrounds of the subjects. for simplification, we do not show the structure of the tongue papillae. we show a taste bud that is the unit of lingual gustatory papillae. during viral-induced inflammation, the oro-nasal epithelia will be infiltrated by macrophages that will release the pro-inflammatory cytokines such as il-6 and tnf-α that may aggravate the epithelial integrity and lead to clinical symptoms such as loss of oro-naso-sensory (ons) functions. beside the implication of ace2, the viral-induced generalized inflammation in covid-19 patients would also affect the integrity of the olfactory epithelium. chronic rhinosinusitis has been shown to trigger alterations in the olfactory mucosa, such as goblet cell hyperplasia, squamous metaplasia, and loss of supporting cells and olfactory neurons, associated with infiltration of proinflammatory immune cells [50] . we propose that sars-cov-2 might affect the integrity or regeneration/renewal of the olfactory epithelium, impacting the physiological function of olfactory sensory neurons (figure 2 ). hence, we can cite the example of sendai virus which has been shown to impair olfaction by reducing the regeneration of the olfactory epithelium and olfactory bulb in the mouse [51] . in in vitro experiments on murine olfactory neurons infected with this virus, the number of odorant-responsive cells were decreased. by using a plausible transgenic mouse model, lane et al. [52] have demonstrated that the induction of tnf-α expression triggered inflammation in the olfactory epithelium and the reversal of tnf-α expression restored the olfactory function in these animals, demonstrating that inflammation is an important factor involved in the loss of olfactory the duration and intensity of sars-cov-2-induced inflammation will also depend on pre-existing inflammation (like in obesity) and genetic or epigenetic backgrounds of the subjects. for simplification, we do not show the structure of the tongue papillae. we show a taste bud that is the unit of lingual gustatory papillae. during viral-induced inflammation, the oro-nasal epithelia will be infiltrated by macrophages that will release the pro-inflammatory cytokines such as il-6 and tnf-α that may aggravate the epithelial integrity and lead to clinical symptoms such as loss of oro-naso-sensory (ons) functions. beside the implication of ace2, the viral-induced generalized inflammation in covid-19 patients would also affect the integrity of the olfactory epithelium. chronic rhinosinusitis has been shown to trigger alterations in the olfactory mucosa, such as goblet cell hyperplasia, squamous metaplasia, and loss of supporting cells and olfactory neurons, associated with infiltration of pro-inflammatory immune cells [50] . we propose that sars-cov-2 might affect the integrity or regeneration/renewal of the olfactory epithelium, impacting the physiological function of olfactory sensory neurons ( figure 2 ). hence, we can cite the example of sendai virus which has been shown to impair olfaction by reducing the regeneration of the olfactory epithelium and olfactory bulb in the mouse [51] . in in vitro experiments on murine olfactory neurons infected with this virus, the number of odorant-responsive cells were decreased. by using a plausible transgenic mouse model, lane et al. [52] have demonstrated that the induction of tnf-α expression triggered inflammation in the olfactory epithelium and the reversal of tnf-α expression restored the olfactory function in these animals, demonstrating that inflammation is an important factor involved in the loss of olfactory sensory neurons and olfaction sensitivity. the olfactory mucosa is very sensitive to macrophage-secreted inflammatory cytokines, such as macrophage inflammatory protein-1α (mip-1a) and monocyte chemoattractant protein-1 (mcp-1), that may influence the renewal/regeneration of nasal epithelial cells [53] . as regards taste dysfunction, ace2 was highly expressed by tongue epithelial cells, but to a lesser extent by buccal and other tissues of the mouth cavity [54] . these observations suggest that the tongue is equipped with a sars-cov-2 entry route, but we do not know whether taste papillae and taste bud cells (tbcs) express the ace2 receptor. we would like to introduce toll-like receptors (tlrs) that act as receptors for viral rna, and are abundantly expressed on taste bud cells, particularly on type ii and type iii cells [55] . the activation of tlrs by the administration of exogenous ifn-γ led to inflammation in taste bud cells and, consequently, to cell death. the autoimmune pathologies in humans or experimental rodent models have clearly demonstrated that inflammation, associated with infiltration by il-6 and ifn-γ in gustatory epithelium, impacts taste perception [56] [57] [58] . moreover, administration of exogenous ifn-γ, via stat-1 signaling, induced apoptosis of taste bud cells [59] . these observations strongly support that oral taste papillae inflammation may contribute to low oro-sensory perception of sapid molecules. beside the peripheral mechanism, different brain areas might be involved in the loss of taste and smell in covid-19. there are several reports indicating that covid-19 patients also suffer from neurological complications, such as skeletal muscle injury, delirium and acute cerebrovascular disease [47] . chigr et al. [60] have proposed that this virus might accede to the olfactory cortex either by the nasopharyngeal cavity or directly by hematogenous spread. there is no direct report on the entry of sars-cov-2 into the brainstem; however, clinical features such as vomiting, nausea and loss of appetite suggest a perturbation in the dorsal vagal complex (dvc), which belongs to the medulla oblongata, the lowest region of the brainstem that controls several physiological functions, including food intake. in the dvc, the nucleus of tractus solitaris (nts) is known to regulate food intake, not only via the vagus nerve that connects the gut, but also via chorda tympani and glossopharyngeal nerves that connect directly to the gustatory taste papillae in the tongue [61] . ralli et al. [62] have proposed that sars-cov-2 could infect the olfactory receptors in the nasal epithelium, through which it may travel to the olfactory bulb and certain brain structures, such as the medulla oblongata. this hypothesis was based on the observations in animal experiments wherein intranasal administration of sars-cov, a strain similar to sars-cov-2, could enter the brain via the olfactory nerves and spread to the thalamus and brainstem [48] . sars-cov-2, in analogy to sars-cov34 and mers-cov13 infection in transgenic mice, might attain the brainstem [63] . indeed, using the murine model of hcov infection, it was shown that sars and oc43 were able to enter the olfactory bulb via the nasal route and reach the central nervous system (cns) [64] . moreover, ct scans and mri of covid-19 patients demonstrated "bilateral inflammatory obstruction of the olfactory clefts" [65] . though we do not have experimental animal data on sars-cov-2 entry, we can state that sars-cov-2 may enter the cns, using the olfactory pathway [63] , and exert its action via ace2 that has been detected in the central nervous system [66] . the question arises whether the loss of ons perception can be considered as an early marker of sars-cov-2 infection. we should be very cautious in this regard, as the methods that have been used for the assessment of ons defects are self-reported examinations. generally, the investigators employ either a 3-armed forced choice (3-afc) test or a comparison with 6-n-propylthiouracil (prop) tasting with and without sodium chloride for oral chemosensory perception, and for the detection of olfactory thresholds, rose smell and n-butanol are employed. by using these techniques, one can be sure about the decrease (or increase) in taste detection thresholds. however, in none of the reports on covid-19 patients, such tests were employed. why do all the covid-19 subjects not complain of the loss of smell? is there any genetic or epigenetic predisposition? before going into detail, we would like to emphasize that a reduced oro-sensory perception would trigger high consumption of palatable food, thus either leading to obesity or worsening this pathology [67, 68] , though we should not ignore the implication of the food addiction component, particularly for sweet food and those rich in fat [69, 70] . the studies conducted on healthy and obese participants suggested that the latter group exhibited lower sensitivity than the former for sweet and sour taste [71] . diet-induced obesity, by maintaining mice on a high-fat diet for ten weeks, resulted in low taste bud cell number and taste-evoked calcium signaling in obese mice [72] . similar observations have been reported for bitter and salt tastes in obese subjects [73] . as regards fat taste perception, there was a decreased perception of dietary fatty acids in obese rodents and human beings [61, 74, 75] . the decrease in taste sensitivity to different taste qualities might be due to partially functional taste receptors/sensors, caused by obesity-induced downregulation [75] , genetic polymorphism [75] [76] [77] [78] or epigenetic signatures [79] . the olfaction is not only important for the detection of sense of smell, but also to appreciate the palatability of a hedonic food, as the retro-nasal detection of flavors is brought about by nasal sensory epithelial cells [80, 81] . as regards the olfactory cue, there was a significant influence of bmi on olfactory thresholds, which were increased with increasing body weight in obese subjects [82, 83] . patel et al. [84] reported that high bmi was associated with subjective olfactory dysfunction in obese patients. by employing the olfactory threshold-discrimination-identification (tdi) test, pastor et al. [85] observed that olfactory discrimination power was lesser in obese subjects than control participants. like taste modalities, the genetic polymorphism of olfactory receptor genes [85, 86] or their hypermethylation [87] , also contributes to obesity. the decreased smell perception in obesity is a multicomponent phenomenon that involves not only nasal epithelial receptor activation, but also different brain areas, such as the limbic system, thalamus and piriform cortex, as well as amygdala, which project to the orbitofrontal cortex [88] . beside the afore-mentioned factors that bring about a decrease in ons, we should not forget to mention the role of cytokine-induced (generalized or tongue-specific) inflammation in obesity. the mouse taste bud cells have been shown to produce both tnf-α and il-10 in the microenvironment of taste papillae [89, 90] . in a plausible study, kaufman et al. [74] showed that an increase in tnf-α in the tongue of obese mice was associated with a significant reduction in taste bud and taste progenitor cells in tongue papillae. moreover, tnf-α null mice were protected from obesity-induced reduced number of taste bud cells, and administration of exogenous tnf-α brought back taste buds to degeneration [91] . the adipose-specific deletion of sel1l in mice maintained on a high-fat diet resulted in reduced adiposity and showed neither an increase in tnf-α concentrations nor any sign of taste bud cell atrophy. these observations clearly indicate that tnf-α released from hyperplasic/inflamed adipose tissue in obesity may trigger a loss in gustatory taste perception. moreover, lps-induced inflammation was also found to decrease the lifespan of mature taste bud cells [92] . as regards olfactory perception, inflammation and obesity, a link between apoptosis and inflammation has been recently reported in the olfactory mucosa of obese mice fed with a moderate high-fat diet, where a significant increase in activated caspase-3 was associated with a marked loss of olfactory sensory neurons and their axonal projections, paralleled with an increased expression of iba-1, suggesting an increase in proinflammatory cells [92] . hence, if the diet-induced obese mice are re-fed a normal diet and return to normal weight, the loss in olfactory perception is also reinstated. in vitro, tnf-α has been shown to induce cell death in olfactory epithelial explants [93] . in transgenic mice, the expression of tnf-α resulted in the loss of olfactory neurons and odor perception. as regards il-6, its concentrations were found elevated in the blood of patients suffering from hyposmia [94, 95] . a perusal of above-mentions observations clearly suggests that obesity is associated with the loss of ons, and inflammation in the oro-naso epithelia plays an important role in this phenomenon. figure 2 shows that sars-cov-2 infection will install (or aggravate) an inflammatory state both in the lingual and nasal epithelia. in the lingual taste buds, the virus-induced inflammation will attenuate the gustatory perception of different taste qualities, whereas in the olfactory sensory neurons, the virus-triggered inflammation may contribute to decreased olfactory perception of odorants. it is also possible that sars-cov-2, by penetrating the olfactory bulb, may enter the brainstem and modulate ons. why do all covid-19 patients not exhibit a change in ons perception? it is possible that the alteration in oro-olfactory epithelium functions might be secondary to viral infection, which may depend on genetic (or epigenetic) and other life-style-related build-up of the patients. nonetheless, we can infer that obese subjects are at high risk for sars-cov-2 infection as they already exhibit a low ons capacity for different taste modalities. hence, the existing gustatory and olfactory sensory deficiency, due to obesity, will mask sars-cov-2-induced diminished taste and smell sensation and, thus, may aggravate the patient's health. sars-cov-2 infection may further aggravate the ons functions; mask the obesity-induced inflammation, including loss of taste and smell; and render the obese subjects more vulnerable and prone to severe pathophysiological consequences such as rti, leading to death. by now, we have observational/self-reported studies, but data regarding the duration and the time of the onset and reversal of ons symptoms in this infection are lacking. we need a complete follow-up study of these patients as a function of time on the loss of ons. as mentioned previously, we also lack the proper set-up for the detection of olfactory and taste thresholds. we still do not know whether sars-cov-2 infection alters the taste bud renewal/turn-over and taste bud physiology either upstream or downstream of the detection of sapid molecules. it is too early to predict clearly that sars-cov-2-induced changes in ons might be due to its direct or indirect deleterious effects on brain regions such as the insula, caudal orbitofrontal and anterior cingulate cortex that control the integration of both taste and smell information [96] . while we have mentioned that tongue epithelium expresses ace2 receptors [54] , we still do not know which cell type (type i, ii or iii) expresses this receptor. this information will be important to correlate the loss of a particular taste modality as type ii cells express sweet, bitter and umami receptors; type i cells express salt receptors; and type iii cells are involved in sour sensing [74, 75] . the vistas in the eating behavioral physiology with regard to sars-cov-2 infection require more detailed investigations in covid-19 patients as gustatory and olfactory receptors are also expressed in other tissues such as those in the gut, which is the main site of the release of small peptides (such as cholecystokinin and peptide-yy) that control eating behavior via the vagus nerve [97] . similarly, the olfactory bulb also expresses receptors for a number of appetite-regulating hormones and peptides such as insulin, leptin, ghrelin and orexin [98] . it is now well established that the gut microbiome of obese subjects is shifted from bacteriodetes to fermecutes, a pro-inflammatory phylum, and the effects of this change on sars-cov-2 infection susceptibility should be explored in the future. does this viral infection promote a particular microbiome in the gut and ons epithelia? a recent report has outlined that there is a significant persistent alteration in the gut microbiome in covid-19 patients [99] . can the strategies to alter the intestinal microbiota decrease the severity of sars-cov-2 infection? we think that sars-cov-2 infection is much more dangerous than what is reported now and a significant amount of clinical information remains undiscovered. this study was supported by a grant from the french national research agency (anr-11-labx-0021-lipstic). the authors 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possible roles of caspase 1 (ice), caspase 2 (ich-1), and caspase 3 (cpp32) velicu, i. interleukin 6 in hyposmia experience-dependent neural integration of taste and smell in the human brain olfactory receptors in non-chemosensory tissues olfaction under metabolic influences alterations in gut microbiota of patients with covid-19 during time of hospitalization key: cord-277803-7p1qu2rf authors: rubino, francesco; cohen, ricardo v; mingrone, geltrude; le roux, carel w; mechanick, jeffrey i; arterburn, david e; vidal, josep; alberti, george; amiel, stephanie a; batterham, rachel l; bornstein, stefan; chamseddine, ghassan; del prato, stefano; dixon, john b; eckel, robert h; hopkins, david; mcgowan, barbara m; pan, an; patel, ameet; pattou, françois; schauer, philip r; zimmet, paul z; cummings, david e title: bariatric and metabolic surgery during and after the covid-19 pandemic: dss recommendations for management of surgical candidates and postoperative patients and prioritisation of access to surgery date: 2020-05-07 journal: lancet diabetes endocrinol doi: 10.1016/s2213-8587(20)30157-1 sha: doc_id: 277803 cord_uid: 7p1qu2rf the coronavirus disease 2019 pandemic is wreaking havoc on society, especially health-care systems, including disrupting bariatric and metabolic surgery. the current limitations on accessibility to non-urgent care undermine postoperative monitoring of patients who have undergone such operations. furthermore, like most elective surgery, new bariatric and metabolic procedures are being postponed worldwide during the pandemic. when the outbreak abates, a backlog of people seeking these operations will exist. hence, surgical candidates face prolonged delays of beneficial treatment. because of the progressive nature of obesity and diabetes, delaying surgery increases risks for morbidity and mortality, thus requiring strategies to mitigate harm. the risk of harm, however, varies among patients, depending on the type and severity of their comorbidities. a triaging strategy is therefore needed. the traditional weight-centric patient-selection criteria do not favour cases based on actual clinical needs. in this personal view, experts from the diabetes surgery summit consensus conference series provide guidance for the management of patients while surgery is delayed and for postoperative surveillance. we also offer a strategy to prioritise bariatric and metabolic surgery candidates on the basis of the diseases that are most likely to be ameliorated postoperatively. although our system will be particularly germane in the immediate future, it also provides a framework for long-term clinically meaningful prioritisation. bariatric surgery has been used for decades to treat patients with severe obesity. in 2016, global guidelines established through the diabetes surgery summit (dss), an international consensus conference series, formally recognised gastrointestinal surgery as a standard therapy for type 2 diabetes; this practice is known as metabolic surgery. 1 during the coronavirus disease 2019 (covid19) outbreak, under unprecedented pressure to free up inpatient capacity, and because of intraoperative risks for viral contagion among patients and staff, hospitals worldwide have been obliged to postpone most elective operations, including bariatric and metabolic surgery. increased hazards of severe covid-19 complications in patients with obesity, type 2 diabetes, or both, 2-5 further support the rationale for a pause in elective surgery during the peak of the pandemic. the return to normal services will be gradual, with surgeons competing for reduced capacity to address a backlog of elective procedures. hence, access to bariatric and metabolic surgery will continue to be constrained. given the uncertainty regarding the effects and duration of the covid-19 outbreak, combined with the progressive nature of obesity, diabetes, and related conditions, delaying bariatric and metabolic surgery could increase the risks for morbidity and mortality in surgical candidates. the risk of harm, however, is variable among individuals, depending on the type and severity of disease and their indications for bariatric and metabolic surgery. the traditional, weightcentric criteria for patient selection in bariatric surgery, which are still commonly used today, do not reflect severity of disease, 6 and they therefore cannot be used to prioritise treatment based on actual clinical needs. furthermore, physical distancing policies and continued lockdowns might limit adherence to lifestyle interventions, worsening metabolic deterioration among candidates for bariatric and metabolic surgery. additionally, reduced access to nonurgent care during the covid-19 pandemic might impede postoperative monitoring for potential surgical and nutritional complications. a clear and urgent need therefore exists for strategies to mitigate harm to patients during and after the covid-19 pandemic. these approaches should include non-surgical interventions to optimise metabolic and weight control in patients awaiting surgery, telemedicine protocols for postoperative surveillance, and use of appropriate criteria to triage surgical candidates during a foreseeable period of reduced capacity for elective surgery. to address these issues, the dss 1 organisers directed a group of international experts to assess the effect of the covid-19 pandemic on candidates for surgical treatment of obesity and type 2 diabetes. our specific aim was to develop criteria to help prioritise bariatric and metabolic surgery for when elective surgery is resumed and beyond. elective surgery refers to operations that can be planned and scheduled in advance. these procedures, however, are not optional, because they can have important, lifechanging implications. when access to elective surgery is reduced, doctors should prioritise patients with the greatest need or with a greater risk of harm from delayed treatment. in some health-care systems, elective surgery is categorised into urgent, semi-urgent, or non-urgent. 7, 8 urgent elective surgery is required within 30 days for conditions that might deteriorate quickly. semi-urgent conditions are those that, although not likely to deteriorate quickly, could reasonably cause severe pain or dysfunction or further harm if delayed beyond 3 months. non-urgent elective surgery is planned for conditions that are unlikely to cause substantial discomfort, dysfunction, or harm if treated within 1 year. although some complications from bariatric and metabolic operations can require emergency surgical treatment (eg, haemorrhage, leak, or intestinal obstruction), most bariatric and metabolic procedures represent genuine elective surgery. to date, however, no consensus exists for criteria to identify urgent, semi-urgent, or nonurgent indications in bariatric and metabolic surgery on the basis of the type and severity of patients' conditions. there are many reasons why most bariatric and metabolic operations should be suspended during the most intense phase of the covid-19 pandemic, including infection risks among patients and staff, factors inherent to the operations, and increased hazards of severe covid-19 complications among patients with obesity or type 2 diabetes. laparoscopic surgery involves aerosol-generating techniques such as carbon dioxide, pneumoperitoneum, electro cautery, and ultrasonic shearing. these techniques could easily increase the risk of viral contagion for staff, 9, 10 including with severe acute respiratory syndrome coronavirus 2 (sars-cov-2). upper gastrointestinal endoscopy (another aerosol-producing procedure) is also commonly done before bariatric and metabolic surgery. patients undergoing major surgery are at risk of lifethreatening inflammatory complications such as infection (including from viruses), the systemic inflammatory response syndrome, and sepsis. 11 although there is no conclusive evidence that laparoscopy or upper endoscopy can promote covid-19 transmission, postponing elective metabolic and bariatric interventions during the acute phase of the covid-19 outbreak seems sensible, except for urgent revisional surgery or emergency endoscopic interventions for complications (eg, haemorrhage, stoma stenosis, or leaks). despite the potential for a higher risk of contagion, the laparoscopic approach in bariatric and metabolic surgery is associated with substantial benefits compared with traditional open surgery, especially in patients with severe obesity. these benefits include lower rates of mortality and complications (including pulmonary and procedural), and shorter hospital stays. 12, 13 for these reasons, laparoscopic access should remain the preferred approach over open techniques when elective bariatric and metabolic surgery resumes. appropriate personal protective equipment should be used, however, given the increased risk of sars-cov-2 infection for staff. obesity increases the risk of complications from viral respiratory infections. during the 2009 influenza h1n1 pandemic in california, 91% of people who died had obesity, and higher bmi was associated with mortality. 14 in patients admitted to intensive care for sars-cov-2, class 2-3 obesity (bmi >35 kg/m²) is an independent risk factor for disease severity. 5 similarly, patients with diabetes have augmented risk for severe covid-19 and mortality. [2] [3] [4] [5] several mechanisms have been suggested to increase the risk of complications from viral infections in obesity and type 2 diabetes, including low-grade chronic inflammation with overproduction of proinflammatory cytokines, reduced natural killer cell number and activity, and impaired antigen-stimulation responses. [15] [16] [17] another factor that might have a role in the relationship between obesity, diabetes, and increased risk for complications is that sars-cov-2 enters host cells by binding to the angiotensinconverting-enzyme 2 (ace2) receptor. ace2 transforms angiotensin 2 to angiotensin, 14-20 thereby reducing vaso constriction, sodium retention, inflammation, and metabolic degeneration. 21 chronic hyperglycaemia down regulates ace2 expression, 22 and further reduction of ace2 during covid-19 infection could contribute to hyperinflammation and respiratory failure in patients with type 2 diabetes. 23 people with obesity are also prone to hypoventilation syndrome, cardiovascular disease, 24 heart failure, 25 and other conditions that could increase the risk of covid-19 mortality. when elective bariatric and metabolic surgery resumes, the pandemic will be contained, but sars-cov-2 will probably still circulate in the population. given the risks of severe complications from covid-19 in patients with obesity and type 2 diabetes, we recommend that covid-19 screening should be mandatory preoperatively for patients considering bariatric and metabolic surgery. class 2-3 obesity and type 2 diabetes, the most common indications for bariatric and metabolic surgery, are associated with reduced quality of life and increased morbidity and mortality. their ability to cause lifethreatening complications, however, varies depending on the severity or stage of disease and the burden of comorbidities. the degree of harm from delaying metabolic and bariatric surgery depends on each patient's condition, the surgical efficacy at different stages of disease, and the availability and effectiveness of nonsurgical therapies to control disease progression while awaiting surgery. understanding the prognostic factors of morbidity and mortality in obesity and type 2 diabetes can help to define criteria for surgical prioritisation. diabetes is a major cause of morbidity and death, including from cardiovascular, renal, neurological, and retinal complications. approximately two-thirds of people with diabetes die of cardiovascular disease, with a relative risk 1·8-2·6 times greater than in people without diabetes. 26 the biological progression of type 2 diabetes, characterised by declining β-cell function and continuing insulin resistance, is manifested clinically by deteriorations in multiple parameters, including hba 1c , fasting, and postprandial glucose levels. the uk prospective diabetes study 27 reported significant associations between hyperglycaemia and development of diabetes complications or death, and a 21% risk reduction for any diabetes-related endpoint with each 1% absolute hba 1c reduction. factors beyond hyperglycaemia can also influence type 2 diabetes prognosis. in the triad study, 28, 29 predictors of all-cause mortality at 4 years and 8 years of study follow-up included older age, male sex, non-hispanic white race, lower education and income, longer duration of diabetes, lower bmi, hypertension, macrovascular disease, retinopathy, nephropathy, and neuropathy. among the specific predictors of cardiovascular mortality were also treatment with insulin (with or without oral medication), higher ldl cholesterol, history of nephropathy, transient ischaemic attack, stroke, angina, myocardial infarction, coronary artery and peripheral vascular disease, and use of antihypertensive or cholesterol-lowering medications. obesity increases the risks of many other illnesses, including diabetes, hypertension, dyslipidaemia, liver disease, coronary artery and cerebrovascular disease, many cancers, cholelithiasis, infertility, psychosocial dys function, osteoarthritis, chronic kidney disease, and now also covid-19. together, these complications power fully reduce quality of life and exacerbate obesity-associated mortality. even before covid-19, obesity reduced life expectancy by 5-20 years. 30 notably, higher all-cause mortality is associated with obesity class 2 (bmi 35-39·9 kg/m²) and 3 (bmi ≥40 kg/m²), corresponding to candidates for bariatric surgery, but not with class 1 obesity (bmi 30-34·9 kg/m²). 31 obesity hypoventilation syndrome and obesity-associated heart failure substantially increase mortality. obesity hypoventilation syndrome represents the combination of obesity and chronic daytime hypercapnia. 32, 33 the prevalence of obesity hypoventilation syndrome is highest among patients with a bmi of more than 50 kg/m². 34 mortality from untreated obesity hypoventilation syndrome can be as high as 24% at 1·5-2 years after diagnosis. 35 obesity heart failure is associated with increased mortality, and for each 5-unit increase in bmi, heart failure-related mortality increases by 1·4 times. 36 since bmi alone does not reflect obesity-related mortality and morbidity, staging systems such as the king's obesity criteria 37 and edmonton obesity staging system (eoss) 38 have been developed to assess individual patients' risk on the basis of evidence of subclinical, established, or endstage comorbidities. 39 retrospective application of eoss to data from the national health and nutrition examination survey showed that patients in stages 2-4 of eoss have increased all-cause mortality compared with stages 0 or 1. this finding supports the idea that the presence, type, and severity of obesity-related complications, in addition to bmi, 39 should inform decision making about the prioritisation of treatment, especially surgery. non-alcoholic fatty liver disease is characterised by excess hepatic fat. its more aggressive form, non-alcoholic steatohepatitis, includes hepatocyte injury, inflammation, and fibrosis. [40] [41] [42] these two conditions affect 20-25% of the western population, with rates rising worldwide. 40,43 66% of patients with obesity and diabetes have non-alcoholic fatty liver disease or non-alcoholic steatohepatitis. 44, 45 non-alcoholic steatohepatitis can lead to cirrhosis (in 15-20% of cases), liver failure, or hepatocellular carcinoma. 46 beyond liver-related mortality, non-alcoholic steatohepatitis can substantially increase microvascular and macrovascular complications, and cardiovascular mortality in patients with obesity and type 2 diabetes. [40] [41] [42] [43] 47, 48 non-randomised trials suggest that roux-en-y gastric bypass resolves the histological features of non-alcoholic steatohepatitis in up to 80% of patients. 49, 50 randomised clinical trials and observational studies show that in patients with all classes of obesity, bariatric and metabolic surgery promotes greater long-term weight loss than the best available non-surgical interventions, regardless of the operation chosen. 47, [51] [52] [53] multiple obser vational studies also indicate that bariatric and metabolic surgery lowers long-term risk of all-cause mortality compared with matched non-surgical patients. [54] [55] [56] [57] [58] [59] data from eight observational studies involving a total of 635 642 patients suggest that bariatric and metabolic surgery is associated with a reduced risk of all types of cancer (odds ratio [or]=0·72; 95% ci 0·59-0·87) and obesity-associated cancer (or=0·55; 95% ci 0·31-0·96). [60] [61] [62] without exception, each of the 29 all-cause mortality studies published to date shows that patients who have bariatric and metabolic surgery live longer than matched nonsurgical controls. 54-59,63,64 concerning type 2 diabetes, at least 12 randomised controlled trials comparing bariatric and metabolic surgery with conventional diabetes therapies (ie, lifestyle plus medication) in patients with type 2 diabetes show that surgery is superior for control of hyperglycaemia, reduction of cardiovascular and overall mortality risk, improvement in quality of life, and reduction in risk of renal complications. 1, 65, 66 the safety of bariatric and metabolic surgery compares favourably with that of most elective operations, including hysterectomy, chole cystectomy, and knee replacement. surgical treatments for diabetes are highly cost-effective, with the cost per quality-adjusted lifeyear ranging between us$3200 and $13 000. 1, 65, 67 based on this evidence, dss guidelines, which have been formally endorsed by 56 worldwide medical or scientific organisations and recognised by payers worldwide, recommend the consideration of bariatric and metabolic surgery for appropriate candidates (including those with only class 1 obesity), who do not achieve adequate glycaemic control with medical therapy. 1 the delay of bariatric and metabolic surgery that is occurring due to covid-19 will augment the burden of disease among surgical candidates. this increase will particularly affect patients with type 2 diabetes, given that metabolic surgery causes remission of hyperglycaemia in most cases. 65 the likelihood of hyperglycaemia remission, however, depends upon how soon an operation is done during the natural history of diabetes. algorithms designed to predict surgical remission (eg, diarem-2, ad-diarem, diabetter, and abcd) [68] [69] [70] [71] consistently show that longstanding disease is one of the most powerful indicators of failure to achieve this benefit. 72 remission rates drop off notably after 10 years of diabetes. moreover, the sos study 73 reported substantially lower type 2 diabetes remission among patients with only 4 years of known disease than in those with 2 years of known disease. thus, delaying metabolic surgery reduces the chances of diabetes remission. delayed metabolic surgery might cause even greater harm to patients with type 2 diabetes who are at higher risk of microvascular and macrovascular complications and mortality, especially when medications and lifestyle interventions are not achieving adequate metabolic control. patients without diabetes but with severe respiratory (obesity hypoventilation syndrome), cardiac, or renal complications of obesity, and individuals for whom weight reduction is crucial to advancing time-sensitive and life-saving treatments (eg, organ transplants) also have greater risks of harm from delaying bariatric and metabolic surgery. patients with surgically remediable metabolic diseases, especially diabetes, incur more health-care costs per day than do those without these conditions. all studies that compared costs for 1-5 years between surgical and non-surgical patients found that pharmacy expenses decrease substantially after bariatric and metabolic surgery compared with matched non-surgical patients, [74] [75] [76] [77] 78 primarily due to lower diabetes medication costs. 69 hence, metabolic surgery decreases daily health-care costs, especially for patients requiring multidrug therapy. the longer surgery is delayed for these patients, the less costsaving it becomes. various non-surgical options can be used to mitigate the harm from delaying bariatric and metabolic surgery and to manage patients who have had surgery (panel 1). regarding the need to optimise glycaemic control in patients with type 2 diabetes, especially those with advanced microvascular or macrovascular complications, 79 we considered available evidence of pharmacological strategies that promote weight loss, such as glucagon-like peptide-1 receptor agonists (glp-1ra) or sodium/glucose cotransporter 2 (sglt-2) inhibitors, or both. 80 glp-1ras reduce hba 1c by about 1% 81 while promoting clinically relevant weight loss. 82 sglt-2 inhibitors, however, might be contraindicated with covid-19, because of concerns about potential subclinical vascular congestion and risk of acute metabolic decompensation associated with these drugs. 83 we also considered available data regarding the efficacy of dietary or pharmacological interventions for weight loss, 84, [85] [86] [87] [88] or both, as a strategy to achieve weight loss or weight maintenance in patients with multiple weightresponsive comorbidities who face prolonged waiting times for bariatric and metabolic surgery. regarding strategies to maximise surgical outcomes in patients who have already had surgery, our recommendations are based on results from studies investigating the efficacy of pharmacological approaches in people with persistent or recurrent type 2 diabetes after surgery. among these individuals, a recent study 89 showed that the glp-1ra liraglutide can reduce hba 1c by 1·2%, with up to 5% additional weight loss. we reviewed existing evidencebased recommendations for postoperative nutritional care 79 to define safe and pragmatic methods of virtual consultation by telemedicine (panel 1). even before the covid-19 pandemic, metabolic and bariatric surgery was underused for many reasons, including misconceptions and stigma about obesity and bariatric surgery. 90 such barriers might further penalise candidates for this surgery in times of limited resources. given the seriousness of the diseases that require metabolic and bariatric surgery, clinicians, hospital managers, and policy makers should ensure that these operations are not further delayed because of the widespread misconception that they are a last resort. 