key: cord-322724-7l1668bf authors: challener, douglas; shah, aditya; o'horo, john c.; berbari, elie f.; binnicker, matthew j.; tande, aaron title: in reply repeated testing in sars-cov-2 infection date: 2020-08-10 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.08.006 sha: doc_id: 322724 cord_uid: 7l1668bf nan to the editor: we appreciate the points raised by lippi et al regarding our article describing repeat testing for sars-cov-2 infection. 1 in summary, the authors emphasize that repeat testing may be helpful in improving the negative predictive value of testing and ensuring that cases of covid-19 are identified. the authors include evidence supporting the conclusion that identification of the sars-cov-2 virus is directly related to the number of nasopharyngeal swabs that are collected and also emphasize the importance of case-finding in control of the pandemic. in general, we agree that repeat testing may be helpful in certain situations of ongoing high suspicion for active infection where alternative approaches are not feasible; however, we believe that testing should not be applied indiscriminately in a resource-constrained situation. several studies have suggested that the number of unique patient specimens tested for sars-cov-2 is directly related to the positive identification of the virus and that there may be a high false-negative rate of molecular testing. 2, 3 the study by zhang et al reported 41 hospitalized patients with an initial negative pcr test who had at least one positive result on subsequent testing. however, the timing between tests was not reported in this manuscript, which raises the possibility that some of the patients could have become infected following their first test. no laboratory test has 100% sensitivity, and we agree that the likelihood of detecting infected individuals will increase if they are tested more frequently. this characteristic of laboratory testing is not unique to sars-cov-2, but could be applied to molecular testing for many other infectious diseases. however, widespread indiscriminant repeat testing is not currently possible. unfortunately, supply chain challenges continue to limit the widespread availability of sars-cov-2 pcr testing in the united states. tests should be used in an efficient manner and guided by principles of diagnostic stewardship. 4 we agree that there may be a role for repeat testing in patients with high clinical suspicion of low utility of repeat real-time pcr testing for sars-cov-2 in clinical specimens distinct characteristics of covid-19 patients with initial rrt-pcrpositive and rrt-pcr-negative results for sars-cov-2 false-negative results of initial rt-pcr assays for covid-19: a systematic review mayo clinic strategies for covid-19 diagnostic stewardship: an essential element in a rapidly evolving covid-19 pandemic covid-19 testing: the threat of false-negative results 5 these strategies, in combination with strategic use of repeat testing will preserve limited resources and provide the best route towards ending the sars-cov-2 pandemic. key: cord-260402-9b1ltcf1 authors: lang, adam edward; yakhkind, aleksandra title: more than meets the eye: the similarities between covid-19 and smoking date: 2020-08-11 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.08.008 sha: doc_id: 260402 cord_uid: 9b1ltcf1 nan to the editor: research shows that cigarette smoking upregulates ace2, the receptor by which sars-cov-2 gains entry to the host resulting in covid-19, in the lungs and therefore potentially leads to increased morbidity [1] . however, the virus and smoking share far more similarities than meet the eye. as part of a tobacco treatment campaign implemented at the beginning of the pandemic at mcdonald army health center, the authors performed a literature search and found that sars-cov-2 and smoking both contribute to myocarditis, thrombosis, immune impairment, and increased inflammation. sars-cov-2 leads to an increase nf-κb, tnf-alpha, and lymphocyte dysregulation. smoking leads to an increase of neutrophil counts and can cause neutrophil-to-lymphocyte ratio elevation. together, this can contribute to the development of and worse outcomes in patients with ards [2] . fibrin deposition in pulmonary vasculature, which is increased in both covid-19 and smoking, is thought to contribute to the development of ards. tissue factor (tf), which initiates the extrinsic coagulation cascade, is expressed highly by alveolar macrophages and epithelial cells. inflammatory cytokines and regulators including tnf-α and nf-κb upregulate tf expression, leading to fibrin deposition, further inflammation and microvascular permeability in the lungs [3] . sars-cov-2 and smoking upregulate this cytokine release and lead to an increased risk of coagulopathy [4, 5] . the upregulation of ace2 in smokers may predispose this population to an increased risk of sars-cov-2 infection. the host cell transmembrane protease, serine 2 (tmpsrss2), which primes the sar-cov-2 s protein for entry, may also be upregulated in smokers [6] , which would further increase the odds of viral infectivity. from a cardiovascular perspective, nt-probnp, ldh and ferritin have been shown to be predictors of poor outcomes and cardiac tissue damage in those with covid-19 [7] . smoking has been shown to cause elevations in all of these parameters, potentially contributing to the detrimental impact of sars-cov-2 on the myocardium [8] [9] [10] . while the lungs are a gateway to the body for both tobacco smoke and sars-cov-2, they each exhibit harmful systemic effects throughout the body. our goal is to bring awareness to the similar and potentially synergistic ways in which smoking and sars-cov-2 cause harm in order to guide research and work towards a better understanding of both conditions. ace-2 expression in the small airway epithelia of smokers and copd patients: implications for covid-19 covid-19 and smoking: how and why we implemented a tobacco treatment campaign therapeutic modulation of coagulation and fibrinolysis in acute lung injury and the acute respiratory distress syndrome isth interim guidance on recognition and management of coagulopathy in covid-19 acute effects of cigarette smoking on platelet-dependent thrombin generation smoking-mediated upregulation of the androgen pathway leads to increased sars-cov-2 susceptibility mild versus severe covid-19: laboratory markers serum and salivary lactate dehydryogenase levels as biomarkers of tissue damage among cigarette smokers association of serum ferritin levels with smoking and lung function in the korean adult population: analysis of the fourth and fifth korean national health and nutrition examination survey relation of smoking status to serum levels of n-terminal pro-brain natriuretic peptide in middle-aged men without overt cardiovascular disease j o u r n a l p r e -p r o o f key: cord-292398-3b2e8x8z authors: siuka, darko; pfeifer, marija; pinter, bojana title: vitamin d supplementation in the covid-19 pandemic date: 2020-06-06 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.05.036 sha: doc_id: 292398 cord_uid: 3b2e8x8z nan the covid-19 pandemic has severe short-term and long-term consequences on individuals, health systems, and economies. considering the studies on the role of vitamin d in the prevention of acute respiratory infections, supplementation of vitamin d may be reasonable also for the prevention of sars-cov-2 infections and reducing morbidity and mortality in covid-19 high-risk patients. vitamin d deficiency is more common in older age groups, smokers, obese, and patients with chronic diseases such as diabetes, hypertension, various gastroenterological diseases, and also in african americans. 1 the high-risk groups that have more complications and higher mortality in covid-19 coincide with groups that have a high incidence of vitamin d deficiency. we believe that vitamin d deficiency might be one of the important risk factors for covid-19 complications and higher mortality. studies of vitamin d replacement have demonstrated that vitamin d ameliorates innate immunity (the immediate response of macrophages to invading viruses and bacteria in the mucous membranes), 2 thereby reducing the incidence and severity of acute respiratory infections. 3 this effect requires a sufficient serum level of 25(oh)d3 being crucial for macrophages to activate it into hormone d (calcitriol), which activates genes for the synthesis of antimicrobial factors destroying viruses (such as sars-cov-2), fungi, and bacteria. 2 also, vitamin d modulates the cellular immune response and, as expected, attenuates the cytokine storm, 4 the event so fatal in sars-cov2-induced pneumonia. therefore, we suggest it would be reasonable to supplement vitamin d in subpopulations at risk of vitamin d deficiency and unfavorable covid-19 outcomes, as well as in individuals already infected with sars-cov-2 to achieve optimal 25(oh)d3 concentrations as quickly as possible. it is challenging to conduct evidence-based medicine in cases such as the covid-19 pandemic. to the best of our knowledge, there are no data on the effects of vitamin d in sars-cov-2 infection, then again, there are reliable data on the beneficial effects of cholecalciferol in attenuating viral respiratory infections in people with low levels of vitamin d. the european centre for disease prevention and control makes this argument and encourages healthcare professionals to take actions that are logical in their own right, based on previously known findings in related fields: "public health authorities should recognize that extra-scientific factors (e.g. feasibility of implementing scientific advice, time pressure, socio-political factors, institutional factors, economic interests, pressure from neighboring countries etc.) are inherent to the decision-making process. these factors will also influence the implementation of any proposed response measures. decisions should therefore always be evidence informed, but they will very rarely be purely evidence based." 5 in slovenia, in the view of covid-19 pandemic, medical doctors were urgently advised by leading experts to supplement vitamin d in high-risk and fragile individuals and in covid-19 patients. with this letter to the editor we address the broader medical community to consider vitamin d supplementation in high-risk patients for adverse covid-19 outcomes, urgently. vitamin d deficiency in adults: when to test and how to treat vitamin d modulation of innate immune responses to respiratory viral infections vitamin d supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data regulation of cytokine responses by seasonality of vitamin d status in healthy individuals european centre for disease prevention and control. considerations relating to social distancing measures in response to covid-19 -second update key: cord-299150-1noy0z88 authors: desai, aakash; kulkarni, amit; rajkumar, s vincent; gyawali, bishal title: clinical trial endpoints in severe covid-19 date: 2020-06-06 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.05.025 sha: doc_id: 299150 cord_uid: 1noy0z88 nan since the first outbreak in wuhan, china in late december 2019, the coronavirus disease 2019 (covid-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (sars-cov-2) has already tolled 230,000 deaths. although most of the patients are asymptomatic or have minimal symptoms, patients with severe covid19 often require hospitalization [1] . mortality in patients admitted to intensive care units (icu) or those requiring mechanical ventilation is as high as 25% [2, 3] . there is an urgent need to develop effective therapy for severe covid19 that improves mortality. however, clinical trials of agents tested for severe covid19 may not necessarily test for mortality outcomes as the primary endpoint, as was highlighted in the press release of the recent remdesivir trial. since drugs improving mortality in severe covid-19 is the most important endpoint to achieve both from clinical and public policy standpoint, we evaluated the type of primary endpoints currently being assessed in randomized controlled trials (rcts) in severe covid19. we searched www.clinicaltrials.gov to identify clinical trials for "severe covid19" as of april 30th, 2020. we included only phase iii and interventional trials. we excluded prophylaxis, prevention, and treatment trials with no mention of "severe covid" in the title. we then extracted information on the primary endpoint of each eligible study. two authors (a.d and a.k) independently performed the data extraction and analysis. of the 50 trials identified initially, 19 trials (with 17 study drugs) satisfied our inclusion and exclusion criteria and were included in the final analysis. of these, 16/19 (84.2%) trials were randomized studies and 13/16 (81.2%) of these were placebo-controlled trials. the most common study drugs in the intervention arm were hydroxychloroquine alone (5/19, (26.3%)), followed by remdesivir and methylprednisolone (2/19, (10.5%)) ( table 1) . among the 19 trials, we found 12 different primary endpoints. all cause hospital mortality 4/19 (21%), change in pao2 to fio2 ratio 3/19 (15.8%), and composite primary endpoints that included mortality and time to clinical improvement 2/19 (10.5%) were the most common primary endpoints studied. (figure 1 ). our analysis found that only 6/19 (30%) ongoing phase iii rct in severe covid19 have mortality as the standalone primary endpoint or a part of composite endpoint. this finding is surprising given the urgent need for effective drugs that can alter the natural history of severe covid19 and reduce mortality. most of the other primary endpoints being assessed are unproven surrogate clinical endpoints or biomarker-based endpoints. some surrogate clinical endpoints like length of time to clinical improvement (10.5%), hospital stay (5.3%) may offer meaningful information from a cost of care or resource perspective but these studies are not powered to detect mortality benefit. given that mortality is as high as 25% in severe covid19 who need icu care and average time to death is 3-6 days [2, 3] , the number of mortality events needed and follow-up time do not pose an impediment for analysis of mortality as the primary endpoint. furthermore, as the pandemic subsides, we may lose valuable time to enroll patients into well-designed rcts to obtain definitive answers for treatment efficacy. although our search results may not be comprehensive given the non-uniformity in the definition of severe covid19 among all trials, our findings do raise serious concerns about the use of surrogate measures, in current and ongoing clinical trials for severe covid19. any endpoint other than mortality reduction may not be relevant at the time of a pandemic with a virus that has high mortality rates. we must prioritize discovery of a drug that truly reduces mortality rather than squandering resources in finding a drug that may make us complacent but not improve any meaningful outcomes. clinical characteristics of coronavirus disease 2019 in china presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with covid-19 in the new york city area baseline characteristics and outcomes of 1591 patients infected with sars-cov-2 admitted to icus of the lombardy region, italy key: cord-280123-44206n7t authors: lucey, michael r.; stanfield, dylan title: the heightened risk of fatty liver disorders in the time of covid-19 date: 2020-10-22 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.10.020 sha: doc_id: 280123 cord_uid: 44206n7t nan the pre-covid reasons for the growth in obesity/metabolic syndrome on the one hand, and alcohol use disorder (aud) on the other are complex, but the trends are unequivocal. median bmi, and prevalence of diabetes mellitus, both markers for nonalcohol related fatty liver disorders have been increasing for the past 30 years [1] . there is an undeniable link between socioeconomic status and the risk of obesity [2] . one study from the university of michigan health system demonstrated that for every 1 percent increase in prevalence of persons with low-income status there was a 1.17 percent increase in rates of overweight/obese students within their population [3] . data taken from the national epidemiological survey on alcohol and related conditions showed that between 2001-2002 and 2012-2013, harmful levels of drinking have been on the rise. furthermore, the growth in high-risk drinking and dsm-iv alcohol use disorder (aud) was seen in women, older-adults, racial/ethnic minorities, and lower income/educational levels [4] . tapper and parikh have shown that the greatest increases in alcohol-associated liver deaths between 2009 and 2016 occurred in drinkers in the 25-34 years age range. the advent of covid-19 is likely to exacerbate, albeit indirectly, the prevailing fatty liver diseases. one reason is the age-old tendency to eat and drink more when facing adversity. but more than that, we need to consider how chronic stress and deteriorating psychosocial health are the consequence of quarantine without a predictable end. when combined with financial hardship from loss of income in the face of covid-19, we have created the environment for alcohol-and non-alcohol-related hepatic steatosis. indeed, while the quarantines and lockdowns persist, alcohol sales both online and in retail stores have continued to spike. one poll administered early on in the pandemic to 2,200 adults revealed nearly one in five individuals was drinking more alcohol than prior to covid-19, and this rate was even higher among younger populations [5] . proceedings. [6] they used the mayo clinic biobank to ask the question: how do alcohol consumption, body mass, and fatty liver disorder interact? after removing patients with known hepatic steatosis, and those with incomplete data, they were left with 18,506 subjects, enrolled from april 9, 2009 through march 31, 2016. in a median follow-up of nearly 6 years, 684 developed fatty liver. from this dataset, they were able to look at the associations between steatosis, body mass and alcohol use. their analysis shows that increased body mass and alcohol, particularly with heavy alcohol use, interact in the path to fatty liver, whereas moderate alcohol consumption by persons with normal bmi and overweight is associated with lower mortality. how should we interpret these data? the apparent protective benefit of low dose alcohol consumption by persons with normal or moderately elevated bmi is counterintuitive, although there are some prior data for a protective effect [7] . conversely, the thrust of the more recent world literature has been to discourage alcohol consumption [8] [9] [10] . for example, the conclusion of a panel of experts in 2016 was that 'the level of consumption (of alcohol) that minimizes health loss is zero' [11] . the present study reiterates the harm caused by a combination of excessive consumption of alcohol and obesity. given what we know about the heightened risks of eating and drinking to excess in the time of covid-19, peeraphatdit et al. have sounded a timely warning, and given us compelling reasons for increased vigilance against a pandemic of fatty liver disorders. will the covid-19 pandemic worsen the obesity epidemic? the relationship between childhood obesity, low socioeconomic status, and race/ethnicity: lessons from massachusetts prevalence of 12-month alcohol use, high-risk drinking, and dsm-iv alcohol use disorder in the united states covid-19 pandemic brings new concerns about excessive drinking a cohort study examining the interaction of alcohol consumption and obesity in hepatic steatosis and mortality effect of chronic alcohol consumption on the development and progression of non-alcoholic fatty liver disease (nafld) alcohol and the global burden of disease burden of liver diseases in the world global burden of alcohol use disorders and alcohol liver disease alcohol and the global burden of disease -authors' reply key: cord-026738-6jtcf4mz authors: berbari, elie f.; williams, amy w.; williamson, mary j.; caine, natalie a.; nath, karl a.; farrugia, gianrico title: mayo clinic strategies for covid-19 introduction date: 2020-06-13 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.06.005 sha: doc_id: 26738 cord_uid: 6jtcf4mz nan :xx-xx. covid-19 = coronavirus disease 2019 sars-cov-2 = severe acute respiratory syndrome coronavirus 2 coronavirus disease 2019 , the disease caused by severe acute respiratory syndrome coronavirus 2 (sars-cov-2), was declared a pandemic by the world health organization on march 11, 2020. as of may 28, 2020, there were nearly 1.7 million confirmed covid-19 cases in the united states and more than 100,000 deaths. 