90 eventually, the covid-19 crisis will abate, and elective operations will resume, leaving an enormous backlog of patients who would benefit from bariatric and metabolic surgery. how should we prioritise whom to serve first with limited resources? at a broad level, the answer is simple. if patients are well enough to be safe surgical candidates, preference should be afforded to those with the greatest risk of morbidity and mortality from their disease, if it is probable that this risk can be reduced by surgery. this logic would apply, for instance, to many surgical candidates with poorly controlled type 2 diabetes or substantial metabolic, respiratory, or cardiovascular disease. traditional bmi-centric criteria for patient selection, however, tend to skew access to bariatric and metabolic surgery in the opposite direction. despite strong evidence that surgery achieves its greatest health benefits among patients with type 2 diabetes, a minority of those who have such operations have preoperative type 2 diabetes or cardiometabolic disease. 91 furthermore, in many publicly funded health-care systems (eg, uk national health service), candidates for bariatric and metabolic surgery are currently placed on a single elective surgery waiting list, regardless of their indication. priority is established largely on a first-come first-served basis, rather than on non-surgical options to mitigate harm from delaying surgery • glycaemic control should be optimised in patients awaiting metabolic surgery for type 2 diabetes, especially for those with advanced microvascular or macrovascular complications; this is desirable to prepare for surgery and also in case of severe acute respiratory syndrome coronavirus 2 infection • in patients who do not achieve glycaemic targets with lifestyle modifications and metformin, the addition of a glucagon-like peptide-1 receptor agonist (glp-1ra) or sodium/glucose cotransporter 2 (sglt-2) inhibitor, or both, can advance the combined goals of improving metabolic control and causing weight loss or limiting weight gain; use of sglt-2 inhibitors, however, is not recommended in the case of acute coronavirus disease 2019 (covid-19) infection because of concerns about potential subclinical vascular congestion and risk of acute metabolic decompensation associated with these drugs • for patients with multiple weight-responsive comorbidities who face prolonged waiting times for surgery, dietary or pharmacological interventions for weight control might become necessary • diets with higher protein content and lower glycaemic index can be effective and should be considered • among patients already taking weight-loss medications, efforts should be made to continue the drug(s) until surgery is scheduled, since rapid weight regain is predictable when they are discontinued • in countries where weight-loss medications (eg, phentermine, orlistat, glp-1ras, naltrexone-bupropion, and phenterminetopiramate) are accessible, clinicians could consider their use when weight loss or weight maintenance is important, such as for patients with multiple weight-responsive comorbidities • telemedicine strategies that are supervised by specialist bariatric and metabolic surgery providers should be used • in people with persistent or recurrent type 2 diabetes after surgery, weight-reducing diabetes medications (eg, glp-1ras) should be considered; weight maintenance should also be encouraged in patients with type 2 diabetes remission to mitigate risk of disease recurrence • there is insufficient evidence to justify deviations from current evidence-based recommendations for postoperative nutritional care in patients who have had bariatric and metabolic surgery • to minimise risk of nutrition-related complications, providers should engage with patients at the same intervals as in current guidelines • clinical signs (eg, weight, visual changes, rash, weakness, oedema or anasarca, and neuropsychiatric signs), and symptoms (eg, nausea, tingling, bowel-habit changes, and fatigue) of nutritional deficiency must be assessed during virtual clinic sessions • routine laboratory tests (eg, albumin, thiamine, b12, vitamin a, vitamin d, iron, and calcium) should not be deferred but obtained at standard intervals, particularly for patients who had operations with greater risk of nutrient malabsorption, such as long-limb diversionary procedures • urgent face-to-face meetings and laboratory tests are mandated when symptoms suggest severe biochemical deficiencies or surgical complications (eg, intestinal obstruction or acute cholecystitis) • misconceptions and stigma about obesity and bariatric and metabolic surgery might further penalise candidates for surgical treatment of obesity and diabetes in times of limited resources; clinicians, policy makers, and hospital managers should recognise the seriousness of the diseases that require metabolic and bariatric surgery and ensure that these operations are not further delayed • given the risks of severe complications from covid-19 in patients with obesity and type 2 diabetes, covid-19 screening should be mandatory preoperatively for patients considering bariatric and metabolic surgery • despite the potential higher risk of contagion for staff, the risk and benefit of a laparoscopic approach remain favourable for patients and should be preferred over the use of open techniques • appropriate personal protective equipment should be used as recommended by professional bodies and public health agencies to minimise risk for staff and operators clinical need. this approach is comparable to putting all colorectal surgery candidates on the same waiting list with similar priority, regardless of whether their diagnosis is cancer or benign neoplasia. a strong need therefore exists for clinically sound criteria to help prioritise access to surgery in times of pandemics with limited resources. these criteria can also inform future waiting list management and decision making about the structure of surgical services. the prioritisation of any elective operation should seek to facilitate access according to clinical need, maximise equity of access, and minimise the harm from delayed access. we have adapted previous categorisations of elective surgery 7 to define an objective prioritisation system reflecting these principles for bariatric and meta bolic operations (panel 2; figure) . given the factors contributing to morbidity and mortality in obesity and type 2 diabetes, surgical prioritisation should be based on disease-specific consider ations. for patients with type 2 diabetes, we suggest that surgery be prioritised for patients at increased risk of morbidity and mortality. this risk would be indicated by poor glycaemic control despite maximal medical therapy, use of insulin, previous cardiovascular disease, albuminuria and chronic kidney disease, non-alcoholic steatohepatitis, or multiple cardio metabolic comorbidities. 28 insulin use is a meaningful prioritisation criterion because it correlates with increased cardiovascular mortality 28 and reduced quality of life. 92 moreover, metabolic surgery reduces or abolishes the figure: examples of conditions that warrant expedited access to bariatric and metabolic surgery aha=american heart association. the severity of obesity-associated symptoms (eg, mobility issues or joint pain as a consequence of extremely high bmi, regardless of comorbidities) must also be considered when establishing priorities. equally important is the effect of obesity-related conditions that increase morbidity and mortality (eg, obesity hypo ventilation syndrome, chronic kidney disease, or severe obstructive sleep apnoea). 38 the availability of non-surgical options that slow disease progression (ie, pharmacological diabetes treatments achieving adequate glycaemic control) reduces need for prior itisation. expedited access to surgery should also be considered when bariatric and metabolic operations are used as adjuvant therapy to enable other time-sensitive treatments that are made unfeasible or unsafe by excess weight, poor metabolic control, or both (figure). many candidates for bariatric and metabolic surgery are at high risk of morbidity and mortality from comorbid conditions. for these patients, access to surgical treatment should be prioritised on the basis of disease-focused clinical needs, rather than primarily on bmi, to mitigate harm from delaying surgery. this approach is especially needed in periods in which access to surgery is reduced, as in the current covid-19 pandemic. societal crises often spur developments that provide benefits long after the storm passes. disease-oriented, medically meaningful strategies to triage patients seeking metabolic surgery after the covid-19 crisis should help prioritise patients in more urgent need, both now and long into the future. fr conceived the idea for this initiative. fr, rvc, gm, cwr, jim, dea, jv, and dec reviewed relevant medical literature and prepared the first draft of this report. ga, saa, rlb, sb, gc, sdp, jbd, rhe, dh, bmm, apan, apat, fp, prs, and pzz provided additional input in the appraisal of evidence and in manuscript preparation. all co-authors participated in the development of the recommendations and reviewed and approved this report. we did a rapid narrative literature review for this personal view. for references about the effect of viral infections including coronavirus disease 2019 (covid-19) on diabetes, obesity, and laparoscopic surgery, we searched pubmed for articles in english published between jan 1, 2002, and april 10, 2020. we used combinations of terms such as "sars", "h1n1", "coronavirus", "covid-19", "sars-cov-2", "diabetes", "obesity", "bmi" "laparoscopy", "endoscopy", "severe acute respiratory syndrome", "acute respiratory distress syndrome", and "co-morbidities". we also reviewed recent guidelines from professional organisations and public health agencies about elective surgery and the covid-19 pandemic. for evidence about the benefits of bariatric and metabolic surgery, the predicting factors of morbidity and mortality from type 2 diabetes, obesity, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis, and the classification of elective surgery, we reviewed recently published systematic reviews and consensus statements by major scientific societies and relevant individual articles cited in these documents. members of the expert panel were selected on the basis of their previous participation in the diabetes surgery summit series and their relevant expertise. additional experts were also invited to join the group and provide complementary expertise or ensure global representation, or both. a subgroup of the expert panel did a first appraisal of the evidence and draft recommendations, and they generated the first draft of the report, synthetising the literature review in response to each specific query. the entire expert group then engaged in online discussion to further appraise the evidence and refine the final consensus recommendations. 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nutrition, metabolic, and nonsurgical support of patients undergoing bariatric procedures pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2020 efficacy and safety of sodium-glucose cotransporter 2 inhibitors (sglt-2is) and glucagon-like peptide-1 receptor agonists (glp-1ras) in patients with type 2 diabetes: a systematic review and network meta-analysis study protocol semaglutide induces weight loss in subjects with type 2 diabetes regardless of baseline bmi or gastrointestinal adverse events in the sustain 1 to 5 trials consensus recommendations for the management of diabetes in patients with covid-19 diets with high or low protein content and glycemic index for weight-loss maintenance two-year sustained weight loss and metabolic benefits with controlled-release phentermine/ topiramate in obese and overweight adults (sequel): a randomized, placebo-controlled, phase 3 extension study weight loss with naltrexone sr/bupropion sr combination therapy as an adjunct to behavior modification: the cor-bmod trial xenical in the prevention of diabetes in obese subjects (xendos) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial adjunctive liraglutide treatment in patients with persistent or recurrent type 2 diabetes after metabolic surgery (gravitas): a randomised, double-blind, placebo-controlled trial joint international consensus statement for ending stigma of obesity bariatric, metabolic, and diabetes surgery: what's in a name? related factors of quality of life of type 2 diabetes patients: a systematic review and meta-analysis effect of laparoscopic roux-en y gastric bypass on type 2 diabetes mellitus key: cord-288255-p8uzrsbd authors: goossens, gijs h.; dicker, dror; farpour-lambert, nathalie j.; frühbeck, gema; mullerova, dana; woodward, euan; holm, jens-christian title: obesity and covid-19: a perspective from the european association for the study of obesity on immunological perturbations, therapeutic challenges, and opportunities in obesity date: 2020-08-13 journal: obes facts doi: 10.1159/000510719 sha: doc_id: 288255 cord_uid: p8uzrsbd accumulating evidence suggests that obesity is a major risk factor for the initiation, progression, and outcomes of coronavirus disease 2019 (covid-19). the european association for the study of obesity (easo), as a scientific and medical society dedicated to the promotion of health and well-being, is greatly concerned about the concomitant obesity and covid-19 pandemics and their impact on health and society at large. in this perspective, we will address the inherent immunological perturbations and alterations in the renin-angiotensin-aldosterone system in patients with obesity and covid-19, and discuss how these impairments may underlie the increased susceptibility and more detrimental outcomes of covid-19 in people with obesity. clearly, this has important implications for preventive measures, vaccination, and future therapeutic strategies to combat covid-19. furthermore, we will highlight important knowledge gaps and provide suggestions for future research and recommendations for policy actions. since many new reports on covid-19 rapidly appear, the present perspective should be seen as a focus for discussion to drive forward further understanding, research initiatives, and clinical management of covid-19. coronavirus disease 2019 (covid19) , the infectious disease caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (sars-cov-2), was declared a pandemic by the world health organization on march 11, 2020 [1] and continues to spread across the globe. although hospital admission rates for patients with covid-19 depend on community testing and admission criteria, it has been estimated that one in 5-10 adults has illnesses requiring hospital admission [2] , with rates of admission to the intensive care unit (icu) in china, europe, and the united states ranging from 5 to 32% [3] [4] [5] [6] [7] [8] [9] [10] [11] . the european association for the study of obesity (easo), as a scientific and medical society dedicated to the promotion of health and well-being, is greatly concerned about the collision of the obesity and covid-19 pandemics and its impact on individuals, families, communities, health systems, and society at large [12] . early identification of individuals who are especially susceptible to developing severe covid-19 and will be admitted to the icu is crucial. obesity is a gateway to many noncommunicable diseases (ncds) [13, 14] , and people with obesity in general seem to have an elevated risk of hospitalization, serious illness, and mortality. with the rising prevalence of obesity has come an increasing awareness of its impact on communicable disease. indeed, as a consequence of the 2009 h1n1 influenza a virus pandemic, obesity was identified for the first time as an independent risk factor for increased disease severity and mortality in infected individuals [15, 16] . a recent meta-analysis, which was published in early april 2020, provided evidence that obesity-related complications are major risk factors associated with covid-19 [17] . furthermore, people with obesity were more likely to require acute care and admission to the icu, intubation, and mechanical ventilation [18] [19] [20] [21] [22] [23] , especially among those younger than 60 years [20] . a recent report from france has provided additional evidence for the strong association between obesity and severe complications from covid-19 [24] . moreover, it has consistently been demonstrated that old age, male sex, and chronic major comorbidity, including obesity, are associated with increased mortality in patients with covid-19 [5] [6] [7] [8] . since obesity and obesity-associated comorbidities often cluster together, the independent contribution of each factor to the development and progression of covid-19 has not been determined in many studies. interestingly, however, a large prospective observational cohort study, in which more than 20,000 hospital inpatients with covid-19 in the united kingdom during the growth phase of the first wave of this outbreak were enrolled, has very recently demonstrated that obesity was an independent risk factors for high mortality [11] . together, these findings highlight the detrimental outcomes of covid-19 in people with obesity and underscore the importance of continuous obesity management and care during the covid-19 pandemic. in this perspective, we will address the inherent immunological perturbations and increased activity of the renin-angiotensin-aldosterone system (raas) in obesity and how this may increase covid-19 susceptibility in people living with obesity. furthermore, we will discuss therapeutic challenges, highlight knowledge gaps, and provide suggestions for future (research) strategies. evidence from studies in humans indicates that people with obesity are characterized by systemic low-grade inflammation, higher susceptibility to infections, dampened immune response to infectious agents, as well as higher morbidity and mortality associated with infections, and demonstrate an impaired immune response to vaccinations and antimicrobial treatment [25] [26] [27] [28] . in this section, we will discuss the link between obesity, immunological perturbations, increased activity of the raas, and elevated susceptibility to and severity of covid-19. clearly, this has important implications for prevention and treatment strategies during the current collision of the obesity and covid-19 pandemics. compelling evidence suggests that the excess adipose tissue mass in people with obesity directly contributes to the immunological perturbations in obesity. adipose tissue is a highly dynamic, metabolically active organ that plays a central role in many physiological processes, including immunity and inflammation [29, 30] . in healthy conditions, adipose tissue produces and releases a multitude of factors, including pro-and anti-inflammatory factors, to maintain tissue homeostasis [31] . it is well established that the enlarged fat cells (hypertrophic adipocytes) in the expanded fat mass in people with obesity are characterized by a proinflammatory phenotype, which is closely associated with obesity-related complications and ncds such as type 2 diabetes, cardiovascular diseases, and several types of cancer [29, 30] . in addition to detrimental autocrine and paracrine effects of a proinflammatory adipose tissue microenvironment in obesity, increased secretion of multiple proinflammatory cytokines (for example, interleukin-6 [il-6] [32, 33] ) together with reduced secretion of adiponectin by obese adipose tissue seem to contribute to sustained low-grade systemic inflammation in obesity and obesity-related ncds in humans [29, 30, 34, 35] . importantly, adipose tissue inflammation is not only caused by secretion of proinflammatory factors from adipocytes, but also by infiltration of various populations of specialized, proinflammatory immune cells [30, 35] . macrophages exert a key role as part of the innate immune system by phagocytosis of harmful pathogens and apoptotic or necrotic cells. in obesity, the population of proinflammatory macrophages within adipose tissue is increased, and these cells become metabolically activated, secrete proinflammatory cytokines, and engage in inflammatory crosstalk with other immune cells [30, 36] , thereby contributing to a proinflammatory phenotype of adipose tissue as well as systemic low-grade inflammation. innate immunity is the first line of defense against virus invasion. once primed by the earlier innate response, lymphocytes of the adaptive immune system continue the control and removal of pathogens. viral infection of mammals activates intracellular pattern recognition receptors that sense pathogen-associated molecular patterns. the recognition of pathogen-associated molecular patterns results in subsequent cytolytic immune responses, mainly through type i interferons and natural killer cells. adaptive immunity also contributes to viral clearance via activated cytotoxic t cells that destroy virus-infected cells, and via antibody-producing b cells that target virus-specific antigens [37] . thus, t cells exert a prominent role in the response to infection by supporting the function and activation of other immune cells such as macrophages, as well as by regulating the activity of different t cell subsets, to produce pro-and anti-inflammatory factors [35] . together, these distinct populations of immunologically adaptive immune cells play a critical role in combating pathogens. while the majority of studies investigating the relationship between obesity and inflammation have focused on the role of macrophages, more recent studies clearly point to an important role for the adaptive immune system. several studies have implicated proinflammatory t and b cell phenotypes in obesity-related adipose tissue inflammation [38] . importantly, obesity dampens and delays the adaptive immune response to infection, with reduced efficacy of both t and b cell responses in obesity, as extensively reviewed elsewhere [25, 35, 36] . many factors that could potentially impact the immune response are impaired in obesity, including increased leptin concentrations, altered immune cell metabolism, and epigenetic factors, and may therefore underlie the impaired immune response to infectious disease in obesity [39] . intriguingly, a growing body of evidence supports the notion that impaired immunological responses to infection in people living with obesity are driven by perturbations in t cell activation and function [35] . interestingly, recent studies have demonstrated that the innate immune system, like the adaptive immune system, is able to adopt a long-term activated phenotype by previous encounters with microbial stimuli, leading to an increased immune response upon secondary stimulation ("trained innate immunity") [34] . although the association between obesity and trained immunity remains elusive, several known inducers of trained immunity such as cytokines and (saturated) fatty acids are elevated in people with obesity [34] . inherent immunological deficits in obesity may contribute to more detrimental outcomes in people with obesity when encountering covid-19. as mentioned earlier, people with obesity exhibit an impaired immune response to infectious agents, increased viral load and life cycle, and experience poorer outcomes and recovery from infections [25] [26] [27] . in line with an impaired immunological response to infection, reduced effectiveness of antivirals and vaccination has been found in people with obesity [25, 26] , leaving them more vulnerable to infection. indeed, a lower cd8+ t cell response and a more pronounced decline in influenza antibody titers 1 year after vaccination have been reported in people with obesity compared to individuals with normal weight [40] . the latter finding is indicative of an inadequate immune response to influenza virus in obesity, which is likely explained by defects in activation and function of cd4+ and cd8+ t cells [41] . taken together, perturbations in both the innate and adaptive arms of the immune system are present in people with obesity, and this likely has important implications for the prevention and treatment of covid-19-associated complications, as will be discussed later. the invasion and pathogenesis of sars-cov-2 are associated with the host immune response. the antiviral immune response is crucial to eliminate the invading virus, but a robust and persistent antiviral immune response might also cause massive production of inflammatory cytokines and damage to host tissues [42] . the overproduction of cytokines caused by aberrant immune activation is known as a cytokine storm. in fact, in the late stages of coronavirus disease, including sars, middle east respiratory syndrome, and covid-19, cytokine storms are a major cause of disease progression and eventual death [43] [44] [45] . in covid-19 patients, elevated plasma concentrations of both proinflammatory th1 and anti-inflammatory th2 cytokines were found [3] . notably, patients admitted to the icu had higher plasma concentrations of il-2, il-7, il-10, granulocyte colony-stimulating factor, interferon gamma-induced protein 10, macrophage chemoattractant protein 1, macrophage inflammatory protein 1α, and tumor necrosis factor alpha compared to those not admitted to the icu [3] . il-6 is a key inflammatory cytokine that plays a critical part in the inflammatory cytokine storm, and it has been found that plasma il-6 concentrations were above the normal range in patients with severe symptoms of covid-19 compared with healthy individuals and those with milder symptoms [46] [47] [48] . il-6-producing cd14+ cd16+ inflammatory monocytes were significantly increased in patients with covid-19, and this subset of immune cells was further increased in patients admitted to the icu [49] . in agreement with these findings, in particular covid-19 patients with severe pneumonia seem to have substantially lower lymphocyte counts and higher plasma concentrations of a number of inflammatory cytokines, including il-6 and tumor necrosis factor alpha [3, 48, 50] , providing further evidence that cytokine storms may play a crucial role in covid-19 severity. sars-cov-2 infection may affect primarily t lymphocytes, particularly cd4+ and cd8+ t cells. indeed, it has been reported that cd4+ t cells, cd8+ t cells, and natural killer cells [48] , as well as the expression of interferon gamma by cd4+ t cells [47] , were reduced in severely ill patients compared with those with mild disease symptoms. since cytokine storms determine disease progression and mortality [43] [44] [45] , early identification and appropriate treatment of this hyperinflammatory status are important in patients with covid-19 [51] . it has been proposed that a combination of clinical and laboratory tests of ferritin, lymphocyte or leukocyte counts, platelet counts, erythrocyte counts, and sedimentation rate could be used to identify patients with covid-19 at high risk of hyperinflammation [51] . interestingly, results from a recent retrospective study, stratifying patients with covid-19 by survival or disease severity, have suggested that percentage of circulating lymphocytes, levels of c-reactive protein, il-6, procalcitonin, and viral load (orf1ab ct) could predict prognosis (survival/nonsurvival) and guide classification (moderate/severe/critically ill) of covid-19 patients, with percentage of circulating lymphocytes being the most sensitive and reliable predictor for disease typing and prognosis [52] . of note, it has recently been reported in the uk biobank community cohort that the apoe e4e4 allele predicts severe covid-19, independent of preexisting dementia, cardiovascular disease, and type 2 diabetes [53] . since apolipoprotein e exerts atheroprotective and anti-inflammatory effects (including modulation of macrophage phenotype and cd4+ and cd8+ lymphocytes) and has previously been implicated in viral infections [54] , apolipoprotein e genotype might be considered in prediction models for covid-19 severity. together, these findings imply that evaluation of cytokine profiles and immune cell subsets in patients with sars-cov-2 infection, and a deeper understanding of the underlying processes, will significantly contribute to better treatment strategies and clinical management of covid-19 [37] . to summarize, there are clear parallels between obesity and covid-19 in terms of immunological perturbations. as outlined above, available evidence suggests that obesity is a major risk factor for the initiation and progression of covid-19. based on the available evidence, it is tempting to postulate that increased activity of the raas explains why covid-19 is more prevalent and is related to more detrimental outcomes in people living with obesity, as will be discussed below. the raas comprises several vasoactive peptides involved in many key physiological processes in humans. the raas has long been recognized as an important regulator of renal electrolyte homeostasis and blood pressure [55] [56] [57] . the dipeptidyl carboxypeptidase angiotensin-converting enzyme (ace) rapidly converts angiotensin i (ang i) to ang ii, which is the major effector peptide of the raas [55] [56] [57] . different raas components are present in a variety of tissues such as the adrenal gland, kidney, liver, heart, blood vessels, brain, lung, and adipose tissue, implying that these tissues have the ability to locally synthesize ang ii [55] . importantly, ang ii mediates proinflammatory signaling, thrombotic processes, cell growth, reactive oxygen species generation, and fibrosis and contributes to pathological changes of organ structure and function [55, 57] . multiple lines of evidence have established that increased raas activation is involved in the pathophysiology of obesity-related diseases, including type 2 diabetes [58] and cardiovascular diseases [59] . ace2 is a monocarboxypeptidase that mitigates the deleterious actions of ang ii by converting it into the heptapeptide ang-(1-7) [60, 61] . ace2 has been identified as the functional receptor for sars-cov-1 [62] as well as the sars-cov-2 receptor [63] [64] [65] . the spike glycoprotein on the viral envelope of sars-cov-2 binds to ace2 on the surface of human cells for intracellular invasion [64, 65] . following binding, ace2 activity is downregulated through multiple mechanisms, which prevents it from converting ang ii into ang-(1-7) [66] . the interaction between the sars viruses and ace2 has been proposed as a potential factor in their infectivity [67, 68] . like other raas components, ace2 is expressed in many tissues, including the lungs, cardiovascular system, gut, kidneys, pancreas, testis, central nervous system, and adipose tissue [60] . it has been suggested that alveolar macrophages expressing ace2 are the primary target cells for sars-cov-2 infection, and these activated macrophages may play a major role in the cytokine storm during covid-19 [69] . in agreement with this, immune-mediated lung injury and acute respiratory distress syndrome are associated with adverse outcomes in patients with covid-19 [43] . thus, ace2 expression and/or activity in target tissues might facilitate entry of sars-cov-2 spike protein, induce the cytokine storm and, therefore, determine the severity of complications and prognosis in patients with covid-19 [70] . in line with ace2 downregulation following sars-cov-2 binding to ace2, circulating ang ii concentrations were markedly elevated in a small cohort of 12 patients with covid-19 compared to healthy controls and were linearly associated with viral load and lung injury [71] . this provides a direct link between tissue ace2 downregulation, increased ang ii action, and the increased risk of multiorgan damage from sars-cov-2 infection. obesity is characterized by increased activation of the systemic and local adipose tissue raas [55, 57] . since the expression of several raas components is increased in adipose tissue of people with obesity and ang ii has deleterious effects in multiple organs, it is tempting to postulate that ace2 in adipose tissue may provide a critical link between obesity, ncds, and the susceptibility to and severity of covid-19. moreover, since aging is accompanied by an increased abdominal fat mass, it may well be that the adipose tissue-sars-cov-2-raas axis at least partially contributes to the higher risk of covid-19-associated complications and more detrimental outcomes in elderly. clearly, further mechanistic studies in humans are needed to elucidate the interplay between the raas and sars-cov-2. until now, there is no approved effective vaccine or drug for sars-cov-2 infection, and the most common treatment for patients with covid-19 is supportive care. certain compounds have been shown to inhibit sars-cov-2 infection in cell culture models [72, 73] . interestingly, a sars-cov-2 hace2 transgenic mouse infection model has recently been developed [74] . the infected mice generated typical interstitial pneumonia and pathology that were similar to those of covid-19 patients. strikingly, pre-exposure to sars-cov-2 could protect these mice from severe pneumonia [74] . since there is currently no specific antiviral therapy against sars-cov-2, the hace2 mouse may provide a valuable preclinical model to investigate potential vaccines and therapeutic agents before moving to clinical trials in humans. in response to the covid-19 pandemic, an overwhelming number of clinical trials have been registered to test a variety of preventive and therapeutic strategies [75] . since covid-19 rapidly evolved and requires immediate clinical treatment due to its relatively high mortality, extensive preclinical evidence concerning the feasibility, safety, and efficacy of pharmacological interventions is mostly lacking [75] . thus, the scientific quality of many clinical covid-19 studies is of serious concern. although multiple antiviral drugs have been used in clinical practice [5, 76] , their safety and efficacy remains to be established. current covid-19 studies are mainly based on repurposing existing pharmacological agents with proven effectiveness in other conditions that seem to share a comparable pathophysiology with covid-19 [77] . this approach takes advantage of existing detailed information on human pharmacology and toxicology to enable rapid clinical trials and regulatory review. given the importance of immune imbalance in the pathogenesis of sars-cov-2 infection, several immune-modulating drugs that regulate different aspects of inflammation are currently being tested for their efficacy in the treatment of severe covid-19 [37, 75] . since hyperinflammation is an important determinant of tissue damage, organ failure, and disease outcome in covid-19, immunosuppression might reduce mortality in patients with severe symptoms [43, 51] . of note, antiviral immunity is required to recover from covid-19, which implies that the use of (broad) immunosuppressants in patients with this disease should be carefully considered, taking the extent of (hyper)inflammation, viral load or replication status, disease stage, and pharmacokinetics of immunosuppressants into account, in particular in more vulnerable populations such as people with obesity. chloroquine and hydroxychloroquine. chloroquine and hydroxychloroquine, initially used as antimalarial drugs and widely used in several infectious, rheumatological, and other immunological diseases [78] , are currently under investigation for the prevention and treatment of covid-19 [37, 75] . these agents both increase the endosomal ph required for sars-cov-2 endocytosis and cell fusion, and chloroquine further interferes with glycosylation of the sars-cov-2 receptor, ace2 [79] . in line with these findings, it has recently been shown that chloroquine is highly effective in the control of sars-cov-2 infection in vitro [72] . the use of antimalarial drugs such as (hydroxy)chloroquine was associated with lower infection risk compared to other immunosuppressants [80, 81] . although results of a small, uncontrolled trial suggested that hydroxychloroquine accelerated virus load reduction and disappearance in patients with covid-19 [82] , this study has been criticized [83] . furthermore, a randomized clinical trial indicated that hydroxychloroquine treatment may have clinical benefits in patients with covid-19 [84] . importantly, however, no evidence of clinical efficacy has been reported [85] [86] [87] , and a retrospective analysis of data from patients hospitalized with confirmed sars-cov-2 infection even demonstrated increased overall mortality in patients treated with hydroxychloroquine [88] . moreover, since (high-dose) chloroquine may induce arrhythmias, caution is needed on the use of (hydroxy)chloroquine to treat covid-19 [89] . selective jak1/jak2 blockade. selective blockade of janus kinase (jak) by synthetic molecule compounds (i.e., targeted synthetic immunosuppressants) may reduce viral invasion and induce immune suppression. indeed, it has been predicted that the selective jak1 and jak2 inhibitor baricitinib might reduce the ability of the sars-cov-2 virus to infect lung cells [90] . in addition, the immunosuppressive function of baricitinib might also be of benefit to the hyperactive immune status in severe cases of covid-19 [37] . another specific jak1/jak2 inhibitor, ruxolitinib, has been successfully used for the treatment of secondary hemophagocytic lymphohistiocytosis [37] , a disease entity that like covid-19 is also characterized by an uncontrolled cytokine storm [91] . several clinical trials are underway to assess the efficacy of these selective jak1/jak2 blockers [37, 75] . blockade of cytokine receptors. blockade of proinflammatory cytokine receptors and its downstream signaling pathways using monoclonal antibodies (i.e., biological immune-modulating drugs) seems a potential intervention to combat the inflammatory cytokine storm in patients with covid-19. tocilizumab, a recombinant humanized monoclonal antibody against the il-6 receptor, binds both the membrane and soluble forms of the il-6 receptor, thereby suppressing the jak signal transducer and activator of transcription signaling pathway, thus lowering the release of inflammatory molecules [92] . many clinical trials to examine the efficacy of this agent are currently ongoing, but promising results of tocilizumab treatment in severe covid-19 cases have recently been reported, with suggested remission of lung lesions in 95% of patients [93] . likewise, since il-1 was increased in some patients with covid-19 [3] , blockade of the proinflammatory il-1 pathway might reduce hyperinflammation in covid-19. indeed, a retrospective cohort study of patients with covid-19, acute respiratory distress syndrome, and hyperinflammation managed with noninvasive ventilation outside of the icu showed that il-1 blockade with high-dose anakinra in patients with covid-19 was safe and associated with clinical improvement in 72% of patients [94] . obviously, confirmation of efficacy will require controlled clinical trials that are currently ongoing [37, 75] . other immunosuppressants that are currently being tested for their potential in patients with covid-19 include leflunomide, which also inhibits virus replication, and thalidomide [37] . furthermore, due to their rapid immunosuppressive effect, corticosteroids are frequently used in hyperinflammatory conditions (including covid-19) to control immune-mediated damage of lung tissue. although the efficacy of corticosteroids in patients with covid-19 remains to be further investigated, promising first