1 this unprecedented worldwide crisis has created numerous challenges for existing health care systems, but it has also spurred innovation. before the covid-19 pandemic, mayo clinic had embarked on its strategic vision leading to 2030, named bold. forward., which encompasses strategies to cure, connect, and transform health care. early alignment with these 3 strategies has allowed mayo clinic to be more effective in responding to the covid-19 pandemic. in january 2020, mayo clinic activated its hospital incident command system across all locations in anticipation of a substantial surge in covid-19 cases. between february and may of 2020, task forces and initiatives were created and implemented to guide, prepare, and support the institution during this unprecedented crisis. in this special series of commentaries, we describe 21 of the various mayo clinic initiatives and responses to covid-19 (table) . one commentary describes the necessary elements of an effective hospital command center and the system-wide response to the pandemic. another describes changes in local and federal regulations that served as catalysts for mayo clinic to provide home monitoring of patients with covid-19 and to substantially increase telemedicine options for virtual visits. the use of enhanced prediction analytics and artificial intelligence has helped define our response and guide resource utilization and prioritization. those tactics are described along with other prevention strategies, including requirements for personal protective equipment. it also became increasingly apparent in the preparedness phase that we needed proper diagnostic stewardship for testing utilization as well as testing strategies to improve prevention and treatment of covid-19. our practice now uses artificial intelligence and smart tools for contact tracing of exposed health care workers. mayo clinic has also established a virtual medical team and other services to support patients with covid-19. new workflows and safety pathways have been created in many clinical areas, especially in the emergency department, intensive care units, outpatient practices, and surgical and procedural practices. these new teams and workflows are described in the commentaries. task forces were formed and programs organized to engage divisions and department chairs as needs became evident. research studies were designed to address gaps in our knowledge of and therapies for covid-19, ranging from studies in the basic sciences to several large clinical trials. during the crisis, mayo clinic halted all elective and semielective procedures, which resulted in a backlog of patients without covid-19 who need care. in these commentaries, strategies are shared that allowed mayo clinic to safely reactivate its large, integrated multispecialty practice (both the inpatient and outpatient services) during this new-normal state. novel educational interventions, including various types of virtual interactions, were quickly implemented to ensure that we continued to deliver high-quality educational experiences for our graduate students, residents, and fellows when their in-person clinical rotations were temporarily suspended. the commentaries also highlight how mayo clinic is reaching out to our neighboring communities during this pandemic. importantly, we will discuss major lessons learned thus far around rapid change management strategies, effective we hope that this series of commentaries will be useful to you and to your organizations during this and any future pandemic or other extremely challenging health care situations. world health organization. coronavirus disease (covid-19) pandemic strategic approaches for promoting resiliency of health care workers 18. community engagement with vulnerable populations 19. avoiding a medical education quarantine during the pandemic 20. health care after the covid-19 pandemic and the influence of telemedicine 21. the silver lining for health care during and after the pandemic editing, proofreading, and reference verification were provided by scientific publications, mayo clinic. key: cord-329779-5sauq4gp authors: sanchis-gomar, fabian; lavie, carl j.; perez-quilis, carme; henry, brandon m.; lippi, giuseppe title: in reply – association of renin angiotensin system blockers with outcomes in patients with covid-19 date: 2020-09-14 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.09.011 sha: doc_id: 329779 cord_uid: 5sauq4gp nan to the editor: current guidelines and health professional recommendations endorse the continuation of both anti-hypertensives angiotensin-converting enzyme (ace) inhibitors (aceis) and/or angiotensin receptor blockers (arbs) for managing hypertension (htn) during the covid-19 pandemic. we have repeatedly emphasized that it is highly unlikely that the use of acei/arbs would be associated with increased severity or mortality risk in patients with covid-19. 1, 2 in the meta-analysis of garg et al., 3 which included studies published until may 31, 2020, both mortality or severe disease risk were not increased among j o u r n a l p r e -p r o o f patients using aceis/arbs. however, it was noted that administration of these drugs might reduce mortality in patients with htn. in a recent study, not included in their meta-analysis, lópez-otero et al. 4 finally, in a recent systematic review, nunes 6 concluded that the use of aceis is not associated with higher rates of covid-19 mortality, recommending additional clinical trials to confirm the safety profile of these drugs in this setting. in a recent study performed by members of our group, the circulating levels of angiotensin ii (angii) were measured in patients with covid-19. 7 despite a case series from china which reported extremely high angii in patients with covid-19, 8 in our cohort of 30 covid-19 patients, circulating angii were normal regardless of covid-19 severity, with no significant differences between covid-19 patients and healthy controls. 7 although circulating levels of angii may not reflect the local lung milieu, it seems unlikely that angii is a driver of systemic disease in covid-19. though ace2 expression is likely attenuated by sars-cov-2 binding, this data suggests that angii is readily metabolized in alternative metabolic pathways, resulting in normal circulating levels. this finding is consistent with the clinical study by lópez-otero et al. 4 in which no beneficial association of acei/arb use was found for covid-19 severity or mortality, as would be expected given the normal circulating j o u r n a l p r e -p r o o f levels of angii. we hence suggest that the potential benefits of acei/arb usage observed in some covid-19 studies may be more attributable to effective intervention for a modifiable risk factor for poor covid-19 outcomes (i.e. htn), with efficacious therapy minimizing htn-induced endothelial dysfunction and end-organ injury that would otherwise be susceptible to further deterioration with sars-cov-2 infection. only retrospective observational studies regarding the potentially deleterious effects of aceis/arbs in covid-19 patients have been conducted to-date, and these findings need to be confirmed in prospective randomized controlled trials (rct). to the best of our knowledge, there are several ongoing rcts, and new and more reliable results will emerge shortly. studies in randomized covid-19 patients like the brace corona trial (nct04364893), evaluating whether continuing or interrupting acei/arb therapy, are underway; results from this study will be presented at the forthcoming european society of cardiology meeting. overall, due to the lack of evidence on negative mortality effects of acei/arb in covid-19 patients, we reaffirm our previous advice that discontinuing these drugs for managing htn at the time of covid-19 pandemic remains clinically unjustified. in reply -angiotensin-converting enzyme 2 and the resolution of inflammation: in support of continuation of prescribed angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers angiotensin-converting enzyme 2 and anti-hypertensives (angiotensin receptor blockers and angiotensin converting enzyme inhibitors) in coronavirus disease 2019 (covid-19) association of renin angiotensin system blockers with outcomes in patients with covid-19 impact of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on covid-19 in a western population. cardiovid registry age and multimorbidity predict death among covid-19 patients: results of the sars-ras study of the italian society of hypertension mortality and use of angiotensin converting enzyme inhibitors in covid 19 disease -a systematic review circulating plasma levels of angiotensin ii and aldosterone in patients with coronavirus disease 2019 (covid-19): a preliminary report clinical and biochemical indexes from 2019-ncov infected patients linked to viral loads and lung injury key: cord-276194-4sfc7hal authors: vijayvargiya, prakhar; garrigos, zerelda esquer; castillo almeida, natalia e.; gurram, pooja r.; stevens, ryan w.; razonable, raymund r. title: in reply–the “perfect cytokine storm” of covid-19 date: 2020-05-29 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.05.016 sha: doc_id: 276194 cord_uid: 4sfc7hal nan to the editor:we read with great interest the letter by testori regarding our review article "treatment considerations for covid-19: a critical review of the evidence (or lack thereof)," 1 testori pointed out the important association of pro-inflammatory cytokines in the pathogenesis of coronavirus disease 2019 , which could account for the worse outcome in older individuals. strategies to combat the pro-inflammatory state, using multiple investigational compounds, are in the pipeline as potential treatment modalities for covid-19. in france, the corimuno-19 platform was designed and set up as a series of multicenter randomized controlled trials (rct) to evaluate the efficacy of immunomodulators and other treatments for covid-19. as part of this platform, one open-label rct (corimuno -toci) showed that the use of tocilizumab, an interleukin-6 receptor inhibitor, was associated with a significantly lower ventilation requirement (invasive or noninvasive) or death at day 14. however, the final report of this rct has not yet been released for peer-review. 2 as mentioned in our review article, there are several other rcts that are currently being conducted to assess il-6 inhibition in covid-19. an artificial intelligence platform, benevolentai, identified baricitinib, a janus kinase (jak) inhibitor, as another potential option to battle the cytokine storm associated with covid-19. 3, 4 in addition to its anti-inflammatory properties, baricitinib can have antiviral properties by preventing the adaptor-associated protein kinase 1 (aak1) and cyclin g-associated kinase (gak)-mediated endocytosis of the virus. baricitinib will be tested as one of the drugs in the national institute of allergy and infectious diseases (niaid) adaptive covid-19 treatment trial (actt). as we emphasized in our review article, the appropriate timing for the use of these anti-inflammatory agents will be critical. it is important to reiterate that the host inflammatory response plays a vital role in the immune defense against the infection and curbing the inflammatory state may decrease the response mounted by the host's immune system. since the online publication of our review, the investigational rna-dependent rna inhibitor, remdesivir, has been granted emergency use authorization in united states food and drug administration based on preliminary data obtained from the actt. the press release of this trial stated a 31% faster time to recovery in remdesivir arm compared to placebo (11 days versus 15 days, respectively, p<0.001). 5 the scientific community is eagerly awaiting the release of the clinical trial results. interestingly, another study, conducted in china, did not demonstrate any significant clinical benefit with remdesivir use. there was no difference in 28-day mortality between the two groups, and the degree of viral decline was similar. however, this study was underpowered to detect significant differences due to low accrual as a result of the decline in severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection rates. 6 the author highlighted the recent reports of prolonged detection of sars-cov-2 in some individuals. howevever, the presence of viral nucleic acid in respiratory samples can be a reflection of nonviable genetic material. the viability of virus material in these patients has not been conclusively demonstrated. nonetheless, we agree with his comment that there is an urgent need for the development of antiviral therapies and vaccines. indeed, there are many parallel and collaborative efforts to advance this goal, at an extraordinary pace, and some using novel rnai and plasmid dna based approaches. in the meantime, multicenter trials such as world health organization solidarity trial, niaid actt, and european corimuno-19 cohort and discovery trial strive to generate evidence to determine the optimal treatment for covid-19. the ongoing climate change, disruption of natural ecosystems, and human migration guarantee that we remain at risk for pandemics in the foreseeable future. knowledge generated will not only help us fight the current pandemic, but our lessons will also prepare us to prevent and maybe better coordinate our response for the future pandemics treatment considerations for covid-19: a critical review of the evidence (or lack thereof) tocilizumab improves significantly clinical outcomes of patients with moderate or severe covid-19 pneumonia baricitinib as potential treatment for 2019-ncov acute respiratory disease covid-19: combining antiviral and antiinflammatory treatments. the lancet infectious diseases nih clinical trial shows remdesivir accelerates recovery from advanced covid-19 remdesivir in adults with severe covid-19: a randomised, double-blind, placebo-controlled, multicentre trial. the lancet financial support and conflict of interest disclosure: rrr serves as the principal investigator on clinical trials for tocilizumab and sarilumab. none of the other authors have any conflicts of interest that would influence the manuscript. key: cord-273150-bz617ovx authors: john, teny m.; malek, alexandre e.; shpall, elizabeth j.; mulanovich, victor e.; adachi, javier a.; raad, issam i.; aitken, samuel l.; hamilton, alexis ruth; jain, nitin; klein, kimberly; martinez, fernando; rezvani, katayoun; jacob, ceena n.; cherian, sujith v.; manzano, joanna-grace m.; wegner, robert; muthu, mayoora title: migratory pulmonary infiltrates in a patient with covid-19 infection and the role of corticosteroids date: 2020-06-24 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.06.023 sha: doc_id: 273150 cord_uid: bz617ovx nan introduction: the emergence of 2019 novel coronavirus has led to a global pandemic and has threatened the life of millions of people. this disease is caused by the severe acute respiratory syndrome coronavirus 2 (sars-cov-2) that results in respiratory failure, multiple organ dysfunction and death. 1 little is known about the spectrum of clinical presentations of covid-19 in cancer patients. 2 herein, we present a patient with chronic lymphocytic leukemia who developed organizing pneumonia (op) as a late manifestation of covid-19 after an initial improvement, who was successfully treated with corticosteroids. a 62-year-old woman with chronic lymphocytic leukemia (cll), hypertension, and type 2 diabetes mellitus presented with low-grade fever, cough, and shortness of breath of one-week duration. her cll was treated with rituximab initially that was switched to ibrutinib three months earlier but was discontinued a few days before her hospitalization due to palpitations and arthralgia. on admission, she was hypoxic, requiring supplemental oxygen at 2 l/min to maintain oxygen saturation, spo2 > 93%, and in atrial fibrillation with no hemodynamic instability. laboratory studies were significant only for elevated crp at 74 mg/l (normal < 10mg/l). nasopharyngeal swab specimen for reverse transcriptase-polymerase chain reaction for sars-cov-2 was positive, but negative for other respiratory viruses. computed tomography (ct) scan of the chest showed bilateral ground-glass opacities (figure 1, panel a) . the patient was enrolled in john 4 the mayo clinic covid-19 expanded access program for convalescent plasma (ccp) on day 9 of her illness and received one dose of ccp. the patient's respiratory status rapidly improved the day following ccp transfusion, maintaining spo2 on room air. after three days, the patient developed daily low-grade fevers and increasing shortness of breath, requiring supplemental oxygen via nasal cannula. infectious disease workup, including blood cultures and fungal serum markers, were negative. a repeat chest ct, on day 17 of illness ( figure 1, panel b) , revealed new and migratory ground-glass opacities in both lungs that were consistent with an organizing pneumonia (op) pattern. patient was started on intravenous methylprednisolone at 1mg/kg/day, which resulted in improvement in oxygenation and resolution of fever. she was discharged in stable condition after seven days of corticosteroids. our case may present a rare clinical course of covid-19. given the radiological appearance of migratory lung infiltrates and rapid improvement with corticosteroids, we hypothesize that this is op due to the associated hyper-inflammation phase commonly seen in the later stages of covid-19. 3 moreover, acute fibrinous and organizing pneumonia, a subtype of organizing pneumonia is described in covid-19; which could be the case in our patient, although it cannot be confirmed without a tissue biopsy. 4 although we conjecture that this is likely the explanation in our case, other plausible mechanisms of op in our patient are a) an immune activation-like phenomenon following cessation of ibrutinib or b) augmentation of immune response by convalescent plasma. 5 bruton tyrosine kinase (btk) inhibitors are involved in toll-like receptormediated signaling and triggering of inflammatory cytokine and chemokine release. 6 john 5 ibrutinib, a highly potent inhibitor of btk, is considered to protect against lung injury in covid-19. 6 corticosteroids are not currently recommended in the management of hospitalized patients with covid-19 unless there is a separate indication like asthma or chronic obstructive pulmonary disease or in intubated patients with acute respiratory distress syndrome. 7 op as a delayed presentation of covid-19, should be considered for which corticosteroids have significant benefit. moreover, given the increasing use of convalescent plasma, op as a possible downstream consequence should be investigated. characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72314 cases from the chinese center for disease control and prevention cancer patients in sars-cov-2 infection: a nationwide analysis in china longitudinal ct findings in covid-19 pneumonia: case presenting organizing pneumonia pattern john 6 time to consider histologic pattern of lung injury to treat critically ill patients with covid-19 infection covid-19 and convalescent plasma: frequently asked questions the btk-inhibitor ibrutinib may protect against pulmonary injury in covid-19 infected patients infectious diseases society of america guidelines on the treatment and management of patients with covid-19 figure legend: figure 1: axial ct chest images on day 7 (day of admission, panel a) and day 17 after symptom onset (panel b), showing new and migratory lung infiltrates suggestive of organizing pneumonia key: cord-298368-vuxp0l50 authors: suh, gina a.; shah, aditya s.; kasten, mary j.; virk, abinash; domonoske, cynthia l.; razonable, raymund r. title: mayo clinic strategies for covid-19 avoiding a medical education quarantine during the pandemic date: 2020-06-20 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.06.011 sha: doc_id: 298368 cord_uid: vuxp0l50 nan the coronavirus disease 2019 pandemic has disrupted the traditional medical training of residents and fellows. suspension of large-group, face-toface interactions is certainly needed to flatten the curve of covid-19 transmission. therefore, in-person conferences have been suspended to keep learners safe, and clinical medicine is increasingly being practiced virtually, with the human touch to care restricted. however, these changes substantially challenged our ability, as faculty, to supervise learners and ensure that our programs delivered high-quality education during the pandemic. herein, we discuss creative ways to deliver educational conferences and provide web-side interactions that foster the growth of trainees. to protect everyone involved from potential exposure to covid-19, we implemented various strategies in order to provide educational conferences, including technology-based solutions such as zoom (zoom video communications, inc), skype for business (microsoft), webex (cisco systems), and slido (slido). these platforms allow for educational interactions between faculty and learners while ensuring physicaldistancing directives. in some conferences, we have used a hybrid approach of live streaming combined with a small group of in-person attendees representing various aspects of clinical care and research, who comprise an expert panel. one to 4 trainees present clinical cases to conference attendees, who include other fellows, faculty, and members of the division. a faculty moderator facilitates an interactive discussion based on questions submitted online by attendees. another key component of medical education for trainees is hands-on patient care supplemented by teaching rounds. traditionally, this education is best accomplished through in-person interaction; however, the pandemic has challenged this approach, requiring rapid adaptation of teaching techniques. 1 mayo clinic implemented a moratorium on bedside group-teaching rounds to limit provider exposures to potentially infected patients, as well as to adhere to an institutional mandate to preserve personal protective equipment. we therefore had to find innovative ways to achieve our mission of clinical education and faculty supervision. for patient care and inpatient consultations, we utilized all available technology, including in-room tablet computers with video interface capability, when available, and in-room telephones for direct patient interviews. 2 the various teams, especially consulting and primary care services, worked to improve all forms of communication. before web-side teaching rounds, trainees and members of the primary care service would discuss overnight events, pertinent physical examination findings, and questions from the consulting teams. after these discussions, the trainees conducted patient interviews using the computer-assisted video or in-room telephone. the teaching rounds by faculty supervisors followed (via zoom, webex, skype, or teleconferences) and included case discussions as well as daily didactic teaching on selected topics from faculty and fellows. a similar approach was implemented in the clinics, where virtual visits using telemedicine resources, including video conferencing, and telephone visits were besides providing continued training, it was imperative for the institution and individual training programs to provide trainees with additional support for mental and physical health during the emotionally and psychologically taxing pandemic. at mayo clinic, support is given through employee assistance programs, the ombudsman program, and a direct communication path to program leadership and mentors. in addition, we have defined and developed active processes to seek feedback and troubleshoot problems that might arise during medical training. these processes include direct communication via chief medical trainees (residency and fellowship) or an ombudsman serving as a liaison between program leadership and trainees. other committees, such as the diversity and inclusion committee, have also been actively involved in helping trainees with specific challenges, including supporting international trainees concerned about family members living abroad. the medical education committee has sought active feedback from trainees about how to improve their medical training during the pandemic and how to provide for a balance between the trainees remaining actively involved in care of covid-19 patients and continuing to enrich their non-covid-19 education. in conclusion, our programs have proven that medical education does not have to be quarantined during the covid-19 pandemic. the pandemic has certainly challenged our educators to find innovative approaches to continue the mission of teaching, and we believe our approaches have been highly successful for several reasons. we learned that online technologies can effectively facilitate meaningful interactions and discussions of topics in real time without compromising outstanding patient care. key clinical faculty participated in all aspects of the changes made, which was essential to our success, as was real-time feedback from faculty and trainees. likewise, the resilience and engagement of fellows and trainees in adapting to innovative and new methods of learning and health care delivery was admirable. collectively, our graduate education program adapted to the crisis with agility and took a more holistic approach to implementing new learning strategies, which was essential not only for the care of our patients and colleagues but also for continuing to provide exemplary education to our trainees. editing, proofreading, and reference verification were provided by scientific publications, mayo clinic. the role of telehealth in the medical response to disasters medical education during pandemics: a uk perspective key: cord-268470-dgxn32ls authors: sharma, abhishek; garg, akash; rout, amit; lavie, carl j. title: obesity is associated with more critical illness in covid-19 date: 2020-07-02 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.06.046 sha: doc_id: 268470 cord_uid: dgxn32ls nan to the editor: in follow-up to recent major state-of-the-art review on obesity and outcomes in sars-cov-2 (covid-19), 1 we have additional data regarding the relationship of obesity with outcomes in patients with covid-19. clearly, obesity and metabolic syndrome have been shown to affect both innate and adaptive immunity, leading to increased infection severity. 1, 2 this is very important since current statistics indicate that three-fourths of the united states (us) population are either overweight or obese by body mass index (bmi) criteria, and currently over 42% meet criteria for obesity by bmi ≥30 kg/m 2 . more alarmingly, currently over 9% of the us population meet criteria for severe or morbid obesity (class iii obesity) by bmi ≥40 kg/m 2 . 1,2 certainly, many other countries across the globe are experiencing marked increases in the prevalence and severity of obesity, 1,2 which may be particularly problematic in covid-19 and other such pandemics. we performed a rapid review and meta-analysis to evaluate whether obesity is associated with worse outcomes in patients with covid-19. the present study was conducted in accordance with the prisma guidelines. we performed a comprehensive search in the medline and medrvix.org databases for studies published between january 01, 2019 and may 31, 2020. the following key words were used for search in different combinations: "coronavirus 2019", "covid-19", "sars-cov2", "obesity", "body mass index", and "outcomes". studies reporting the relationship between bmi (non-obese vs. obese) and outcomes among hospitalized patients with covid-19 were included for analysis. three reviewers (as, a.g. and a.r.) screened the study titles and abstracts for relevance followed by full manuscript evaluation. the following data was collected from included studies: baseline characteristics, proportion of subjects classified by bmi categories (< 30 kg/m 2 vs. >30 kg/m 2 ), and percentage of hospitalized patients. the primary outcome was critical illness in this rapid review and meta-analysis, obesity was associated with a 39% increased risk of critical illness, defined by individual study protocol as icu admission, need for imv, or hospice admission or death. considering the very high prevalence of obesity among adults in the us and worldwide, and even severe obesity approaching nearly a tenth of us adults, this increased critical illness is a worrisome sign. 2 patients with obesity also have more endothelial dysfunction, as well as respiratory and renal diseases that could worsen covid-19 outcomes. however, probably most importantly, covid-19 coronavirus attaches to the angiotensin converting enzyme 2 (ace2) receptors in the lungs and organs. 1 obese patients have insulin resistance and activation of the renin angiotensin aldosterone system. 1 the presence of ace2 may enable the entry of sars-cov-2 into adipocytes, which makes adipose tissue an important viral reservoir. 1 therefore, adipose tissue, which is more abundant in obesity, might also be infected by sars-cov-2 and allow spread to other organs, thus explaining the more severe covid-19 disease in obesity. 1 the prevention of obesity in the first place and, especially, its progression to more severe forms, is desperately needed for future pandemics, as well as for the primary and secondary prevention of diabetes mellitus and cardiovascular disease. 2 in this covid-19 pandemic, clinicians should recognize the marked increased risks associated with obesity, and these patients need more aggressive triage and treatment. our study has several limitations. due to lack of patient level data, the results in our study were not adjusted to baseline patient characteristics. several studies analyzing the relationship between obesity and clinical outcomes have reported results after adjusting for different confounders. due to differences in the variables used to adjust results in these studies, we have not performed the pooled analysis of those adjusted confidence interval and odds ratio. further, studies did not have long term follow up data and most patients were still hospitalized without a definite outcome i.e. mortality, thus caution should be exercised before extrapolation of our results to long term outcomes. despite these study limitations, however, our data of a 39% increase in worse outcomes associated with obesity strongly supports the recent paper in mayo clinic proceedings. 1 obesity and outcomes in covid-19: when an epidemic and pandemic collide healthy weight and obesity prevention: jacc health promotion series association of obesity with disease severity among patients with covid-19 obesity and covid-19 severity in a designated hospital in shenzhen, china (3/13/2020) 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 in patients younger than 60 years is a risk factor for covid-19 hospital admission covid-19 in critically ill patients in the seattle region -case series factors associated with hospitalization and critical illness among 4,103 patients with covid-19 disease in new york city clinical characteristics of covid-19 in new york city risk factors associated with clinical outcomes in 323 covid-19 hospitalized patients in wuhan, china characterization and clinical course of 1000 patients with coronavirus disease 2019 in new york: retrospective case series obesity is associated with worse outcomes in covid-19: analysis of early data from obesity and covid-19: an italian snapshot. obesity (silver spring) prevalence of obesity among adult inpatients with covid-19 in france severe obesity, increasing age and male sex are independently associated with worse in-hospital outcomes, and higher in-hospital mortality, in a cohort of patients with covid-19 in the bronx key: cord-292606-tqjmg3qb authors: testori, alessandro title: the “perfect cytokine storm” of covid-19 date: 2020-05-29 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.05.015 sha: doc_id: 292606 cord_uid: tqjmg3qb nan i have read with great interest the recent article by vijayvargiva et al 1 proceedings. the vast majority of the deaths caused by severe acute respiratory syndrome coronavirus 2 (sars-cov-2) are patients over the age of 55, which died of acute respiratory distress syndrome (ards). at the histological level ards is characterized by an intense inflammatory response occurring in the lungs of patients. 2 human aging is associated with an up-regulated inflammatory response. 3 inflammation is involved in the mechanisms underlying the pathogenesis of several age-associated diseases such as cardiovascular disease, type 2 diabetes, alzheimer disease (ad), parkinson disease, rheumatoid arthritis (ra), and osteoporosis. elderly individuals have lost the ability to control and contain inflammatory processes to the same degree of which younger individuals are capable. the innate immune system plays a central role in inflammation and is also key in its ability to slow down and arrest inflammatory processes. interleukin-10 (il-10) and c1-esterase inhibitors (c1-inh) are two molecules that help contain and slow down inflammatory processes, while interlukin-6 (il-6) promotes and intensifies inflammation (though it has also some anti-inflammatory properties in muscle cells). given the up-regulation of inflammatory processes with aging, it is not surprising that ards is usually more severe and more lethal in the elderly resulting in death rates over 50% in the current epidemic. but this "cytokine storm" is not limited to the lungs, and also involves the kidneys, causing renal insufficiency and failure, and the vascular system, causing a vasculitis which is at first visible in the toes and is now known as "coronavirus toes." the "cytokine storm" does not spare the central nervous system (cns) either, resulting in headaches, altered mental status, confusion or inability to arouse and the loss of the sense of smell, which is reportedly one of the early symptoms of the disease. 36% of patients experienced some type of neurological symptom. on the mild end of the spectrum, people commonly experienced the loss of taste and smell. headache was reported in 13% of the patients, dizziness was observed in about 17%, and muscle inflammation and nerve pain occurred in about 19%. autopsy reports have revealed brain tissue edema and partial neuronal degeneration in deceased patients. to effectively treat the "citokine storm" tocilizumab (actemra) has been used to block the pro-inflammatory action of il-6, and seems to have been helpful in anecdotal cases (3 patients treated in italy). c1-esterase inhibitor (berinert, cynrize, ruconest) could also be tested to see if it is capable slow the inflammatory response. but these are very expensive medications and difficult to produce rapidly in quantities. using them to treat tens of thousands of patients may prove impossible because of cost and logistics. il -10 is another anti-inflammatory molecule that could be tested and it could be administered via a genetherapy approach using naked plasmid dna vectors 4 engineered to produce il-10 inside the recipient cells, thus reducing the cost and simplifying production. it would be more cost-effective for treating many thousands of patients. covid-19 infection involves multiple organs and systems, with symptoms developing rapidly over 2-14 days. most infections however produce mild or minimal symptoms and up to 80% of persons infected may have mild disease or even be asymptomatic. reports from italy indicate that some individuals have remained positive to nasal swabs for covid-19 for at least 50 days since their initial positive test, and after having apparently healed from the illness. there is one case of a person that has had positive nasal swabs for 57 days. this raises the possibility that some individuals, after recovering from their illness may become asymptomatic carriers of the virus for extended periods of time, further complicating efforts at containing the pandemic and requiring that patients be tested after their recovery to make sure they clear the virus. this means that antivirals and vaccines will be needed. countries need to invest in technologies like dna vaccines 5 and antiviral gene therapy strategies, like rnai technology, which is an ideal tool for inhibiting viral replication in host cells as the sirna can interact with certain viral genes and silence their expression. 6 dna based therapeutics can be developed immediately after a virus dna sequence becomes known. modular plasmid vectors could be created that allow to switch one viral sequence for another and produce a new vaccine with minimal manipulation. the same applies to rnai vectors. these strategies are also likely to be much more costefficient than other methods, a consideration that becomes important as the population needing treatment expands. we need to develop detailed protocols now on how to quickly produce vaccines and antivirals, that can be adapted to future viral pandemics. we also need to develop protocols for the most effective containment and mitigation strategies, so they can be implemented without hesitation in future emergencies. alessandro testori, md immunoe health research centers longmont, colorado treatment considerations for covid-19: a critical review of the evidence (or lack thereof) the acute respiratory distress syndrome inflammatory networks in ageing, age-related diseases and longevity progress and prospects: naked dna gene transfer and therapy generation and characterization of dna vaccines targeting the nucleocapsid protein of severe acute respiratory syndrome coronavirus inhibition of sars-cov replication by sirna key: cord-294728-fefkvg0a authors: vick, dan j. title: glucose-6-phosphate dehydrogenase (g6pd) deficiency and covid-19 infection date: 2020-06-06 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.05.035 sha: doc_id: 294728 cord_uid: fefkvg0a nan to the editor: one unsettling aspect of the covid-19 (sars-cov-2) pandemic is the variable susceptibility to infection. some people who are exposed remain asymptomatic, others experience mild to moderate symptoms, while still others become severely ill and die. hospitalization rates increase with age and approximately 90% of hospitalized patients have underlying medical conditions. 1 however, this doesn't account for a number of otherwise healthy or younger patients who are severely affected. other suggested factors include genetic determinants. a condition that should be considered is glucose-6-phosphate dehydrogenase (g6pd) deficiency. this x-linked recessive disorder with numerous allelic variants affects some 400 million people worldwide, with higher prevalence in africa, the mediterranean region, and asia. decreased production of g6pd results in deficient levels of nadph and reduced glutathione, causing oxidative stress and red blood cell destruction. although frequently asymptomatic, patients may develop hemolytic anemia triggered by certain infectious agents and medications. 2 there is evidence to suggest an association between g6pd deficiency and increased susceptibility to, and severity of illness with, covid-19 infection. wu et al. 3 found that g6pd deficiency enhanced infection of cells with coronavirus 229e (hcov 229e). using g6pd-deficient fibroblasts and g6pd-knockdown cells derived from human lung epithelial cells subjected to viral inoculum in vitro, they found that viral gene expression was higher in these cells compared with control cells. production of viral particles in the deficient cells was also higher over time, indicating that g6pd activity modulates this production. further, the g6pd deficient cells were more susceptible to hcov 229e mediated cell death. sars-cov-2 may have a similar effect on cells in g6pd deficient patients. spain and italy have been particularly affected by the covid-19 pandemic, with case fatality rates of 12.0% and 14.2%, respectively, as of this writing. 4 g6pd deficiency is more common in the mediterranean region. on the italian island of sardinia alone, the prevalence ranges from 10% to 15%. 5 the allelic variants of g6pd deficiency in the mediterranean region tend to manifest more significant phenotypic presentations. although other factors may account for severity of illness in these countries, g6pd deficiency should be considered. reports from the united kingdom and the united states show increased numbers of covid-19 infection among members of minority groups. in the u.k., 63% of the first 106 health care and social workers who died from the virus were black, asian, or minority ethnic (bame). bame individuals make up 34% of patients admitted to u.k. icus, although they only account for 17% of the population in the u.k. 6 in the u.s., african americans have been more significantly affected than other races. yancy 7 noted the infection rate in 131 predominantly black counties is 137.5/100 000 and the death rate is 6.3/100 000. these rates are three times and six times higher, respectively, than what is found in mostly white counties. preexisting medical conditions and adverse socioeconomic determinants of health may explain some of this disparity. however, g6pd deficiency is common among blacks and asians. in a study of 63,302 u.s. military personnel, 2.5% of males and 1.6% of females overall were deficient. prevalence was higher among african american males (12.2%) and females (4.1%), as well as asian males (4.3%). 8 g6pd deficiency may play a role in covid-19 severity of illness and death in these groups. vascular endothelial dysfunction and coagulopathy have been suggested as complications of covid-19, based on a report of large vessel ischemic stroke occurring in five u.s. patients under age 50, including two without preexisting conditions. similar cases have occurred in china and singapore. 9 coagulopathy has also been observed in people with g6pd deficiency. albertsen et al 10 chloroquine has infrequently been reported to cause hemolysis in g6pd deficient patients and caution is advised for its use. 11 hydroxychloroquine, its molecular variant, is generally considered safe. both antimalarial drugs are being trialed as possible treatments for covid-19. however, a recent report described an acute hemolytic episode occurring in a covid-19 patient with g6pd deficiency who was treated with hydroxychloroquine. 12 hydroxychloroquine may increase the oxidative stress in covid-19 patients with g6pd deficiency, thereby serving as a trigger for hemolytic anemia. studies are needed to determine whether a positive correlation exists between g6pd deficiency and covid-19, with respect to increased susceptibility to infection and severity of illness. this is important for several reasons. first, it will allow for identification of a subset of covid-19 patients for whom close monitoring and supportive care may be critical. second, certain treatments, such as hydroxychloroquine, may be contraindicated in these patients. third, identification of this relationship may suggest other therapies, such as use of antioxidants, that may prove beneficial for treating covid-19. finally, such information will be important for people with known g6pd deficiency to guide their decisions and actions to prevent covid-19 infection. hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease 2019 -covid-net, 14 states glucose-6-phosphate dehydrogenase deficiency glucose-6-phosphate dehydrogenase deficiency enhances human coronavirus 229e infection covid-19 dashboard glucose-6-phosphate dehydrogenase (g6pd) deficiency in nonarteritic anterior ischemic optic neuropathy in a sardinian population exclusive: deaths of nhs staff from covid-19 analysed covid-19 and african americans prevalence of glucose-6-phosphate dehydrogenase deficiency in u.s. army personnel large-vessel stroke as a presenting feature of covid-19 in the young fatal haemolytic crisis with microvascular pulmonary obstruction mimicking a pulmonary embolism in a young african man with glucose-6-phosphate dehydrogenase deficiency haemoglobinopathies and g.-6-p.d. deficiency in laos acute hemolysis by hydroxychloroquine was observed in g6pd-deficient patient with severe covid-19 related lung injury key: cord-255389-2fufd0ba authors: razonable, raymund r.; carmona porquera, eva m.; vergidis, paschalis; wilson, john w.; marshall, william f. title: mayo clinic strategies for covid-19 clinical guidance and the delivery of care for patients with coronavirus disease 2019 date: 2020-06-23 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.05.037 sha: doc_id: 255389 cord_uid: 2fufd0ba nan coronavirus disease 2019 (covid-19) is challenging medical communities worldwide. as the contagious severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection spread rapidly across countries and continents, innovations beyond traditional health care delivery were needed to provide patient care. for large health care institutions such as mayo clinic, the development of institutional management guidance is essential to standardize and monitor clinical practice. herein, we describe our strategies for developing and successfully implementing a clinical guidance that assists our health care providers in caring for patients with sars-cov-2 infection. the creation of a standardized management approach for a recently identified infectious disease with no known effective drug therapy has been our biggest hurdle. this hurdle was complicated by the urgency for institutional guidance in the face of a rapidly expanding pandemic. since sars-cov-2 is a communicable infection that threatens the safety of our health care providers, we also needed to develop innovative means of patient care delivery. continuous real-time assessment of the rapidly expanding medical literature is a core component of our task of developing our clinical guidance. our partnership with the rapid literature review task force, a group assigned to review and appraise the evolving literature about covid-19, has been instrumental in our workflow. the initial data that served as our framework were gathered from publications originating from china, where the pandemic began. from clinical experiences of other countries and communities that were ahead of the pandemic curve, we learned what treatment regimens were used and which drugs had failed or held promise. 1 furthermore, the initial reports on the epidemiology, clinical course, and outcomes of covid-19 helped us develop strategies aimed to prevent, diagnosis, and treat the disease. 2 the clinical guidance continues to evolve as more data emerge from the us experiences in new york city and the seattle area. from the outset, it was evident that a successful institutional response to the viral pandemic would be achieved only through multidisciplinary collaboration. 2 we therefore engaged with multiple medical specialties to develop our clinical guidance, including hospital medicine, general internal medicine, anesthesiology, pulmonary critical care medicine, clinical microbiology, infectious diseases, infection prevention and control, radiology, cardiovascular medicine, hematology, nephrology and hypertension, pharmacy, and nursing, among others. each group was delegated to brainstorm and develop their best general and specialty-specific practices in covid-19 management. because no drug therapy has proven effective against covid-19, our preferred approach for determining the best therapy for patients has been to utilize data from clinical trials of investigational compounds, including trials being conducted at mayo clinic. 