results of the large randomised evaluation of covid-19 therapy (recovery) trial have very recently been published [95] . these preliminary data indicated that in patients hospitalized with covid-19, dexamethasone treatment (6 mg once daily for up to 10 days versus usual care) reduced 28-day mortality among those receiving invasive mechanical ventilation or oxygen at randomization, but not among patients not receiving respiratory support [95] . alternative immune-modulating strategies currently under clinical investigation for the treatment of covid-19 include stem cell therapy and convalescent plasma treatment [37, 75] , but the results of these trials are not yet available. it is likely that the many controlled clinical trials that are currently ongoing will reveal whether certain of these immune-modulating drugs may prove beneficial in patients with covid-19. the "sars-cov-2-raas axis" may provide an opportunity to leverage the different aspects of raas inhibitors to mitigate the viral-induced injuries and disease severity in patients with covid-19. ace inhibitors and ang ii type 1 receptor blockers (arbs) mitigate the deleterious effects of unopposed ang ii action through the ang ii type 1 receptor [55] , which in turn decreases blood pressure, inflammation, and lung injury, among other beneficial effects [66] . given the link between obesity, increased raas activity, (adipose tissue) inflammation, and more detrimental outcomes of covid-19 in people living with obesity, it is interesting to note that long-term arb treatment also decreased the adipose tissue gene expression of macrophage infiltration markers in people with obesity [96] . furthermore, it has previously been demonstrated in rodents that ace inhibitors and arbs may upregulate ace2 expression [97] , which might in theory increase viral entry into the cell. therefore, it has been speculated that such modulation of raas activity might be harmful in people at risk or in patients with covid-19 [98, 99] . noteworthy, however, ace2 levels are often high in diseased states, likely secondary to high raas activity [66] . in contrast, it has been hypothesized that ace2 may be beneficial rather than detrimental in patients with lung injury, based on preclinical data and retrospective human studies demonstrating that raas inhibition decreases lung injury and improves survival, while simultaneously decreasing viral load in animal models with viral infections that utilize the ace2 receptor [66, 70] . importantly, however, the effects of raas modulators on tissue-specific ace2 levels and activity in humans are currently not well understood. several recent reports have consistently found that the use of raas inhibitors was not associated with the risk of sars-cov-2 infection, the risk of severe covid-19 among those infected, or the risk of in-hospital death among those with a positive test [100] [101] [102] [103] [104] . further controlled clinical trials are needed, and underway, to investigate the safety and efficacy of raas inhibition and treatment with recombinant human ace2 to tackle the covid-19 pandemic, as well as to provide a better mechanistic understanding of the effects of raas modulation on tissue-specific ace2 levels [75] . importantly, the putative cardiometabolic consequences of pharmacological agents directly targeting ace2 should be carefully investigated. it is likely that multiple disease peaks will occur before herd (population) immunity is established. a major scientific challenge will be to align the results of small clinical studies during the current "first covid-19 peak" and, based on these outcomes, initiate a set of wellcontrolled large clinical trials in later disease peaks to provide the scientific evidence needed for approval of pharmacological agents to combat the covid-19 pandemic. inadequate preclinical studies impose a high risk of failure in clinical trials and may increase the risk of ambiguous findings. traditional systematic reviews and meta-analyses only retrospectively include published studies to provide an evidence base for interventions [105] . with respect to covid-19, most of the registered covid-19 trials have small patient sizes, and it will take quite some time before data are published [75] . in order to maximize the value of small clinical studies with suboptimal study designs and to minimize bias of ongoing and future covid-19 trials, prospective meta-analysis approaches may be considered [106] . prospective meta-analyses predefine eligible studies for inclusion before the results of these clinical trials have been published in order to objectively address planned high-priority research questions for which previous evidence is scarce, but where new studies are rapidly emerging [107] . since this approach may serve as an innovative solution to generate reliable data for guiding clinical management and regulatory decision-making [107] , results from several clinical trials that are investigating the same intervention for patients with covid-19 with compatible study designs and outcome measures could be combined. importantly, this approach would require methodological expertise as well as the willingness and feasibility to work together and share data [106] . although large, randomized, controlled trials of sars-cov-2 vaccines are currently the most efficient, generalizable, and scientifically robust path to establishing vaccine efficacy, controlled human infection models (chims) have also been proposed as a strategy for accelerating sars-cov-2 vaccine development [108] . chims require infecting healthy persons with a well-characterized microorganism in order to study pathogenesis, characterize the immune response, and elucidate the efficacy of vaccines or therapeutics. sars-cov-2 chims could minimize the uncertainty about exposure or disease acquisition inherent in field trials, thereby reducing the number of participants needed to establish the desired end point, and elucidate the duration of immunity conferred by vaccines undergoing field trials [108] . importantly, ethical considerations related to sars-cov-2 chims have been raised as to whether the societal benefits are sufficient to justify the risks posed by deliberately exposing humans to sars-cov-2 [109] [110] [111] . furthermore, it is crucial to obtain a better understanding of putative interindividual differences in treatment responses. this may, among others, be related to differences in health status, pharmacokinetics (i.e., reduced drug clearance in individuals with impaired liver or kidney function) [37] , and vaccine effectiveness [112] . therefore, careful characterization of patients (i.e., detailed phenotyping) is crucial to optimize treatment responses for different subgroups of patients, taking age, sex, body fat mass and distribution, and (distinct) obesityrelated complications into account, among other factors. since obesity is a major risk factor for the development and progression of covid-19, consideration of the adiposity-based chronic disease conceptual framework of obesity [113] may be of particular importance in this case. improved strategies to deal with the dual challenges posed by the obesity and covid-19 pandemics are urgently needed. to accomplish this, a better understanding of disease pathophysiology and progression as well as vaccination and treatment opportunities are required. the current covid-19 pandemic highlights the importance of understanding shared disease pathophysiology, which may steer therapeutic choices to prevent or dampen the complications of covid-19, especially in vulnerable populations with higher risks of worse clinical outcomes such as people living with obesity and related ncds. detailed phenotyping of patients with covid-19 is essential to identify individuals or subgroups at increased risk of developing this disease and to better predict disease progression and outcomes. in particular, the putative role of (abdominal) adipose tissue in the development and progression of covid-19 warrants further investigation. the many ongoing clinical trials in patients with covid-19 will likely reveal the potential effects of different therapies. at the same time, the rapidly emerging clinical data require ongoing scrutiny to understand not only the risks and benefits of single drugs to tackle covid-19, but also the interaction with pharmacological agents commonly used in people with obesity and related ncds, including type 2 diabetes and cardiovascular diseases, who are especially at risk of or hospitalized with sars-cov-2 infection. the issues discussed in this perspective have important implications for people living with obesity, health systems, and society at large. the covid-19 pandemic will pass, but it is likely that multiple peaks will follow in the near future. in the past few months there have been a tremendous number of misleading claims about covid-19, mostly on social media, intended to cause confusion about vaccination as a way to protect against infection. researchers can and should contribute to tackling deliberately misleading and/or false information, for example by collaborating with organizations responding to such disinformation and by engaging the public in scientific discussions [114] . researchers must report research findings accurately and in an unbiased manner and should be transparent about all scientific aspects throughout the hopefully successful journey to safe and effective covid-19 vaccines and treatments. the easo will continue collaboration and discussion with its members and relevant stakeholders to discuss important issues related to preventive measures, access to care, vaccination, and future therapeutic strategies to combat the covid-19 pandemic, and will continue to advocate for the importance of research and surveillance during and after the covid-19 pandemic. the easo therefore calls on the european commission and all member states to work together to ensure that prevention and intervention strategies to manage obesity and related ncds are more readily available. obesity should be prioritized because of its major impact on the development of ncds, especially during the present covid-19 pandemic, but also thereafter to dampen the number of future covid-19 cases. since many new reports on covid-19 rapidly appear, the present perspective should be seen as a focus for discussion to drive forward our understanding, research initiatives, as well as clinical management of covid-19. all authors declare no conflict of interest in the development of this perspective, which was authored under the auspices of the easo. g.h. goossens, d. dicker, n.j. farpour-lambert, g. frühbeck, d. mullerova, e. woodward, and j.-c. holm are members of the executive committee of the easo 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of a new coronavirus clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan, china hlh across speciality collaboration, uk. covid-19: consider cytokine storm syndromes and immunosuppression validation of predictors of disease severity and outcomes in covid-19 patients: a descriptive and retrospective study apoe e4 genotype predicts severe covid-19 in the uk biobank community cohort apolipoprotein e -a multifunctional protein with implications in various pathologies as a result of its structural features possible involvement of the adipose tissue renin-angiotensin system in the pathophysiology of obesity and obesity-related disorders angiotensin ii receptors and angiotensin ii receptor antagonists physiology and pathophysiology of the adipose tissue renin-angiotensin system the renin-angiotensin system in the pathophysiology of type 2 diabetes role of the renin-angiotensin-aldosterone system and proinflammatory mediators in cardiovascular disease angiotensin-converting enzyme 2: sars-cov-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the discovery of ace2 newly recognized components of the renin-angiotensin system: potential roles in cardiovascular and renal regulation angiotensin-converting enzyme 2 is a functional receptor for the sars coronavirus sars-cov-2 cell entry depends on ace2 and tmprss2 and is blocked by a clinically proven protease inhibitor a pneumonia outbreak associated with a new coronavirus of probable bat origin evolution of the novel coronavirus from the ongoing wuhan outbreak and modeling of its spike protein for risk of human transmission. sci china life sci understanding the reninangiotensin-aldosterone-sars-cov axis: a comprehensive review cryo-em structure of the 2019-ncov spike in the prefusion conformation receptor and viral determinants of sars-coronavirus adaptation to human ace2 alveolar macrophage activation and cytokine storm in the pathogenesis of severe covid-19 renin-angiotensin-aldosterone system inhibitors in patients with covid-19 clinical and biochemical indexes from 2019-ncov infected patients linked to viral loads and lung injury remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-ncov) in vitro a human monoclonal antibody blocking sars-cov-2 infection pathogenesis of sars-cov-2 in transgenic mice expressing human angiotensin-converting enzyme 2 ongoing clinical trials for the management of the covid-19 pandemic recent discovery and development of inhibitors targeting coronaviruses rapid repurposing of drugs for covid-19 current and future use of chloroquine and hydroxychloroquine in infectious, immune, neoplastic, and neurological diseases: a mini-review chloroquine is a potent inhibitor of sars coronavirus infection and spread predictors of major infections in systemic lupus erythematosus previous antimalarial therapy in patients diagnosed with lupus 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as potential treatment for 2019-ncov acute respiratory disease haemophagocytic lymphohisticytosis -an underrecognized hyperinflammatory syndrome. rheumatology (oxford) current approaches in the grading and management of cytokine release syndrome after chimeric antigen receptor t-cell therapy. ther clin risk manag effective treatment of severe covid-19 patients with tocilizumab interleukin-1 blockade with highdose anakinra in patients with covid-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study effect of dexamethasone in hospitalized patients with covid-19: preliminary report. medrxiv valsartan improves adipose tissue function in humans with impaired glucose metabolism: a randomized placebo-controlled double-blind trial effect of angiotensin-converting enzyme inhibition and angiotensin ii receptor blockers on cardiac angiotensin-converting enzyme 2. circulation are patients with hypertension and diabetes mellitus at increased risk for covid-19 infection? can angiotensin receptor-blocking drugs perhaps be harmful in the covid-19 pandemic? effects of angiotensin ii receptor blockers and ace (angiotensin-converting enzyme) inhibitors on virus infection, inflammatory status, and clinical outcomes in patients with covid-19 and hypertension: a single-center retrospective study cardiovascular disease, drug therapy, and mortality in covid-19 renin-angiotensin-aldosterone system blockers and the risk of covid-19 renin-angiotensin-aldosterone system inhibitors and risk of covid-19 association of renin-angiotensin system inhibitors with severity or risk of death in patients with hypertension hospitalized for coronavirus disease 2019 (covid-19) infection in wuhan, china systematic review or meta-analysis? their place in the evidence hierarchy overwhelming covid-19 clinical trials: call for prospective meta-analyses a guide to prospective meta-analysis accelerating development of sars-cov-2 vaccinesthe role for controlled human infection models human challenge studies to accelerate coronavirus vaccine licensure ethics of controlled human infection to address covid-19 extraordinary diseases require extraordinary solutions increased risk of influenza among vaccinated adults who are obese the abcd of obesity: an easo position statement on a diagnostic term with clinical and scientific implications the epic battle against coronavirus misinformation and conspiracy theories key: cord-316260-1t3ifsfi authors: nogueira-de-almeida, carlos alberto; ciampo, luiz a. del; ferraz, ivan s.; ciampo, ieda r.l. del; contini, andrea a.; ued, fábio da v. title: covid-19 and obesity in childhood and adolescence: a clinical review()() date: 2020-08-04 journal: j pediatr (rio j) doi: 10.1016/j.jped.2020.07.001 sha: doc_id: 316260 cord_uid: 1t3ifsfi objective: to identify factors that contribute to the increased susceptibility and severity of covid-19 in obese children and adolescents, and its health consequences. sources: studies published between 2000 and 2020 in the pubmed, medline, scopus, scielo, and cochrane databases. summary of findings: obesity is a highly prevalent comorbidity in severe cases of covid-19 in children and adolescents; social isolation may lead to increase fat accumulation. excessive adipose tissue, deficit in lean mass, insulin resistance, dyslipidemia, hypertension, high levels of proinflammatory cytokines, and low intake of essential nutrients are factors that compromise the functioning of organs and systems in obese individuals. these factors are associated with damage to immune, cardiovascular, respiratory, and urinary systems, along with modification of the intestinal microbiota (dysbiosis). in severe acute respiratory syndrome coronavirus 2 infection, these organic changes from obesity may increase the need for ventilatory assistance, risk of thromboembolism, reduced glomerular filtration rate, changes in the innate and adaptive immune response, and perpetuation of the chronic inflammatory response. conclusions: the need for social isolation can have the effect of causing or worsening obesity and its comorbidities, and pediatricians need to be aware of this issue. facing children with suspected or confirmed covid-19, health professionals should 1) diagnose excess weight; 2) advise on health care in times of isolation; 3) screen for comorbidities, ensuring that treatment is not interrupted; 4) measure levels of immunonutrients; 5) guide the family in understanding the specifics of the situation; and 6) refer to units qualified to care for obese children and adolescents when necessary. since december 2019, the world has been surprised by the appearance, in china, of a severe pneumonia caused by a new type of coronavirus, an infection that spread rapidly throughout countries, being considered a pandemic three months later; the disease received the name coronavirus disease 2019 (covid-19). 1, 2 as in adults, but less frequently, children with comorbidities ---chronic kidney and lung diseases, malignancies, diabetes, obesity, sickle cell anemia, immune disorders, chromosomal abnormalities, heart disease, and congenital malformations ---are more likely to develop severe conditions from covid-19. 3--6 the present review aims to identify the factors that contribute to the increase in the susceptibility and severity of covid-19 in obese children and adolescents, and its health consequences, to collaborate for better clinical care of these patients. although less frequently, covid-19 affects the pediatric age group. some studies indicate that incidence of covid-19 among children and adolescents can reach 5% of confirmed cases, 7 being slightly higher in males. 3, 8 in addition, it presents with less severity when compared to adults. in the united states, in march 2020, hospitalization rates among individuals under the age of 17 ranged between 0.1 and 0.3/100,000 inhabitants. 9 likewise, mortality among children and adolescents has been shown to be low. an epidemiological study in china with 2135 individuals under 18 years of age described only one death; infants presented, proportionally, a greater number of severe and critical cases. 8 in a systematic review 10 involving 2228 patients under 16 years of age, two deaths were found, one of which was the same reported in the chinese study. 8 jped 903 1---13 +model covid-19 and obesity in childhood and adolescence: a clinical review 3 children and adolescents seem to acquire sars-cov-2 mainly through contact with infected family members. 4,11---13 however, the role of children and adolescents in transmission remains unclear; 12 the presence of sars-cov-2 in the oropharynx and stools of asymptomatic and symptomatic individuals has been described 14---16 and viral load does not differ from that of adults. 17 vertical transmission seems to be rare, with few cases described. 18---20 to date, no viable viral particles have been identified in breast milk, although sars-cov-2 rna has been detected in three samples. 21 one study reported the presence of anti-sars-cov-2 iga in breast milk of women who recovered from covid-19. 22 tests to identify the virus in the umbilical cord, placenta, and amniotic fluid have also been negative. 23---26 the incubation period observed in a series of 11 studies involving individuals under the age of 16 was two to 25 days (mean = 7). 13 most children and adolescents affected by covid-19 have mild to moderate symptoms, with a significant percentage of asymptomatic patients; 13, 27 among those with severe symptoms, a small percentage will require intensive care 13 and the highest proportion appears to be concentrated in children under 1 year of age. 28 a systematic review found that, in 13 newborns infected with sars-cov-2 during perinatal period, most remained asymptomatic or had mild symptoms. 29 the most common symptoms of sars-cov-2 infection among children and adolescents are cough and fever; sore throat, sneezing, myalgia, wheezing, fatigue, rhinorrhea, nasal obstruction, diarrhea, and vomiting; hypoxia and dyspnea are uncommon findings; 10, 11, 13, 27, 30 in a chinese study with people under 16 years of age with sars-cov-2 infection, 28.7% presented with tachypnea. 4 discrete changes ---such as leukocytosis, leukopenia, lymphopenia, and small elevation of acute phase proteins ---were the most common laboratory alterations. 4, 13, 30, 31 radiographic changes are generally less pronounced than in adults, with unilateral or bilateral irregular opacification standing out in some case series. 3, 4, 13, 31 in a systematic review that analyzed chest computed tomography of under 18 age patients, 'ground glass' opacification was observed in 37.8% of examinations, most commonly unilateral in lower lobes, and was considered mild. 32 the reasons for the lower severity of covid-19 in pediatric age group remain unanswered. some hypotheses have been raised: less exposure to sars-cov-2 due to social isolation and closure of schools; lower frequency of comorbidities and exposure to smoking when compared to adults; and greater capacity for pulmonary regeneration. 33, 34 children have less angiotensin-converting enzyme 2 (ace-2) expression than adults, making the process of internalizing the virus less efficient 35 and may have more effective trained innate immunity, which is an innate memory response of medium duration, due to increased exposure to viruses and vaccines. 33, 34, 36 this phenomenon has been used to explain the lower death rates by covid-19 in countries that carry out universal bcg vaccination, compared to those that do not adopt such strategy. 33, 34, 37 furthermore, children and adolescents do not have the immunosenescence observed in older individuals, a phenomenon characterized by, among other features, a chronic inflammatory state. 33, 34, 38 finally, particularities of the expression of ace-2 in younger individuals, as observed in animal models, 39 could limit consequences of the decreased expression of that enzyme caused by the invasion of pneumocytes by sars-cov-2, 34 especially those related to the elevation of angiotensin-ii. 40 the relationship between obesity and viral diseases has been studied for several years. during the h1n1 epidemic, this area gained particular interest, as it was observed that obese patients had a higher risk of developing the disease, longer intensive care unit (icu) stay, and higher mortality. 41 this fact was demonstrated even for children, with impairment in immune response, especially cellular, to influenza virus, and also inadequate vaccine response when they were obese. 42 recently, during the covid-19 epidemic in canada, obesity was the third most prevalent demographic factor among children admitted to the icu, behind only those with serious associated diseases, immunosuppression, and cancer. 6 in new york, obesity was the most prevalent comorbidity among 50 severe cases of covid-19 affecting children and adolescents. 43 regarding covid-19, observations at the beginning of the pandemic demonstrated the existence of risk factors, such as arterial hypertension, cardiovascular diseases, diabetes, chronic respiratory conditions, and cancer; 44 however, obesity was later included in this list. 45 in march 2020, wu et al., 46 describing the characteristics of 280 chinese patients, found a statistically significant difference between the bmi of patients with mild and moderate conditions (23.6 kg/m 2 ) and severe ones (25.8 kg/m 2 ), but this fact did not attract the attention of these researchers, because they were unable to demonstrate the independence of bmi as a risk factor. simonet et al., 47 in april 2020, showed a high prevalence of obesity among patients with covid-19 exposed to mechanical ventilation. in addition, the proportion of people who needed this intervention increased according to bmi, reaching 85.7% when bmi was over 35 kg/m 2 . 47 finally, they found that obesity was a risk factor regardless of age, gender, or presence of diabetes or hypertension, and the risk of requiring invasive mechanical ventilation was 7.36 times higher when patients with a bmi greater than 35 kg/m 2 were compared to those with bmi less than 25 kg/m 2 . 47 other studies confirmed these findings: bhatraju et al., 44 reporting the first cases in the seattle region (united states), found a mean bmi of 33.2 among 24 critically ill patients admitted to the icu. among italians hospitalized for covid-19, busetto et al. 48 found that those with overweight and obesity, even if younger, needed assisted ventilation and intensive care more frequently than patients with normal weight. data from new york, regarding 770 patients, showed that obese people were more likely to have fever, cough, and dyspnea, in addition to significantly higher rates of icu admission or death. 49 more recently, with accumulated data from three different populations, a systematic review confirmed obesity as an independent risk factor for greater severity of covid-19, including admission to the icu. finally, a very relevant finding was the demon-jped 903 1---13 +model stration, by yates et al., 50 that the risk of acquiring the disease is greater among obese people. it is still not possible to explain why the number of children affected and their manifestations vary among different regions. 51 the effects of pediatric obesity on covid19 are not yet adequately studied and some data are inferences due to the lack of considerable number of studies published on this subject in this age group. the three main risk factors that link obesity to covid-19 demonstrated for adults 52 are also present among children and adolescents: chronic subclinical inflammation, impaired immune response, and underlying cardiorespiratory diseases. virtually all comorbidities found in adults can be observed during childhood and adolescence, 53 and obese children have inadequate immune responses to other infections, such as bacterial pneumonia, 54 a common severe complications of covid-19. studies in animal models show that rats fed a high-fat diet have increased expression of ace-2 in lungs, which may help explain the greater severity of the disease among obese individuals. 55 zhang et al. showed that obesity predisposes to high mortality due to covid-19 even in young patients, aged 14 years and older 56 and it is considered that it is precisely the high prevalence of obesity among young people that can shift the age curve of mortality in countries where the prevalence of overweight is higher in this group. 57 the mechanisms involved include numerous aspects related to obesity itself and also to its comorbidities, 6 and it should be emphasized that the risks may be present even in mildest cases of obesity. 58 below, each will be covered in detail. in childhood and adolescence, even in the presence of obesity, type 2 diabetes mellitus is relatively uncommon. 59 the high pancreatic capacity of insulin production, characteristic of younger individuals, allows compensation to occur as a result of hyperinsulinism, which has a high prevalence associated with obesity. 60 although glycemia frequently remains at normal levels, the entire pathophysiological process is present, leading to several health repercussions, such as dyslipidemia, arterial hypertension, non-alcoholic steatohepatitis, micronutrients deficiencies, increased oxidative stress, and hyperuricemia. in situations of intense metabolic activity, such as during immune response to coronavirus infection, beta cells are required to produce a high amount of insulin, which may not be achieved when they are already working at their limit; 61 sars-cov-2 can also lead to rupture of beta cells, through interaction with ace-2, further aggravating this process. 61 in addition, insulin resistance leads to a reduction in phosphoinositidyl 3-kinase, impairing the vasoprotective and anti-inflammatory effects of nitric oxide. 62 dyslipidemias are highly prevalent among obese children and adolescents, 60 and low concentrations of hdlcholesterol and increased ldl-cholesterol are proven risk factors for progression of endothelial dysfunction and atherosclerosis. 63 in new york, obesity was the most important risk factor for necessity of respiratory support among 50 pediatric cases of covid-19. 43 normal respiratory physiology is usually impaired in obese patients, including children and adolescents. 64 as the lung is one of the main targets and leads to greater risks for patients with covid-19, this aspect must always be considered. in fact, hematosis is impaired in obesity, which becomes even more relevant when the exchange areas are reduced due to coronavirus action. 65 the pressure exerted by abdominal adiposity on the lungs, through the diaphragm, also acts to limit the movement of respiratory muscles, with less oxygen saturation 66 and worsening clinical presentation due to the lower lung volume of obese patients. 67 in addition, some comorbidities linked to obesity may contribute to a higher risk of pulmonary infections, such as the presence of asthma, which is highly prevalent among obese children, 68 and obstructive sleep apnea. 69 regarding asthma, the same inflammatory mechanisms linked to leptin and il-2, which explain the high prevalence and severity of this disease in obese children, 70 are also involved in the severity of covid-19. finally, in addition to aspects related to impaired lung function, obese children have low exercise tolerance, which closes a vicious circle. 71 cardiac anatomy changes linked to obesity is recognized even in very young children, in whom hypertrophy of left ventricle is observed, related to the degree of obesity and blood pressure, among other structural changes. 72 obese children and adolescents have higher blood pressure, which increases potential endothelial injury, one of the bases of covid-19 pathophysiology. 72 children, especially obese ones, treated with antihypertensive drugs that inhibit angiotensin-converting enzyme or block angiotensin receptors, have increased expression of ace-2, increasing their susceptibility to coronavirus. 73 childhood obesity increases risk of cardiovascular disease later in adulthood, and the explanation for this phenomenon lies in the fact that endothelial dysfunctions, in association with insulin resistance, effectively start during childhood. 74 the intima layer of arteries is thickened in obese children, foreshadowing the onset of atherosclerosis, which occurs very early. 75 endothelial dysfunction occurs even in the mildest cases of obesity. 76 hardening of the arteries, associated with impaired nitrogen performance and chronic oxidative stress, has been implicated in changes linked to the severity of covid-19, such as inflammation of endothelium, myocarditis, multiple organ failure, severe acute respiratory syndrome, and venous thromboembolism. 62 recent data from post mortem anatomopathological studies shows inclusion of coronavirus structures in endothelial cells, possibly through the use of ace-2 receptors in the endothelium by the virus; in these cases, accumulation of inflammatory cells, venous congestion in small pulmonary veins, and inflammation of the endothelium in the intestinal circulation have been found. 77 leptin, which is usually elevated among obese people, damages endothelium leading to less nitric oxide production and increased expression of monocyte chemoattractant protein-1, contributing to the inflammatory infiltrate in vascular cells. 62 perivascular adipose tissue contributes to vasoconstriction and endothelial dysfunction through the production of inflammatory mediators, oxidative stress, and reduction in nitric oxide production. 62 one of the most relevant aspects for understanding the severity of covid-19 among obese patients is related to inflammatory issues. 78 after coronavirus contamination, most patients develop immune defense mechanisms, which include processes related to inflammation, and this happens in a modulated way, so that the host organism is not harmed. however, some patients trigger an uncontrolled process, known as a cytokine storm, which causes tissue damage and intense homeostatic dysregulation, leading to damage of several organic functions, especially regarding the respiratory area.79 obese patients are known to have chronic subclinical inflammation, characterized by a permanent inflammatory state, albeit of mild intensity. 80 high serum concentrations of c-reactive protein and il-6 prove this process 61 which can start early. it is believed that, at least in part, this process is due to cytokines, particularly adipokines with inflammatory properties, produced by adipose tissue 61 and also the drop in adiponectin, which has anti-inflammatory properties. 81 obese people, including children and adolescents, with covid-19 are at increased risk of developing coagulopathy associated with poor clinical outcomes. chronic inflammation leads to negative regulation of anticoagulant proteins (tissue factor pathway inhibitor, antithrombin, and the protein c anticoagulation system). however, it leads to positive regulation of procoagulant factors (tissue factor pathway inhibitor) and adhesion molecules (p-selectin), in addition to increases in thrombin generation and enhanced platelet activation, increasing the risk of thrombosis. 62 in severe sars-cov-2 infections, risk of venous thromboembolism is important, as a significant percentage of patients show elevated levels of d-dimers, while others meet clinical criteria for disseminated intravascular coagulation (dic). 62 severe infections and sepsis are a leading cause of dic, and proinflammatory and immune activation observed in severe covid-19 is likely sufficient to trigger dic. 82 obesity causes several structural, metabolic, and hemodynamic changes in the kidneys, leading to a lesser functional reserve of this organ. 83 ectopic deposition of fat in renal sinus is responsible for increasing its weight and volume. hemodynamic changes lead to increased renal plasma flow and glomerular filtration rate, greater absorption of water and sodium by proximal tubules, glomerular stress, tubular hypertrophy, and glomerulomegaly, which in turn cause proteinuria and secondary glomerular sclerosis, cul-minating in chronic kidney disease. 84 the increase in body weight and consequent reduction in urinary ph predispose to urinary lithiasis due to increased excretion of urinary oxalate, sodium, phosphate, and uric acid; obesity can also favor the appearance of some types of neoplasia in renal tissue. 85 the dysregulation of lipid metabolism and hormonal responses also play a role in deterioration of renal function. oxidative stress caused by increased fat deposition promotes inflammation, cellular hypertrophy, increased mesangial matrix, apoptosis, endothelial dysfunction, and renal fibrosis. 86 fatty acids released by adipocytes stimulate secretion of tumor necrosis factor (tnf)-alpha by macrophages, resulting in increased secretion of il-6 in adipocytes, amplifying inflammation in renal tissue. while tnf-alpha plays a fundamental role in progression of renal fibrosis, the increase in intracellular lipids has a nephrotoxic effect (culminating in glomerulosclerosis), compromising the structure and functioning of mitochondria, which contributes to progression of kidney disease. 87 increased insulin production and insulin resistance contribute to mesangial expansion and renal fibrosis, and the observed activation of the renin-angiotensin-aldosterone system, since the vasoconstrictor effect of angiotensin ii on renal arterioles leads to increased production of endothelin-1, stimulating proliferation of mesangial matrix, sodium retention, and vasoconstriction of renal arterioles. 88 coronavirus can cause acute kidney damage in up to 15% of cases, which contributes to mortality. aggression is due to direct cytotropic effect induced by the virus through ace-2, which is highly expressed in the kidney, 89 and inflammatory response caused by cytokines due to activation of the renin-angiotensinaldosterone system. 90, 91 in addition, acute tubular necrosis and thrombotic effects secondary to endothelial dysfunction are also observed in covid-19. 92 intestinal microbiota is a complex ecosystem with thousands of bacterial phyla and several species distributed throughout digestive tract. it is mostly composed of anaerobic microorganisms and about 90% of fecal bacteria belong to two phylogenetic lineages: firmicutes and bacteroidetes. 93 colonization occurs from birth and is individually different, changes over time, and can be influenced by eating habits or diseases, such as obesity and metabolic syndrome. several studies have demonstrated a correlation between firmicutes/bacteroidetes ratio in both obese children and adults, suggesting intestinal dysbiosis. 94 regarding patients with covid-19, there are reports of intestinal dysbiosis and a decrease in intestinal lactobacillus and bifidobacterium populations, and some hospitalized patients were treated with probiotics in order to regulate microbiota balance and reduce risk of infection secondary to bacterial translocation. 95 obesity in childhood and adolescence alters entire immune system, changing concentrations of cytokines and proteins and the number and function of immune cells. this imbalance leads to a pro-inflammatory state, resulting in the onset or exacerbation of several diseases such as asthma, allergy, atopic dermatitis, and sleep apnea. 96 in relation to covid-19, whose severe conditions evolve with an intense and severe systemic inflammatory reaction (cytokine storms), the imbalance of immune system observed in obesity may contribute to a worse clinical outcome. 