1-3 we partnered with 2 task forces to ensure that our patients would benefit from potentially effective therapies: the research task force, a group that coordinates all covid-19 research at the institution, and the covid-19 treatment review panel, a group of 5 faculty members tasked with overseeing our clinical trials. likewise, we developed a covid-19 treatment registry that allows us to monitor our clinical practice and optimize our management guidance on the basis of our evolving clinical experience. acceptance by frontline medical providers is critical to the successful implementation of the covid-19 clinical guidance. we sought to gain its acceptance through effective communication by using various channels, including divisional and departmental conferences, conference calls, and group emails. the clinical guidance has been continually updated and made available to health care providers on a dedicated institutional covid-19 webpage. later on, our partnership with askmayoexpert, an online resource that delivers mayo clinic-vetted medical knowledge, ensured greater visibility within the institution and elsewhere. 3 developing a collaborative team approach started early on during conceptualization of the clinical guidance. 2, 3 in the process, our medical providers took ownership and implemented the guidance recommendations, which encompassed various aspects of covid-19 medical care from the time of disease diagnosis until patient recovery. a dedicated covid-19 infectious diseases consult service was created to directly assess and advise other health care providers on the medical care of patients with suspected or confirmed covid-19. this clinical team rapidly developed expertise in covid-19 care because they served as consultants to frontline health care providers. this team also facilitated access to investigational drugs undergoing clinical trials through partnership with the covid-19 treatment review panel. promotion of telemedicine is central to the clinical guidance. the practice of inpatient telemedicine has been a preferred method of health care delivery in select situations to limit exposures of our health care providers and to preserve personal protective equipment. the availability of outpatient telemonitoring services allowed patients with covid-19 to receive medical care and monitoring while in quarantine in the safety of their own homes. the covid-19 clinical guidance continues to evolve as new information is gathered from our clinical experience and as updated management strategies are published in the literature. this ongoing reappraisal and updates to our real-time clinical guidance document ensures that it remains relevant to the rapidly evolving field. the clinical guidance for the treatment of covid-19 is a product of a multidisciplinary collaborative effort. the preparation of this management guidance started well in advance of the anticipated arrival of sars-cov-2 in our community. support from divisional, departmental, and institutional leadership was instrumental in its successful implementation. learning from the experiences of others, engaging stakeholders, building consensus, providing support, and real-time reassessing and continued adjusting of the clinical guidance were the key strategies in its ongoing development. successful implementation of the clinical guidance involves effective communication, continued collaborations, feedback, and monitoring. our perspectives should serve as a framework in the development of management strategies for novel, emerging, and re-emerging infections. treatment considerations for covid-19: a critical review of the evidence (or lack thereof) a collaborative multidisciplinary approach to the management of coronavirus disease-19 in the hospital setting editing, proofreading, and reference verification were provided by scientific publications, mayo clinic. key: cord-317668-cc5oyiwp authors: wieland, mark l.; doubeni, chyke a.; sia, irene g. title: mayo clinic strategies for covid-19 community engagement with vulnerable populations date: 2020-06-22 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.05.041 sha: doc_id: 317668 cord_uid: cc5oyiwp nan the coronavirus disease 2019 (covid-19) pandemic has impacted vulnerable populations disproportionately, including those affected by socioeconomic disadvantage, racial discrimination, low health literacy, immigration status, and limited english proficiency. african americans, hispanics, and native americans are dying at considerably higher rates across the country than whites. 1 these differences mirror existing disparities in other preventable health conditions and stem from risks that are rooted in the social determinants of health. socioeconomic disadvantage with disparate living and working conditions has likely increased the risk of acquisition and spread of covid-19 in vulnerable communities. preexisting disparities in chronic diseases that are associated with worse covid-19 outcomes and less access to health care have resulted in a higher case-fatality rate. current evidence and our experience suggest that community engagement may be a strategy for addressing the disproportionate prevalence and mortality of covid-19 in minority communities, which are manifestations of long-standing structural and societal inequities. community engagement, "the process of working collaboratively with and through groups of people… to address issues affecting the well-being of those people," 2 can help empower communities in promoting covid-19 prevention and containment. in community-engaged research (cenr) partnerships, community members and researchers collaborate through all phases of research. these partnerships are thus uniquely poised to assess and respond to the pandemic with community partners. they have the organizational and technical experience to reach vulnerable community members and address unmet needs. authentic cenr partnerships foster credibility with vulnerable communities through existing trusting relationships, which is needed for real-time collaboration during crises. herein, we describe some of the cenr approaches used at mayo clinic in response to the needs of medically underserved and socioeconomically disadvantaged communities. the approaches are undergirded by principles of community engagement as well as frameworks for socioeconomic issues and social determinants of health. critical to the design of effective cenr interventions are bidirectional communication, colearning, and understanding of unmet needs and existing assets. 3 mayo clinic cenr partnerships have observed several factors that negatively affected local communities. while credible covid-19 information had been translated into many languages and was widely available, that information was not reaching immigrant communities. the problem was exacerbated in some communities by a legacy of mistrust of health care institutions. community partners observed disruption of health care for populations with preexisting systemic barriers to using telehealth during the rapid shift to virtual-visit platforms. we then learned that these populations lacked access to testing and rapid results, which would reduce virus transmission, and that people and organizations in some minority communities, including faith-based organizations and health centers, were unprepared for the effects the virus would have in their communities. these barriers were compounded by unstable working conditions that often resulted in unsafe situations for vulnerable populations who comprise a disproportionate share of essential workers in some sectors or in layoffs, making access to health care even more complicated. neighborhoods with higher housing density, more housing insecurity, and more multigenerational households made social distancing difficult. additionally, multiple partners across mayo clinic catchment areas access to testing for their patients. for the african-american community, an adaptation of the cerc model evolved into a virtual town hall, which was hosted by a cross-sector team of clinicians, researchers, policy leaders, and community leaders. several lessons are emerging from this work. cenr is important but not sufficient. we continue to learn about social consequences of the crisis and know that a rapid, coordinated, and sustained response is needed across sectors and disciplines that places community voice at its center. for example, community health center partners needed telehealth infrastructure support to provide ongoing care, but this was not feasible within the cenr framework. we have also learned that a virtual environment needs to evolve to maintain ongoing engagement with community members, even though making the change may be disruptive at first. early in the crisis, we paused many community engagement activities because of the need for social distancing and the disruption of institutional operations. the disparities that emerged suggested that community engagement activities should have been accelerated instead. an opportunity was also missed to shorten response time by having the partnerships do more to promote greater general awareness of the potential for pandemic and the need for preparedness. thus, a multidisciplinary team is essential, given the scale of the pandemic and the pervasive health and social consequences. clear communication with institutional leaders is also important to ensure that they understand needs of the underserved, even as they grapple with fiscal and operational challenges in their institutions. the social and structural determinants of health have been understood for decades, and such determinants are also relevant to the disparities in health care that are exacerbated by the current covid-19 crisis. the focus of multisector collaboration and community engagement should be to inform programs and policies that will eliminate the disproportionate impact of pandemics on vulnerable communities. indispensable to such initiatives are collaborative, community-led solutions in removing structural barriers to health equity that currently exist. the covid tracking project. the covid racial data tracker community engagement key function committee, task force on the principles of community engagement processes, and outcomes: a health equity-focused scoping meta-review of community-engaged scholarship leveraging community engaged research partnerships for crisis and emergency risk communication to vulnerable populations in the covid-19 pandemic enfermedad del covid-19 preventing cardiovascular disease: participant perspectives of the faith! program office of health disparities research. native american research outreach editing, proofreading, and reference verification were provided by scientific publications, mayo clinic. key: cord-324660-w81jgw7p authors: guharoy, roy title: medication shortages: a matter of national security—time for action date: 2020-08-01 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.06.025 sha: doc_id: 324660 cord_uid: w81jgw7p nan to the editor: as noted by choo and rajkumar 1 in the june 2020 issue of mayo clinic proceedings, the covid-19 (coronavirus disease 19) pandemic has exposed extreme vulnerabilities in our nation's drug supply chain. the fragility of the drug supply chain was not created overnight and has been brewing for over a decade. frequent generic drug shortages and quality deficiencies are compromising standard of care, producing waste, and increasing costs. for example, antibiotic shortages contribute to resistance, when clinicians are forced to use broad-spectrum agents. today, 80% of active product ingredient (api) manufacturers are located overseas, 2 with the majority being obtained from india and china. india, a large manufacturer of finished products, obtains 70% of apis from china. 3 china has a virtual monopoly on the apis required to make critical drugs such as antibiotics, antihypertensives, and many others. although the united states remains a global leader in drug discovery, we have almost completely transitioned manufacturing abilities to overseas because of lower production and labor costs. the united states' overreliance on importing apis from overseas has created a devastating impact on our public health with a potential for catastrophic events in the event of a war, trade conflict, or pandemic such as covid-19 and impacting our national security. as expected, the united states is waiting in line with every other country for essential drugs during the current pandemic. although there are no easy or fast solutions to this problem, we must act now. in addition to choo and rajkumar's recommendations, the following steps may be considered with the ultimate goal of domestic manufacturing of most of the essential lifesaving drugs to protect our patients from harm. d designate the pharmaceutical industry as a high-priority infrastructure critical to national security (like the aviation and energy sectors) to allow the federal government to coordinate efforts during shortages or national crises. d develop an essential national security drug supply list that includes medications for which a supply interruption could cause an immediate risk to public health. d create a national agency to monitor, plan, and identify potential manufacturers in the event of a shortage. d manufacture products in multiple locations to protect the supply chain in the event of a natural disaster or other threats. d strengthen federal oversight of manufacturers to ensure the highest product integrity and require manufacturers to provide transparency related to source of apis and quality issues. d develop a partnership between the private and public sectors acting as a united cohort to uncover incentives to drive actions to ensure domestic production of essential drugs. d require manufacturers to report to the us food and drug administration (fda) immediately on discovery of an interruption, disclosing the reason and the expected time to resolution. d create a national database for tracking of essential drug supplies and use predictive analytics to identify surge, production problems, and future shortages. editor's note: when publishing a letter that comments on an article published previously in mayo clinic proceedings, it is the journal's policy to invite the author(s) of the referenced article to publish a response. drs choo and rajkumar were fully supportive of the letter by guharoy and did not feel any response from them was necessary. to the editor: we read the recent commentary medication shortages during the covid-19 crisis by drs choo and rajkumar with great interest. 1 as supply chain management leaders at mayo clinic, we appreciate the attention these authors draw towards the issue of drug shortages and drug costs. one of the interesting observations we have made from the supply chain perspective while navigating the coronavirus disease 2019 (covid-19) pandemic is that the impacts on drug cost from covid-19 have been minimal in the retail segment and are more significant in the hospital sector. this phenomenon is a result of costly inpatient care for covid-19 and there are currently no effective commercially available drug therapies that are being routinely used in the ambulatory setting. 2 due to the high cost of covid-19 inpatient care within health care, we project that the cost containment recommendations of medicare price negotiations and controls of deductibles/rebates suggested by drs choo and kumar will have minimal impact on drug costs at this time (there could be a benefit if new therapeutic agents emerge in the future or if brand name drugs are used for covid-19 patients). one potentially highly impactful and easy to implement public policy solution we call attention to is the need to remedy unintended effects of the drug efficacy study implementation and unapproved drugs initiative programs. these programs were implemented to provide review of drugs that have been available for decades and that had not completed formal food and drug administration review. because of these programs and abuses by manufacturers, dramatic escalation of cost and expense for certain older drugs that were once generic continue to occur. 3, 4 the most egregious example in the hospital sector over the past decade is the dramatic rise in the cost of vasopressin, a drug that has been around for over 80 years and that is now among the top 25 drugs expenditures in hospitals as of 2019 and has patent protection until 2032. 5 because of the high use of vasopressin in critically ill covid-19 patients and the greater than 6000% price increase that has occurred after completing the unapproved drugs initiative process, vasopressin will likely become a top 10 drug expense within the hospital sector by the end of 2020. inflation for vasopressin since undergoing approval through the unapproved drugs initiative has been and continues to be dramatic. as result of covid-19, the manufacturer parr pharmaceuticals will experience further massive windfall profits and inflict billions of dollars of unreasonable costs for managing critically ill patients over the next decade. policy adjustments that address unintended consequences of the drug efficacy study implementation and unapproved drugs initiative programs could prevent further economic harm related to vasopressin pricing and avoid similar abuses in the future. medication shortages during the covid-19 crisis: what we must do treatment considerations for covid-19: a critical review of the evidence (or lack thereof) the fda unapproved drugs initiative: an observational study of the consequences for drug prices and shortages in the united states estimating the impact of food and drug administration's unapproved drug initiative on drug prices and sales national trends in prescription drug expenditures and projections for 2020 mayo clinic proceedings key: cord-256422-4crdzojb authors: garg, aakash; rout, amit; sharma, abhishek; fiorello, brittany; kostis, john b. title: association of renin angiotensin system blockers with outcomes in patients with covid-19 date: 2020-09-14 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.09.010 sha: doc_id: 256422 cord_uid: 4crdzojb nan to the editor: conflicting findings have been reported regarding the safety of angiotensin converting enzyme inhibitors (acei) and angiotensin receptor blockers (arbs) during the covid-19 pandemic. 1, 2 in reference to the recently published review outlining the relationship between renin angiotensin system (ras) and covid-19 infection, 3 we present additional data regarding the association of ras inhibitors with outcomes in patients with covid-19. covid-19 pandemic affecting more than 4.5 million people across the globe has caused significant morbidity and mortality. 4 angiotensin converting enzyme 2 (ace-2) has been implicated in the entry of sars-cov-2 virus into host cells. 5 since renin angiotensin system (ras) antagonists have been suggested to upregulate ace2 in few animal models, concerns have been raised that these drugs might be associated with increased risk of infection or severe disease from covid-19. 6, 7 whether such patients on ace inhibitors (aceis) or angiotensin receptor blockers (arbs) should continue these drugs has become a matter of debate. accordingly, we performed a meta-analysis to study the cumulative evidence for association of acei/arb use with risk of mortality and severe illness with covid-19. a comprehensive search in electronic databases (medline and embase) was performed for studies published between november 01, 2019 and may 31, 2020. the following key words were used for search in different combinations: "coronavirus 2019", "covid-19", "sars-cov-2", "renin angiotensin system", "angiotensin converting enzyme", "angiotensin converting enzyme inhibitors", "acei", "angiotensin receptor blockers"; "arb", and "outcomes". inclusion criteria were studies published in peerreviewed journals and reporting outcomes based on acei/arb use in covid-19. two j o u r n a l p r e -p r o o f reviewers (a.g. and a.r.) screened the study titles and abstracts followed by full manuscript evaluation. from individual studies, we collected baseline characteristics of patients including proportion of patients with htn and those taking acei/arb. the primary outcome was in-hospital mortality. secondary outcome was severe/critical illness [need for intensive care unit, invasive mechanical ventilation, or mortality] as defined per individual study protocol. we used the cochrane review manager 5.3 for statistical analysis. random-effects model with mantel-haenszel method was used to calculate the pooled odds ratios (or) with 95% confidence intervals (ci) for each end-point. this meta-analysis was conducted in accordance with the prisma guidelines. 8 after initial screening and full text review, 15 studies were identified to report outcomes based on acei/arb use in patients with confirmed covid-19. 1, 2, 5, [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] one study was excluded due to retraction by the authors. 10 accounting for worse outcomes in these patients. 21 while the role of ace2 as cellular receptor for sars-cov-2 entry into host cells is proven, human studies have been inconclusive with respect to the effect of ras inhibitors on ace2 levels. 22 furthermore, contradictory to the speculation that ras inhibitors-mediated ace-2 upregulation might increase risk of infection, ace2 expression has been actually suggested to protect against severe lung injury in these patients. 23 there are several limitations to our study. first, our pooled analyses were based on observational studies that have inherent risk of bias due to confounding variables. patients taking acei/arbs have increased burden of other comorbidities that might make them more prone to fatality. however, despite this potential bias, we observed no association of acei/arb use with increased risk of mortality or severe illness. second, ascertainment of drug data is limited in individual retrospective studies. it remains unknown whether continuation or withdrawal of these drugs during hospitalization influenced outcomes in patients admitted with covid-19. in conclusion, our study provides reassurance that there is no increased risk of mortality or severe illness in patients using acei/arb compared to non-users. in patients with hypertension, ace/arb use might be associated with reduced mortality, however these findings need to be confirmed in prospective randomized controlled trials. association of inpatient use of angiotensin converting enzyme inhibitors and angiotensin ii receptor blockers with mortality among patients with hypertension hospitalized with covid-19 renin-angiotensin-aldosterone system inhibitors and risk of covid-19 angiotensinconverting enzyme 2 and antihypertensives (angiotensin receptor blockers and angiotensin-converting enzyme inhibitors) in coronavirus disease 2019 (covid-19) china novel coronavirus investigating and research team. a novel coronavirus from patients with pneumonia in china angiotensin-converting enzyme 2 is a functional receptor for the sars coronavirus effect of angiotensin-converting enzyme inhibition and angiotensin ii receptor blockers on cardiac angiotensin-converting enzyme 2 covid-19 and renin angiotensin blockers: current evidence and recommendations. circulation preferred reporting items for systematic review and meta-analysis protocols (prisma-p) 2015 statement cardiovascular disease patients infected by 2019-ncov cardiovascular disease, drug therapy, and mortality in covid-19 association of use of angiotensin-converting enzyme inhibitors and angiotensin ii receptor blockers with testing positive for coronavirus disease 2019 (covid-19) renin-angiotensin-aldosterone system blockers and the 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 effects of arbs and aceis on virus infection, inflammatory status and clinical outcomes in covid-19 patients with hypertension: a single center retrospective study. hypertension covid-19 with different severity: a multi-center study of clinical features clinical course and outcomes of 344 intensive care patients with covid-19 risk factors for severity and mortality in adult covid-19 inpatients in wuhan renin-angiotensin system inhibitors improve the clinical outcomes of covid-19 patients with hypertension. emerg microbes infect use of renin-angiotensin-aldosterone system inhibitors and risk of covid-19 requiring admission to hospital: a case-population study raas inhibitors and outcome in patients with sars-cov-2 pneumonia. a case series study. hypertension potential effects of coronaviruses on the cardiovascular system: a review renin-angiotensin-aldosterone system inhibitors in patients with covid-19 a crucial role of angiotensin converting enzyme 2 (ace2) in sars coronavirus-induced lung injury key: cord-318205-qxkel0ww authors: parkulo, mark a.; brinker, todd m.; bosch, wendelyn; palaj, arta; deruyter, marie l. title: risk of sars-cov-2 transmission among coworkers in a surgical environment date: 2020-10-22 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.10.016 sha: doc_id: 318205 cord_uid: qxkel0ww health care workers are at high risk for contracting coronavirus disease 2019 (covid-19). however, little is known about the risk of transmission between coworkers. the objective of this study was to determine the risk of transmission of severe acute respiratory syndrome coronavirus 2 (sars-cov-2) between coworkers in a surgical environment. this was an observational study of 394 health care workers in a surgical environment who were exposed to 2 known sars-cov-2–positive coworkers. standard infection precautions were in place at the time of the exposure. all 394 exposed workers initially underwent nasopharyngeal swab testing for sars-cov-2 using the polymerase chain reaction technique. of the original group, 387 were tested again with the same technique 1 week later. of 394 sars-cov-2–exposed health care workers initially tested, 1 was positive. no new positive cases were found on repeated testing of 387 participants 1 week later. the risk of transmission of sars-cov-2 in a health care unit with universal masking and appropriate hand hygiene is low. this should provide some reassurance to surgical practices as they reopen. infections of sars-cov-2 (severe acute respiratory syndrome coronavirus 2) among health care workers is a serious consequence of the coronavirus disease 2019 (covid-19) pandemic. of the covid-19 cases reported to the us centers for disease control and prevention (cdc) between february 12 and april 9, 2020, that contained information about workers, 19% were identified as health care personnel. most were never hospitalized, but 27 deaths were reported. 1 many health care workers have reportedly become ill with the virus, but data on the risk of infection from other coworkers are limited. 2, 3 here we report the outcome of a widespread surveillance program in a surgical area which was implemented as a result of health care workers testing positive for sars-cov-2 at mayo clinic, jacksonville, florida. at the time of the study, standard precautions for a surgical environment were in place, and n95 masks or powered airpurifying respirators were only to be used for patients with known or suspected covid mayo clinic hospital is a medium-sized (304-bed) hospital in jacksonville, (table 1 ). employee health determined that 394 other employees worked in the surgical area at the same time as the index cases, and all were recommended to undergo sars-cov-2 pcr testing as surveillance. none refused. the cdc risk assessment levels for most personnel, including the 2 index cases, were designated as "unknown" (n=40) or "not available" (n=347); 5 employees were categorized as "high risk" because of extensive exposure to the index cases, and 4 were designated "low risk." these employees spanned multiple departments and work roles ( table 2) . of the 394 employees initially tested, 393 were negative, and 1 was positive (positive surveillance case, in the "unknown" risk category). results were available for all within 24 hours. further review of the positive surveillance case showed that symptom onset was on march 18, 12 days before the confirmatory pcr test (table 1) . no potential community exposure was identified, and it was determined to be an unknown exposure. no new positive cases were identified. of 7 employees who did not complete subsequent testing, 2 were determined not to be exposed and 5 did not complete testing. of the 5 employees who did not complete subsequent testing, 4 were not placed in quarantine, did not report symptoms, and did not receive further pcr or serologic testing. the other employee was placed in isolation on april 3 because of reported symptoms of headache, sinus congestion, postnasal drip, and cough on april 2. review of work history showed that this employee had contact with index case 1 on march 27. this employee's symptoms were improving on april 5. the employee was confirmed symptom free on april 9 and was cleared to return to work starting april 10 because the initial test was negative and it had been 14 days since the exposure date. no further pcr or serologic testing was performed. of the 394 employees tested in the surveillance program, 8 were placed in isolation for 14 days because of symptoms, and 17 without symptoms were placed in quarantine for 14 days because of high risk of exposure or recent travel. an interesting aspect of this study is the discovery that the surveillance case had symptoms that predated those of the index cases and was working in the surgical area more extensively than either of the index cases during a time of potential infectivity. because no definitive source of infection was identified for index case 2, it is possible that they were exposed to the surveillance case. more robust contact tracing, potentially through the use of real-time location monitoring systems, may have been able to make a stronger case for that scenario. real-time monitoring systems with rapid information about contacts also may have decreased the number of personnel requiring testing. 4 j o u r n a l p r e -p r o o f anosmia as a symptom. this was not a recognized symptom at the time of the study but has since been added as a symptom associated with covid-19. 5 at the time of the study, the institution was using the cdc test-based strategy for return to work. this strategy has since been abandoned in most circumstances because of long periods of positivity that most likely are not indicative of ongoing infectivity. 5 support for this point in our study is that the surveillance case continued to test positive for almost 8 weeks after the onset of symptoms. 6 the covid-19 pandemic has placed considerable strain on the health care workforce, and many health care workers are at risk for contracting the disease. 7, 8 this study, strengthened by excellent participant compliance and follow-up, shows that the risk of contracting the disease from coworkers in a low-prevalence environment (in the community and the institution) with standard precautions is very low. of note, even though standard precautions were in place, surgical mask use was very prevalent in this area as part of standard precautions. although this study is limited by being performed at a single location with low prevalence of overall disease in the community and the hospital at the time of the surveillance, it should provide some reassurance to health care workers as hospitals and other medical establishments pursue reopening practices to patients. the results could also potentially be extrapolated to nonsurgical areas with the adoption of universal masking protocols at most institutions. 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 abbreviations: app, advanced practice provider; crna, certified registered nurse anesthetist. characteristics of health care personnel with covid-19: united states prevalence of sars-cov-2 infection in previously undiagnosed health care workers at the onset of the us covid-19 epidemic. medrxiv doctors and healthcare workers at frontline of covid 19 epidemic: admiration, a pat on the back, and need for extreme caution use of a real-time locating system for contact tracing of health care workers during the covid-19 pandemic at an infectious disease center in singapore: validation study us department of health and human services. coronavirus disease 2019 (covid-19): symptoms of coronavirus we thank the mayo clinic in florida covid testing center team: luanne key: cord-269568-vwkawh6x authors: ten hulzen, richard d.; fabry, david a. title: impact of hearing loss and universal face masking in the covid-19 era. date: 2020-08-03 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.07.027 sha: doc_id: 269568 cord_uid: vwkawh6x nan abbreviations: covid-19 = coronavirus disease 2019; db = decibel; ed = emergency department; ffp = filtering face piece; fm = frequency modulation; hz = hertz; icu = intensive care unit; n95 mask = a particulate-filtering face mask that filters at least 95% of airborne particles; ppe = personal protective equipment; psaps -personal sound amplification products; sars-cov-2 = severe acute respiratory syndrome-coronavirus-2. in the current coronavirus disease 2019 (covid-19) pandemic, health and government officials are encouraging, even mandating, community-wide face mask wearing (i.e., universal masking) to reduce potential pre-symptomatic or asymptomatic transmission of severe acute respiratory syndromecoronavirus-2 (sars-cov-2) to others. there are three major categories of masks being used to limit the airborne transmission of large respiratory droplets and infectious agents: a respirator, or filtering face piece (ffp), such as a n95 mask; medical face masks, such as a surgical or procedure mask; and nonmedical masks, such as commercially-or self-made masks usually made of cloth or other textiles. based on mechanistic plausibility and the desire to reduce sars-cov-2 transmission and community impact, universal masking is recommended as a means of source control of both symptomatic and pre-symptomatic/asymptomatic individuals to prevent the spread of infectious respiratory droplets to others. in addition to universal masking, the community can mitigate the risk of transmitting and acquiring sars-cov-2 by physical distancing (> 6 feet apart), remaining at home, avoiding crowded or public places, working remotely from home, respiratory etiquette, frequent handwashing, and avoiding unnecessary hand-face contact. 1 health care facilities may also restrict family members and interpreters from accompanying patients during surgery, emergency department (ed) visits, intensive care unit (icu) stays, or hospitalizations. while these measures arguably are epidemiologically-appropriate, the negative impact these measures have had on the short supply of masks and other personal protective equipment (ppe) has been widely reported. in addition, universal masking is a barrier to clear empathetic communication. we'd like to call attention to the negative impacts of universal masking and social distancing in both health-care and community settings for individuals with hearing loss. approximately 14.1% of american adults (27.7 million) aged 18 and over report some difficulty hearing. 2 hearing loss impacts all age groups, yet it is more prevalent among unscreened older adults-who are also likely to be without hearing assistance. for 60-69 year-olds, the prevalence for hearing loss affecting speech intelligibility was 39.3%. 2 in addition, covid-19 fatality rates are higher in older adults who are frail with other comorbidities. current policies often require patients to be unaccompanied by supporting family members. this can be detrimental to effective communication, patient safety, and quality healthcare with individuals with hearing loss who cannot understand attenuated and distorted speech nor gain clues from lip-reading and facial expressions due to universal masking. a recent study showed each type of mask wearing causes a low-pass filter effect attenuating the higher frequencies (2000-7000 hertz, or db for the n95 mask (respirator/ffp). 3 while both age-related hearing loss and ffp masking portend substantial high-frequency region (2000-4000 hz) inaudibility and speech understanding reduction compared to normal hearing individuals when no mask is worn, the addition of a noisy background setting (e.g., ed/icu) further confounds this and makes communication extremely difficult, if not impossible. social distancing also has an impact on speech audibility. sounds rapidly become quieter as they travel away from their sources. the decibel (db) scale logarithmically quantitates the relative intensities of sound-a sound with an intensity of half that of a reference sound corresponds to a decrease of little more than 3 db. the inverse square law states that doubling the distance reduces the sound intensity to a quarter of its initial value. if the distance is doubled, then a 6 db reduction in sound intensity is noted. while conversational distances between two talkers in the united states typically ranges from 1.5 to 3 feet, the currently recommended social distancing of at least 6 feet (which translates to a doubling or even quadrupling of the distance) means the sound pressure level drops by 6 to 12 db, or more. social healthcare professionals should recognize that, with the loss of visual cues (i.e., lip reading) and support systems (e.g., family members), current covid-19 policies such as universal masking, social distancing, and unaccompanied patients may "unmask" significant hearing loss-related issues that previously had been diminished or ignored. personal sound amplification products (psaps) tend to work best for individuals with rather mild hearing loss, while those with more advanced hearing loss may benefit from further audiologic evaluation for hearing aids or even cochlear implants. hospitals and clinics may wish to consider loaner amplification systems (e.g., hearing aids) or use a fm system where the physician uses a microphone lanyard)-however this may be a challenging endeavor given the issues of cost, device decontamination, and potential cross-infection. additional resources and temporary recommendations for healthcare facilities are continually updated and available online (https://www.nad.org/covid19-communication-access-recs-for -hospital/). 6 healthcare professionals • speak slightly louder, and with a minimally-reduced rate • rephrase-rather than repeating the same words, shouting, exaggerated pronunciation, etc. • take turns when speaking • optimize positioning (i.e., face-to-face, not moving around or walking) • use low-tech methods (e.g., pen-and-paper, clear partitions) • use high-tech methods (e.g., wi-fi enabled tablets, video chat apps on smartphones) • use video-conferencing platforms (e.g., telemedicine, unmasked, without ppe) • use clear (or clear-paneled) masks to improve visibility of facial expressions / lip-reading cues • use personal sound amplification products (psaps) • use loaner hearing aids or frequency modulation (fm) systems along with a microphone lanyard • use scribes or professional support staff to assist healthcare professionals with hearing loss a fm = frequency modulation; ppe = personal protective equipment; psaps = personal sound amplification products european centre for disease prevention and control declining prevalence of hearing loss in us adults aged 20 to 69 years speech blocked by surgical masks becomes a more important issue in the era of covid-19. the hearing review effect of facemasks on empathy and relational continuity: a randomized controlled trial in primary care time to take hearing loss seriously covid-19: deaf and hard of hearing communication access recommendations for the hospital. nad website key: cord-315388-8sv00zqz authors: ghosh, ritwik; chatterjee, subhankar; dubey, souvik; lavie, carl j. title: famotidine against sars-cov2: a hope or hype? date: 2020-06-06 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.05.027 sha: doc_id: 315388 cord_uid: 8sv00zqz nan title: famotidine against sars-cov2: a hope or hype? to the editor: 2019-coronavirus disease (covid-19) is globe-trotting and thousands of researchers and stakeholders are spending repose-less days and sleepless nights in search of effective therapies. currently, the entire research sphere is dealing with a pandemic triad: hypes, hypotheses and hopes. in the absence of a specific anti-viral or vaccine against the novel severe acute respiratory syndrome-corona virus (sars-cov2), "repurposing" of old time-tested medications are being tried. famotidine is the most recent addition to this trend, creating a lot of hustle among the public and stirring criticism in the scientific arena [1] . a phase 3 trial titled "multi-site adaptive trials using hydroxychloroquine for covid-19" (match) [nct04370262] has already been launched inconspicuously [1, 2] . this randomized, doubleblind clinical trial (n=1170) has been designed to compare clinical outcomes between two armsviz. one receiving hydroxychloroquine (hcq) 200mg plus famotidine (360mg/day intravenous) and the other receiving hcq plus placebo. famotidine will be administered for a maximum of 14 days or to hospital discharge, whichever will come earlier [2] . in this briefing we will try to enlighten some facts regarding whether it is possible for famotidine to have a beneficial effect in covid-19 truly or is it just hitting the castle in a don quixotic way. antithetical to the initial belief, sars-cov2 is a multi-systemic illness with an array of manifestations protean in disease progression, severity and outcome. the key pathogenesis revolves around the "cytokine storm" occurring due to disruption of delicate balance between pro-inflammatory and anti-inflammatory mediators and a depressed immune system [3] . the most climacteric role for resolution of viral infection will be imparted upon the complex interplay between innate and adaptive immune system in the host. while an irrefutable pathogenesis and an efficacious vaccine is still a dream, attenuation of perpetual hyperinflammation is the bull's eye at this moment. it is not the maiden time that the scientists have decided to "repurpose" the drug famotidine, an age-old antacid, to combat a viral disease. the effects of histamine on different substrates of immune system and immunomodulatory effects of h 2 receptor antagonists (h 2 ra) are wellrecognized [4] . through binding with h 2 r and modulating the effector pathways mediated by protein kinase a (pka), famotidine potentially regulates innate and adaptive immune responses. and proliferation, mast cell degranulation and dendritic cell (dc) response [5] . innate immune system function is potentially boosted by stimulatory effects of h2ra on its effectors i.e. macrophages, neutrophils, monocytes, dcs, natural killer (nk) cells, nk-t cells and the adaptive system is filliped by activation of helper t cells (th1, th2, th17), regulatory t cells, cytotoxic cd8+t cells [6] . it has been documented that famotidine completely demolishes h2r mediated negative effects on cytokine production, especially tumor necrosis factor (tnf)-α, interferon-γ) [7] , on lipopolysaccharide-induced tnf-α production, b7-1 expression on monocytes [8] and also curtails the inhibitory effects of histamine on production of th-1 mediated cytokine release [9] . h 2 ra has been attempted in many other conditions, like cancer, viral infection, bone remodeling, burn management, and vaccine potency-enhancer, among other conditions, with mixed results [6] . previously h2ra has been used with some success against human immunodeficiency virus [10, 11] , human papilloma virus [12] , herpes simplex virus [13] , epstein-burr virus [14] , chronic hepatitis b infection [15] . ranitidine bismuth citrate has been shown to inhibit the nucleoside triphosphate hydrolase and dna unwinding activities of the sars-cov helicase and hinders its replication [16] . although the above mechanistic explanations sound reasonable, the real outcomes in clinical trials might be completely futile as evidenced previously [11] . the unpublished chinese data which received publicity in the press claiming that the mortality rate for covid-19 patients on famotidine was 14% compared to 27% for those not on the drug, reported not to be statistically significant [1] .however, before concluding anything from this, one needs to analyze actual complete data along with the confounders. moreover, scientists' claims of famotidine having anti-protease like effects [1] have not stemmed from any strong published evidence, but rather on the evidence of the negative pharmacokinetic effects of famotidine on protease inhibitors [17] . the dosage of famotidine being used in the match trial is nearly 10 times greater than the usual dosage employed for severe forms of peptic ulcer diseases. although famotidine is a timetested and safe drug, excessive inhibition of gastric acid secretion might precipitate pneumonia [18] . cardiac failure and arrhythmias have also