79 adipocytokines, especially leptin, play an important role in this process, as they influence number and function of immune cells through directly effects on cell metabolism. in this context, there may be an increase in cytotoxic and effector t-cells (th1 and th7) and m1 macrophages and, in parallel, a reduction in treg cells and m2 macrophages. however, other molecules that are influenced by nutritional status also act on immunity, which may be increased (il-1␤, il-6, il-8, il-10, il-1ra, resistin, visfatin, tnf-␣, mcp-1, mif, mip1 alpha and beta) or reduced (adiponectin, il-33) in obese patients. 62 in addition, imbalance between actions of lymphocytes treg and cd17+ also contributes to the proinflammatory state observed in obesity. 97 furthermore, in obesity, macrophages cells constitute about 40% to 60% of cells of immune system derived from visceral adipose tissue; these macrophages are mostly activated (m1) and secrete high amounts of tnf-alpha, il-6, il-12, il-1b, mcp-1, and nitric oxide. 97 nutrition plays an important role in immune and inflammatory response, since some nutrients modulate cellular and humoral defense systems, either by modifying formation of inflammatory mediators or interfering with cellular signal transduction pathways. nutrients have an immunomodulatory action by stimulating the cell-mediated response, modifying the balance between pro-inflammatory and antiinflammatory cytokines, and attenuating depletion of tissue nutrients. 98 immune response depends on the sufficient supply of nutrients and adequate nutritional status has been considered an important element for coronavirus capacity response. zhang & liu, 99 in a systematic review, showed that some nutrients are fundamental for adequate response to coronavirus: vitamins a, c, d, and e; omega 3 fatty acids; and the minerals zinc and iron. a suitable qualitative and quantitative supply allows to maintain and repair defense systems, which require adequate energy and structural support. 100 obesity has peculiarities that may impair immune response, because diet often has characteristics that can lead to ''hidden hunger.'' this is because, despite eating above energy needs, quality is not adequate; numerous studies point to vitamin and mineral deficiencies in those with excess weight. 101 among the most common nutritional deficiencies, hypovitaminosis d stands out, not only linked to insufficient intake, but also, and mainly, to the displacement of part of the organic pool to adipose tissue due to the lipid affinity of this vitamin. 102 additionally, it is known that a sedentary lifestyle is characteristic of obese children, causing the practice of physical activities outdoors ---which would increase exposure to sun and skin formation of vitamin d ---to be reduced in this group. 102 several studies have linked hypovitaminosis d to an increased risk of severe covid-19, 78 which makes this issue particularly relevant in the pediatric obese popu-lation, where the prevalence of this deficiency is high. 103 vitamin d (vd) has immunomodulatory effects, and activated t-lymphocytes and antigen presenting cells, such as macrophages and dendritic cells, express vd receptor in their membranes, leading to anti-proliferative and immunosuppressive effects on immune system cells. it inhibits secretion of il-12 by macrophages, a fundamental cytokine in differentiation of cd4+ t-lymphocytes in th1 cells. 104 by decreasing activation of th1 response and production of pro-inflammatory cytokines (il-2, interferon-␥, tnf-␣), vd contributes to the targeting and activation of th2 response, favoring greater secretion of anti-inflammatory cytokines, such as il-4. 104 this immunosuppression mechanism is important to minimize deleterious effects in transplants, and in autoimmune and inflammatory diseases. although vd induces th2 response, it also induces expression of antimicrobial peptides in neutrophils and monocytes, as well as promotes an increase in phagocytic capacity and rapid release of reactive oxygen species. 104 induction of cathelicidins and defensins, caused by vd, reduces viral replication and concentration of proinflammatory cytokines that have potential for lung injury in cases of covid-19. 105 additionally, hypovitaminosis d has repercussions for disorders with potential impact on covid-19, such as arterial hypertension, hepatic steatosis, and hyperuricemia. 106 omega-3 fatty acids are considered essential lipids for humans. eicosapentaenoic (epa) and docosahexaenoic (dha) fatty acids are biologically more potent immunomodulators than alpha-linolenic acid. epa and dha decrease activity of nuclear transcription factors that promote transcription of genes that encode proteins with pro-inflammatory action, such as tnf-␣ and il-1␤. 107 in addition, epa and dha compete with arachidonic acid (omega-6) in the constitution of plasma membrane phospholipids and, consequently, for the metabolism of cyclooxygenase in cell membrane, modulating the production of prostaglandins and leukotrienes. 108 higher concentrations of epa and dha favor synthesis of series-3 prostaglandins and series-5 leukotrienes, which attenuate inflammatory response; and inhibit production of series-2 prostaglandins and series-4 leukotrienes, which depress thecytotoxic activity of macrophages, lymphocytes, and natural killer cells, 109 with a consequent reduction in synthesis of pro-inflammatory cytokines such as il-1, il-6, and tnf-␣. 107 immunomodulation exerted is dependent on omega-3/omega-6 ratio: a 1:5 ratio does not impair immune response; however, western diets provide a ratio of 1:15 to 1:50, with pro-inflammatory effects. 110 consumption of omega-3 fatty acids, especially dha, is low in most countries in the world, including brazil. 111 although omega-3 precursors are present in vegetable oils, their conversion into dha is low and the very excess of omega-6 intake diverts the converting enzymes, further impairing the formation of dha and contributing to a high deficiency prevalence. inadequate proportion of omega-3/omega-6, common in obese children, 112 leads to loss of modulation of immune response, which may contribute to exacerbation of inflammatory reactions, in addition to aggravating cardiometabolic risks. 113 vitamins a, e, and c are fundamentally found in fruits and vegetables, usually little consumed by children and adolescents, including obese ones. 114 impaired nutritional status of these vitamins may impact immune response. 115 immune cells are at constant risk of oxidative damage by jped 903 1---13 +model covid-19 and obesity in childhood and adolescence: a clinical review 7 free radicals, which can permanently impair their ability to respond to pathogens. increased amounts of free radicals in activated macrophages are part of normal response. vitamin e (ve) acts as an antioxidant and protects the cell membrane against reactive oxygen species. 114 animal studies have shown that ve supplementation increases resistance to infections, including influenza viruses. 116 vitamin a (va) guarantees the regeneration of the mucosal barriers damaged by infection and supports protective function of macrophages, neutrophils, and natural killer cells. 117 it is also necessary for adaptive immunity and plays a role in development of t-and b-cells. like vd, va can prevent production of il-12 cytokines by macrophages, decreasing activation of the th1 response and increasing th2. 117 va deficiency impairs th2 response, which culminates in a lack of il-4 and fails to induce iga, impairing salivary iga response to influenza virus infection, and intestinal response to cholera toxin. 117 vitamin c (vc) contributes to the integrity of the epithelial barrier and accumulates in phagocytic cells, such as neutrophils, which improves chemotaxis; phagocytosis; production of reactive oxygen species; and induces microbial death. 118 it also contributes to apoptosis and removal of neutrophils, which have suffered cell death, from infection sites, reducing necrosis and possible tissue damage. 118 vc seems to promote differentiation and proliferation of b-and t-cells, probably due to its genetic regulatory effect. 118, 119 deficiency also impairs cytotoxic capacity of neutrophils and t-lymphocytes. 114 vc supplementation appears to be able to prevent and treat respiratory and systemic infections, 118, 119 and a recent review highlights vc, as well as zinc and vd, as micronutrients with stronger evidence regarding their role in immunity. 120 in relation to iron, obese children are at risk for iron deficiency anemia 121 due to the low nutritional quality and low iron bioavailability of the diet 122 and anemia has been widely demonstrated in this group. 123 in addition to inadequate intake, hepcidin, the main controller of iron absorption, has increased expression in obese individuals, contributing to the condition by reducing absorption of iron by enterocytes and their export by macrophages and hepatocytes, increasing splenic and hepatic sequestrations. 124 due to the fact that they have similar nutritional sources, zinc deficiency is also believed to be present among obese children in the same way as iron deficiency, and this has been demonstrated in studies in pediatric age group. 125 it should be noted that, in addition to its immunological role, zinc also participates in insulin and leptin metabolism, which can aggravate metabolic dysregulations in obese children, contributing to inadequate inflammatory response. 126 zinc acts as a cofactor for the enzyme superoxide dismutase, which reduces cellular oxidative stress and decreases activation of signaling pathways that promote inflammatory response. 127 it induces monocytes to produce il-1 and il-6, and to inhibit the production of tnf-␣, and is also involved in regulation of peroxisome proliferator-activated receptors (ppars), whose activation is positively correlated with decrease in inflammatory response. the direct influence of zinc on immune system is due to its ability to stimulate activity of enzymes involved in mitosis. 128 zinc deficiency is related to decreased production of cytokines and interferon-␣ by leukocytes, atrophy of the thymus and other lymphoid organs, and changes in the proportion of lymphocytes. 128 if, on the one hand, obese patients exhibit covid-19 with particular characteristics, on the other hand, the pandemic has also led to socioeconomic changes that may impact childhood obesity, 129 especially among the poorest. 130 in this sense, an important study projected the impact of covid-19 pandemic on the prevalence of childhood obesity in united states, according to different scenarios: 131 closing schools for two months; school closures for two months associated with a 10% drop in physical activity in two subsequent months of summer; adding two more subsequent months of closed schools; adding two more subsequent months of school closures. the increase in prevalence of obesity would be 0.640, 0.972, 1.676, and 2.373 percentage points, respectively. in italy, pietrobelli et al. 132 followed 41 obese children and adolescents during three weeks of lockdown in verona and found no changes in vegetables consumption, but observed increased consumption of fruits, chips, red meat, and sugary drinks; the time spent in sports activities was reduced by two and a half hours per week and, in contrast, sleep period increased by 0.65 h/day; and the most impactful data refers to screen time, which increased by 4.85 h/day. an interesting aspect is the idea often disseminated in lay texts that physical activity should be avoided to protect immunity and supposedly that exercise could reduce body's defenses, a fact that has not been scientifically demonstrated, even among athletes. 133 on the contrary, physical activity is important for the proper formation of vd when performed outdoors. 102 in fact, with regard to situations related to sedentary lifestyle, such as watching tv or playing video games, changes occur that are related to higher risk of obesity, such as high consumption of fast food and sugar-sweetened beverages, 134 in addition to sleep disorders. 135 in relation to this last aspect, the covid-19 pandemic brings high risks for health, as several factors can contribute to quality and duration of sleep being unsatisfactory, such as stress in face of illness, interruption of activities in the morning, time available for screen use, etc. 132 in this sense, in addition to predisposing to weight gain and abdominal adiposity, sleep disorders have other health repercussions, such as insulin resistance, deterioration in food quality, poor school performance, and sedentary lifestyle. 136 living with stress during covid-19 pandemic, in addition to bringing risks of deterioration of immunity, 137 may have consequences for pediatric health, in particular for nutritional and emotional areas. 138 one such consequence refers to the worsening of sleep quality, discussed above. additionally, stress increases food consumption, activates brain reward centers that raise interest in highly palatable foods (sugar, salt, and lipids), increases emotional instability, and worsens quality of life. 138 due to the prolonged time of social isolation, another aspect demonstrated in the united states was a drop in adherence to immunization programs, due to the fear of taking children to vaccinate. 139 finally, a brazilian study showed a high incidence of peri-obstetric mortality due to covid-19 140 and this fact, in cases where delivery is feasible, may lead to a large number of infants being deprived of breastfeeding, known as a protective factor against obesity. 141 the present review has two important limitations. the first is that it is not possible, currently, to carry out a systematic review of the literature with the expected rigor in study classification, since most of published data is based on observations made less than a year ago and, generally, refer to observational and cross-sectional studies. the second is that there are few publications referring to the pediatric age group, which means that some information is, in fact, inferences about the approach to the disease in children and adolescents, based on what is observed in adults. when the patient presents with mild covid-19 symptoms, the treatment is only symptomatic and recovery is usually complete, 142 ranging from supportive measures for mild cases (isolation, hygiene, rest, hydration, and attention to food intake) to invasive hospital procedures, such as mechanical ventilation. the convalescence period may range from one to three weeks in mild case, or up to six weeks for the most severe. 143 non-obese children are usually asymptomatic and even less susceptible to the infection. 144 in these cases, telemedicine alternatives have been proposed in order to help families receive adequate guidance without the need to travel. 129 however, for those who develop the most severe forms, the coexistence of obesity can hinder therapy and worsen prognosis, since the inflammatory condition is as severe as in adults. 145 also, extensive involvement of the cardiopulmonary system is frequent 146 and respiratory disorders such as pickwick syndrome, obstructive apnea, and surfactant dysfunctions may be present. 147 there are also technical issues, such as the fact that many pieces of equipment may not adequately adapt to the obese patient 148 and the greater difficulty of intubation of obese patients, which may lead to the occurrence of lesions and longer periods of hypoxia while the procedure is being completed. 148 nursing care is always more difficult: the possibility of more precarious hygiene and secondary contamination, as well as harder venipuncture and more likelihood to cause injury; control procedures such as blood pressure measurement and cardiac auscultation are more difficult and more error-prone; and the risk of bedsores during intensive care unit stay is always higher the higher the patient's weight. 149 for families, supportive measures that provide high quality information and guidance to help them make decisions on medications, the need to go to the emergency room, and how to conduct emergency care are essential. 129 for adolescents, adequate information can often aid to minimize extreme behaviors, both in the aspect of excessive fear, for some, and in the sense of invulnerability, for others. 150 fig . 1 shows a brief synopsis regarding the relationships between obesity and covid-19. in conclusion, obesity in childhood and adolescence can be considered a risk factor for greater susceptibility and severity of covid-19 and is associated with nutritional, cardiac, respiratory, renal, and immunological alterations, which may potentiate the complications of sars-cov-2 infection. the need for social isolation can have the effect of causing or worsening obesity and its comorbidities, and pediatricians need to be aware of this issue. it is necessary that health professionals, when faced with the care of children with suspected or confirmation of covid-19, carry out the assessment of 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and youth united states adolescents' television, computer, videogame, smartphone, and tablet use: associations with sugary drinks, sleep, physical activity, and obesity relationship between sleep duration and childhood obesity: systematic review including the potential underlying mechanisms the immunopathobiology of t cells in stress condition: a review the mutual effects of covid-19 and obesity effects of the covid-19 pandemic on routine pediatric vaccine ordering and administration ---united states the tragedy of covid-19 in brazil: 124 maternal deaths and counting every month matters: longitudinal associations between exclusive breastfeeding duration, child growth and obesity among wic-participating children coronavirus disease 2019 and children: what pediatric health care clinicians need to know the immune system and covid-19: friend or foe? kaushal r, editors. reopening us schools in the era of covid-19: practical guidance from other nations hyperinflammatory shock in children during covid-19 pandemic clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with sars-cov-2 obesity as a risk factor for complications during acute respiratory infections in children the obese child in the intensive care unit what evidence informs the nursing care of people with class iii obesity in an acute care setting? a scoping review attitudes and psychological factors associated with news monitoring, social distancing, disinfecting, and hoarding behaviors among us adolescents during the coronavirus disease 2019 pandemic the authors declare no conflicts of interest. key: cord-265139-x7g3jcjm authors: zaiou, mohamed title: the emerging role and promise of circular rnas in obesity and related metabolic disorders date: 2020-06-16 journal: cells doi: 10.3390/cells9061473 sha: doc_id: 265139 cord_uid: x7g3jcjm circular rnas (circrnas) are genome transcripts that are produced from back-splicing of specific regions of pre-mrna. these single-stranded rna molecules are widely expressed across diverse phyla and many of them are stable and evolutionary conserved between species. growing evidence suggests that many circrnas function as master regulators of gene expression by influencing both transcription and translation processes. mechanistically, circrnas are predicted to act as endogenous microrna (mirna) sponges, interact with functional rna-binding proteins (rbps), and associate with elements of the transcriptional machinery in the nucleus. evidence is mounting that dysregulation of circrnas is closely related to the occurrence of a range of diseases including cancer and metabolic diseases. indeed, there are several reports implicating circrnas in cardiovascular diseases (cvd), diabetes, hypertension, and atherosclerosis. however, there is very little research addressing the potential role of these rna transcripts in the occurrence and development of obesity. emerging data from in vitro and in vivo studies suggest that circrnas are novel players in adipogenesis, white adipose browning, obesity, obesity-induced inflammation, and insulin resistance. this study explores the current state of knowledge on circrnas regulating molecular processes associated with adipogenesis and obesity, highlights some of the challenges encountered while studying circrnas and suggests some perspectives for future research directions in this exciting field of study. whole-genome sequencing studies reveal that our genome comprises approximately 3 to 3.2 billion base pairs of dna, but merely 1-2% of those pairs correspond to the annotated exons of protein-coding genes. the remaining 98-99% have been referred to as "junk dna" or "dark matter" with no obvious function in the cell [1] . currently, major scientific advances in the field that have occurred upon implementation of novel and sensitive molecular approaches to genome-wide transcriptome analysis [2] , have totally changed the way we look at the vast "noncoding" regions of the human genome. what was once considered "junk dna" because of its lack of function is now viewed as a treasure. it is becoming known from multiple studies that junk dna can be almost entirely transcribed, generating a huge number of functional transcripts commonly referred to as noncoding rnas (ncrnas) although many of their functions remain enigmatic [3, 4] . according to the biological functions of ncrnas, they can be classified into infrastructural and regulatory types. infrastructural ncrnas include ribosomal rnas (rrnas), transfer rnas (trnas), and small nuclear rnas (snrnas) and are typically expressed constitutively, whereas regulatory ncrnas consist mainly of micrornas (mirnas), long noncoding rnas (lncrnas), circular rnas (circrnas), and piwi-interacting rnas (pirnas). inconsistent with the "central dogma of biology" that describes the flow of genetic information from gene to mrna and finally to protein, ncrnas are generally not further translated into proteins [5] . although they do not encode proteins, these rna molecules can still be endowed with critical regulatory function and may help orchestrate a hidden layer of gene regulation networks [6] . as a matter of fact, circumstantial evidence revealed that ncrnas can act as critical switches that fine-tune target gene expression [7, 8] . from a clinical perspective, several transcriptomic studies have unveiled that a large number of ncrnas can be altered in major diseases [9] clearly hinting towards the potential therapeutic application of these rna molecules in disease therapy. as stated before, there are different types of ncrna transcriptomes with varied functions; among the most relevant are small ncrnas such as mirnas (18-24 nucleotides (nt.)), lncrnas (>200 nt.), and circrnas (median length is~530 nt.). in recent years, considerable attention has focused on circrnas, which are distinguished from their linear counterparts by the unique structure of covalently closed continuous loop lacking 5 cap and 3 poly-adenylated tails [10] . this feature makes circrnas remarkably stable and resistant to degradation by exonuclease and rnases, therefore, they are proposed as new generation of predictive biomarkers and potential therapeutic targets for many diseases. even though evidence of their biological relevance and clinical significance in human disease pathogenesis is continuously emerging, our current knowledge of circrnas remains preliminary in metabolic diseases and obesity in particular. additionally, to the very best of my knowledge, there is hardly any comprehensive coverage on the role of circrnas in the pathogenesis of obesity. hence, the next sections will discuss relevant literature in the field and highlight some of the key aspects of circrnas and challenges ahead. contrary to conventional splicing forming a linear rna, circrnas are generally derived from precursor mrna back-splicing, a molecular event in which a downstream 5 splice site is joined to a downstream 3 splice site to form a covalently closed circular structure [11] . even though the specific and detailed mechanisms mediating circrnas biogenesis are not fully understood, several models have been proposed, including direct back-splicing with arthrobacter luteus (alu) elements and inverted repeats complementation, lariat-driven circularization (exon skipping), and rna-binding-protein (rbp) mediated models [12] . based on their sequences, circrnas can be generally classified into three categories: i) exonic circrnas (ecircrnas), which are generated only from the exon regions, account for most (over 80%) known circrnas, and are found mainly in the cytoplasm; ii) circrnas derived from lariat introns (cirnas) predominantly located in nuclei; and iii) circrnas derived from exons with retained introns (eicirnas) and can be mainly found in nuclei [10, 11, 13] (figure 1 ). previous analysis of the number of circrnas from their host genes revealed that one gene could produce multiple circrna isoforms, with nearly 50% of the host genes expressing one circrna at significantly higher levels [14] . concerning circrnas turnover, exosomes have been proposed as one of the mechanisms by which these transcripts might be cleared from the cell [15] , but further studies are required to explore the regulatory factors involved in the control of circrnas metabolic turnover. pre-mrna can also be spliced in the noncanonical manner "backsplicing", wherein a downstream splice donor site is joined to an upstream splice acceptor site to produce circular rna molecules. three different types of circrnas can arise from different genomic positions and combinations, including: (1) exonic circrnas (ecircrnas), (2) exon-intron circrnas (eicirnas), and (3) circular intronic rnas (cirnas). the formation mechanisms and potential functions of these circrna types are discussed in the text. according to the published literature, circrnas share several features. they are highly stable in cells due to their unique structure, and with most species, the average half-life period of these molecules is about 48 h which is much longer than that of mrnas (10 h) [16] . however, this may not be the case for exonic circrnas in serum, presumably due to circulating rna endonucleases. circrnas are evolutionarily conserved among species, diverse, often show tissue or development stage-specific expression patterns and have determined subcellular localization [16] [17] [18] . the abundance of circrnas relative to their linear rna counterparts varies between cell types [19] . they are abundant in exosomes and often found in extracellular fluid (like saliva, blood, and urine) with an expression level ten times higher than that of linear mrnas [20] . their size ranges from hundreds to thousands of nucleotides, while most of these rna species in mammals and plants are hundreds of nucleotides [16, 21] and usually contain between one and five exons [18] . although the exact function of most circrnas is still ambiguous, several studies have indicated that circrnas may control multiple biological processes via a variety of mechanisms. they can serve as mirna sponges, which in turn influence target mrna translation [18, 22] . in other words, circrnas that contain mirna recognition elements (mres) can interact with mirnas by stable complementary base pairing [23, 24] to inhibit their activity, and thus, effectively alter their role in the pre-mrna can also be spliced in the noncanonical manner "back-splicing", wherein a downstream splice donor site is joined to an upstream splice acceptor site to produce circular rna molecules. three different types of circrnas can arise from different genomic positions and combinations, including: (1) exonic circrnas (ecircrnas), (2) exon-intron circrnas (eicirnas), and (3) circular intronic rnas (cirnas). the formation mechanisms and potential functions of these circrna types are discussed in the text. according to the published literature, circrnas share several features. they are highly stable in cells due to their unique structure, and with most species, the average half-life period of these molecules is about 48 h which is much longer than that of mrnas (10 h) [16] . however, this may not be the case for exonic circrnas in serum, presumably due to circulating rna endonucleases. circrnas are evolutionarily conserved among species, diverse, often show tissue or development stage-specific expression patterns and have determined subcellular localization [16] [17] [18] . the abundance of circrnas relative to their linear rna counterparts varies between cell types [19] . they are abundant in exosomes and often found in extracellular fluid (like saliva, blood, and urine) with an expression level ten times higher than that of linear mrnas [20] . their size ranges from hundreds to thousands of nucleotides, while most of these rna species in mammals and plants are hundreds of nucleotides [16, 21] and usually contain between one and five exons [18] . although the exact function of most circrnas is still ambiguous, several studies have indicated that circrnas may control multiple biological processes via a variety of mechanisms. they can serve as mirna sponges, which in turn influence target mrna translation [18, 22] . in other words, circrnas that contain mirna recognition elements (mres) can interact with mirnas by stable complementary base pairing [23, 24] to inhibit their activity, and thus, effectively alter their role in the posttranscriptional regulation of target gene expression. to cite a few examples, the cerebellar degeneration-related antigen 1-antisense circrna (cdr1as, also known as cirs-7), which is highly expressed in the mammalian brain and upregulated during neuronal development [25] , contains up to 74 binding sites for the mir-7 and can act as a decoy or sponge for this mirna [18] . in human cells, knockdown of cdr1as expression suppresses mir-7 expression and affects insulin secretion, cell proliferation and the pathobiology of myocardial infarction [26] [27] [28] . likewise, sex determining region y (sry)-derived circrna (circsry), which is expressed in murine testis and harbors 16 mir-138 conserved binding sites, has also been shown to act as a mirna sponge [23, 24] resulting in gene expression dysregulation. in addition to circrnas found in the cytoplasm compartment, a fraction can accumulate inside the nucleus (cirnas and eicirnas) where they control gene expression at the transcriptional level. these intron-retaining circrnas can interact with upstream promoters, rna polymerase ii (pol ii), and other proteins of the transcription machinery to regulate their parental gene expression in some circumstances [29] [30] [31] . for example, the cirnas, ci-ankrd52 and ci-sirt-7, are able to accumulate at transcription sites and enhance their parental genes expression, ankyrin repeat domain 52 (ankrd52) and sirtuin 7 (rirt7) respectively, through interaction with pol ii elongation complex [30, 32] . circeif3j and circpaip2, two exon-intron circrnas, are an additional example of circrnas exclusively localized in the nucleus and able to regulate the transcription of their parental genes through interactions with u1 small nuclear rna (snrna), pol ii, and promoter regions [29] . in addition, circrnas may also be implicated in alternative splicing regulating transcription, translation, and mirna levels [18] . circrnas can also serve as protein decoys or antagonists to influence gene expression and cellular function. in line with this, rna-binding proteins (rbps) harbor specific sequences to bind their specific rna targets and regulate several cellular and molecular processes [33] . the interaction between circrnas and rbps was explored recently and was shown to affect the fate of their target mrnas. for instance, circular rna poly (a) binding protein nuclear 1 (circpabpn1) can recruit the rbp human antigen r (hur) to suppress its interaction with pabpn1 mrna, which leads to reduced pabpn1 translation [33] . in vascular tissue, circular antisense noncoding rna in the ink4 locus (circanril) sequesters pescadillo homologue 1 (pes1) which is an essential 60s-preribosomal assembly factor to impair rrna maturation, resulting in apoptosis [34] . circfoxo3 interacts with p21 and cyclin-dependent kinase (cdk2) to form a complex that impacts cell survival and proliferation [31] . additionally, several circrnas have been shown to bind, store, and even insulate rbps from specific subcellular sites [35] , but the exact mechanism of dynamic interactions between circrna transcripts and various proteins remains partially explored. advances in this field may come from the emergence of novel high-throughput experimental technologies and innovative machine learning models for predicting rbp-binding sites on rnas. in this context, a new computational model designated circslnn is now available to predict potential rbp sites in circrna sequences [36] . although circrnas have been defined as a distinct class of ncrnas that do not code for proteins, intriguingly, recent studies have indicated that some circrnas may have an unexpected protein-coding potential [37] , when recognized by ribosomes in the presence of internal ribosome entry sites (iress) [38, 39] . like lncrnas, certain circrnas may contain putative short open reading frames (orfs) with the capacity to encode small peptides [40] . there are multiple examples in the literature of specific circrnas that can encode peptides or proteins. for instance, circ-znf609 can make a protein functioning in muscle development [41] . the circβ-catenin that is derived from the β-catenin gene has been shown to encode a novel 370-amino acid β-catenin isoform [42] . zhang et al. reported that the circular form of linc-pint (long intergenic non-protein coding rna, p53 induced transcript) can be translated into a small peptide to suppress glioblastoma cell proliferation [43] . however, in which condition is circrnas translation prevalent and what role do the putative peptide/protein products play are important questions that must be asked. in addition, even though several mechanisms for circrnas translation have been proposed [39, 43] , further in-depth studies are required which may help to unravel the mystery of these rnas species. moreover, if the translation process of circrnas turns out to be true, this could represent additional evidence that these transcripts are functional molecules. such a new perspective could be considered as the first step to understanding the hidden human proteome encoded by ncrnas and highlight specific avenues for future research. in addition to the above-mentioned functions, it has been suggested that circrnas found in these extracellular vesicles could serve as essential messengers for inter-cellular/inter-tissue cross-talk as released exosomes can be taken up by other cells [15, 44, 45] . it has also been indicated that circrna can serve to protect mrna from degradation. as an example, a circrna named circpan3 appears to protect mrnas encoding the cytokine receptor subunit il-13rα (il13ral) from an mrna decay protein, k-homology splicing regulatory protein (ksrp), and promote the production of il-13rα1 in crypt mouse multipotent intestinal stem cells [46] . other studies have indicated that circrnas could play a role in the storage, sorting, and localization of mirnas [47] . nevertheless, despite the significant progress toward understanding circrnas molecular biology, a unified explanation for the function of most of these rna species is still lacking and knowledge of their regulatory mechanisms remains rudimentary. additionally, it is not known how circrnas are retained in the nucleus or exported to the cytoplasm. all these limitations may slow advances to develop circrnas as biomarkers and therapeutic tools for specific diseases. although the state of the current knowledge of circrnas biology is at a very early stage, mounting evidence points to their role as master regulators of gene expression in many diseases including metabolic disorders. in accordance with this observation, a growing number of studies revealed the dysregulation of circrnas in association with the pathophysiology of several diseases such as diabetes, hypertension, cardiovascular diseases (cvd), and other metabolic perturbations [48, 49] . for example, the aberrant expression of certain circrnas was associated with the development of diabetes. in islet cells, the overexpression of cdr1as significantly increased insulin mrna level and granule secretion in β cells via cdr1as/mir-7 pathway [27] . in heart function, existing evidence showed that the heart-related circrna (hrcr) can prevent cardiac hypertrophy and heart failure by acting as an endogenous sponge for mir-223 [50] . furthermore, circrna myocardial infarction-associated circular rna (micra) showed prognostic significance as a biomarker for risk stratification of heart failure after myocardial infarction [51] . circznf609, one of the abundantly expressed circrnas in endothelial cells, was significantly upregulated upon hypoxia and high glucose exposure in vitro, as well as in patients affected by diabetes mellitus, hypertension, and coronary heart disease [52, 53] . in atherosclerosis, cdkn2b-as1 or anril is perhaps one of the molecularly best-studied circrnas. based on previous studies, circanril is an antisense circrna generated by the 9p21 locus, whose single nucleotide polymorphisms (snps) have been linked to genome-wide association studies (gwas) on atherosclerotic vascular disease, as well as to type 2 diabetes mellitus (t2dm) and other diseases [34, 54] . additionally, circanril has been found to confer atheroprotection by controlling rrna maturation and modulating pathways of atherogenesis [34] . there is also growing evidence that circrnas are closely linked to non-alcoholic fatty liver disease (nafld), a disorder that is caused by a plethora of factors including hepatic lipid accumulation, adipose tissue and mitochondrial dysfunction, a high-fat diet, obesity, a chronic inflammatory state, insulin resistance (ir), and genetic and epigenetic factors [48, 55] . finally, although more functional circrnas are being gradually identified and some advances have been achieved in atherosclerosis, diabetes, hypertension, and cvd, the role of circrnas in connection with dysregulated adipogenesis and obesity remains largely elusive and needs to be explored further. the next section focuses mainly on relevant circrna networks implicated in obesity from an epigenetic perspective. obesity and its metabolic consequences have been considered as one of the most threatening health burdens of modern times. multiple investigations have brought forward evidence that obesity is a complex condition with multiple etiologies which develop as a joint effect of a variety of factors such as biological, genetic, social, environmental, and behavioral determinants [56, 57] . the pathogenesis of overweight and obesity has been associated with altered adipose tissue metabolism and represents an important driving factor for many human metabolic disturbances and serious comorbidities including t2dm, cvd, and certain types of cancer [58, 59] . in addition to its association with chronic diseases, obesity is also thought to increase the risk of developing severe forms of respiratory failure. indeed, emerging studies revealed a strong association between obesity and the ongoing pandemic of coronavirus disease (covid-19), which is caused by infection with severe acute respiratory syndrome coronavirus 2 (sars-cov-2) [60, 61] . thus, the inexorable global rise of obesity will be the toughest challenge to face and demands novel and more effective therapies. evidence for a large contribution of genetic variation to inter-individual differences in body mass index (bmi) comes from twin, human