been reported with high doses of intravenous famotidine administration [19] . considering its relative cheapness, wide availability and prior experiences as an anti-viral agent, famotidine might usher some hope; however, we must wait for the trial results. until then hoarding and therapeutic misadventure with this drug must be condemned. new york clinical trial quietly tests heartburn remedy against coronavirus multi-site adaptive trials using hydroxycholoroquine for covid-19 (match) hlh across speciality collaboration, uk. covid-19: consider cytokine storm syndromes and immunosuppression comparison of immunomodulative effects of the histamine-2 receptor antagonists cimetidine, ranitidine, and famotidine on peripheral blood mononuclear cells in gastric cancer patients histamine receptor 2 modifies dendritic cell responses to microbial ligands immunomodulatory properties of cimetidine: its therapeutic potentials for treatment of immune-related diseases histamine receptor 2 is required to suppress innate immune responses to bacterial ligands in patients with inflammatory bowel disease cytokine responses of intraepithelial lymphocytes are regulated by histamine h(2) receptor histamine inhibits lipopolysaccharide-induced tumor necrosis factor-alpha production in an intercellular adhesion molecule-1-and b7.1-dependent manner the effect of histamine type 2 receptor antagonists on human immunodeficiency virus (hiv) replication: identification of a new class of antiviral agents a placebocontrolled trial of ranitidine in patients with early human immunodeficiency virus infection treatment of viral warts with cimetidine: an open-label study cimetidine prevents recurrent erythema multiforme major resulting from herpes simplex virus infection cimetidine, ranitidine, and epstein-barr virus infection cimetidine synergizes with praziquantel to enhance the immune response of hbv dna vaccine via activating cytotoxic cd8(+) t cell bismuth complexes inhibit the sars coronavirus effects of the h2-receptor antagonist famotidine on the pharmacokinetics of atazanavir-ritonavir with or without tenofovir in hiv-infected patients use of acid-suppressive drugs and risk of pneumonia: a systematic review and meta-analysis complete atrioventricular block and cardiac arrest following intravenous famotidine administration key: cord-030903-hhhjwoei authors: sinsky, christine a. title: implementing telemedicine in primary care: learning lessons from electronic health records date: 2020-08-27 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.07.017 sha: doc_id: 30903 cord_uid: hhhjwoei nan christine a. sinsky, md t he common narrative is coronavirus disease 2019 happened, payment and policy barriers were quickly lowered and voila, telemedicine, a technology for which adoption had been slow over the past decade, is, within a matter of months, in widespread and successful use. fait accompli. on to this narrative has been grafted the hopes that telemedicine will solve other persistent problems, particularly in primary care. 1 as with any other technology, the divine is in the details. the challenges for primary care are deep and structural. inequity in payment for cognitive versus procedural care 2 ; conflating how primary care has been valued with its value; equating the payment allocated for primary care services with the difficulty in their mastery (contributing to the assumption that lesser training is of little consequence in primary care); and a shrinking scope of practice for physicians within the specialty are among the reasons our health system has not benefitted fully from what a well-supported, well-organized model of primary care has to offer. certainly, telemedicine cannot solve the structural causes above, but can it improve capacity and access while also reducing time pressure and burnout? if this is possible, what are physicians and their teams doing during now inperson visits that is not necessary and could be eliminated? arguably, it should require even more time rather than less to accurately read the fewer signals available from patients during a video visit and to be sure that the real reason for the visit, the third or fourth complaint, reaches the surface. twenty years ago, electronic health records (ehrs) were anticipated as a technology that would improve quality, efficiency, and professional mastery. all of our patients' information would be at our fingertips whether we were at the clinic, the hospital, or at home. clinical decision support, popup reminders, and hard-stops during order entry would make us better physicians. and yet the ehr was not the savior of primary care, 3 but instead, for all of its benefits, its burdens fell disproportionately to primary care physicians. many tasks take more time when performed on the ehr. 4 in addition, with the mistaken beliefs that technology will allow the physician to do other role types, work and that this work can magically be accomplished in the interstitial time between other work, time pressure for physicians intensified after ehr implementations. tasks previously managed by receptionists, transcriptionists, medical records clerks, et cetera, have been shifted to physicians; work has spilled over into home, 5 stealing time from family, friends, and personal well-being 6 ; and the ehr provided vastly more opportunities for monitoring, measuring, 7 reprimanding, and penalizing physicians. what are the lessons learned that could ensure that similar stumbles do not befall the promising technology of telemedicine? design, implement, and regulate with teams in mind in each encounter, whether in-person or video, there is too much to be done by just one person, and it is too important to leave to chance. the doctor cannot singlehandedly do all the work of the visit and do it well; this mindset blinded many to the risks to patient safety, patient trust, and professional well-being associated with many ehr implementations. there is no need to repeat those mistakes with telemedicine. providing patients undivided attention is one of the most powerful tools in any physician's toolkit. multitasking, which is really task switching, 8 is hazardous. during a remote visit, because there are fewer cues to read, the physician must be fully attentive to all available, rather than simultaneously transcribing the visit note, entering orders, sending medications to the pharmacy, ticking off performance measures, and composing the billing invoice. humans have a finite cognitive bandwidth; the more time spent on clerical tasks, the less available for deep clinical work. health care is not just a series of transactions for which anybody will do, but is built on relationships. diagnostic accuracy and therapeutic adherence are greater, and waste reduced, in the context of a trusting ongoing relationship. 9 telemedicine is not inherently transactional, and by bringing the physician and team closer into patients' lives it can support and enhance relationships. to realize this potential, however, a priority must be placed on continuity and relationships. it is important to avoid thinking that a physician can somehow do more in less time during video rather than in-person visits. work that physicians and others perform outside of the encounter is still work and takes time. likewise, work that occurs at home is work, and deserves to be counted. some tasks are quicker when done with a technology assist and at other times work on a technology platform can take more time. it all needs to be counted and understood. invest in the science of practice teamwork, planning, and efficient workflows are essential. not every problem is best suited to a technological fix. in fact, technology, such as artificial intelligence, 1 used to compensate for an underlying disorganized system of care 1 can be cumbersome and costly. for example, appropriately scheduling patients from the outset saves time and improves patient experience. at the end of today's appointment, the team can set up the next appointment, with all associated tests for prevention and chronic illness monitoring, customized to this particular patient, accommodating the patient's preference for an inperson or virtual appointment. 10 no need then for a last-minute "schedule sweep" 1 to cancel the patient after an algorithm deemed their appointment unnecessary. likewise, centralizing population health as the primary vehicle for prevention and chronic illness care can be an unnecessary source of further fragmentation, 9 depersonalization, and waste within the health care system. instead, using an organized system of care, all of the patient's annual needs for prevention and chronic illness monitoring can be arranged at a single, coordinated appointment rather than being fragmented, with the patient contacted 1 month for their mammogram, the next month for their pneumococcal vaccine, and at yet another time for their urine test for microalbumin. a registry, whether managed centrally or more personally at the local level by the patient's team, can catch those patients who fall through the cracks of an organized system, but to use it as the primary vehicle by which to manage populations is cumbersome and reduces customization at the level of the individual experience. during the storm that is coronavirus disease 2019, telemedicine arrived with a bang and is thankfully here to stay. it will take time to understand all of its risks and benefits, the appropriate patients for in-person versus virtual care, and to develop the optimal models of teamwork for this platform. let us not repeat the mistakes encountered when ehr implementations were anticipated through rose colored glasses, but rather look with clear eyes to the lessons from the past generation's technology challenges. retooling primary care in the covid-19 era medicare payment for cognitive vs procedural care: minding the gap e-nirvana: are we there yet? tethered to the ehr: primary care physician workload assessment using ehr event log data and time-motion observations allocation of physician time in ambulatory practice: a time and motion study in 4 specialties electronic health records and burnout: time spent on the electronic health record after hours and message volume associated with exhaustion but not with cynicism among primary care clinicians us physician practices spend more than $15.4 billion annually to report quality measures quantifying the impact of health it implementations on clinical workflow: a new methodological perspective care fragmentation, quality, and costs among chronically ill patients putting pre-visit planning into practice key: cord-302513-u9n56pnb authors: breitinger, scott; gentry, melanie t.; hilty, donald m. title: key opportunities for the covid-19 response to create a path to sustainable telemedicine services date: 2020-10-01 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.09.034 sha: doc_id: 302513 cord_uid: u9n56pnb nan "there have been as many plagues as wars in history; yet always plagues and wars take people equally by surprise," wrote albert camus in his 1947 novel, the plague. 1 the current coronavirus pandemic is sweeping through every continent, leaving health care systems scrambling to screen, diagnose, and treat covid-19 patients -and to deal with the public health repercussions secondary to social distancing. worsening morbidity and mortality related to behavioral health and substance abuse are ubiquitous sequalae to epidemics and disasters, and covid-19 has unsurprisingly demonstrated the same pattern. 2 in march 2020, federal and state agencies implemented rapid regulatory changes to expand and enhance the use of telehealth for those affected by covid-19. this included: • temporary easing of telehealth restrictions for medicare beneficiaries, • reimbursing providers at the same rate as in-person consultations for video with acceptable reimbursement mechanisms for telephone and text communications as well, • many states providing waivers for out-of-state practitioners, and • temporary easing of controlled substance prescribing limitations as defined by the ryan haight online pharmacy consumer protection act. there is a deep resonance with camus' observation regarding the predictability with which pandemics take civilizations by surprise. the covid-19 pandemic has exposed and amplified systemic deficits in health care systems' ability to manage the secondary j o u r n a l p r e -p r o o f breitinger 3 health effects of psychosocial isolation, economic strain, and cultural turmoil. obsolete regulations of telemedicine that have been temporarily modified demonstrate opportunities for policymakers to transform temporary successes into permanent adaptations. during the covid-19 era, telemedicine has been an essential method to ensure the continuation of health care services while allowing for social distancing and reducing rates of covid-19 transmission. studies show rates of telemedicine increasing upwards of 6-to 7-fold during the covid-19 era. 3 the expansion of video-based care has been an effective means of seeking care for many patients. 3, 4 however, many other patients have been left behind in this rapid switch to video-based carepotentially worsening health care inequities -particularly for those without access totechnology. some systems (e.g., mayo clinic, veterans health administration) have patients go to a care facility in the system to use equipment, and other countries direct patients to use equipment in malls or libraries, while this is less common in the united states. this disparity in access has made telephone visits an equally important component of the recent telehealth expansion. 4 telemedicine is an important tool to expand care delivery, though it may not be applicable in every health care setting or clinical scenario. telemedicine has been shown to be effective with similar clinical outcomes and high levels of patient satisfaction across diverse areas of health care including psychiatry, cardiac rehabilitation, and orthopedics. 5 some aspects of care may require help from in-person clinicians for parts of the physical examination or a medical intervention to effectively evaluate and manage patients, particularly for urgent or emergent situations. 5 consumer demand for telehealth services has long outpaced the implementation of such programs within health care organizations. the covid-19 pandemic has led to rapidly increasing demand for such services. with the increased exposure and comfort with virtual health care amongst patients and providers, the demand for expanded access to telehealth services is not likely to wane once the pandemic has passed. importantly, while routine and low intensity telemedicine services can keep financial revenue in rural communities, 5 theoretically revenue could be redirected from already struggling rural hospitals to larger health care organizations better equipped to make this rapid transition to digital care. in turn, this could reduce the financial sustainability of rural clinical facilities that also provide acute medical care. for this reason, precaution and foresight are essential in both policy and operational planning to ensure financial sustainability of complex care for underserved and rural populations. if telemedicine is to continue as a critical component of health care delivery, the following regulatory hurdles must be addressed. the ryan haight online pharmacy consumer protection act has been a longtime barrier to the widespread implementation of tele-mental health services due to its restriction on prescribing controlled medications without a face-to-face office visit. 6 these restrictions were lifted by a federal emergency declaration in january 2020. the telemedicine was introduced as a covered service under the medicare program in 1997 but maintained significant limitations based on site of service provision and geography. 7 reimbursement has generally been limited to patients being present at rural originating j o u r n a l p r e -p r o o f breitinger 6 facilities. these restrictions significantly hamper the ability of health systems to develop and sustain telemedicine interventions for older adults and those with disabilities. 8 loosening restrictions on telehealth reimbursement under covid-19 emergency orders has resulted in a dramatic expansion of virtual care, which has allowed for providing crucial medical services to vulnerable patient populations during the covid-19 pandemic. however, as these are temporary measures, it is unknown which, if any of these waivers will remain in place after the emergent covid-19 response period. going forward, a few things are working and should be continued through the following measures: • new legislation governing the centers for medicare and medicaid could extend temporary waivers to support telehealth including expanding the types of covered providers, types of covered services, and importantly, removing restrictions on patient and provider location for telehealth visits. going forward, in response to covid-19: • federal legislation could be used to redefine the "place of service." instead of the site of the patient arbitrarily defined as the virtual place of service, the site of the clinician redefined as the site of care delivery would alleviate the need for providers to have multiple state licenses to practice telemedicine. • expansion of the interstate medical licensure compact to include all states/territories and provide for reduced requirements and fees for telemedicine only licensure. stakeholders across the country must advocate for their individual states to adopt legislation to participate in this compact to help make interstate telemedicine practice more ubiquitous. the expansion of telehealth during the covid-19 pandemic has allowed many providers and patients to experience better access to effective care. this is a unique opportunity to leverage this increased interest and demand for telehealth in creating permanent regulatory changes to improve the access to health care and to build resilience and capability into the health care system before the next unforeseen but inevitable public health crucible arrives. to maintain the progress made possible by this pandemic, some well-intended regulatory parameters of telehealth could be revised to permit greater freedom for patients, providers, health care systems and states to connect patients' needs with effective health care. j o u r n a l p r e -p r o o f the plague. london: penguin the mental health consequences of covid-19 and physical distancing: the need for prevention and early intervention covid-19 transforms health care through telemedicine: evidence from the field digital health equity and covid-19: the innovation curve cannot reinforce the social gradient of health the effectiveness of telemental health: a 2013 review telepsychiatry and the coronavirus disease 2019 pandemic-current and future outcomes of the rapid virtualization of psychiatric care the transition from reimagining to recreating health care is now. nejm catalyst innovations in care delivery geriatric telepsychiatry: systematic review and policy considerations key: cord-328548-5kjq9xqs authors: oliveira j. e silva, lucas; vidor, marcos v.; zarpellon de araújo, vicenzo; bellolio, fernanda title: flexibilization of science, cognitive biases, and the covid-19 pandemic date: 2020-08-27 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.06.037 sha: doc_id: 328548 cord_uid: 5kjq9xqs nan this occurred 10 weeks after china reported to the who a cluster of pneumonia cases. in the context of a pandemic, multiple pressures, such as fear of death and economic collapse, may align. this scenario creates a fertile ground for ingrained cognitive biases, thereby disturbing the systematic approach upon which science usually relies. the senior author of the first published clinical study on the use of hydroxychloroquine for covid-19 had stated in an interview with french newspaper le monde that "doctors can and should think like doctors, not like methodologists." 1 this study attracted attention and exerted influence after the release of its promising results. even though methodological limitations were evident, this work generated several claims about the efficacy of hydroxychloroquine for patients with covid-19. in ordinary times, this manuscript would be scrutinized by an extensive peer-review process that would potentially raise substantive concerns. a subsequent high-profile paper associating the use of hydroxychloroquine with increased mortality in the treatment of covid-19 had to be retracted 2 after scientists pointed out issues such as mismatched mortality rates when compared to australian official reports, no release of the dataset for independent analysis, and lack of thorough ethical review. these are examples of a phenomenon we call the "flexibilization" of science, a part of a vicious cycle underpinned by cognitive biases and triggered by the covid-19 pandemic ( figure) . the term "flexibilization" here refers to a loosening of methodological standards and the development of low-quality studies, leading to the creation of unreliable data and, later in the cycle, of anecdotal evidence. while low-quality evidence may generate new hypotheses that ultimately result in benefits for patients, it can also have the opposite effect. there are several historical examples that show how careful we need to be before making decisions based on the available evidence. 3, 4 in fact, some of these "surprising" results in previously published literature have taught us that therapeutic approaches that were initially found to be promising were instead causing harm to patients. within this context, science and clinical research have been creating rigorous methodological standards in order to produce high-quality studies that allow us to have greater confidence in the evidence while mitigating unnecessary damage. contrary to what was once largely accepted as a normative model, human beings are not usually rational in their decision-making processes, often relying on many heuristics that may have afforded an evolutionary compensation and adaptation for our limited computational capacity. take, for example, our inclination to search for evidence that confirms our prior beliefs, a tendency known as confirmation bias. we are naturally prone to this sort of intellectual ambush, and there is evidence to support that scientists are not immune to these systematic errors. 