linkage, and association studies of large cohorts. heritability estimates for bmi range from 31-90% across different family studies [62] , leaving the remaining variance attributed to environmental factors. however, the genetic variations, measured through familial studies, affecting obesity and variations identified at different loci, together have been estimated to explain no more than 30% of the phenotypic variation [63, 64] . hence, the "missing heritability" could be attributed to many more susceptibility factors that remain to be uncovered. one of the suggested mechanisms that may account for the missing heritability is relative to epigenetic programs. epigenetics can be defined as acquired changes in chromatin structure through cell division that arise independently of an alteration in genomic dna sequences [65] . epigenetic changes are dynamic and potentially reversible marks affecting gene regulation. they can include three main categories: dna methylation, histone modifications, and ncrnas [66] . ongoing research is revealing the extent of the influence of epigenetics in many diseases. in support of this claim, epigenetic differences between individuals have been found to contribute to the explanation of the monozygotic twin discordance rates for common phenotypes [67] . while dna methylation and histone modifications occur at the level of chromatin and are well-recognized as drivers for the disease phenotype, ncrnas represent a relatively new concept in epigenetics and act mainly at the transcriptional and posttranslational levels. concerning obesity, studies have reported that epigenetic change plays a key role in the occurrence and development of this medical condition [68] . in addition to classical epigenetic modifications, a variety of ncrnas have been uncovered in different cells and organs including adipose tissues, many of which are involved in the regulation of adipogenesis and other metabolic processes implying their role in the etiology of obesity [69] . while lncrnas and mirnas are extensively investigated in obesity biology [69] [70] [71] , studies of circrnas in this respect have just begun. despite the established link between circrnas and several metabolic diseases, investigations on the potential connection between circrnas and adipogenesis remain rare. currently, there are few emerging studies extending the scope of the disease-relevant role of circrnas to obesity and underlying mechanisms. hence, a review of examples in the literature, suggesting key regulatory roles of circrnas in many biological processes associated with obesity, including adipogenesis and adipocyte differentiation, is discussed next. animal adipose tissue. emerging evidence from in vitro and in vivo animal studies suggest that circrnas are expressed in adipose tissues and may modulate adipogenesis and lipid metabolism. in this respect, li and colleagues identified several circrnas differentially expressed in the subcutaneous adipose tissue of large white pigs and laiwu pigs [72] . a further analysis revealed that circrna_11897 was the most significantly downregulated, whereas circrna_26852 was the most significantly upregulated; both circrnas were significantly involved in pathways associated with adipocyte differentiation and lipid metabolism [72] (table 1 ). in another study, liu x et al. identified 850 circrnas differentially expressed during subcutaneous adipogenesis in chinese erhualian pigs. these transcripts were shown to be implicated in multiple biological processes including lipid metabolic and cell differentiation processes [73] . more recently, an interesting study indicated that circsamd4a (sterile alpha motif domain containing 4a; also named hsa_circ_0004846) controls adipogenesis in obesity by binding to mir-138-5p [74] . in high-fat diet (hfd)-induced obese mice, mmu_circ_0000529 (the homologous mouse circrna for circsamd4a) knockdown reversed the associated weight gain, reduced food intake, lowered body fat, and increased energy expenditure. it is worth noting that these mice also exhibited increased insulin sensitivity and glucose tolerance [74] . mechanistically, in vitro experiments showed that circsamd4a can bind to mir-138-5p and act as a mirna sponge to subsequently regulate ezh2 expression [74] . in humans, circsamd4a was found to be significantly upregulated in obese compared to lean individuals and its level of expression notably correlated with poor prognosis in obese patients [74] (figure 1 ). functional analysis confirmed that circsamd4a overexpression can regulate preadipocytes differentiation and effectively predict obese human outcomes. a recently published report indicated that the expression of two circrnas, 19:45387150|45389986 and 21:6969877|69753491, was strongly correlated with fat deposition associated genes in chinese buffalo (bubalus bubalis) [75] . in the same context, zhang et al. identified six circrnas, novel_circ_0009127, novel_circ_0000628, novel_circ_0011513, novel_circ_0010775, novel_circ_0006981, and novel_circ_0001494 that were related to yac (bos grunniens) adipogenesis [76] . in cattle adipocytes, circfut10 was found to promote adipocyte proliferation and inhibit adipocyte differentiation via sponging let-7 binding of let-7c [77] . moreover, cirs-7/cdr1as expression levels were decreased both in ob/ob and db/db mice, which were severely obese due to lack of leptin or the leptin receptor, respectively [78] . collectively, these findings suggest that circrnas may participate in adipocyte differentiation and adipose tissue formation through post-transcriptional regulation. human adipose tissue. the past two years have witnessed a significant increase in the number of studies determining the function of circrnas in human adipogenesis and obesity. in a study involving visceral adipogenesis, as many as 4080 circrna species were found to be differentially expressed in human visceral preadipocytes (hpa-v) versus hpa-v that were induced to form adipocytes; among them, 2215 and 1865 circrnas were significantly up-and downregulated, respectively [79] . further validation experiments confirmed that hsa_circ_0136134, hsa_circ_0017650, and hsa-circrna9227-1 were the most upregulated transcripts, suggesting their close association with visceral adipogenesis [79] . in order to screen circrnas involved in adipogenesis and obesity, arcinas and colleagues analyzed the transcriptome of human and mouse visceral and subcutaneous fat by rna sequencing methods [80] . in this study, thousands of adipose circrnas were identified to be regulated during adipogenesis. among these, circtshz2-1 and circarhgap5-2 (the regulatory rho gtpase activating protein 5-2) were revealed to be key regulators of adipogenesis in vitro [80] . moreover, silencing of circarhgap5-2 in vivo resulted in inhibition of lipid droplet accumulation and downregulation of adipogenic markers suggesting that circarhgap5-2 might have a crucial role in maintaining the global adipocyte transcriptional program implicated in lipid biosynthesis and metabolism. interestingly, the proadipogenic function of circarhgap5-2 was found to be conserved in human adipocytes. however, the mechanism by which circarhgap5-2 modulates adipogenesis remains to be determined. these data robustly indicate circrnas are a contributing factor during adipogenesis and adipocyte metabolism. another study by schmidt et al. reported that the overexpression of h19, a maternally imprinted lncrna that plays a role in lipid metabolism, protects against obesity, and improves insulin sensitivity [81] . in samples from patients with metabolic syndrome, a condition that is associated with abdominal obesity and cvd, the level of hsa_circh19 derived from h19 pre-rna, was found to be highly increased and significantly correlated with variables of adiposity including body mass index (bmi), waist circumference, fat percent, high-density lipoprotein cholesterol (hdl-c), and visceral fat area [82] . conversely, silencing of hsa_circh19 promoted human adipose-derived stem cells (hadscs) adipogenic differentiation presumably through the interaction of such a circrna with polypyrimidine tract-binding protein 1 (ptbp1) [82] . another circrna that has attracted substantial attention for its role in various physiopathological processes is circular antisense noncoding rna at the ink4 locus (circanril). genetic variants at the anril gene have been linked with increased risk for t2dm, atherosclerotic cvd, coronary artery disease, myocardial infarction, and obesity [83] [84] [85] . further studies have demonstrated that epigenetic regulation of anril promoter methylation at birth is associated with increased cardiovascular risk [86] and later childhood adiposity [87] . hence, perinatal methylation at anril loci could be a marker for later adiposity. collectively, the results from the above studies demonstrate that several circrnas are differentially expressed in adipose tissue and support a significant role of these rna species in the regulatory networks of adipogenesis. however, the precise role that circrnas play in fat deposition and lipid metabolism remains elusive. deeper understanding of molecular mechanisms controlling the expression of these rnas species is critical to identify new targets for prevention of adipogenesis and therefore occurrence of obesity and obesity-related metabolic disorders. it is widely agreed that ir is strongly associated with obesity and t2dm, although not all individuals with obesity develop ir. overwhelming evidence suggests that obesity-induced inflammation is characterized by the abundance of immune cells, which increase secretion of proinflammatory cytokines that act to perpetuate systemic inflammation, impair glucose tolerance, and cause ir leading to the development of t2dm [88] . furthermore, the role of ncrnas in the regulation of obesity and ir has been already reported [89, 90] . for instance, mir-33 has been shown to play a crucial function in ir and obesity [91] . in humans, mir-122, mir-143-3p, and mir-652-3p have also been reportedly linked with obesity and ir and implicated in the modulation of genes and protein cascades in insulin signaling [92] . furthermore, altered expression of lncrnas has been associated with poor glycemic control, ir, accelerated cellular senescence, and inflammation in diabetes patients [93] . up to now, no studies have specifically exploited the role of circrnas in obesity-ir-t2dm settings, but this scenario will likely change in the future as alterations in many circrnas in association with ir have been noticed. for instance, circhipk3 has been shown to contribute to hyperglycemia and ir via sponging mir-192-5p and upregulating foxo1 [94] . it noteworthy to mention that circhipk3 has already been demonstrated to play a crucial role in diabetes retinas by virtue of its effect on mir-30a-3p [95] . circrna-tfrc (transferrin receptor) has also been associated with ir, and the overexpression of tfrc can aggravate the risk of t2dm and metabolic diseases [96] . even though these studies do not provide a direct link between potential circrna signatures and obesity-related ir, they highlight this matter for further elucidation. chronic low-grade inflammation is now recognized as a hallmark of obesity and a key risk factor for ir and the development of t2dm [88, 97] . excess adiposity typically induces the recruitment of immune cells into fat depots. these immune cells, mainly macrophages, release proinflammatory cytokines/chemokines that can act locally but also systemically after being released into the circulation, therefore activating chronic inflammation which contributes to the development of obesity and associated metabolic disorders [98] . thus, better exploring white adipose tissue inflammation mechanisms and pinpointing the immunological events occurring in this tissue will provide insights into the pathophysiological role of inflammation in obesity and help to manage obesity related diseases. although there has been some progress in the role of ncrnas in adipogenesis, the significance of these rnas in adipose inflammation remains elusive. the implication of some ncrnas in the regulation of obesity-associated inflammation has been suggested previously. as an example, stapleton et al. identified a novel lncrna named macrophage inflammation-suppressing transcript (mist) which was downregulated in both peritoneal macrophages and adipose tissue macrophages from high-fat diet-fed obese mice [99] . moreover, human ortholog of mist was found to be expressed in human adipose tissue macrophages and inversely correlated with obesity and ir. recently, an elegant study by arcinas and colleagues demonstrated a general decrease of circrna transcripts in adipose tissue of hfd mice, suggesting that inflammation may affect circrna biogenesis [80] . this assumption was based on the observation that treatment of differentiated primary mouse subcutaneous adipocytes with soluble tumor necrosis factor (tnf)-α led to significant reduction in circrnas expression [80] . in another study, it was observed that circarf3 (adp-ribosylation factor 3) functions as an endogenous mir-103 sponge to inhibit mir-103 activity, resulting in an increase of tnf receptor-associated factor 3 (traf3) expression and accordingly alleviates inflammation in mouse adipose tissue [100] . subsequent experiments provided more consistent support for the notion that circarf3 is involved in inflammation as adipose inflammation was improved because traf3 blocked the nuclear factor κb (nf-κb)-signaling pathway, promoted mitophagy, and suppressed nod-like receptor family, pyrin domain-containing protein 3 (nlrp3) inflammasome activation and inflammatory cytokine release [100] . on the contrary, another study reported that myeloid cell traf3 promotes metabolic inflammation, insulin resistance, and hepatic steatosis in obesity [101] . these authors further showed that myeloid traf3 may have anti-inflammatory and proinflammatory activities in lean and obese mice respectively, suggesting that, in obesity progression, myeloid traf3 functionally switches its activity from anti-inflammatory to proinflammatory modes. obesity and inflammation have been associated with several complications including t2dm, cvd, hypertension, and stroke [102] . in this perspective, fang et al. [103] indicated that the expression of circankrd36 was upregulated in peripheral blood leucocytes and correlated with chronic inflammation in t2dm, suggesting that circankrd36 can be used as a potential biomarker for screening chronic inflammation in patients with t2dm. as it is estimated that a total of 80% of individuals with type 2 diabetes are obese [104] , it will be interesting to evaluate the role of circankrd36 in obesity inflammatory context. unlike white adipocyte tissue (wat), which primarily stores lipids, brown adipocyte tissue (bat) can promote energy metabolism by decreasing adiposity and increasing energy expenditure. loss of bat activity may contribute to obesity and development of ir. hence, wat browning has gained considerable attention for its potential to reverse obesity and related metabolic complications [105] . a variety of stimuli and factors such as dietary factors, cold exposure, nuclear receptors and ligands, certain drugs, and some ncrnas can induce a phenotypic switch in adipose tissue from wat to bat and regulate browning [106] [107] [108] [109] . although significant progress has been made in understanding the epigenetic molecular mechanisms of wat browning, the role of ncrnas, a novel class of regulatory determinants in this context is still mostly unknown. so far, several mirnas have been identified and characterized to govern wat browning process [107, 110] . moreover, a class of lncrnas has also been shown to regulate brown adipogenesis [80, 111] . with respect to the potential implication of circrnas in such a process, studies are only emerging. in this respect, zhang et al. reported that plasma exosomal cirs-133 derived from gastric cancer patient cells promotes wat browning by targeting the mir-133/prdm16 pathway [112] . in the same manner, circnrxn2 was shown to promote wat browning by acting as a mir-103 sponge (table 1 ) and enhance the expression levels of fibroblast growth factor 10 (fgf10) in hfd mice [113] . nonetheless, these pilot studies provide a great potential therapeutic strategy to reduce the excessive energy stores in obesity. therefore, further investigation of the role of circrnas in wat browning program is needed. circrnas are increasingly being recognized to play essential roles in several diseases including metabolic disorders. they are also emerging as a novel regulatory layer in adipogenesis and lipid metabolism involved in the development of obesity. yet a number of key questions remain: i) while the studies discussed above have confirmed that circrnas display altered expression patterns in adipose tissue and obese individuals, the cell types and tissue origin of circrnas in obesity are not yet fully explored. this is very challenging because obesity is a complicated condition involving many tissues and organs including the muscle, pancreas, liver, and adipose tissue. in addition, there is growing evidence that wat is heterogeneous, and adipocytes are only part of the adipose deposit. furthermore, different types of adipocytes have differing metabolisms and their ability to communicate with other metabolic organs through sending out various signaling molecules and possibly ncrnas may contribute to the regulation of systemic energy homeostasis differently [114, 115] . therefore, part of the solution to these hurdles may be achieved by 1) discriminating the cellular origin of secreted circrnas in order to identify those involved in tissue function in health and dysfunction in disease; 2) identifying potential circrnas mediating inter-organ metabolic communication as well as those that my impact homeostasis in case of organ failure; and 3) characterizing natural circrnas carriers to reach distant organs. ii) the potential role of exosomal circrna signature in the development of obesity and related complications remains largely unknown. several studies found that ncrnas in secreted exosomes can be transferred to target tissues or cells to exert function [116] . furthermore, adipocytes have been shown to produce and release vesicles containing genetic material to communicate with neighboring cells within wat or facilitate metabolic organs crosstalk [117, 118] . clear and convincing evidence of this phenomenon is provided by a recent study showing that adipose tissue can release mirnas in the circulation [115] which can regulate gene expression in other distant metabolic organs. moreover, adipose tissue macrophages in obese mice can secrete mirna-containing exosomes, which cause glucose intolerance and ir when administered to lean mice [116] . with respect to circrnas found in adipose tissues, they may also be released to the circulation inside macrovesicles and have functions in target organs. in support of this assumption, a recent report indicated that adipose-derived exosomes mediate the delivery of circrnas and promote the tumorigenesis of hepatocellular carcinoma (hcc) by regulating the deubiquitination-related mir-34a/usp7 axis [119] . as stated above, a study by zhang et al. revealed that exosomal circrna derived from gastric tumor promotes white adipose browning by targeting mir-133 [112] . moreover, exosomal circrnas have been suggested as circulating biomarkers for the diagnosis of cancer as they have been shown to discriminate patients with cancer from healthy controls [120] . however, how many copies of circrna molecules these exosomes harbor needs to be evaluated. further, more in vitro and in vivo modeling of exosome-mediated circrna communication along with development of sensitive bioinformatic methods and mathematical mass-action models to capture all circrna-target interactions, will undoubtedly provide insight into the function of these exosomal rna species. further stoichiometric analysis is required to better explore circrna-mirna and circrna-rbp interactions. success in addressing all these issues may clarify the controversy surrounding the sponging function of circrnas. iii) circrnas have also been reported to bind, store, and even insulate rbps from specific subcellular sites or act as competitive elements to influence the function of rbps. however, to my knowledge, no one has specifically interrogated the role of circrna-rbp axis in adipose tissue and obesity processes. several rbps have been reported as adipocyte regulators by affecting different aspects of rna processing. for example, the rna-binding protein pspc1 (paraspeckle component 1) has been identified as an adipogenic factor that directly interacts with adipocyte rnas and promotes their export from the nucleus to the cytosol [121] . kh-type splicing regulatory protein (ksrp) targeted deletion has been shown to promote browning of wat through reduction in mir-150 expression [122] . rna-binding protein insulin growth factor 2 mrna-binding protein 2 (imp2) controls energy metabolism by suppressing mrna translation of mitochondrial proton transporter uncoupling protein 1 (ucp1) and other mitochondrial mrnas in bat [123] . more interesting, two recently published studies reported that the rna-binding protein hur protects against obesity and ir [124, 125] . however, it remains unclear as to whether this mechanism involves an interaction with circrnas or not. as stated before, circrnas containing rbp binding sites may serve as sponges or decoys for these proteins and are thus predicted to function as robust posttranscriptional regulators of gene expression. unfortunately, the biochemical stoichiometry between circrnas-mirnas and circrnas-rbps is not yet well determined in adipose tissue. the relative abundance of circrnas, mirnas, and rbps as well as their epigenetics modifications (e.g., hypermethylation) and stoichiometry analysis must be considered for the physiological relevance of any sequestration effect and cross-regulation as it may support the concept that circrnas can serve as protein sponges or decoys to influence their cellular functions. nevertheless, regardless of their function, the potential use of circrnas as biomarkers for obesity and metabolic diseases remains a great promise. iv) although the existing studies support the potential value of circrnas in the diagnosis and therapeutics of obesity, it is too early to consider the feasibility of these molecules as biomarkers and disease therapeutic targets in a clinical obesity setting. as of now, the effectiveness of circrnas has not been explored in large, clinically controlled, and conclusive cohorts, nor their mechanisms of action extensively studied. in addition, potential toxicity, reaction to drugs, immune response, accumulation to other tissues, and adequate carriers of circrnas remain unknown. nevertheless, a greater understanding of these issues is required if we are to see circrnas clinical translation becoming a reality. v) since obesity is a context of metabolic stress associated with dysfunction of numerous biological processes including adipose tissue dynamic, lipid metabolism, insulin signaling pathways, adipokines secretion, systemic inflammation, and mitochondrial activities, it is not clear how all these parameters might affect the machinery of circrnas biogenesis, secretion, transfer, and mode of action. vi) last but not least, given the complexity of obesity pathomechanisms, relying on the pattern of a single circrna for diagnosis and treatment obesity may not be biologically most relevant and sufficiently specific to provide a clinical utility. rather, one should consider a multi-markers approach that combines candidate circrnas/signatures, mirnas, and rbps which may be highly discriminative, accurate, and efficient in predicting obesity and associated metabolic perturbations. to sum up, circrnas have recently emerged as a class of ncrnas with multifaceted roles in the cell. emerging evidence from in vitro and in vivo experimental studies indicates that circrnas are involved in the regulation of adipogenesis and obesity. however, the ongoing efforts to better understand the role of circrnas in adipose tissue and metabolics must include the above-mentioned considerations as they may help accelerate their clinical research. funding: no funding was received for this article. the author declares no conflict of interest. naming 'junk': human non-protein coding rna (ncrna) gene nomenclature targeted rna sequencing reveals the deep complexity of the human transcriptome non-coding rna genes and the modern rna world the dark matter of the cancer genome: aberrations in regulatory elements, untranslated regions, splice sites, non-coding rna and synonymous mutations snapshot: unconventional mirna functions modular regulatory principles of large non-coding rnas circles reshaping the rna world: from waste to treasure unique features of long non-coding rna biogenesis and function determining associations between human diseases and non-coding rnas with critical roles in network control detecting and characterizing circular rnas the biogenesis and emerging roles of circular rnas the biogenesis, biology and characterization of circular rnas the biogenesis, functions, and challenges of circular rnas circular rna profiling reveals an abundant circhipk3 that regulates cell growth by sponging multiple mirnas circular rnas co-precipitate with extracellular vesicles: a possible mechanism for circrna clearance circular rnas are abundant, conserved, and associated with alu repeats circular rnas are the predominant transcript isoform from hundreds of human genes in diverse cell types circular rnas are a large class of animal rnas with regulatory potency correction: cell-type specific features of circular rna expression circular rna: a new star of noncoding rnas widespread noncoding circular rnas in plants circular rna-protein interactions: functions, mechanisms, and identification molecular biology. a circuitous route to noncoding rna natural rna circles function as efficient microrna sponges circular rnas in the mammalian brain are highly abundant, conserved, and dynamically expressed loss of a mammalian circular rna locus causes mirna deregulation and affects brain function the circular rna cdr1as, via mir-7 and its targets, regulates insulin transcription and secretion in islet cells the circular rna cdr1as promotes myocardial infarction by mediating the regulation of mir-7a on its target genes expression exon-intron circular rnas regulate transcription in the nucleus foxo3 circular rna retards cell cycle progression via forming ternary complexes with p21 and cdk2 circular rna participates in the carcinogenesis and the malignant behavior of cancer identification of hur target circular rnas uncovers suppression of pabpn1 translation by circpabpn1 circular non-coding rna anril modulates ribosomal rna maturation and atherosclerosis in humans identifying and characterizing circrna-protein interaction identifying rbp-binding sites on circrnas via sequence labeling neural networks. front. genet translation and functional roles of circular rnas in human cancer initiation of protein synthesis by the eukaryotic translational apparatus on circular rnas extensive translation of circular rnas driven by n6-methyladenosine circ-znf609 is a circular rna that can be translated and functions in myogenesis translation of the circular rna circbeta-catenin promotes liver cancer cell growth through activation of the wnt pathway a peptide encoded by circular form of linc-pint suppresses oncogenic transcriptional elongation in glioblastoma exosomal circrnas: biogenesis, effect and application in human diseases selective release of circrnas in platelet-derived extracellular vesicles il-13 secreted by ilc2s promotes the self-renewal of intestinal stem cells through circular rna circpan3 circular rnas: novel regulators of neuronal development circular rnas as potential biomarkers and therapeutic targets for metabolic diseases circular rnas in hypertension: challenges and clinical promise a circular rna protects the heart from pathological hypertrophy and heart failure by targeting mir-223 the circular rna micra for risk stratification after myocardial infarction signature as potential diagnostic and prognostic biomarker for diabetes mellitus and related cardiovascular complications silencing of circular rna-znf609 ameliorates vascular endothelial dysfunction from genotype to phenotype in human atherosclerosis-recent findings circrna_0046367 prevents hepatoxicity of lipid peroxidation: an inhibitory role against hepatic steatosis fto: the first gene contributing to common forms of human obesity ampk as target for intervention in childhood and adolescent obesity risk factors, and genetic traits in metabolically healthy and unhealthy obese individuals exposing the exposures responsible for type 2 diabetes and obesity obesity a risk factor for severe covid-19 infection: multiple potential mechanisms obesity and impaired metabolic health in patients with covid-19 variation in the heritability of body mass index based on diverse twin studies: a systematic review genetic studies of body mass index yield new insights for obesity biology gwas for bmi: a treasure trove of fundamental insights into the genetic basis of obesity epigenetics: an overview epigenetic regulation of ageing: linking environmental inputs to genomic stability wnt and pparγ signaling in osteoblastogenesis and adipogenesis micrornas in adipose tissue: their role in adipogenesis and obesity the clinical potential of adipogenesis and obesity-related micrornas long noncoding rnas regulate adipogenesis identification and characterization of circrnas of two pig breeds as a new biomarker in metabolism-related diseases a genome-wide landscape of mrnas, lncrnas, and circrnas during subcutaneous adipogenesis in pigs circular rna samd4a controls adipogenesis in obesity through the mir-138-5p/ezh2 axis characterization of circular rnas in chinese buffalo (bubalus bubalis) adipose tissue: a focus on circular rnas involved in fat deposition. animals circrna expression profile during yak adipocyte differentiation and screen potential circrnas for adipocyte differentiation circular rna profiling reveals an abundant circfut10 that promotes adipocytes proliferation and inhibits adipocytes differentiation via sponging let-7 family members circular rnas as novel regulators of β-cell functions in normal and disease conditions circrna expression profiles in human visceral preadipocytes and adipocytes adipose circular rnas exhibit dynamic regulation in obesity and functional role in adipogenesis lincrna h19 protects from dietary obesity by constraining expression of monoallelic genes in brown fat knock-down of circular rna h19 induces human adipose-derived stem cells adipogenic differentiation via a mechanism involving the polypyrimidine tract-binding protein 1 chromosome 9p21 snps associated with multiple disease phenotypes correlate with anril expression anril: molecular mechanisms and implications in human health islet biology, the cdkn2a/b locus and type 2 diabetes risk dna methylation at birth within the promoter of anril predicts markers of cardiovascular risk at 9 years anril promoter dna methylation: a perinatal marker for later adiposity inflammation and insulin resistance macartney-coxson, d. mirna signatures of insulin resistance in obesity micrornas 103 and 107 regulate insulin sensitivity genetic ablation of mir-33 increases food intake, enhances adipose tissue expansion, and promotes obesity and insulin resistance comprehensive functional screening of mirnas involved in fat cell insulin sensitivity among women linking a role of lncrnas (long non-coding rnas) with insulin resistance, accelerated senescence, and inflammation in patients with type 2 diabetes circular rna hipk3 contributes to hyperglycemia and insulin homeostasis by sponging mir-192-5p and upregulating transcription factor forkhead box o1 circular noncoding rna hipk3 mediates retinal vascular dysfunction in diabetes mellitus genetic variants including markers from the exome chip and metabolite traits of type 2 diabetes inflammatory mechanisms in obesity adapting to obesity with adipose tissue inflammation novel long noncoding rna, macrophage inflammation-suppressing transcript (mist), regulates macrophage activation during obesity circarf3 alleviates mitophagy-mediated inflammation by targeting mir-103/traf3 in mouse adipose tissue myeloid cell traf3 promotes metabolic inflammation, insulin resistance, and hepatic steatosis in obesity prevalence and correlates of overweight and obesity among older adults: findings from the canadian national population health survey screening of circular rnas and validation of circankrd36 associated with inflammation in patients with type 2 diabetes mellitus diabetes association annual meeting, 1999: diabetes and obesity the different shades of fat browning of white fat: agents and implications for beige adipose tissue to type 2 diabetes microrna-455 regulates brown adipogenesis via a novel hif1an-ampk-pgc1α signaling network egr1 deficiency induces browning of inguinal subcutaneous white adipose tissue in mice cold-induced browning of inguinal white adipose tissue is independent of adipose tissue cyclooxygenase-2 a. mir-155 regulates differentiation of brown and beige adipocytes via a bistable circuit de novo reconstruction of human adipose transcriptome reveals conserved lncrnas as regulators of brown adipogenesis exosomal circrna derived from gastric tumor promotes white adipose browning by targeting the mir-133/prdm16 pathway circnrxn2 promoted wat browning via sponging mir-103 to relieve its inhibition of fgf10 in hfd mice dynamic cross talk between metabolic organs in obesity and metabolic diseases adipose-derived circulating mirnas regulate gene expression in other tissues adipose tissue macrophage-derived exosomal mirnas can modulate in vivo and in vitro insulin sensitivity exosome-mediated transfer of mrnas and micrornas is a novel mechanism of genetic exchange between cells adipose tissue exosome-like vesicles mediate activation of macrophage-induced insulin resistance exosome circrna secreted from adipocytes promotes the growth of hepatocellular carcinoma by targeting deubiquitination-related usp7 circular rna is enriched and stable in exosomes: a promising biomarker for cancer diagnosis rna-binding protein pspc1 promotes the differentiation-dependent nuclear export of adipocyte rnas ksrp ablation enhances brown fat gene program in white adipose tissue through reduced mir-150 expression igf2bp2/imp2-deficient mice resist obesity through enhanced translation of ucp1 mrna and other mrnas encoding mitochondrial proteins adipose hur protects against diet-induced obesity and insulin resistance the rna-binding protein hur is a negative regulator in adipogenesis this article is an open access article distributed under the terms and conditions of the creative commons attribution (cc by) license key: cord-034066-fsp7e5x5 authors: di figlia-peck, stephanie; feinstein, ronald; fisher, martin title: treatment of children and adolescents who are overweight or obese date: 2020-10-21 journal: curr probl pediatr adolesc health care doi: 10.1016/j.cppeds.2020.100871 sha: doc_id: 34066 cord_uid: fsp7e5x5 nan m anaging the millions of children and adolescents who are either overweight or obese has become a major challenge for the healthcare community. in 1997, an expert committee was convened by the maternal and child health bureau of the health resources and services administration (hrsa), department of health and human services, (dhhs) to develop guidelines for healthcare providers. 1 in 2005, the american medical association, in cooperation with hrsa and the center for disease control and prevention, created an expert committee to update those initial guidelines. 2 and in 2008, the agency for healthcare research and quality of the hhs came out with an evidence-based/technology assessment entitled "the effectiveness of weight management programs in children and adolescents." 3 in addition to these government-sponsored guidelines, recommendations for management of overweight and obesity in this population have been issued by multiple other organizations. the one directive they all have in common is that a multicomponent program that focuses on physical activity, diet, and behavioral change should be the first line of treatment offered. this article highlights the evidence-based data, presents the various ways in which this multicomponent approach can be implemented, and includes the roles of school programs and bariatric surgery as weight management options. family-based group sessions coordinated by a registered dietitian (rd/rdn) are a crucial part of multicomponent interventions. the academy of nutrition and dietetics, which issued its pediatric weight management evidence-based guidelines in 2015, has reported positive weight status outcomes, both shorter-term (6 months) and longer-term (12 months), when group pediatric weight management sessions and family participation are coordinated. 4, 5 individual family and mixed-format (which includes some time with individual families and some group time) approaches have been found to be superior to group-only approaches as per the latest us preventative services task force (uspstf) recommendations. 6 however, including in addition to these governmentsponsored guidelines, recommendations for management of overweight and obesity in this population have been issued by multiple other organizations. the one directive they all have in common is that a multicomponent program that focuses on physical activity, diet, and behavioral change should be the first line of treatment offered. the academy of nutrition and dietetics, which issued its pediatric weight management evidence-based guidelines in 2015, has reported positive weight status outcomes, both shorter-term (6 months) and longer-term (12 months), when group pediatric weight management sessions and family participation are coordinated. 4, 5 some group sessions may offer the opportunity for social support and improve cost effectiveness. 7 the dose of treatment has a strong impact on success. multicomponent behavioral interventions of moderate (26à75 h of treatment contact per year) to high intensity (> 75 h) for obese children and adolescents, ages six and older, have been shown to yield short term improvements in up to 12 months. obtaining a qualitative assessment of a patient's diet with a particular focus on dietary patterns thought to be linked to excess energy intake and adiposity is recommended, as intervening with these patterns can significantly reduce intake and potentially improve nutritional status. 8 tailoring interventions by considering patient and family motivation, as well as readiness for change, is optimal. the family-based approach can be modified based on the age of the patient and the degree of parental involvement. it should be noted that family involvement has been shown to be less effective when the patients are older teens. 9 behavioral treatments at the heart of behavioral treatment for obesity is determining what behaviors are modifiable and what therapies to use to help patients achieve the needed modifications. motivational interviewing (mi), which is a patient-centered counseling style, has been shown to be effective in primary care settings. 