5 for a group of people, once a belief is incorporated, even strong evidence contrary to such belief is not enough for a reinterpretation, a mechanism named belief perseveration. in the extreme case, exposing people to proof that is inconsistent to their understanding might lead them to reject the opposing hypothesis even more strongly, what has been called the backfire effect. for instance, among people highly concerned about vaccine side effects, receiving information about vaccines by the centers for disease control and prevention reduced their intent on vaccinating. 6 in a time urging for cost-effective results, it is important to make a clear distinction between scientific method and scientists. the former is the enterprise that aims to diminish systematic error; the latter is reasonably susceptible for all sorts of biases when not following a systematic approach. when low-quality studies are created, the risk of misinterpretation increases. in the setting of a highly connected world and increasing public exposure, there might be a temptation for researchers to report the results of their findings in an incorrect way, either highlighting benefits or downplaying the harms of a specific treatment. this is called the "spin" of reporting clinical research. 7 since "spin" is highly prevalent in the medical literature, 8 one might speculate on the motivations behind it. in the context of covid-19 pandemic, this seems to be mostly driven by an intrinsic desire to find a treatment that works against a disease that is having an important impact on society across the world. however, other motivations include lack of knowledge about methodological standards, opportunistic publishing, and an intent to influence readers. 9 studies evaluating the impact of "spin" have shown that clinicians are more likely to perceive a treatment as beneficial when "spin" is present. 10 the general public may be more susceptible to be influenced by "spin", especially if they lack the expertise to avoid misinterpretation of research data. this issue could be amplified by the dunning-kruger effect, a cognitive bias in which unskilled individuals tend to overestimate their ability in a given task. during the covid-19 pandemic, the early adoption of new interventions by clinicians and policy makers based on promising but often low-quality data is creating a scenario from which anecdotal evidence may emerge. several countries have endorsed the use of hydroxychloroquine for covid-19 in clinical scenarios outside of the undergoing research protocols. as an example, brazil's ministry of health has released a new treatment guideline for covid-19 recommending the use of either hydroxychloroquine or chloroquine for patients with mild symptoms, such as cough, fatigue, anosmia, or headache, 11 ignoring current best evidence. this off-label use allows for claims of efficacy based on informal reports of patients who recovered from the disease after taking the medication, adding an important layer of confusion and misinterpretation. anecdotal evidence is more likely to emerge from this mild spectrum in which drug efficacy is easily confounded with the natural course of the disease that would otherwise improve with supportive care only. 12 the belief that hydroxychloroquine might be a good intervention for covid-19 led to the hoarding of this medication by the general public and health care workers around the world. this scenario created an uncertainty about drug availability to patients who need this medication, especially for those with rheumatologic diseases and in low-to-middle income countries with high rates of malaria. despite being arguably the lowest quality of scientific proof, there are several reasons to believe that anecdotal evidence, in particular, may be accorded more credence than such evidence truly merits. first, there is a narrative quality to anecdotal evidence that resonates with intuitive patterns of learning. second, the context in which this sort of information is shared usually involves a known person, which might add an affective valence to the message. finally, there is the availability heuristics, which leads people to misjudge the probability of an event being true based on how easily it can be recalled. we emphasize the importance of interrupting the "flexibilization" of science in order to break a vicious cycle that may do more harm than good. while fast-paced clinical studies need to be done during a global crisis, they need to follow methodological standards in order to produce reliable and high-quality evidence. the administrative bureaucracy and procedures to perform a well-designed randomized controlled trial, for example, can be accelerated, but the pandemic should not be an excuse to overlook important aspects of methodological standards. in the era of covid-19, we need to be even more vigilant about our own cognitive biases and limitations, and avoid the "flexibilization" of science as this may exert significant harm to our society. ):105949. 2. mehra mr, ruschitzka f, patel an. retractiondhydroxychloroquine or chloroquine with or without a macrolide for treatment of covid-19: a multinational registry analysis translation of highly promising basic science research into clinical applications why most published research findings are false testing for the presence of positive-outcome bias in peer review: a randomized controlled trial does correcting myths about the flu vaccine work? an experimental evaluation of the effects of corrective information spin" in reports of clinical research reporting and interpretation of randomized controlled trials with statistically nonsignificant results for primary outcomes a new classification of spin in systematic reviews and meta-analyses was developed and ranked according to the severity impact of spin in the abstracts of articles reporting results of randomized controlled trials in the field of cancer: the spiin randomized controlled trial orientações do ministério da saúde para manuseio medicamentoso precoce de pacientes com diagnóstico da covid-19 characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72314 cases from the chinese center for disease control and prevention key: cord-261653-0vtghtp7 authors: andersen, kylie j.; klassen, stephen a.; larson, kathryn f.; ripoll, juan g.; senefeld, jonathon w.; clayburn, andrew j.; shepherd, john r.a.; tseng, andrew s.; wiggins, chad c.; johnson, christopher p.; miller, andrew d.; baker, sarah e.; wright, r. scott; winters, jeffrey l.; stubbs, james r.; joyner, michael j.; van buskirk, camille m. title: recruitment strategy for potential covid-19 convalescent plasma donors date: 2020-09-21 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.09.021 sha: doc_id: 261653 cord_uid: 0vtghtp7 nan coronavirus disease 2019 (covid-19) represents a pandemic and global health crisis. in the first wave of the disease in the us, covid-19 was diagnosed in approximately two million individuals and contributed to over one-hundred thousand deaths. 1 the number of covid-19 diagnoses and related deaths are anticipated to perpetuate in subsequent waves of the disease. 2 the severe acute respiratory syndrome coronavirus-2 (sars-cov-2) which causes covid-19 appears to be a new human pathogen with limited efficacious treatments including the antiviral, remdesivir and the glucocorticoid, dexamethasone. 3, 4 however, there is robust historical precedent to anticipate that human convalescent plasma is a viable option for mitigation and treatment of covid-19. 5, 6 human convalescent plasma leverages the antibody response of a recently-sick and recovered covid-19 patient as a plasma donor. 7 the donated plasma which is rich in neutralizing antibodies to the sars-cov-2 virus is transfused to a currently-sick covid-19 patient to mitigate on-going symptomology and induce passive immunity. 7 thus, the us food and drug administration (us fda) in collaboration with the mayo clinic and national blood banking community developed a national expanded access program (eap) to collect and distribute convalescent plasma donated by covid-19 survivors. 8 theoretically, within four to six weeks of the onset of the us covid-19 outbreak, human convalescent plasma should have been readily available due to the existing plasma collection infrastructure within the blood banking community 9 and the large numbers of covid-19 survivors who could have donated high-titer immunoglobulin-containing plasma. 10 however, logistical issues produced a convalescent plasma fulfillment gap that created an urgent need to develop strategies to recruit eligible donors at national, regional, and local blood centers. thus, the present narrative overviews the strategy developed by our team to identify and recruit covid-19 survivors to donate convalescent plasma at the mayo clinic blood donor center in rochester, minnesota. emerging data from the covid-19 pandemic support the use of convalescent plasma therapy. there is evidence to suggest that sars-cov-2 elicits a robust immune response with high levels of antibodies and immunoglobulins (m and g) between 11-21 days after the onset of covid-19, suggesting a relatively large window of time and high probability of successful extraction of high-titer anti-sars-cov-2 plasma from donors. 10 consistent with this observation, convalescent plasma treated covid-19 patients had large reductions in serum sars-cov-2 j o u r n a l p r e -p r o o f serum viral loads after convalescent plasma infusion, suggesting a viral neutralizing effect of the anti-sars-cov-2 antibodies. 11 some theoretical concerns for the use of convalescent plasma therapy for covid-19 have been raised, including the risk of transfusion-related lung injury (trali), transfusion-related circulatory overload (taco), and antibody-dependent enhancement of covid-19. 12 however, in a large study of 20,000 patients transfused with convalescent plasma there was no signal of toxicity beyond what is expected from plasma use in severely-ill patients. 8, 13 while the efficacy of convalescent plasma remains unknown, preliminary investigations have provided a signal of possible benefit in severely-ill covid-19 patients. 14, 15 thus, recruitment of covid-19 survivors was fundamental to meet the rapidlygrowing demand for convalescent plasma as the pandemic progressed and clinical interest in convalescent plasma therapy increased. rochester, minnesota required a strategy to interface with the community of recovering covid-19 patients and recruit eligible convalescent plasma donors. to accommodate the growing magnitude and geographical spread of covid-19 survivors and the changing convalescent donor eligibility criteria outlined by regulatory agencies and local institutions, we required this strategy to be inherently modifiable. overall, this recruitment strategy utilized a simple survey, an algorithm for triaging donors, a workflow for connecting donors with mayo clinic blood donor center, a team of physician navigators (including medical students) to screen eligible donors, and a support center for donor questions. this strategy may be adopted by other institutions to rapidly increase convalescent plasma donor recruitment. to identify previously-ill recovered covid-19 survivors that satisfied present and changing eligibility criteria to donate convalescent plasma, we employed a brief online survey hosted by the research electronic data capture (redcap) system. 16, 17 to reduce user time-burden this survey was limited only to questions deemed necessary to determine donor eligibility and to maximize the retention of interested volunteers ( table 1) respondents were deemed ineligible to donate convalescent plasma and were immediately excluded from follow up by our team if they i) reported no positive covid-19 laboratory test, ii) submitted an incomplete survey, iii) did not authorize follow up contact by our team, iv) or could not be contacted by our team for follow-up (figure 1) . volunteers were also excluded from follow up by our team if they declined contact authorization at any time. ineligible respondents received an automated email to communicate both our gratitude and the reason for their j o u r n a l p r e -p r o o f ineligibility. this automated email also included a new call to action for interested volunteerswe encouraged the individuals (if eligible) to perform a standard blood donation to prevent future blood shortages and direct them to the aabb website (http://covidplasma.org/) which provides blood donation information. also, our donor service center encouraged interested potential donors who reported covid-19 symptoms but did not receive a covid-19 clinical test to contact their healthcare provider for a serology test and then fill out the recruitment survey again if they were sero-positive. our web-based recruitment survey and all e-mail communications to interested potential donors contained the e-mail address for our convalescent plasma service center. the service center team used available resources from the us fda, mayo clinic, and the blood banking community to support questions regarding donor eligibility and covid-19 testing. 9,18 also, the service center supported the physician navigator team by providing ongoing communication with screened eligible donors. this convalescent plasma donor recruitment strategy had several key strengths: 1) the recruitment strategy had inherent scalability to meet the growing magnitude of recovering covid-19 patients and enabled filtering by donor location to link the volunteer to a convenient donation center. 2) this strategy reduced the administrative and clinical workload associated with screening potential convalescent plasma donors experienced by transfusion staff at the mayo clinic blood donor center. thus, the blood donation team was able to continue collecting apheresis platelet, platelets, and whole blood donations while also scaling up convalescent plasma donations during the ongoing pandemic. 3) the simple web-based screening survey optimized volunteer convenience and the screening algorithm enabled rapid identification of currently eligible volunteers, retained interested volunteers that were not eligible upon initial survey completion, and provided a new call to action for those that did not meet convalescent plasma donation eligibility criteria -perform a standard blood donation, if eligible. our strategy for interfacing with the community of covid-19 survivors may be expanded through the following avenues: 1) by introducing plasma fractionators into our recruitment network, we may recruit donors to contribute to a hyperimmune igg product for covid-19. two important populations of eligible donors would be immediate candidates for the plasma fractionation route: i) individuals that have antibody titers below the threshold thought to be efficacious for covid-19 treatment and ii) volunteers ineligible for standard blood donation, such as multiparous women with human leukocyte antigen antibodies. 2) there is the opportunity to leverage electronic medical records to, upon a positive covid-19 test result, automatically alert the ordering physician to provide the patient with the link to our donor recruitment survey and support center email address. as the availability of serological tests increases, this avenue will enhance the volume of donors that did not receive an initial diagnostic test. survivors. based on the responses to three key questions within the convalescent plasma donor recruitment survey -regarding covid-19 laboratory test result, covid-19 symptomology, and current residence -our team delineated interested volunteers into four categories: i) immediately eligible, ii) soon to be eligible, iii) eligible for other efforts, and iv) ineligible. regardless of the categorization, all respondents authorizing follow-up interactions were contacted by our team of physician navigators or an automatically generated email to engage in additional covid-19 related donor screening or to initiate a new call to action for blood or convalescent plasma donation. expanded details are available in donor recruitment strategy overview. j o u r n a l p r e -p r o o f usa facts. coronavirus locations: covid-19 map by county and state remdesivir for the treatment of covid-19-preliminary report dexamethasone in hospitalized patients with covid-19-preliminary report meta-analysis: convalescent blood products for spanish influenza pneumonia: a future h5n1 treatment? return to the past: the case for antibody-based therapies in infectious diseases the convalescent sera option for containing covid-19 convalescent plasma in 5,000 patients deployment of convalescent plasma for the prevention and treatment of covid-19 antibody responses to sars-cov-2 in patients of novel coronavirus disease 2019 treatment of 5 critically ill patients with covid-19 with convalescent plasma covid-19 convalescent plasma: now is the time for better science safety update: covid-19 convalescent plasma in 20,000 hospitalized patients effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening covid-19: a randomized clinical trial convalescent plasma treatment of severe covid-19: a matched control study. medrxiv research electronic data capture (redcap)-a metadata-driven methodology and workflow process for providing translational research informatics support the redcap consortium: building an international community of software platform partners convalescent plasma key: cord-007864-kxyu5nzp authors: sampathkumar, priya title: dealing with threat of drug-resistant tuberculosis: background information for interpreting the andrew speaker and related cases date: 2011-10-20 journal: mayo clin proc doi: 10.4065/82.7.799 sha: doc_id: 7864 cord_uid: kxyu5nzp nan among infectious diseases, tb is second only to the human immunodeficiency virus (hiv)/acquired immunodeficiency syndrome as the greatest contributor to adult mortality, causing approximately 2 million deaths per year worldwide. the world health organization (who) estimates that one third of the world's population is infected with mycobacterium tuberculosis and that 1 in 8 deaths in the world today is due to tuberculosis. 1 after the discovery and introduction of antituberculosis medications in the late 1940s, there was hope that tb would soon be eliminated. however, after decades of steady decline, the number of reported tb cases began to increase in the late 1980s and early 1990s in the united states. this resurgence was fueled by several factors: the deterioration of the tb public health infrastructure, the onset of the hiv epidemic, increases in immigration of persons from countries where tb was common, and outbreaks in congregate settings such as hospitals and correctional institutions. another important factor resulting in increasing numbers of tb cases is the increase in transmission of multidrugresistant (mdr) strains of tb (table 1 ). in the early 1990s, several outbreaks of mdr-tb occurred in hospitals and correctional facilities in florida and new york, involving more than 250 mdr-tb cases. 2,3 most patients in these outbreaks were coinfected with hiv. the mortality rate was approximately 80%, and the interval between tb diagnosis and death was short, ranging from 4 to 16 weeks. in addition to hospitalized patients and inmates, transmission of mdr-tb to health care workers and prison guards occurred; at least 9 of these workers developed active mdr-tb, and 5 died. globally, 400,000 new cases of mdr-tb occur each year. 4 currently, drug-sensitive tb can be treated with first-line drugs for 6 to 9 months, and 95% of patients can be cured with these regimens. in contrast, mdr-tb requires treatment for 18 to 24 months with second-line drugs (table 2) 5 that are inherently less effective, often poorly tolerated by patients, and much more expensive. under optimal conditions, the cure rate is 70% to 90% but is closer to 50% in diverse clinical practice. extensively drug-resistant tb coincident with the increasing use of second-line drugs to treat the growing numbers of mdr-tb cases, the resistance pattern of tb continued to evolve, and tb that is resistant to both first-and second-line agents, termed extensively drug-resistant tb (xdr-tb), was born. in early 2005, physicians from kwazulu-natal in south africa reported an outbreak of tb with an alarmingly high mortality rate. 6 of 221 patients with mdr-tb, 53 were found to have what is now known as xdr-tb; 52 of the 53 patients died, and the median survival was only 16 days from the time the first sputum sample was collected. extensively drug-resistant tb is defined as tb that is resistant to isoniazid and rifampin (ie, mdr-tb) in addition to being resistant to any fluoroquinolone and at least 1 of the 3 injectable drugs: capreomycin, kanamycin, and amikacin 7 (table 2 ). recent reports suggest that xdr-tb is a global problem ( figure 1 ). 8 it has been identified in all regions of the world but is most frequent in the countries of the former soviet union and in asia. 9,10 estimates from the united states, the republic of korea, and latvia show that 4%, 15%, and 19%, respectively, of mdr-tb isolates were xdr strains. many developing nations lack the ability to test for drug resistance, and hence the number of cases reported thus far may represent only the tip of the iceberg. in the united states between 1993 and 2006, a total of 49 cases of xdr-tb were identified. 9 of these 49 patients, 17 during treatment, and an alarming 12 patients (24%) were lost to follow-up. multidrug-resistant tb and xdr-tb do not seem to be more contagious than other forms of tb. however, their danger lies in the fact that few or no drugs are available to treat these forms of tb. persons who are infected with these strains and who develop active disease often undergo months to years of treatment with toxic medications plus possible surgical treatment, and they are at high risk of dying, especially if they have any form of immunosuppression. m tuberculosis acquires resistance primarily from incomplete or inadequate treatment courses, and the development of xdr-tb essentially points to the worldwide weaknesses in tb management. improper use of antimicrobial therapy for drug-susceptible tb inevitably leads to drug resistance. this improper use includes administration of inappropriate treatment regimens, failure to implement directly observed therapy, and incomplete adherence to or completion of the entire treatment course. the issues with treatment are compounded by the fact that the diagnosis of tb and detection of drug resistance can be challenging. patients in whom the diagnosis of xdr-tb is delayed spread the infection to close contacts who then acquire primary xdr-tb. areas of the world that have high hiv rates are especially at risk for xdr-tb outbreaks because hiv infection predicts extreme vulnerability to tb. conventionally, tb is diagnosed by culturing the organism on liquid or solid media followed by identification of the species and then drug susceptibility testing. since mycobacteria are slow growing, this process can take several weeks and can be technically challenging. this is highlighted in the case of speaker, in whom the initial diagnosis of tb was made in late march. however, he was identified as having only mdr-tb on may 10, and it was not until may 22 that the extent of drug resistance was realized. 