10 a dietitian should be included, as the rdn's knowledge and skill base are critical in the ongoing process of addressing the diverse needs of clients and families. 4, 10 cognitive behavioral management and gradual stepwise change have been explored in depth for childhood and adolescent obesity treatment. individuals get acclimated to recommended changes over time by making adjustments in their dietary patterns and food environment and by learning to set limits on eating unhealthy food. short-term goals are established in order to lead to long-term habits that change the way individuals and their families think about food. cognitive behavioral therapy (cbt) focuses on breaking the negative cycle that is a part of weight-related difficulties in obesity, the "maladaptive daily patterns, cognition that is distorted, and problematic behaviors" cited by wilfley et al. 11 it allows for a restructuring of daily patterns. bloom et al. explores utilizing a form of cbt known as cbt-af to address appetite awareness and cues for eating. 12 caat is an adapted version used with children and adolescents to sensitize them to recognize and respond to internal appetite cues such as hunger and satiety in order to improve their self-regulation of energy intake. results of one study showed a significant reduction in body mass index (bmi) for children in a caat group compared to those in a control group. however, this impact was only studied short term. the researchers concluded that caat holds promise as a treatment modality since overweight and obese children are often less effective in regulating food intake compared to normal weight children. 13, 14 in the transtheoretical model of change, in which change occurs in stages, the readiness of parents for personal change, as well as their readiness to help their children make changes, becomes a pivotal factor for success in a weight management program. 15 tailored messages to parents may help modulate their "decisional balance," (the value of making behavioral changes versus the value of not making any changes) and contribute to the likelihood of treatment success for their children. yet influencing parents so as to influence their children in terms of weight management behaviors can be a challenge. weight loss is a complex behavior which encompasses two separate "domains" of changeà eating habits and physical activity. although these are often considered together, each carries unique challenges with respect to perceived confidence and readiness for change. 16, 17 in a cross-sectional study with a convenience sample of parents (or guardians) of children attending a tertiary care pediatric obesity clinic, parents completed surveys initially and again on follow up visits to assess their readiness for change. 16 those in the action/ cognitive behavioral management and gradual stepwise change have been explored in depth for childhood and adolescent obesity treatment. individuals get acclimated to recommended changes over time by making adjustments in their dietary patterns and food environment and by learning to set limits on eating unhealthy food. maintenance state of change were more likely to be actively making changes to multiple eating behav-iorsài.e. availability of sugar-sweetened beverages (ssbs) and salty snacks, and in physical activity patternsài.e. reaching recommended levels of increased activity and limiting screen time. their children were more likely to be more physically active and to consume less fast food and more fruits and vegetables than the children of parents in the other stages of change. 16 parents who believed their own weight was a health problem were less ready to make changes to their children's diet. 18 these authors suggest that maintaining both parent and patient motivation should be a focal point of treatment and that this may entail a variety of approaches, such as using texting or other electronic devices to assess the stage of change for readiness and decisional support. 18 use of mobile health technology as an adjunct to behavioral based weight management strategies is becoming more common. chen and researchers reported on a convenience sample of self-identified chinese-american adolescents with bmi 85th percentile who participated in a culturally focused intervention called smart start. 19 it provided general health education, wearable fitness trackers, online educational modules, and tailored biweekly text messages. a benefit in outcome occurred in both the control and intervention groups. however, over a six month period, the intervention group, as compared to the control group, had "statistically greater changes" in bmi that were associated with less fast food intake, a lower intake of ssbs, and an increase in physical activity levels and decreased sedentary behavior. 19 overall, mobile health use has shown mixed benefits for weight management in adolescents and young adults. 20 other mobile health initiatives have resulted in weight loss in the experimental groups that was not sustained 21, 22 or have displayed no further benefits above that of the standard care group. 23 researchers have thus noted limited evidence of efficacy of mobile health interventions as a stand-alone treatment modality. 24 the impact of combining the mobile health approach with components of behavior based interventions has been examined by cueto et al. 25 they evaluated the original kurbo app (circa 2014) before it became kurbo ww. 26 designed to promote behavior change and encourage healthy lifestyle choices, it used the evidence-based traffic light diet approach 27 and kurbo health coaching through the incorporation of behavior substitutions and habit formation. 28 although kurbo includes components of behaviorbased interventions proven successful in pediatric and adolescent weight management, it has come under fire for promoting behaviors that can be perceived as overly restrictive and potentially promoting eating disorder behaviors. 29 questions have been raised based on degree of weight loss in young subscribers and whether adequate monitors are in place to determine that degree. prior studies have warned about the potential for "growth velocity to be negatively impacted when caloric intake is restricted," and thus growth velocity must be followed carefully during and after weight loss in older children and younger adolescents, and medical supervision may be warranted. 30, 31 other combined interventions utilizing mobile health apps have yielded partial success. one 12month technology-based program for adolescents with type 2 diabetes "was not sufficient to produce weight loss with the combination of web intervention and group sessions and telephone follow up, but improvements in sedentary behavior and use of behavior change strategies expected to lead to behavior change was evidenced." 32 telemedicine, in theory, should be able to compensate for some of the barriers that prevent access to and utilization of family based comprehensive behavioral interventions for child and adolescent obesity. 33 these barriers include time, transportation, access, cost, scheduling challenges, stigmatization, language barriers and more. [34] [35] [36] [37] rural populations have been studied for feasibility and satisfaction with telemedicine treatment approaches, and results have been comparable to standard treatment outcomes. 38 urban populations can face similar barriers to attendance of programs held in hospitals or university medical use of mobile health technology as an adjunct to behavioral based weight management strategies is becoming more common. settingsà delays in acquiring care, fear of being judged based on native language or residency, and possible stigmatization. 39 consequently, there have been studies here too (even prior to the covid-19 pandemic) regarding the incorporation of telemedicine as a supplemental arm of treatment modalities involving group sessions and mixed formats with medical staff including physicians, nurse practitioners (nps), nurses, psychologists, family counselors, dietitians, physical therapists, exercise specialists, and social workers. 38, 39 with the dramatic increase in the use of telemedicine brought about by the covid 19 pandemic, this modality of treatment will certainly be utilized and studied considerably more in the upcoming months and years. mobile apps have proved an engaging way to involve children in health behavior changes, 40 allowing for delivery of health information in a portable, "entertaining" way. [41] [42] [43] these apps are capable of promoting some of the expert recommendations for healthy eating and physical activity, including setting goals/limits and reducing intake of ssbs, but they often do not go deeper into behavior change. one app, hyperant tm , utilized a set of "hyper activity cards tm " to give children ideas for health-promoting behaviors including physical activity, healthy eating, and sleep. 44 however, it only provides user messages without offering the opportunity for interaction. in a meta-analysis of mobile health technologies for selfmonitoring, darling et al. concluded that self-monitoring techniques using mobile health technologies have a small but significant effect on weight status in children and adolescents. 45 population health initiatives a more "macro approach" for educating and guiding children, adolescents, their families and guardians is called for to achieve greater success in maintaining better health and weight management. several such programs are described below. the choosemyplate teaching initiative from the u.s. department of agriculture (usda) came out of the need for a vehicle to effectively and "with maximum visibility" communicate the 2010 dietary guidelines for americans (dgas) in order to foster a healthier lifestyle. 46 using print and online resources to engage the public, it was translated into several languages, incorporated into health curriculum resources created for nutrition education for children and adults, and promoted to nutrition communicators, educators and the food industry, calling upon them to "get the message out." [47] [48] [49] its message: "americans can achieve a healthier weight by eating more of some foods," was thought to be one that consumers could embrace. when one's plate has a larger proportion of lower calorie vegetables, they, in essence sense, "crowd out' the more calorically dense other foods on the plate like refined grains and high fat proteins. thus, adding foods, rather than taking away foods, can result in a calorie deficit. designed to "impact behavior during meal planning" and "perception during meal consumption," this initiative aimed to be seen by individuals and groups as a positive way of collectively altering energy balance. choosemyplate calls for a shift in consumption patterns. it emphasizes less processed foods and more of whole grains, lower fat and non-fat dairy items over full-fat varieties, water in place of ssbs, and protein alternatives, including leaner meats. along with less saturated fat and added sugars, lower sodium options are promoted. central to this multimodal plan is the plate icon ( fig. 1 ) that replaces the food guide pyramid as both visual cue and accepted standard. 48, 49 the most current recommendations, as per myplate, my wins (see below), directs people to "find your healthy eating style and maintain it for a lifetime" by making half of the meal plate fruits and vegetables (varying the veggies and focusing on whole fruits), making a quarter of the plate grains (half of them whole grains), and making the remaining quarter of the plate proteins (varying the protein routine). individuals are advised to move to low-fat or fat-free milk or choosemyplate calls for a shift in consumption patterns. it emphasizes less processed foods and more of whole grains, lower fat and non-fat dairy items over full-fat varieties, water in place of ssbs, and protein alternatives, including leaner meats. along with less saturated fat and added sugars, lower sodium options are promoted. yogurt for dairy intake, which is depicted alongside on the right of the icon's plate. the "right mix" is based on variety, amount, and nutrition content. the original myplate teaching campaign was revamped to reflect changes in the updated dgas (2015à2020). myplate, my wins, launched in 2015, strongly focuses on food patterns. it added the concept of "a healthy eating style" which can be achieved with "small changes" to promote the goal of getting individuals to realize that "what you eat and drink over time matters and can help you be healthier now, and in the future," messaging that reflected the evolving emphasis of the dgas. the public was encouraged to be more engaged and active in their health, and was invited to virtually share personal experiences with my plate, my wins on social media using #myplatemywins. the present day choosemy-plate.gov website includes printable materials, images, and graphics available as downloadable pdfs, jpgs, and other files-all in the public domain so that no permission is required to print, reproduce, or use them. resources have grown to include a host of topics, from meal planning and food safety to physical activity and seasonal resources. information continues to be available in diverse formats like toolkits, quizzes, infographics, and videos. researchers out of the behavioral health and nutrition department at the university of delaware used myplate to test whether peer education improved selfefficacy, perceptions and attitudes toward healthy eating, and physical activity. 50, 51 they concluded that peer education could promote improved knowledge and attitudes about myplate among college students and increase their self-efficacy, helping them make healthier decisions with regard to food and food intake. the pilot first year experience course curriculum developed at the university became mandatory coursework for all incoming freshmen. 41 a florida study of elementary school children whose families qualified for federal assistance via the supplemental nutrition assistance program (snap), utilized the six-lesson youth understanding myplate (yum) curriculum to teach the students through grade specific activities. the children reported an increase in intake of fruits and vegetables, grains, low-fat/fat-free dairy, healthy snacks, eating breakfast, and physical activity, compared to baseline. 52 5-2-1-0 let's go! is another nationally recognized program that aims to create environments supporting healthy choices, healthy habits, and healthy living within a multi-setting model. [53] [54] [55] [56] developed in maine in 2006 by a group of professionals on a mission to tackle childhood obesity by using evidence-based tools and strategies, it has expanded and gained momentum through its strong, far-reaching program and campaign designed to reach out to families where they live, learn, work, and play. its premise is that if children and families are exposed to the same health message in multiple places across their community, and if those places have policies and environments that support healthy choices, then children and families will be more likely to adopt those behaviors and maintain them in their daily lives. the foundation for change as modeled in the 5-2-1-0 healthy habits message is based on the following daily measures: 5 or more fruits and vegetables, 2 h or less of recreational screen time (tv/ computers to be kept out of the bedroom and no screen time under the age of 2), 1 h or more of physical activity, and 0 the foundation for change as modeled in the 5-2-1-0 healthy habits message is based on the following daily measures: 5 or more fruits and vegetables, 2 h or less of recreational screen time (tv/computers to be kept out of the bedroom and no screen time under the age of 2), 1 h or more of physical activity, and 0 sugary drinks and more water intake (fig. 2) . sugary drinks and more water intake (fig. 2) . though this message has been found to increase awareness and healthy behaviors, it remains to be seen if that will translate to concrete behavioral changes. many pediatric and primary care offices across the country have started to implement 5-2-1-0 let's go! into their practices to potentially impact the health of their patients, as have hospital-based specialty programs. the power kids weight management program of cohen children's medical center at northwell health is the authors' multidisciplinary program for overweight and obese children and adolescents, 8 to 18 years of age. in advance of meeting with program staff or at the initial assessment by the program's registered dietitian nutritionist (rdn), prior to any interventions, the patient or the parent/guardian is asked to fill out a healthy habits questionnaire adapted from and directly correlated to the 5-2-1-0 let's go! program (fig. 3) . one version is for children up to 9 years of age, another for 10 to 18-year-olds, and both are available in spanish as well as english. the power kids questionnaire uses a modified food-frequency survey style to ask questions regarding food and beverages and includes other questions that address time allocation for activity and sedentary pursuits as well as family meal patterns and access to tv. what emerges are overall patterns, habits, and choices, ending with a glimpse as to what the child or adolescent is willing to change. answers to the questions help guide the direction of behavioral, nutritional, and exercise interventions. focusing on domains where program participants exhibit deficiencies, while reinforcing already established positive health-related behaviors, helps to pave the path to successful weight management. the goal is to use the 5-2-1-0 message to encourage the children and adolescents in the program to develop healthy habits that can positively impact what would otherwise be their trajectory for further excess weight gain and the associated comorbidities of obesity. let's move is the comprehensive initiative launched in 2010 by former first lady michelle obama the same day that president barak obama signed the memorandum creating the task force on childhood obesity. in partnership with the alliance for a healthier generation, it is dedicated to solving the problem of obesity "within a generation" so that "children born today will grow up healthier and be able to pursue their dreams." 57 the focus is on creating a healthy start for children, empowering parents and caregivers, providing healthy food in schools, improving access to healthy affordable foods, and increasing physical activity. one of its many ambitious goals is the commitment to giving children a voice and a presence. families are encouraged to recognize that children can create healthy lunches from their own kitchens and express their unique preferences as to what "healthy eating" translates into for them. the healthy lunchtime challenge has drawn representatives from every state and territory in the united states, and the accumulation let's move is the comprehensive initiative launched in 2010 by former first lady michelle obama the same day that president barak obama signed the memorandum creating the task force on childhood obesity. of recipes from the annual challenges is accessible online as "historical material." 57 the let's move! outside program, developed to bridge the growing disconnect between young people and the great outdoors, and to emphasize the need for active play, has been adopted by the ymca of the usa, through its youth development division, using programs and services shown to be instrumental in their diabetes prevention program (dpp) trials. 58 eligible children and adolescents, ages 5à17, representing a wide variety of socioeconomic backgrounds, were recruited for a randomized computer-assisted intervention that included their families, to assess whether eliminating financial barriers to ymca membership could encourage increased physical activity in the environment of a supportive family. 59 extensive resources were available to those who utilized the services. all participants and their parents and guardians were scheduled to attend 4 nutrition classes administered by a registered dietitian (rd) and to return for evaluation at 2, 4, 6, 9, and 12 months. children were randomized to nutrition class only (n = 39) or nutrition class and free family ymca membership (n = 44). nutrition classes did not differentiate between those in the control and treatment groups. of the 36 evaluable participants randomized to treatment, only 27 ever visited the ymca, with a median of 5 visits reported. overall attendance at scheduled study-related visits was poor. only 2 participants in each group attended all 6 scheduled visits. for nutrition classes, at least 1 class was attended by 67% of the treatment group, but only 30% of controls. attendance in the nutrition classes led to improvements in nutritional intake for both groups. four participants in the control group and 1 in the treatment group achieved the target reduction of 2 bmi percentile points. there was a positive, but very small, relationship for ymca attendees between the number of visits and the loss of either bmi or weight, which was not statistically significant. curr probl pediatr adolesc health care, & &&&& another major initiative promoting physical activity and healthy eating among children-(in this case, as young as kindergarten and through 12th grade) that has been studied and evaluated is the nfl play 60 fit-nessgram partnership project, led by teachers in school settings across 32 national football league franchise markets. (its two most popular programs are fuel up to play 60, in collaboration with the united states dairy association (usda), and the nfl play 60 challenge created in conjunction with american heart association (aha). the latter has its own app which originally allowed users to choose an avatar with which to complete a course through a virtual outdoor park while listening to health promoting messages like "make sure you drink enough water today"it no longer includes an "in the game" motion sensor but still gauges and delivers health concepts.) the longitudinal impact of nfl play 60 programming was measured using data based on students from 497 schools who completed fitnessgram assessments annually, starting in 2011 through 2015. for schools that participated in the program, annual improvements in aerobic capacity were significantly greater for both girls and boys, compared with non-programming schools. both girls and boys in participating schools showed annual improvement in bmi healthy fitness zone achievement. students in schools that implemented the program for the entire 4 years tended to have better improvements in aerobic capacity than those in schools enrolled for only 2 or 3 years. 60 it is fair to say that each of the national initiatives described in this section had some impact on nutrition and physical activity for many children and adolescents but that the impact was modest for most and minimal for many. going forward, it can prove useful to combine the messages of these multiple programs into one unified message that can be promoted throughout the country in a way that will strengthen their message and thereby yield a stronger effect on the nutritional and physical activity patterns for the youth of the nation. advances in technology have brought about the proliferation of electronic devices now available to children and adolescents who are spending long durations of time in sedentary activities involving handheld devices and video consuls. current guidelines call for limiting sedentary screen time to 2 h or less. 61 among the many concerns being addressed is that increased time on electronics/screen time becomes a potential source of additional energy intake. in a clever harnessing of this dynamic, health professionals are exploring the use of electronics and gaming for getting children to be more physically active. games like wii/wiiu, xbox connect, nintendo, and variations of them have offered small promise. active video games can acutely increase light to moderate physical activity. however, they are unlikely to impact increased habitual activity or significantly decrease sedentary behaviors. 62 rose et al. in their systematic review of digital interventions for improving diet and physical activity behaviors in adolescents, struggled with the heterogenicity of studies not being conducive to a meta-analysis and urged setting up future research initiatives in digital health as a cost-effective medium for health promotion. 63 a great deal of thought and programing is being directed to creating challenges and monitoring progress with physical activity. and sometimes the unexpected turns up with great outcomes. for a time in 2016, the pok emon go app set off a frenzy of interest in walking, sometimes long distances, to find and catch pok emon avatars. 64 an estimated 9à21 million people used the app and increased their daily step count, with some reaching as many as 15,000 steps a day. 65 step challenges have worked well in the adult population with competitions awarding badges, status recognition, and prizes for accumulating steps. in the early 2000s portable watches that were affordable and fashionable were introduced for use in tracking steps. prior to this, they had only been available at research grade. studies exploring step tracking have shown promising results in that a positive feedback loop is established, whereby accumulating steps reinforces continuation of the activity. efforts at encouraging step initiatives in children and adolescents hone in on impacting their motivation, which is often lacking. 66 research on how to encourage more physical activity among studies exploring step tracking have shown promising results in that a positive feedback loop is established, whereby accumulating steps reinforces continuation of the activity. children and adolescents yields findings on how to most effectively use pedometers in combination with other treatment modalities. organizations including the american medical association (ama) and the united states preventive services task force (uspstf), along with healthcare organizations and professionals abroad, have recommended counseling to promote increased physical activity. 67 pedometers, which are inexpensive and wearable devices, can provide children with objective ways to self-monitor their physical activity. several studies of weight management interventions have shown that children can successfully increase their step count from baseline as part of an intervention. 68 yet these studies fail to consistently demonstrate a significant change in bmi percentile from controlled conditions. 68,69 staiano et al. were able to demonstate weight loss in groups of children issued pedometers as part of a 10week, family-based weight management intervention which included physical activity, nutrition, and behavior modification (as well as money compensation). 68 those in the group issued pedometers and a step count goal increased their daily step count, as well as reduced their bmi and bmi z score significantly more than those issued a pedometer without a step goal count. both groups saw a reduction in bmi and an increase in step count from baseline. these same children issued pedometers (with or without a step count goal) had increased subjective health and increased health-related quality of life. ostendorf et al. examined what leads some people to be consistent exercisers and demonstrated that weight loss maintainers weren't using continuous calorie restriction to maintain their weight. 70 instead, the weight loss maintainers had a much higher energy burn from exercise despite eating approximately the same number of calories per day as the control participants with overweight/obesity. it takes a significant time commitment to achieve the level of activity observed in these weight-loss maintainers. in a commentary on the role of exercise, martin and church challenge researchers to identify the physiological, psychological, and environmental factors that help people maintain weight loss through large amounts of exercise so that strategies can be implemented for future weight loss maintenance success. the benefits of exercise cannot be argued. regular exercise can lower stress, moderate anxiety, and improve overall quality of life; however, there is great variation in these outcomes. 71 targeting the agent of change knowing that parents can be effective in modulating childhood obesity by serving as role models for children's eating and physical activity behavior, and knowing the positive impact parental involvement in childhood obesity efforts carries, golan and crowl compared targeting parents exclusively for treatment with a child-only intervention. 72 group sessions were utilized in this family-based health center intervention treatment, with parents attending 14 onehour support and educational sessions that started as weekly, became biweekly, and then took place once every six weeks with clinical dietitians delivering the topics. two similar groups were established, with 15 families participating in each, discussing such topics as limited responsibilities, nutrition education, eating and activity behavior modification, decreasing stimulus exposure, parental modeling, problem-solving, cognitive restructuring, and coping with resistance. parents were encouraged to practice an authoritative parenting style as opposed to an authoritarian style. 71 in authoritative parenting, "parents are both firm and supportive and then assume a leadership role in the environmental change with appropriate granting of child autonomy," whereas in the authoritarian style, child feeding practices are controlled by the adults 73à77 children in the child-only group were prescribed a 1500 calorie per day diet and participated in 30 one-hour group sessions led by a clinical dietitian. two similar groups were held with 15 children allocated to each. the first 7 sessions were conducted weekly and the remainder were held biweekly for the period of one year. at the end of the intervention, 35% of children in the parents-only group reached a non-obese status, compared to 14% in the child-only group. at the one-year follow-up, or one year after program termination, the weight loss in the children of the parent-only group was statistically significant compared with that of the child-only group. at the two-year follow-up, there was a mean reduction in overweight of 15% in children of the parent-only group and an increase of 2.9% in children of the child-only group. at the seven-year follow-up, both treatment conditions demonstrated substantial weight loss. however, the mean reduction of overweight status was 29% in children of the parent-only group and 20.2% in those of the child-only group; 60% of children of the parent-only group, compared with only 31% of children of the child-only group, were in a non-obese status. seven years after program termination, two (6.6%) of the girls from the child-only group reported eating disorder symptoms (both bingeing and purging); none of the children in the parent-only group reported any eating disorder symptoms. family-based programs require the family to be involved. with more families having both parents in the workforce, present-day parents are less available to their children, which makes it difficult for children and adolescents waiting for them to provide a source of physical activity, to engage them in physical activity, or to accompany them to physical activity. parents are less able to enroll in family-based weight management programs if their work schedules conflict with their ability to use free time to participate. 78 interventions targeting overweight and obese children and adolescents that require a large time commitment, a commitment from family members, travel to the intervention location, and potential cost may be poorly received and underutilized. solutions to some of these challenges could be reached with innovative restructuring, telehealth, or a mixed model that may evolve over time. accordingly, researchers collaborated to examine whether utilizing a school nurse delivered intervention for overweight and obese adolescents would be feasible and acceptable, and whether it would serve to improve common obesogenic behaviors (selected for intervention) while positively impacting bmi. 78 clearly there are potentially modifiable behaviors that are associated with improving overweight and obesity. these include decreasing fast food intake, the amount of screen time, on and off dieting, depressive symptoms, low self-esteem, and weight teasing, on the one hand, as well as increasing fruit and vegetable intake through home availability and having more family meals, plus participating in moderate to vigorous physical activity. 79 they are the behaviors most targeted in nutrition interventions using medical nutritional therapy (mnt) by an rd as part of a comprehensive weight management program. increased frequency of rd visits has been associated with improved bmi outcomes in obese youth participating in these programs: "the probability of success exceeded 78% with one rd visit per month versus 43% with minimal rd exposure." 80 both the choose myplate and the 5-2-1-0 education initiatives target these potentially modifiable behaviors. in conjunction with each other, they can have a synergistic effect. healthcare professionals can use these tools together to impact behavior change sessions and establish simple lifestyle goals. many adolescents engage in extreme weight control behaviors and that number has greatly increased over time, as innumerable studies have shown. one population-based survey of adolescents attending middle and high schools in 1998à99 and again in 2008à09 by project eating and activity among teens and young adults assessed personal, psychological, behavioral, and socio-environmental factors believed to play a role in obesity. it showed that informing adolescents and young adults that increased dieting is associated with the persistence of obesity may help motivate adolescents to use more healthful means of weight management. 81, 82 this study reemphasizes the crucial importance of promoting healthy eating, improving the quality of the home food environment, and increasing physical activity as a means of preventing unhealthy weight loss behaviors. the weight management and healthy living 2015 survey from the hartman group 83 found that consumers are more interested in lasting changes and lifelong healthy eating than in crash dieting. it demonstrated that a campaign like myplate, with its message that individuals can achieve a healthier weight by eating more of some foods and less of others, can have utility in helping consumers make lifestyle changes that prove formidable. studies on energy density by b. j. rolls suggest that decreasing energy density reduces energy intake, independent of the macro nutrient mix, because of effects on satiety. 84 the indication is that diets of low energy density, which are typically rich in vegetables, fruits, legumes, and minimally processed grain products, allow individuals to consume "satisfying portions of food," while simultaneously reducing their energy intake. 84 this concept has been used in her best-selling book series volumetrics and made into a diet plan. 85 another approach which has been used in many interventions is the "traffic light" or "stoplight diet," which groups foods based on their nutrient quality and calorie density such that "red foods" should be consumed rarely, "yellow foods" infrequently, and "green foods" most often. 27 it is predicated on the idea that children can learn to substitute lower energy-dense healthy foods for less healthy higher energy-dense foods and that parents can facilitate this transition via increasing access to healthy foods and decreasing access to less healthy foods by altering food purchasing and food storage habits for the family at large. 86 the vast number of children and adolescents in the united states attend public schools. health and wellness policies and programs have traditionally been an important part of the daily curriculum of the majority of these schools. during the 20th century, mandatory physical education classes and nutrition programs, including the national school lunch program (nslp) and the school breakfast program (sbp), were implemented to address problems including "food insecurity." the current obesity epidemic among children and adolescents in the united states has stimulated the further involvement of local, state, and federal agencies in an attempt to use public schools as a venue to combat this problem. in 2004, the u.s. federal government mandated that all school districts participating in the federal meal program create a school wellness program by establishing a committee that includes individuals impacted by this problem. legislation also required the development of nutrition standards for meals and snacks served in schools, as well as the setting up of goals for physical education. the healthy hunger-free act, passed in 2010, required school districts to measure policy implementation and make these results publicly available. what follows here is a look at the impact of some of these and other programs implemented by the schools. approximately 12.2 million public school students from low-income homes are provided a nutritious breakfast as part of the federal school breakfast program (sbp), which was established in 1966 and permanently authorized in 1975. studies have shown that this may be associated with improved academic performance and a reduction in the number of students affected by food insecurity. 87, 88 the number of students participating in the sbp is less than half of those participating in the national school lunch program (nslp). to increase participation in the sbp, the federal government allows school districts to serve breakfast in the classroom (bic). 89 in new york city, more than 70% of public-school students qualify for free or reduced-price meals. researchers reported in 2013 on the impact of bic on the percentage of children going without morning food, the number of locations where food was consumed, and the estimated calories each child consumed. comparisons were made between schools that offered bic and those that did not. results showed that students in bic schools were significantly more likely to eat more than once in the morning and, on average, ate an estimated 95 additional calories each morning. 89 a similar study in the philadelphia public school system, completed and another approach which has been used in many interventions is the "traffic light" or "stoplight diet," which groups foods based on their nutrient quality and calorie density such that "red foods" should be consumed rarely, "yellow foods" infrequently, and "green foods" most often. 27 approximately 12.2 million public school students from lowincome homes are provided a nutritious breakfast as part of the federal school breakfast program (sbp), which was established in 1966 and permanently authorized in 1975. studies have shown that this may be associated with improved academic performance and a reduction in the number of students affected by food insecurity. 87, 88 published in 2018, found that bic did not affect the combined incidence of overweight and obesity among public school students. 90 however, an increasing incidence and prevalence of obesity among the students was noted. in 2003, arkansas became one of the first states to pass legislation to specifically address the epidemic of obesity. it required annual body mass index (bmi) screenings for all public school students, elimination of elementary school students' access to vending machines, and creation of physical education and nutrition standards via district physical activity and nutrition committees along with input from a child health advisory committee. 91, 92 a study published in 2018 assessing the effectiveness of this policy concluded that it was very unlikely that the arkansas act was having an impact on preventing adolescent overweight and obesity. 93 california began bmi screening during the early part of the first decade of the 21st century. the state collected bmi data annually on fifth, seventh, and ninth grade students. parental notification of the results was optional. in 2001, bmi results were sent to 35% of parents or guardians, which rose to 52% in 2008. notification in fifth and/or seventh grade on subsequent bmi z scores, when compared to no notification, showed no significant difference in reducing the prevalence of obesity among this population of students. 94 one state that offered a program that achieved better success is massachusetts. in a pair-matched, cluster-randomized, and controlled school-based trial using a convenience sample of six public high schools, eligible 9th to 11th graders were recruited to participate in "lookin good feelin good," a school nurse-delivered counseling intervention with one-on-one sessions conducted over two months during the school day, during non-academic classes held in the privacy of the school nurse's office. 95 the 5-3-2-1-0 approach was used "to support making five behavioral changes" by utilizing cognitive behavioral techniques to facilitate changes in selfmanagement behaviors through health knowledge and the development of positive outcome expectations, self-control, and behavioral capacity skills and self-efficacy." targeted adolescents completed behavioral and physiological assessments at baseline, and at 2-month and 6-month follow-ups. at two months, compared to control participants, this intervention was able to impact both increased intake of breakfast, and decreased total sugar and added sugar intake. while these particular positive results were not maintained at further follow-up, other positive outcomes were noted at 6 months when the adolescents in the intervention were more likely to drink soda less than or equal to one time a day and eat at fast food restaurants less than or equal to one time per week compared to controls. total calorie intake and calories from fat did not change significantly between groups. screen time and time spent in moderate to vigorous physical activity were not statistically affected. although there was no statistically significant difference in bmi, students in the counseling intervention schools experienced favorable improvements in their bmi compared to students in the control schools. 95 there are clear factors standing in the way of more successful outcomes. an online survey of u.s. public school administrators completed in 2016 indicates that rarely are evidence-based obesity prevention programs being implemented. 92 many programs focus on students' weights rather than on healthy lifestyles. barriers to implementation include lack of funding, time, and training. the johns hopkins evidence-based practice center completed a study of 124 school-based interventions in 2013 and reported on two kinds of programs that demonstrated high evidence of effectiveness in preventing overweight and obesity in the schoolaged population. these are (1) school-based programs that combined physical activity and diet with a home-based component and (2) school-based physical activity and diet interventions that were combined with a home and community component. 96 medication is only recommended after an unsuccessful attempt at weight loss that includes the adoption of a healthy and age-appropriate diet and an increase in daily physical activity. presently, five medications are approved for adults in the united states for long-term management of obesity. 97, 98 weight loss associated with these ranges from approximately 3%à9%. side effects and adverse reactions are common with each. for adolescents greater or equal to twelve years of age, the only prescription medication approved by the united states food and drug administration (usfda) is orlistat. no medication is approved for use in children less than twelve years of age. [99] [100] [101] orlistat is a lipase inhibitor that blocks the absorption of fat. it is recommended to be taken with each meal. although it has been demonstrated to have a good safety profile, side effects can include cramping, excessive gas, oily spotting, fecal urgency, and abdominal pain. since these side effects occur not infrequently, it can be difficult to maintain compliance with this medication. studies have shown modest weight loss efficacy when orlistat is used along with a comprehensive weight loss program. in the largest study (n = 539) of orlistat use in combination with diet, exercise, and behavioral modification, a bmi reduction of approximately 2.4%, as compared to a placebo group, was seen over a treatment period of one year. 102 the only cardiometabolic benefit seen was a small reduction in diastolic blood pressure. at the present time there are no studies reporting long-term outcomes after cessation of orlistat use. phentermine, a norepinephrine reuptake inhibitor, has been approved by the usfda for short-term use for ages seventeen or older. no randomized clinical trials of phentermine have been conducted in individuals younger than seventeen years. common side effects observed in adults using this medication include rapid heart rate, high blood pressure, anxiety, insomnia, and headache. metformin, a biguanide used predominately for glycemic control in individuals with type 2 diabetes mellitus, has been studied for use in treatment of pediatric obesity along with lifestyle interventions. 103 it does not have usfda approval for this use in children and adolescents at the present time. one systematic review of the benefits and risks of using metformin in treating obesity in this population demonstrated a statistically significant, but very modest, reduction in bmi when combined with lifestyle interventions over the short term. no serious adverse events were reported to occur among individuals in the review. the authors concluded that metformin has not been shown to be clinically superior to other options for treating childhood obesity in the short term. bariatric surgery has become an optional treatment for adolescents who are severely obese. in 2004, an expert panel of pediatric surgeons and pediatricians made recommendations regarding selection criteria for bariatric surgery in individuals less than eighteen years of age. 104 selection criteria included: (1) failed >6 months of organized attempts at weight management, (2) has attained or nearly attained physiologic maturity, (3) >50 bmi, or >40 bmi with an associated severe co-morbidity (i.e. sleep apnea, diabetes, hypertension), (4) demonstrates commitment to comprehensive medical and psychological evaluations both before and after surgery, (5) agrees to avoid pregnancy for at least a year, (6) is capable of and willing to adhere to nutritional guidelines postoperatively, (7) provides informed consent, (8) demonstrates decisional capacity, (9) has a supportive family environment, and (10) surgery would be done in centers that have experience with bariatric surgery and a team of specialists trained to provide long-term follow-up care of the metabolic and psychosocial requirements of the patient and family. as an ancillary study of its observational study of adults undergoing bariatric surgery, the national institute of diabetes and digestive and kidney diseases (nddk) created teen-longitudinal assessment of bariatric surgery (teen-labs). funding was provided to five centers in the united states to enroll at least 200 adolescent bariatric surgical patients to serve as a prospective observational cohort study aimed at assessing the clinical, epidemiological, and behavioral parameters in a select population of adolescents undergoing bariatric surgery. 105 the majority of surgical procedures completed in the study were either gastric bypass (roux-en y), which creates a small gastric pouch that is connected directly to the jejunum, bypassing the upper portion of the small intestine, or the sleeve gastrectomy, which creates a narrow stomach pouch and removes the rest of the stomach. for adolescents greater or equal to twelve years of age, the only prescription medication approved by the united states food and drug administration (usfda) is orlistat. no medication is approved for use in children less than twelve years of age. [99] [100] [101] research published in 2018 has shown an increasing use of vertical sleeve gastrectomy compared to other surgical procedures. 106 multiple publications from the teen-labs study have documented that severely obese adolescents undergoing bariatric surgery, when compared to matched adolescents undergoing medical treatment alone, had better weight loss, improvement in cardiovascular risk markers and better glycemic control. the teen-labs researchers also reported identified risks including specific micronutrient deficiencies and the need for an acceptable rate (13%) of additional abdominal procedures. [107] [108] [109] [110] [111] overall similar findings were obtained by olbers in a prospective nationwide study of 81 swedish adolescents who were severely obese and underwent roux-en y gastric bypass. 112 a single study completed by alqalhtani in saudi arabia reviewed the effects of laparoscopic sleeve gastrectomy in 114 children younger than 14 years of age (mean § sd, 11.2 § 2.5 years). it was concluded that the procedure resulted in significant weight loss, improved growth, and a resolution of comorbidities, without mortality or significant morbidity. teen-labs researchers recently compared 5-year outcomes of gastric bypass in adolescents with those of adults. they reported that adolescents and adults who underwent gastric bypass surgery had similar significant weight loss 5 years after surgery, but adolescents had a higher rate of remission of hypertension and diabetes following gastric bypass than adults. they also found that abdominal operations and short-term nutritional deficiencies were more common among adolescents than adults following surgery. 113 data from another teen-lab study demonstrated that joint pain, physical function, and health-related quality of life improved after bariatric surgery. 114 in 2018, the american society for metabolic and bariatric surgery's (asmba) pediatric committee updated their recommendations for metabolic and bariatric surgery in children and adolescents following a comprehensive literature search. they proposed that metabolic and bariatric surgery is indicated for the following adolescents: (1) bmi >35 or 120% of the 95th percentile with clinically significant comorbidities (whichever is lower), and (2) bmi >40 or 140% of the 95th percentile (whichever is lower). in addition, the patient and family should demonstrate the ability and motivation to adhere to recommended pre-and postoperative treatment. the asmba's recommendations regarding contraindications for surgery included: (1) a medical correctable cause of obesity, (2) an ongoing substance abuse problem (within the preceding year), (3) inability to adhere to postoperative dietary and medication regimens as a result of a medical, psychiatric, psychosocial, or cognitive condition, and (4) current or planned pregnancy within 12à18 months of the procedure. at the same time, their guidelines stated that treatment should not be denied to those adolescents with cognitive disabilities, a history of mental illness, a history of eating disorders that are treated, immature bone growth or low tanner stage. their overall conclusion was that surgery was safe and effective in adolescents, and that early intervention can reduce the risk of persistent obesity as well as end organ damage from longstanding comorbidities. 115 multiple publications from the teen-labs study have documented that severely obese adolescents undergoing bariatric surgery, when compared to matched adolescents undergoing medical treatment alone, had better weight loss, improvement in cardiovascular risk markers and better glycemic control. in 2018, the american society for metabolic and bariatric surgery's (asmba) pediatric committee updated their recommendations for metabolic and bariatric surgery in children and adolescents following a comprehensive literature search. they proposed that metabolic and bariatric surgery is indicated for the following adolescents: (1) bmi >35 or 120% of the 95th percentile with clinically significant comorbidities (whichever is lower), and (2) bmi >40 or 140% of the 95th percentile (whichever is lower). the american academy of pediatrics, as well, has issued guidelines in a policy statement entitled "pediatric metabolic and bariatric surgery: evidence, barriers and best practices," published in 2019. 116 they recommended considering the following factors in deciding on surgery: (1) shared decision-making including patient, parents, medical and surgical providers, (2) bmi and comorbidity, (3) physiological, psychological, and developmental maturity, (4) ability to understand risks and benefits and be able to adhere to lifestyle modifications, (5) decision-making capacity, (6) robust family and social supports before and after the procedure. concluding that there was no evidence to support the application of age-based eligibility, the aap set forth the following indications for adolescent metabolic and bariatric surgery: (1) class 2 obesity: bmi i 35 or 120% of the 95th percentile for age and sex, whichever is lower, and with an associated clinically significant disease, including obstructive sleep apnea (ahi >5), t2dm, increased intracranial hypertension, nash, blount disease, scfe, gerd, and hypertension, and (2) class 3 obesity: bmi 40, or 140% of the 95th percentile for age and sex, whichever is lower without any associated comorbid conditions. multicomponent programs that focus on diet, behavior-change, and physical acitivity are recommended as the first line of treatment for children and adolescents who are overweight or obese. treatment should be guided by the patient's developmental, cognitive, and pubertal stage of development. the range of clinicians and environments providing these services is extensive with most services being provided through multidisciplinary tertiary care clinics and providers. these interventions have been proven to be beneficial in achieving small short-term reductions in bmi. presently, there is both a lack of long-term benefit and evidence that these interventions will reduce the incidence of obesity or the associated cardio-metabolic complications for children and adolescents (and adults) in the future. an almost universal consensus recommends a significant increase in research on all interventions including minority and special-needs populations with coordinated long-term follow-up. school-based programs, pharmacotherapy, and bariatric surgery are additional approaches that are increasingly being utilized for weight loss management; of these, 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surgery asmbs pediatric metabolic and bariatric surgery guidelines pediatric metabolic and bariatric surgery: evidence, barriers, and best practices key: cord-012493-pwbzffo9 authors: alligier, maud; barrès, romain; blaak, ellen e.; boirie, yves; bouwman, jildau; brunault, paul; campbell, kristina; clément, karine; farooqi, i. sadaf; farpour-lambert, nathalie j.; frühbeck, gema; goossens, gijs h.; hager, jorg; halford, jason c.g.; hauner, hans; jacobi, david; julia, chantal; langin, dominique; natali, andrea; neovius, martin; oppert, jean michel; pagotto, uberto; palmeira, antonio l.; roche, helen; rydén, mikael; scheen, andré j.; simon, chantal; sorensen, thorkild i.a.; tappy, luc; yki-järvinen, hannele; ziegler, olivier; laville, martine title: obedis core variables project: european expert guidelines on a minimal core set of variables to include in randomized, controlled clinical trials of obesity interventions date: 2020-01-16 journal: obes facts doi: 10.1159/000505342 sha: doc_id: 12493 cord_uid: pwbzffo9 heterogeneity of interindividual and intraindividual responses to interventions is often observed in randomized, controlled trials for obesity. to address the global epidemic of obesity and move toward more personalized treatment regimens, the global research community must come together to identify factors that may drive these heterogeneous responses to interventions. this project, called obedis (obesity diverse interventions sharing − focusing on dietary and other interventions), provides a set of european guidelines for a minimal set of variables to include in future clinical trials on obesity, regardless of the specific endpoints. broad adoption of these guidelines will enable researchers to harmonize and merge data from multiple intervention studies, allowing stratification of patients according to precise phenotyping criteria which are measured using standardized methods. in this way, studies across europe may be pooled for better prediction of individuals' responses to an intervention for obesity − ultimately leading to better patient care and improved obesity outcomes. obesity is a problem that represents a significant health and economic burden in europe and throughout the world. the prevalence of obesity across european countries has tripled in the last several decades [1] , making it one of the leading public health challenges. a critical part of addressing this global epidemic is to improve the evidence base for more effective treatments for obesity; however, a challenge revealed in the randomized, controlled trials (rcts) of obesity interventions is the remarkable heterogeneity of interindividual and intraindividual responses among adult patients -whether the intervention pertains to lifestyle (dietary, physical activity [pa]), or is a pharmacological or surgical intervention aiming at weight loss. most obesity rcts include a heterogeneous mixture of patients that, despite meeting the inclusion criteria for the study, vary remarkably when it comes to the medical history of their disease, associated complications, and many other factors (including genetics, lifestyle, environmental, and psychosocial factors) that may drive the varying responses to the same intervention. also, different trials take different approaches to measuring the same variable. this emphasizes the need to appropriately stratify patients according to precise phenotyping criteria, as measured using standardized methods, that might predict an individual's response to an intervention: enabling a paradigm shift in individually tailored obesity treatment, going from "one-size-fits-all" to precision medicine. one important clinically relevant question is whether, among the patients who respond poorly to a given therapy, a better response might be achieved by applying a different therapy or by administering the current therapy differently. specific patient characteristics could theoretically provide justification for choosing an alternative treatment either as a first choice or, dependent on poor response, as a second choice, but an increased burden is thus placed on researchers to provide evidence for the benefit of choosing or switching between alternative therapies. even for the largest and most comprehensive published clinical studies on obesity, stratification leads to subgroup analyses with reduced statistical power. moreover, some trials do not report methods for measuring relevant obesity phenotypes in sufficient detail. thus, it is necessary to harmonize and merge the data from multiple intervention studies -but data pooling is only possible with trials that include a common set of variables measured in the same way, including samples that are collected using consistent methods or procedures, described in enough detail. funded by a european grant, a group of european obesity researchers convened in 2018 to create a plan for helping shape future rcts in the field of obesity by identifying the minimal set of variables that should be included in trials of different kinds of obesity interventions, whatever the type and the endpoints of the intervention. the experts intend for this minimal core set to be adopted in future studies while acknowledging that in addition, rcts or other trials will collect data on extra variables, depending on the specific area of focus. as such, the current initiative, called obedis (obesity diverse interventions sharing -focusing on dietary and other interventions) and funded by the joint programming initiative -a healthy diet for a healthy life (jpi hdhl), was created to provide the research community with a blueprint for designing future rcts in order to allow the sharing and merging of datasets, and to enable meaningful subgroup analyses. to achieve this, the obedis experts surveyed the scientific literature, especially the published work on stratifying populations of individuals with obesity. they shared their expert opinions on a recommended minimal core set of variables to be included in all future trials of adult obesity interventions and sought to reach consensus on both these variables and the related assessment methods. the obedis project coordinators, supported by the european association for the study of obesity (easo), invited leading experts to contribute to this consensus on a minimal core set of variables for rcts of obesity interventions. these european researchers represented 13 countries and were chosen for their research record and expertise related to obesity and intervention studies in the field. the total group was comprised of 30 experts (including the 4-person coordination/management team); three scientific advisory board (sab) members; one project manager; one funding agency (jpi hdhl) representative; and one medical writer. the obedis experts were purposely selected from countries with different healthcare models and demographics. these multiple perspectives were considered necessary in the discus-sions, in order to serve the field best by choosing a minimal core set of variables that are applicable across different geographies and cultures. the experts were divided into small working groups according to their expertise. they completed reviews of published rcts in their respective domains and held initial discussions. after this foundational preparatory group work, these experts and sab members met for a 2-day workshop in paris, france, in october 2018, to discuss the recommendations and come to a consensus on a core set of variables to recommend in each domain. a variable is defined as "a property with respect to which individuals in a sample differ in some ascertainable way" [2] . the minimal core set is a set of variables recommended to be measured in all trials for obesity, regardless of the type of intervention. it is understood that over time this core set will be updated according to the scientific advances in each of the identified domains. for a variable to be included in the minimal core set, it was required to fulfill the following criteria: • it provided information that made it likely to impact treatment response, according to the relevant literature (especially studies that aimed to stratify patients) • it was feasible: given that each clinical trial has limits on budget and time as well as research team expertise, the obedis group aimed to minimize the burden of including each variable in future trials. the scientists paid considerable attention to factors that would encourage widespread adoption of these measures by the european obesity research community, especially the overall number of variables that should be systematically collected. the group preferred measures that were: − low-cost or free to utilize/able to be collected with minimal equipment or human resources − less invasive/quick to implement − for questionnaires: available and/or validated in multiple languages or across cultures the group provided an estimate of the average cost of including these measures in a european trial (table 1) . while inclusion of these variables will in some cases introduce additional cost to individual clinical trials, they will also extend the insights made possible by each trial -making the overall research agenda proceed more purposefully and at a lower cost. while the primary purpose of the initiative was to identify a minimal core set, additional relevant variables and/or measures were identified in some cases, and these were included in what was called the "expanded set." each group presented the variables frequently used in the studies to date, and selected them based on their experience, the scientific literature, and their projections about the future direction of the field in each domain. the group then voted on each item in the minimal core set (with the outcome determined by a simple majority). the approach to this obedis project was pragmatic and guided at every turn by the existing body of evidence on interventions for obesity while taking into account the constraints of the minimal core set. the experts understand that few trials will restrict themselves to only this core set and will collect additional variables depending on their specific aims and outcomes. trial investigators may opt to carry out more detailed measurements for a certain variable when it corresponds to the main objective of the study -and in this case, regardless, the obedis group recommends collecting the overlapping measures in the minimal core set to facilitate data integration on a larger scale. the obedis work with european experts occurred in parallel with a similar united states initiative funded by the national institutes of health: the adopt (accumulating data to optimally predict obesity treatment) core measures project [3] . in the obedis workshop, the experts noted that the existence of this parallel work highlights the need for such efforts in the field. obedis scientists wish to connect ideas across these two projects and build joint efforts in the same direction, for the overall benefit of the field globally. the expert guidelines detailed herein represent a practical advancement in the field of research on obesity interventions. below, the results are described in four categories -environment and context, lifestyle, subject characteristics, and complications -with a final section looking ahead to implications for future medical practice. table 1 summarizes the variables and methods. issues pertaining to obesity interventions are covered in a separate paper. the obedis experts unanimously agreed that standard operating procedures (sops) are of critical importance, because only with consistent harmonized procedures can data be pooled across studies. the recommended detailed assessment methods for these measurements are detailed in the supplementary materials (for all online suppl. materials, see www. karger.com/doi/10.1159/000505342). no living entity exists in isolation: across the biological sciences, researchers consider environmental influences as major drivers of behavioral change. various environmental factors are considered relevant in obesity, since they may contribute to the emergence and maintenance of the condition and relevant behaviors. the context where patients live and work may also impact response to interventions, making contextual factors potentially useful for patient stratification at baseline. medical history of obesity minimal core set recommended variables: • age at onset of obesity • maximal and minimal body weight after 18 years of age • variation of body weight during the past 3 months • previous attempts to lose weight and weight maintained after weight loss • etiology: categories from hebebrand et al. [4] • parental history, including history of bariatric surgery expanded set recommended variables: • body weight self-monitoring the medical history of obesity is a recall of weight-related events and problems experienced by the patient. in adult obesity, the medical history of the disease is important because factors in the history of a patient can not only affect the course of weight gain and loss through the lifespan but may modulate the response to a specific type of intervention. medical history variables in three main categories are relevant to intervention responses: the development of the current obesity state and previous attempts to treat it; the disease etiology; and variables related to conception and perinatal history. comorbid medical conditions that may influence intervention outcome, or disorders for which the treatment influences outcome, are discussed elsewhere in this paper. in considering the development of the patient's current obesity state, the obedis group recommends documenting both the age of the onset of obesity, and the maximal and minimal body weight during adulthood. the age at obesity onset is important because occurrence prior to age 18 can influence the development of complications later on [5] . meanwhile, minimal and maximal body weight in adulthood are also relevant; in particular, using maximum body mass index (bmi; rather than using bmi at the time of study) to assess mortality risks leads to stronger associations between excess weight and mortality [6] . another potentially important factor is recent body weight fluctuations [7] ; the group recommended assessing weight changes over the past 3 months. assessing body weight self-monitoring behaviors is not recommended for the minimal core set of variables but may be included in the expanded set. previous attempts to treat obesity are also relevant: for instance, in some studies a greater number of previous weight loss attempts predicted greater weight loss [8] and some evidence suggests weight cycling may increase the likelihood of future weight gain [9] . data for the minimal core set should include: the number of attempts, whether the patient has undertaken individual/group behavioral interventions (pertaining to nutrition/pa/psychology), whether treatment included obesity drugs or bariatric surgery, and the maximal weight loss and weight regain as a result of these attempts. the etiology of the patient's obesity may affect response to intervention. in most individuals with obesity, the disease is multifactorial -that is, resulting from the complex interaction of many genetic/epigenetic and environmental factors. however, in cases where a defined etiological factor can be identified (a genetic mutation, for example), the obedis group recommends using the categories outlined in hebebrand et al. [4] . trained medical staff should be able to identify syndromic obesity to either avoid the inclusion of these patients if the trial is not specific to genetic obesity or include these patients as a separate subgroup. factors related to periconceptional and perinatal history of the patient may also affect response to obesity interventions [10] : family disease history, maternal obesity before conception, complications and health conditions during pregnancy (including maternal gestational diabetes), magnitude of gestational weight gain, preterm or term birth, and birth weight (macrosomia). typically, not all of this information is known to the patient, but in the minimal core set the obedis group recommends assessing two particularly important factors prior to conception: parental obesity [11] and maternal history of bariatric surgery. no standardized medical history questionnaire for obesity is in use throughout europe. various standardized questionnaires exist to assess some of the above items, but many are not available in different european languages. thus, the obedis group recommends assessing the above medical history variables via custom questionnaire (self-report), specified in the supplementary materials. where available, medical records (registers or electronic medical charts) may be used to corroborate the information. the group agrees that, in the future, researchers should set about developing a standardized clinical questionnaire related to the medical history of obesity, which would be translated into different languages for use by researchers and healthcare professionals across europe. a further endeavor -which would prove extremely valuable for research purposes -is to develop a european register of health information that included data on medical history, health status, and treatment of individuals over time. basic background information minimal core set recommended variables: • number of years of education and country both education and other measures of socioeconomic status, such as income, may modify intervention outcomes for certain kinds of obesity interventions. variations across education level were observed for the outcome suicide and self-harm when comparing a dietary/lifestyle modification program and bariatric surgery [12] ; a similar pattern was found for the outcome of sleep medication use [13] . in higher-income countries, an inverse association tends to exist between educational attainment and obesity [14] . number of years of education is widely used for assessing patient educational attainment [15] and is recommended in this context. while this measure does not allow complete comparability of data between countries, the minimal core dataset would ideally specify the country along with the number of years of education. minimal core set recommended variables: • quality of life (qol): eq-5d-5l health profile scores, overall self-rated health status, and index value qol is a subjective factor that is defined by the world health organization (who) as "an individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns" [16] . health-related qol is a broad-ranging, multidimensional assessment of one's own health; it is an outcome measure that is frequently assessed along with handicap: "a disadvantage for a given individual that limits or prevents the fulfillment of a role that is normal for that individual" [17] . given that health is "a state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity" [18] , a complete assessment of health status -especially in chronic diseases -should include both objective measures (using a biomedical framework) and subjective measures (using a psychosocial framework; e.g., qol) [19, 20] . in the field of obesity research, health-related qol can be an independent outcome variable for assessing the effectiveness of therapeutic strategies for obesity, complementary to the degree of weight loss and to the improvement in complications [21, 22] . in addition to its outcome value, qol can also have predictive value (i.e., prediction of biopsychosocial outcomes) and discriminative value (e.g., differentiating between patients with or without other medical conditions) [23] . qol is an important variable in economic evaluation of healthcare interventions, as it is used to calculate quality-adjusted life years, the most commonly used effect measure in cost-effectiveness analyses. qol, as a patient-reported outcome, is assessed using self-administered questionnaires. many questionnaires have been validated in the field of obesity [for reviews see 24, 25] . the obedis group used several criteria (consistent with the general criteria above) to choose the most suitable qol questionnaire: type of concept assessed (i.e., assessment of qol, but not symptoms/functional status or handicap), brevity, convergent validity, cross-cultural validation (particularly important in this european work), and copyright (including no or limited fees for use). the european group agrees that the eq-5d-5l satisfies the greatest number of criteria for suitability of widespread use -especially cross-cultural validation, minimal number of items, and free copyright. this tool, designed in 1990 by the euroqol group (comprised of international multidisciplinary researchers devoted to measuring health status), was revised in 2005 and validated in 2011 [26, 27] . the questionnaire includes five dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression, and an overall visual analog scale. importantly, it has been validated in patients with obesity and who have undergone obesity surgery, and is sensitive to change [28, 29] . in cases where the main goal of the study is related to qol, however, an additional obesity-specific measure may be useful to assess this parameter in more depth. while human behaviors vary substantially and occur in a complex interplay with an individual's social and physical environments, characterization of specific behavior patterns is useful for predicting clinical outcomes. discussed in this section are behaviors and lifestyle factors that affect energy balance, weight loss, and/or weight maintenance. eating behavior, defined as an individual's food and beverage consumption and habitual eating patterns [30] , is a complex and important modifiable behavior that directly affects weight and nutritional status through the lifespan. in obesity, assessment of eating behavior is necessary given the dual burden of disease and potential undernutrition. obesity interventions that target eating behavior mostly aim to decrease energy intake to induce negative energy balance -a necessary condition for weight loss. modification of dietary intake is a well-known requirement for successful treatment of adult obesity [31] . the benefits of dietary interventions for obesity go beyond weight loss, since a body of evidence shows that changes in dietary quality per se may decrease the risk of various comorbid health conditions and even reduce all-cause mortality [32, 33] . dietary intake constitutes a critical factor that interfaces with genetic heterogeneity and metabolic phenotypes, resulting in different health outcomes; for example, dietary fat intake can interact with genotype and/or phenotype to affect the risk of obesity [34, 35] . in addition, dietary fatty acid exposure can also interact with sex and genes together to predict the development of the metabolic syndrome [36, 37] . many dietitians and nutrition scientists recognize the need to move from populationbased nutrition to personalized subgroup-based nutrition [38] . obesity is highly heterogeneous, so personalized or targeted interventions are warranted [39] but a major challenge is to determine which diet-related variables stratify individuals into groups that will respond to a given intervention. for all adult trials on obesity interventions, regardless of whether they focus on diet, the obedis group recommends assessing both dietary intake and overall diet quality. the obedis group acknowledges, however, the particular difficulty of identifying dietary assessment tools applicable to the broad range of cultural and geographic groups across europe. while obtaining data on energy, and macronutrient and micronutrient intake is a major objective, the various assessment tools that exist are each appropriate for a specific country or region. dietary intake is a detailed account of which foods and beverages are consumed, and in what quantities, during a set period of time. initiatives exist (beyond the scope of these guidelines) that propose the most appropriate dietary assessment method in order to collect good quality dietary data, depending on the study objectives. the group recommends assessing this parameter in the minimal core set using a food frequency questionnaire (ffq); the experts put forth the epic-norfolk ffq for consideration [40] , while noting that the ffq used in each trial should be validated according to the country in which it is being used. a 3-day weighed food record is appropriate for detailed studies where greater insights and links to biological readouts are required; such an assessment may capture short-term changes as a result of intervention. in the expanded set of variables (or depending on the study question) the experts recommend the use of a 3-day weighed food record, which is more suitable for detecting the effects of an intervention. reviews like dao et al. [41] can help researchers select and implement the most appropriate dietary assessment method(s) to collect highquality dietary data. the group also recommends in the minimal core set an assessment of dietary quality, while acknowledging that the healthy eating indices applicable in europe are linked with country-specific dietary guidelines and guidelines for pa. the dutch healthy diet index [42, 43] was cited as a useful tool; however, the experts emphasize that the index used in a given trial must be adapted according to local guidelines and habits. the group also notes that in some contexts, it is important to use additional measures for tracking specific components of diet: for example, fiber intake or sugar-sweetened beverage consumption or the consumption of processed food. the group agrees the nutrition community should invest in the design and validation of assessment tools for dietary intake (included validated smartphone apps) that improve upon the ones currently available. dietary intake assessment is highly challenged by the lack of accurate biomarkers, particularly in relation to energy intake and macronutrient intake, whilst micronutrient status may be more feasible. biomarkers of dietary compliance were discussed by the obedis experts. such biomarkers are required to provide subjective insight in relation to habitual diet, as well as compliance to dietary interventions. however, those currently available have inherent limitations; for example, serum fatty acids only provide a short-term and limited assessment/reflection of dietary fatty acid intake. these biomarkers are not recommended for the minimal core set, but the experts note the critical importance for trials with free-living interventions of having an objective measure of compliance to identify nonresponse due to either noncompliance or lack of biological response. when faced with stress, individuals exhibit differences in eating patterns: approximately 40% increase and 40% decrease their energy intake, while around 20% do not change [44] . regardless of whether overall energy intake is increased, however, stress begets a shift toward choosing foods higher in sugar and fat. hyper-palatable foods may act as a distress coping mechanism, particularly in those who have previously associated intake with relief [45] . dieting constitutes a risk factor for emotional eating, since stress and negative affect can be consequences of energy restriction, and paradoxically, may lead to food-related coping strategies [46] . there may also be a biological basis for emotional eating, as individuals who exhibit this pattern demonstrate a blunted hypothalamic-pituitary-adrenal axis response to cortisol that leads to increased food intake [47] . emotional eating is associated with current and prospective weight, and interacts with perceived stress, negative life events, and short sleep duration [47] . greater weight loss success has been associated with decreased emotional eating score during a behavioral weight loss program [48] . eating in response to distress may also influence the timing of meal consumption -and because recent studies have indicated that meal timing in relation to sleep phase is an important factor for weight regulation, clinical trials should capture individuals' tendency toward emotional eating. the recommended tool for assessing these behaviors in the obedis minimal core set is the emotional pa is any bodily movement produced by the contraction of skeletal muscles that results in energy expenditure (ee) above resting levels [50] , while exercise is a subtype of pa: one that is planned, structured, repetitive, and designed to improve or maintain physical fitness, physical performance, or health [50] . pa helps adjust energy balance in those with obesity. yet when diet is held constant, individuals in different bmi categories may experience different effects of pa on weight [51] . overall, studies report inconsistent results on how increased pa (including exercise training) affects weight loss; however, an inverse association has been shown between pa and longterm weight gain [52] , although it is recognized that relatively high levels of pa might be required. there is general agreement that a major benefit of pa in subjects with obesity is prevention of weight regain after weight loss [53] . studies show pa attenuates many health risks that are associated with overweight or obesity, and importantly, numerous health benefits result from increased pa even with no weight loss or only modest weight loss [54] . current evidence indicates that pa, at levels that are feasible to perform in subjects with overweight or obesity, only results in modest weight loss [52] . sb is defined as any waking behavior characterized by an ee equal to or lower than 1.5 metabolic equivalent tasks (or met, with 1 met representing ee by a subject at rest, sitting); this includes behaviors carried out while sitting, reclining, or lying [55] . independent of pa levels, sb is associated with a higher risk of cardiometabolic disease and other complications. decreasing sb is promoted in parallel with interventions that aim to increase habitual pa [55] . the obedis group agrees on the importance of including both objective and subjective measures of pa and sb in each clinical trial. objective data on both of these can be gathered most commonly using an accelerometer -a type of movement sensor that is feasibly used in large-scale studies to quantify pa intensity and duration as well as sb duration, including breaks in sedentary time, with minimal inconvenience to the participant. the group recommends this method while noting several limitations: when worn on the hip, accelerometers typically miss upper body movement; neither do they provide data on body posture nor data in cycling or aquatic activities [56] . the required accelerometer data comprises pa level as well as week day time in sb and weekend day time in sb. a subjective measure of pa and sb is also needed to add important information, such as the specific types of activities performed, the perceived level of exertion during exercise, and additional information about the context (place, time) of the pa. for these purposes, the group put forward a short questionnaire called the paffenbarger physical activity questionnaire. this widely used instrument is available in multiple languages and has ten questions that focus on moderate-to-vigorous pa, ranging from common activities such as stair climbing and walking to specific leisure activities [57] . in addition to pa and sb, physical fitness is an important patient characteristic that may also relate to outcomes of the intervention(s). physical fitness is a physiological attribute determining a person's ability to perform muscle-powered work, and it has been defined as "the ability to carry out daily tasks with vigor and alertness, without undue fatigue, and with ample energy to enjoy leisure-time pursuits and respond to emergencies" [52] . one major component of physical fitness is crf. high crf is associated with greater longevity and reduced cardiovascular risk in all bmi categories [58, 59] . while the usual measure of crf is maximal oxygen uptake (vo 2 max, or maximal aerobic power) during an exercise test [60] , requirements for specialized equipment and expertise render it impractical for the minimal core set. the obedis experts instead recommend the use of the 6-min walk test [61] , a field submaximal exercise test for assessment of physical function that requires a 30-m hallway and no specialized training or equipment. the test measures the distance an individual can quickly walk on a flat, hard surface over a period of 6 min, and it can be used to predict vo 2 max [62, 63] . the expanded set, however, may include the chester step test as a measure of crf: in this validated assessment of aerobic capacity, the participant is asked to step on and off an elevated platform in time with an audible metronome beat [64] . another important component of physical fitness is muscular fitness. a measure of muscle strength, as an important component of muscular fitness, is therefore also recommended for the minimal core set, since the evidence in aggregate shows that muscle strength is associated with reduced mortality in all bmi categories and that resistance training (designed to increase muscle strength), even without weight loss, improves health risk [53] . more importantly, weight loss treatments may be associated with decreases in muscle strength, especially if the treatment does not include exercise. the southampton grip-strength measurement is chosen for this purpose [65] . given these recommendations, the group notes an added value of the assessment methods in the minimal core set: some of the chosen methods are useful for assessing several variables. this is the case for the use of accelerometers to assess both pa and sleep behaviors; grip strength to measure both muscular fitness and (in the expanded set) sarcopenia; and the 6-min walk test to predict crf. habitual pa, sb, and physical fitness all must be measured at baseline (before any exercise training or intervention occurs) and at the end of an intervention; in trials longer than 6 months, these variables should be measured every 6 months. minimal core set recommended variables: • sleep duration and timing • presence of sleep apnea: stop-bang expanded set recommended variables: • sleep duration and timing: accelerometry sleep is influenced by the circadian clock -a self-sustained molecular oscillator, which aligns endogenous rhythms with daily exogenous signals to coordinate metabolism and behavior [66] . ample data show mistimed sleep contributes to "chronodisruption" [67] or "circadian-phase misalignment" [68] and promotes weight-related pathologies [69, 70] . commonly, sleep disruption occurs because of atypical work schedules: night shift work patterns are associated with the risk of overweight/obesity -especially abdominal obesity -and permanent night shifts appear to confer a higher risk than rotating night shifts [71] . a lesser degree of chronodisruption called "social jetlag," however, can result from social activities and has been associated with an increased bmi [72] . given these data, the obedis group recommends systematically recording whether individuals work on atypical schedules (specifically: the presence of night shift work and permanent night work), and whether they experience social jetlag. although the munich chronotype questionnaire (mctq) is sometimes used for these purposes, the obedis group recommends a shorter custom assessment (see supplementary material) for patients to self-administer. quantitative sleep data acquired from an accelerometer may be used (as part of the expanded set) in trials where resources allow. prolonged wakefulness and sleep deprivation are hallmarks of modern lifestyles. across cross-sectional and longitudinal studies, individuals' sleep duration shows a somewhat in consistent pattern of association with obesity [73] . experimental data suggest that sleep restriction increases food intake and alters ee [74] . the obedis group advocates for a basic assessment of sleep duration in the minimal core set. specific questionnaires exist that capture various dimensions of sleep, including sleep duration, but many are subject to copyright restrictions and/or lack validated translations into different languages. for assessing sleep duration, the obedis group recommends a custom, self-administered questionnaire (shown below). in individuals with obesity, disordered breathing during sleep is prevalent. well-documented is the idea that obstructive sleep apnea (osa) overlaps with obesity-related risks [75] and impacts metabolic risk [76] . use of the osa therapy continuous positive airway pressure (cpap) may also change energy balance or metabolism [77] , with potentially positive effects on glycemic control [78] . the presence of osa and the use of cpap should therefore be assessed. while the gold-standard objective measure of osa is the apnea-hypopnea index with nocturnal polysomnography, the obedis group recommends subjective assessment using a brief questionnaire called the stop-bang [79] . this questionnaire, which is freely available, was created to screen for symptoms of osa in surgical patients and in all individuals. it can be completed in approximatively 1 min and has good predictive ability for mild, moderate, and severe osa [80] . cpap use may be assessed using a custom questionnaire item. minimal core set recommended variables: • perceived stress: perceived stress scale (pss) previous research has indicated the necessity for simultaneous assessment of sleep and stress in trials on obesity [81] . poor sleep and emotional stress are predictors of incident obesity and may have an additive role [82] . not only does perceived stress associate with bmi, waist circumference, and serum triglyceride level [83] , but also, those with poor sleep and incident obesity appear to have the greatest emotional stress and the shortest subjective sleep duration [84] . perceived stress is the degree to which situations in life are appraised as stressful by the individual. the expert group recommends subjective assessment of individuals' stress levels via the pss [85] . as the most widely used psychological instrument for measuring the perception of stress, the scale includes direct queries about a patient's current levels of experienced stress. the items on the questionnaire are general, easy to grasp, and require a total of 2 min for completion. an additional advantage of the tool is the availability of validated versions in many languages. all trials involving individuals with obesity include measures of participants' characteristics, including anthropometric measures, body composition, and/or ee. aspects of hormonal status are also important characteristics to consider in trials, as detailed below. anthropometry, body composition, and ee minimal core set recommended variables: • weight and bmi • anthropometry (waist, hip, neck circumference) • fat mass and fat-free mass: dual energy x-ray absorptiometry (dxa) expanded set recommended variables: the who defines obesity as "a condition of abnormal or excessive fat accumulation in adipose tissue, to the extent that health may be impaired" [86] . in clinical trials on obesity, researchers must quantify this increased adiposity in a way that allows comparisons between alligier et al.: obedis core variables project www.karger.com/ofa subjects, and over time in the same subject. patient-reported data are not adequate for these purposes. the obedis experts acknowledge that the study of body composition assessment methods is rapidly moving forward, far beyond basic calculations of bmi, and this may present an important opportunity for identifying precise body composition subgroups that may respond predictably to an intervention. bmi -calculated from measures of a subject's height and weight -is the simplest and most frequent way of classifying an individual as underweight, normal weight, overweight, or obese, and is therefore recommended for inclusion in the minimal core set. although the relationship between bmi and all-cause mortality has been confirmed [87] , bmi as a "surrogate measure" of obesity does not directly capture large interindividual variation in excess adipose tissue. this makes bmi misleading for individuals who exhibit differences in proportions of lean body mass and fat mass (for instance, elite athletes and those with sarcopenia) [88] . indeed, going beyond a patient's bmi adds valuable additional information about health [89] [90] [91] . recent work shows it is the excess fat that constitutes a risk factor for a range of comorbid diseases: type 2 diabetes (t2d), ischemic heart disease, hyperlipidemia, sleep apnea, certain forms of cancer, and others [92] . further anthropometric measures -waist, hip, and neck circumferences -are recommended in all clinical trials focusing on obesity, as ways to assess subjects' fat distribution. ample evidence shows increased central or android fat distribution (assessed via waist-toheight ratio) is associated with greater risk to health [93, 94] compared to more peripheral or gynoid fat distribution. adding waist circumference to other anthropometric measures is valuable for predicting metabolic phenotypes [95] and a rationale even exists for how variables that include waist circumference directly affect intervention response [96] . waist-tohip ratio predicts cardiovascular morbidity and mortality in those with obesity and t2d [97] [98] [99] . in addition, neck circumference has been shown valuable for identifying excess body weight [100, 101] and associates with the presence or severity of different comorbidities [102] [103] [104] . many options exist for more precise measurements of body composition. available methods, each with their pros and cons, include bioelectrical impedance analysis (bia), magnetic resonance imaging, computerized tomography scan, air displacement plethysmography (bod pod), underwater weighing, and dxa. body weight, bmi, or variables derived from weight alone are unable to distinguish between fat-free mass and fat mass, yet these components have specific medical relevance: increased fat-free mass may be found in athletes, who are not obese despite a high body weight/bmi; decreased fat-free mass is characteristic of a pathological condition called sarcopenia (or sarcopenic obesity), which needs to be detected; and fat-free mass is a determinant of ee (see below). meanwhile, the visceral component of total body fat has unique physiological characteristics, which influence diseaserelated processes in the body [105] . increased visceral adipose tissue in those with obesity is associated with an increased risk of metabolic (glucose intolerance, t2d) and cardiovascular disease (cvd). the obedis group agrees that precisely capturing the amount and distribution of body fat is required for the minimal core set of variables. at present, however, no easy methods exist for assessment. bod pod and bia are two-compartment models (capturing fat mass and fat-free mass), while dxa is a three-compartment method (dividing the body into fat mass, lean body mass, and bone mineral content). this relatively accurate, noninvasive method enables rapid measurement of percent body fat, although it remains dependent on several assumptions (namely, the constancy of fat-free mass composition) and exposes participants to a small dose of ionizing radiation. but because dxa is validated for those with obesity, it is the obedis group's recommendation. the use of dxa, a method that requires specialized equipment, is an exception to the general principle of simplicity in the obedis minimal core set, but the group agrees that the potential predictive value of dxa-generated data is sufficiently great to enable rapid progress in the field. in cases where trial limitations in budget, equipment, or expertise render it impossible to incorporate dxa, the group recommends bia or plethysmography as an alternative to measuring fat mass and fat-free mass. overall, the expert group concurs that the field needs more research and development on easy and inexpensive tools for precise measurements of body composition. energy balance in obesity may be important for prediction of intervention outcomes [106] . ee is one component of energy balance, and hence, highly relevant for evaluating body weight changes. a subject's ee is likely to change in the course of an intervention, as it can vary with changes in body weight [107] or fat-free mass; changes in the composition of body weight gained or lost; adaptive thermogenesis (thyroid hormones, sympathetic nervous system, brown adipose tissue); and pharmacologic agents [108] . twenty-four-hour ee is the sum of basal metabolic rate (bmr), adaptive thermogenesis (food, thermoregulation, etc.), and pa/exercise thermogenesis; it can be measured in freeliving individuals with doubly labelled water, but this method is expensive and restricted to a few specialized centers. resting ee can be measured by indirect calorimetry -but again, this method is not feasible in all centers, and accurate measurements require very strict conditions (overnight fast; no pa prior to measurement, requiring that measurement is done on inpatients; thermoneutrality, etc.). bmr varies according to body composition (mainly fat-free mass), and hormonal status (thyroid hormones, sympathetic nervous system/catecholamines, brown adipose tissue). bmr can be predicted with equations based on body weight or body composition: bmr = a • body weight + b (where a and b are different for males and females); or bmr = a • fat-free mass + b (where a and b are identical for both males and females). expressing results as kcal expended per kg body weight or per kg fat-free mass invariably underestimates values in overweight/obese individuals and should not be used. results should instead be expressed as percentages of predicted value based on validated equations (mifflin jeor or others; see supplementary materials). ee is an essential feature for metabolic phenotyping, but direct measurement of ee should be included in the obedis expanded set rather than in the minimal core set. the energy requirements of individuals included in a study can instead be predicted based on the bmr prediction equations above, multiplied by a pa level of 1.1-1.9 for pa level [109] . measurement of ee may nonetheless be highly relevant in some mechanistic studies, since variations in bmr may occur during interventions due to changes in body weight/fat-free mass (body composition-dependent changes) and changes in tissue (fat-free mass) metabolic activity. such measurements are best done by open-circuit indirect calorimetry using standardized procedures. simultaneous measurement of body composition is strongly recommended for data interpretation. endocrine and gynecological system alterations can occur in obese individuals, and many different measurements give insights into these complications; these include markers of thyroid status, that can be related to regulation of energy balance, and markers of gonadal axis in both sexes [110, 111] . among these hormones, the group recommends the measurement of tsh to assess thyroid function; fsh and lh may be used in the expanded set to confirm, when necessary, menopausal status in women. in both males and females, androgens might provide valuable additional information; however, should their measurement be included, it should be mandatorily accomplished by mass spectrometry-based assays [112] . a panel of peptides and cytokines is usually characterized in studies focusing on obesity, including leptin, as a marker of body fat; adiponectin, as a predictor of metabolic dysregulation; tumor necrosis factor alpha and interleukin-6, as markers of inflammation; ghrelin, as a hunger signal; glucagon-like peptide-1 and peptide yy as a measure of satiation signal function. consequently, measurement of each of these hormones may be included in clinical trials for obesity, according to the specific research question. however, preanalytical and analytical issues related to the measurement of most of these substances dramatically affect the consistency of the results. assay standardization and harmonization among labs are urgently needed to generate normative values. in addition, mass spectrometry-based assays for the quantitative and qualitative (isoforms, posttranslational modifications, etc.) assessment of peptide hormones are regarded as promising for their thorough characterization; however, the introduction of such techniques into routine clinical labs does not appear feasible in the near future. the many complications of obesity are of interest because of their associations with poorer overall health and with more complex clinical management. these comorbid conditions, and the medications taken to ameliorate them, may affect response to intervention. the major comorbid conditions in obesity are addressed in this section. type 2 diabetes minimal core set recommended variables: • fasting glycemia (two measurements) • hemoglobin a1c: hplc-ce or hplc-ms • fasting insulin and insulin-derived insulin sensitivity indices • family history of diabetes expanded set recommended variables: • hyperinsulinemic-euglycemic clamp obesity is associated with alterations in normal endocrine and metabolic functions, leading to a number of pathological conditions: among these, t2d -affecting around 30-40% of obese individuals [113] . although metabolically healthy obese individuals exist, epidemiological evidence shows a high incidence of metabolic syndrome in those with obesity [114] . in patients with both obesity and t2d, interventions that lead to successful weight management substantially improve outcomes related to metabolic control [115] . response to interventions may also be modified by the use of various antidiabetic medications, which might affect weight either positively or negatively [113] . the obedis group recommends including several t2d-related variables in all clinical trials on obesity interventions: two measurements of fasting plasma glucose for assessing t2d, hemoglobin a1c (hba1c) for screening and monitoring of glycemic control, and fasting insulin as a surrogate marker for insulin resistance as well as indicating the secretory capacity of the beta cells. hba1c measurement is recommended both for assessing blood glucose control in people with diagnosed t2d, and for diagnosing the disease or its early stages ("prediabetes"). the group agrees that c-peptide could take the place of fasting insulin as a marker of remaining insulin secretion. further, insulin-derived insulin sensitivity indices should be calculated [116] : homeostatic model assessment of insulin resistance (homa-ir) represents the presence and extent of insulin resistance; whereas homa-beta reflects beta cell function. both calculations are mainly used in clinical studies. several additional factors related to t2d are important to know -the individual's family history of t2d (to indicate possible genetic risk), as well as current medication and dosages. recommendations on specific methods for each of these parameters are detailed in table 1 . there are more invasive measures of insulin secretion and sensitivity (hyperinsulinemic-euglycemic clamp, intravenous glucose tolerance test, etc.) and more comprehensive measures of key aspects of metabolic flexibility, but these tests are not feasible for all large-scale clinical interventions. minimal core set recommended variables: • smoking habits • blood pressure and heart rate: automatic blood pressure device • total cholesterol, high-density lipoprotein cholesterol, triglyceride • inflammation: c-reactive protein (crp) • heart electrical activity: 1-to 5-min electrocardiography (ecg) • crf: 6-min walk test individuals with obesity often exhibit disordered vascular and heart function, and an elevated risk of cvd. intervention strategies may be modified by the presence of cvd or its various risk factors [117] . most cvd risk is driven by age plus three other major cvd risk factors in addition to diabetes; namely, high cholesterol, high blood pressure, and smoking, together accounting for about 80% of population-attributable risk [118] . cardiovascular risk algorithms exist [119] [120] [121] [122] , but due to the imprecise estimates they provide and the factors that are included in these algorithms, they may not prove useful in the context of short-term interventions for obesity. while risk scores were not included in the minimal core set, the obedis group proposes measuring smoking status as well as several parameters related to vascular and cardiac function, which may help, now and in the future, to stratify individuals in order to optimize intervention outcomes. assessment of current smoking habits in the minimal core set is achieved using two custom questions: number of cigarettes per day and duration of smoking. related to vasculature (atherosclerosis), the group recommended obtaining data on selected serum biomarkers: total cholesterol, high-density lipoprotein cholesterol, triglycerides, and high-sensitivity crp (hscrp). fasting hscrp is included as a surrogate marker of inflammation, and crp appears to be one of the best-established cvd risk markers [123] [124] [125] [126] [127] while having the advantage of being analyzed in a standardized and relatively inexpensive way. additional measures relevant to cvd, including blood glucose and insulin concentrations, which capture insulin resistance and beta-cell function [128] , are covered in the t2d section. the adipokine interleukin-6 also seems promising [129] , and is recommended for the expanded set, with the recommendations about its measurement proposed in the supplementary materials. among the variables related to cardiac function that could potentially modulate response to interventions for obesity, the following are recommended by the obedis group for assessment: blood pressure, cardiopulmonary function, and electrical activity of the heart as measured by ecg. it is well-established that blood pressure may be modified by certain interventions, with weight loss causing important decreases in blood pressure [130] . despite somewhat limited reproducibility for automatic blood pressure devices, the group recommends using these in order to reduce human error. as an indirect but validated way to assess crf, the group identifies the 6-min walk test [131] [132] [133] [134] rather than the determination of maximal aerobic capacity (vo 2 max), which is expensive and has a poor association with fat mass and the loss thereof [135] [136] [137] . finally, the group recommends performing a 1-to 5-min ecg as detailed in table 1 . although not fully validated for hard endpoints, 1-to 5-min ecg is often used in small intervention clinical trials [138] and predicts cardiovascular death; thus, it may be used as a noninvasive means of risk stratification [139] . assessing the presence of osa is also essential, since osa is associated with hypertension and an increased risk for cvd and t2d [140] . these measures are detailed in the section on sleep behaviors. minimal core set recommended variables: • nonalcoholic fatty liver disease (nafld) fibrosis score (nfs) and fibrosis-4 index (fib-4): alt, ast, ggt, platelet count, and albumin from blood • alcohol intake: who audit questionnaire obesity comes with an increased risk of different forms of nafld: steatohepatitis (increased liver triglycerides), possibly progressing to fibrosis (irreversible scarring of the liver) [141] . tracking the occurrence of these liver conditions is deemed important for the minimal core set, as these conditions may affect a subject's response to intervention. to detect fibrosis noninvasively, most guidelines [142, 143] recommend using the fib-4 or the nfs, both of which are low cost and straightforward. given the relationship of alcohol intake to liver disease, the obedis group also recommends a brief assessment of alcohol intake using the who's audit questionnaire [144] . other long-term obesity complications: osteoarthritis and cancer minimal core set recommended variables: • qol: eq-5d-5l expanded set recommended variables: • pain-related physical functioning: womac va 3.0 over the long term, besides the significantly increased risk of cvd and t2d, obesity confers an increased risk for several other conditions: major medical complications (cancer), and functional complications (arthrosis). data on these conditions are part of a comprehensive assessment of the obesity phenotype. obesity increases the risk for osteoarthritis, a degenerative condition of joint pain and dysfunction [145] . the presence of this condition is normally assessed through specific selfadministered validated osteoarthritis questionnaires. but (pain-related) physical functioning is the most important factor related to osteoarthritis that may change with an intervention [146] , and the obedis group decided this factor is adequately assessed by an overall qol questionnaire. the addition of a specific osteoarthritis questionnaire to the qol questionnaire recommended above would provide marginal improvement in predictive ability. in the expanded set of variables, however, investigators may want to include the western ontario and mcmaster universities (womac va 3.0) osteoarthritis index, a self-report questionnaire covering hip and knee osteoarthritis [147] . those with obesity experience cancer at a higher rate than the general population [148] and a patient's history of cancer may be relevant to the exclusion criteria in a clinical trial. once a patient is enrolled in a trial, however, investigators may want to track cancer occurrence. the obedis group decided that including cancer data in the minimal core set was not necessary; because of the long delay before cancer occurrence, the following data need only be collected in cohorts with more than 5 or 10 years of follow-up: date of diagnosis and cancer type (according to the international classification of diseases). the data should be obtained from medical records where possible and validated by independent medical experts. several areas of analysis have the potential to advance precision medicine within the field of obesity: tissue phenotyping, as well as genetics, and omics. it is already known that researchers may gain insights into the molecular underpinnings of variability in weight loss by precisely analyzing different body tissues in individuals with obesity [149] : apart from components of blood, urine, and stool, this may include biopsies and/or assessments of white adipose tissue, skeletal muscle, and the liver. precise phenotyping of patients by tissue analysis is a promising area within the field of obesity; some studies have successfully used this approach to identify subgroups of participants that have increased susceptibility to obesity or that will predictably respond to a treatment [150, 151] . however, the complexity of these methods rules them out for the minimal core set at present. in the future, patients may be stratified based on the presence of specific genetic markers. data from family, twin, and adoption studies show that both body weight (40-70%) and body fat distribution are highly heritable [152] . heritability also seems to play a role in the nature, magnitude, and/or timing of response to obesity interventions [153] : studies have shown genetic influences on dietary interventions [154, 155] and heritability of response to bariatric surgery (roux-en-y) [156] . obesity-related gene expression may be attenuated by pa. this field is expected to advance rapidly over the next few years and zero in on very specific genetic markers for patient stratification. beyond human genes, advances in high-throughput technologies for analysis of biologic molecules have created the potential for defining the biological characteristics of those with obesity with great precision. new omics technologies enable examination, not only of a patient's genome, but also of complete sets of transcripts, proteins, and metabolites. analyses that fall under the category of omics are those that provide "a comprehensive, or global, assessment of a set of molecules" [157] : genomics, epigenomics (reversible modifications of dna or dna-associated proteins across the genome), proteomics, metabolomics (small molecule types), microbiomics, lipidomics, transcriptomics, and others. already, findings from omics studies have identified important avenues of research in obesity: for instance, epigenomic studies have mechanistically linked aspects of the environment before conception with the probability of becoming obese later in life [158, 159] , while weight loss induced by gastric bypass surgery affects a patient's dna methylation and gene expression profile [160] . the analyses mentioned above are key components of certain obesity intervention studies, depending on their aims. the obedis group considered the pros and cons of including genetic and omics data, as well as tissue analyses, in the minimal core set for all obesityfocused clinical trials; the group concludes that at present, the ability of these tests to explain variability in weight loss is not great enough to justify the added costs. the group strongly suspects, however, that as costs fall and evidence increases, researchers will soon have adequate justification for including such analyses in all trials. in anticipation of the probability that certain blood measurements may yield new insights in the near-term future, biobanking is highly recommended by the group -whole blood where possible, but at a minimum, samples of whole blood dried on paper. dried blood spots are suitable for many potential future measurements, and also have the advantages of easy and low-cost collection and storage. the obedis group agrees that consent is another important issue to address for this field: a challenge is to develop sops around consent, which will allow sharing and reuse of omics and other data over the long term and as new discoveries are made. the group envisions a set of consent-related sops implemented across europe, adapted to local circumstances. the expert consensus detailed herein represents a practical advancement in the field of obesity research -with the group members supporting the adoption of these variables in future clinical trials, collected systematically either before or both before and after intervention. the group fully expects to add further variables to this minimal core set as more data become available in each of the identified domains or remove variables if they do not impact differential treatment response. basic and preclinical research should, of course, continue in tandem, building a larger context for informing better intervention strategies and identifying the appropriate adult patient groups for each specific intervention. the translational potential of the work begun here is therefore of high value: over time, this project should enable more efficient convergence of evidence to support better care for those with obesity. the obedis group sees the ability to pool datasets and compare very large numbers of trial participants as key to the advancement of "precision" or "personalized" medicine. in the future, when a clinician encounters a newly referred adult patient with obesity, he or she will be able to group the patient according to baseline characteristics and suggest a tailored intervention plan, backed by robust data. the obedis workshop and the resulting guidelines, achieved only through the support of easo, 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