10 recent advances in molecular biology and understanding of the molecular mechanisms of drug resistance in tb have led to newer diagnostic tools, some of which can provide information on susceptibility patterns in days. 11 a pilot study to evaluate some of these tests is currently under way in south africa. 12, 13 speaker was smear negative (ie, no tuberculosis bacilli were visible on microscopic examination of his sputum); hence, the risk of tb transmission from him is low but not zero. subsequently, the centers for disease control and prevention has recommended that all his copassengers on 2 international flights be tested for tb. 14 this has caused a great deal of anxiety in the general public about the risk of infections related to air travel. globally, more than 1 billion passengers travel by air annually. it is a common perception that airplanes are breeding grounds for microorganisms. many people erroneously attribute upper respiratory tract symptoms after air travel to infections acquired on the airplane as a result of poor air quality. in reality, from a microbiologic standpoint, the quality of air on modern commercial aircraft is carefully controlled and is much better than that in similar enclosed places on the ground. 15 ventilation rates provide a total of 20 to 30 air exchanges per hour (the recommended rate for hospital isolation rooms for patients with tb is 6-12 exchanges per hour). most modern aircraft have recirculation systems that recycle up to 50% of cabin air. however, this air is passed through high efficiency particulate air filters, similar to the ones used in hospitals, that remove 99.9% of particulate matter, bacteria, fungi, and viruses that are between 0.1 and 0.3 µm. the tubercle bacillus is approximately 0.5 to 1.0 µm and thus is removed by high efficiency particulate air filters. 16 air enters and leaves the cabin at approximately the same seat row, and little front to back airflow occurs ( figure 2 ). this air circulation pattern means that essentially the cabin is divided into sections, and spread of airborne particles from a passenger is limited to the section in which he or she is seated. this is borne out by the fact that in reports of airborne disease transmission on aircraft, transmission has generally occurred to people close to a contagious passenger (within 2 rows) for a long time (>8 hours). important exceptions are when flights are delayed, the aircraft is parked on the ground, and the aircraft ventilation system is not operating. 18 according to the us department of transportation, "if the ventilation system is not operating, passengers should not stay aboard the plane for more than 30 minutes." transmission of tb on board a commercial aircraft during long-distance flights has been reported several times, [19] [20] [21] [22] but no case of active tb disease resulting from exposure on board has been identified subsequently. in all instances, transmission occurred to passengers seated within 2 rows of the index case. the who first published guidelines regarding tb and air travel in 1998 and revised them in 2006 in response to increased concerns about resistant forms of tb and improved international collaboration in dealing with infectious disease risks. 17 the latest guidelines can be accessed at http://whqlibdoc.who.int/hq/2006/ who_htm_tb_2006.363_eng.pdf. these guidelines provide specific recommendations for passengers, airline crews, health authorities, and airlines and are applicable to all domestic and international airlines worldwide. instances in which the risk of tb transmission on airplanes may be increased are listed in table 3 . isolation and quarantine are public health strategies that aim to control exposure to infections. isolation refers to the separation of persons who have a specific infectious illness from those who are healthy to stop the spread of that illness. in contrast, quarantine refers to the separation and restriction of movement of persons who, although not yet ill, have been exposed to an infectious agent and therefore may become infectious. local, state, and tribal jurisdictions are primarily responsible for isolation and quarantine within their borders. the federal government has the primary responsibility to prevent interstate spread of disease and to prevent the introduction of communicable diseases from foreign countries into the united states. 23 the communicable diseases for which federal isolation and quarantine are authorized by presidential order are infectious tb, cholera, diphtheria, plague, smallpox, yellow fever, viral hemorrhagic fevers, sars, and influenza with pandemic potential. this federal quarantine provision was last invoked in 1963 to deal with a patient infected with smallpox, but local public health authorities exercise the right to enforce isolation more frequently. in fact, a person with xdr-tb is currently incarcerated in a phoenix jail for failing to comply with a physician's instructions to wear a mask in public. 24 summary it remains unclear how speaker became infected with xdr-tb. additionally, it may never be known whether he understood the fact that he had a serious and potentially communicable form of tb and still chose to ignore medical advice or whether he simply did not understand all the implications of his diagnosis. his trans-atlantic multicountry odyssey highlights the fact yet again that spread of infectious agents via global air travel remains a very real threat and that international cooperation remains vital to limit the spread of infections. moreover, this case draws attention to the fact that tb remains a great threat to humanity worldwide; in the words of us representatives eliot l. engel and gene green "we'll get nowhere on tb till we tackle it everywhere." 25 priya sampathkumar, md division of infectious diseases mayo clinic rochester, minn epidemiologic notes and reports nosocomial transmission of multidrug-resistant tuberculosis among hiv-infected persons-florida nosocomial transmission of multidrug-resistant tuberculosis to health-care workers and hivinfected patients in an urban hospital-florida global incidence of multidrugresistant tuberculosis infectious diseases society of america. treatment of tuberculosis extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and hiv in a rural area of south africa notice to readers: revised definition of extensively drug-resistant tuberculosis extensively drugresistant tuberculosis-united states statement by julie l. gerberding, md, mph, on recent case of extensively drug resistant tb: cdc's public health response. available at: www newer diagnostics for tuberculosis and multi-drug resistant tuberculosis fast action urged to halt deadly tb centers for disease control and prevention (cdc). cdc investigation of traveler with extensively drug-resistant tuberculosis (xdr tb): questions and answers for passengers and flight crew on affected flights health issues of air travel the microbiological composition of airliner cabin air tuberculosis and air travel: guidelines for prevention and control an outbreak of influenza aboard a commercial airliner exposure of passengers and flight crew to mycobacterium tuberculosis on commercial aircraft transmission of mycobacterium tuberculosis associated with air travel transmission of multidrug-resistant mycobacterium tuberculosis during a long airplane flight exposure to mycobacterium tuberculosis during air travel fact sheet: legal authorities for isolation and quarantine man with drug-resistant tb locked up. usa today we'll get nowhere on tb till we tackle it everywhere. houston chronicle key: cord-285569-ei9w19i7 authors: shah, aditya; kashyap, rahul; tosh, pritish; sampathkumar, priya; o’horo, john c. title: guide to understanding the 2019 novel coronavirus date: 2020-02-28 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.02.003 sha: doc_id: 285569 cord_uid: ei9w19i7 nan a cluster of cases of pneumonia caused by a novel coronavirus, covid-19, was first reported in wuhan in the hubei province in china in late december 2019. since then, several thousand cases have been reported in mainland china, with spread to over two dozen countries. although many comparisons to other coronavirus epidemics have been made, the potential impact of this coronavirus is uncertain. we seek to summarize what is known about covid-19, compare this epidemic to prior coronavirus outbreaks, and provide a primer on novel coronaviruses for practicing clinicians. coronaviruses are widespread among mammals and birds. the widest varieties of genotypes infect bats, but 2 subtypes infect humans: alpha and beta coronaviruses. 1 beta coronaviruses include severe acute respiratory syndrome coronavirus (sars-cov), middle east respiratory syndrome coronavirus (mers-cov), and the coronavirus variant covid-19 virus first described in wuhan. in humans, these coronaviruses have short incubation periods, ranging from days for sars-cov and weeks for mers-cov, with the covid-19 appearing to fall in between the two. 2, 3 although information about the covid-19 is emerging, sars-cov and mers-cov provide some context for understanding the public health significance of coronaviruses. sars-cov was first noted in the guangdong province of china in november 2002. 4, 5 the index case was a physician from that province who then traveled to hong kong and infected several others. subsequently, sars-cov resulted in over 8000 cases and approximately 750 deaths occurred worldwide over the next several months. the outbreak finally ended in july 2003. [4] [5] [6] severe acute respiratory syndrome coronavirus typically presented with fever and symptoms of lower respiratory tract infection with radiographic evidence of pneumonia or acute respiratory distress syndrome (ards). sars-cov disproportionately impacted health care workers (hcws) in countries with the most reported cases. however, in countries with relatively few cases, transmission was much rarer. this finding suggests that infection control measures are adequate to interrupt transmission to hcws, but consistency is critical because the greater number of opportunities for lapses in the hardest hit centers likely led to more hcw infections. 7 the incubation period of sars-cov is between 2 and 10 days. 8 diagnosis is based on polymerase chain reaction testing. treatments attempted included corticosteroids and ribavirin, which were not found to be beneficial. supportive care remains the cornerstone of care for sars-cov, although in vitro studies suggest that antivirals developed in the wake of the ebola virus epidemic may inhibit sars-cov replication as well. 9 mers-cov mers-cov was first reported in september 2012. 10 the virus was isolated from sputum of a man in saudi arabia hospitalized with a respiratory tract infection. 10 since then, more than 2400 cases of mers-cov have been reported to the world health organization (who) in and around the arabian peninsula. 11 periodic infections and localized outbreaks have continued. similar to sars-cov, presentation is typically fever with symptoms of lower respiratory tract infection and radiographic evidence of pneumonia or ards. other manifestations might include renal failure, anorexia, nausea, vomiting, diarrhea, abdominal pain, and disseminated intravascular coagulation. again, hcws were disproportionately infected, although a large number of those cases were mild or asymptomatic. 7 the incubation period of mers-cov ranges from 1 to 14 days. diagnosis is made by identifying the virus in respiratory samples by polymerase chain reaction testing. treatment is largely supportive, 11 focusing on management of complications of sepsis and ards in intensive care units. antivirals such as ribavirin and interferonbased treatments have had questionable benefit, but the role for these treatments remains experimental. 12 epidemiology most recently, a novel strain of the coronavirus, covid-19, was identified in wuhan, a city in the hubei province of china. 3 initial cases were associated with a seafood market that also sold live animals. 2 the seafood market was shut down and disinfected to contain what was thought to be a zoonotic infection, ie, one that is transmitted from animals to humans. despite this intervention, the reported number of persons infected increased rapidly, and on january 21, 2020, chinese health authorities first reported human-tohuman transmission including transmission to hcws. since then, case counts have been increasing rapidly. 13 cases have now been reported outside mainland china, with the spread of cases internationally to several countries in asia, europe, north america, and to australia. person to person transmission has been reported to family members, other close contacts, and to hcws. initial reports suggest an incubation period similar to the incubation period of sars-cov and mers-cov. 2 the clinical features are also rather similar to these viruses: fever, cough, chest tightness, dyspnea, and difficulty breathing. 14, 15 severe cases with ards have been reported, with this being a leading reason for admission to the intensive care unit. 2 gastrointestinal symptoms have been reported in 10% of cases, a higher proportion than seen with other coronaviruses. the novel coronavirus also is associated with fewer upper respiratory tract symptoms and lower respiratory symptoms than other coronaviruses. 14 fever is a prominent symptom, present in 98.6% of cases. 16 between 20% and 25% require intensive care unit admission. patients admitted to icu had higher serum white blood cell counts, lower serum albumin, liver function test disorders, and higher d-dimer. 14 significantly, severe cases appear to cluster in the elderly, and thus far, severe disease has not been widely reported in children. 16 the centers for disease control and prevention (cdc) has issued interim guidance for hcws. 17 novel coronavirus should be suspected if patients meet the criteria described in table 1 . the who uses similar criteria for case identification. the current approach includes early diagnosis and identification, prevention of spread, and management of complications. 18 optimal supportive care with appropriate isolation and infection control precautions are cornerstones of treatment. health care professionals who encounter suspected cases should contact local infection control and public health offices regarding potential cases and appropriate next steps based on regional resources and protocols. many unknowns remain regarding covid-19. the exact mode of transmission has not been established. it appears that most transmission occurs by droplet spread, ie, large droplets that are generated when a patient coughs or sneezes. protection against this type of transmission involves use of face masks with eye protection, gloves, gowns, and hand hygiene. there is concern that airborne transmission may also be playing a role. this possibility is more problematic because airborne infectious particles can remain suspended in the air for long periods, the infection can be transmitted to larger numbers of people including those not in close contact with the index case, and protective measures include wearing a respirator and patient placement in negative air pressure rooms that may not be available at all medical centers. at the present time, the cdc recommends a combination of airborne precautions (patient placement in a negative air pressure room, hcws to wear respirators), contact precautions (hcws to wear gloves and gowns for all patient contact), and use of eye protection for patients hospitalized with suspected covid-19 infection. an initial report suggested transmission from an asymptomatic individual to several other people who attended business meetings with the index case. this has since been reported to be inaccurate. 19 table 2 presents a comparison of clinical symptoms of the 3 coronavirus strains that have caused worldwide outbreaks. as more cases are identified, the epidemiology and clinical characteristics of this disease will be better elucidated. the release of the viral genome sequence has made it possible for the cdc to create a rapid molecular diagnostic test for covid-19. the test received expedited approval from the fda and the test is being made available to state health departments and selected commercial laboratories. at this time the test is only performed at the cdc but it is likely that the test will be made available at several state health departments in the near feature. the currently available diagnostic tests for other coronaviruses (eg, filmarray respiratory panel [biofire diagnostics]) do not detect the covid-19. because of the potential for transmission to laboratory workers from patient specimens, the cdc recommends that laboratory workers use a class 2 biological safety cabinet and personal protective equipment when processing specimens with potential to generate fine particulate matter. decontamination of work surfaces and equipment with environmental protection agencyeregistered hospital disinfectant is of paramount importance. 21 when transporting suspected case specimens, the international air transport association guidelines for dangerous goods must be followed. 21 response and public health impact chinese officials closed the fish market initially suspected as the source of the virus on january 1, 2020. on january 20, china china was initially lauded for its efforts to control the outbreak, including the construction of a 1000 bed medical facility in less than 10 days. more recently, the death of a chinese physician li wenlinag, who was reprimanded by chinese authorities for sounding the alarm about a cluster of pneumonia in december, has rekindled misgivings about how china is handling the situation. at the time of this report, there have been more than 35,000 confirmed cases of covid-19, with more than 800 confirmed deaths (figure) . 27, 28 deaths appear to be occurring predominantly in the elderly, with a median age of 75 years in reported cases, but lately, younger patients have died as well. mayo clin proc. n xxx 2020;nn(n):1-7 n https://doi.org/10.1016/j.mayocp.2020.02.003 www.mayoclinicproceedings.org of china. in addition to the suffering and loss of life, the impact on the global supply chain is likely to be very significant as china as a whole, and wuhan in particular, are major manufacturing hubs. there are fears that we are on the verge of a global pandemic. we are better prepared today than we have ever been in the past to limit the spread of infections in health care facilities in the united states. the cdc has provided conservative guidance on infection control measures to be used for a patient with the covid-19 infection, but this is dependent on early recognition. there are no specific features that distinguish this infection from other respiratory viral infections. following standard precautions, a set of infection control principles that recommend common sense precautions, including providing a mask to persons with a cough in outpatient settings, promoting hand hygiene, and asking sick individuals to maintain social distancing, are key to controlling rapid spread of the covid-19 and all respiratory infections in general. middle east respiratory syndrome coronavirus: another zoonotic betacoronavirus causing sars-like disease estimating the potential total number of novel coronavirus (covid-19) cases in wuhan city novel coronavirus (covid-19). world health organization website severe acute respiratory syndrome the severe acute respiratory syndrome summary of probable sars cases with onset of illness from 1 lack of sars transmission among healthcare workers, united states sars: epidemiology, clinical presentation, management, and infection control measures coronavirus susceptibility to the antiviral remdesivir (gs-5734) is mediated by the viral polymerase and the proofreading exoribonuclease. mbio isolation of a novel coronavirus from a man with pneumonia in saudi arabia middle east respiratory syndrome: what clinicians need to know middle east respiratory syndrome investigating an outbreak. centers for disease control and prevention website clinical features of patients infected with 2019 novel coronavirus in wuhan a novel coronavirus from patients with pneumonia in china clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan, china novel coronavirus: interim guidance for healthcare professionals. centers for disease control and prevention website world health organization. infection prevention and control. world health organization website transmission of 2019-ncov infection from an asymptomatic contact in germany human-to-human transmission confirmed in china coronavirus estimates of sars death rates revised upward interim laboratory biosafety guidelines for handling and processing specimens associated with 2019 novel coronavirus (covid-19) cnhubei website statistics of key performance indicators for china's civil aviation industry in coronavirus: what airport measures are in place to detect sick passengers? the guardian website us confirms first case of china virus as death toll reaches six. international business times website coronavirus: a visual guide to the outbreak china coronavirus death toll climbs to 106 as government scrambles to contain outbreak. nbc news website key: cord-325938-hb6fvgem authors: dobler, claudia c.; murad, m. hassan; wilson, michael e. title: non-invasive positive pressure ventilation in patients with covid-19 date: 2020-10-08 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.10.001 sha: doc_id: 325938 cord_uid: hb6fvgem nan much of the debate around the coronavirus disease 2019 pandemic in the popular press has focused on invasive (via endotracheal tube or tracheostomy) ventilation of severely sick patients and potential ventilator shortages. amid increasing concerns of medical professionals about the harms associated with invasive ventilation, there is interest to explore the role of non-invasive positive pressure ventilation (nippv) in the treatment of acute hypoxemic respiratory failure (ahrf) and acute respiratory distress syndrome (ards) due to in this commentary we aim to summarize what is known about the role of nippv in patients with ahrf and ards due to covid-19 and other viral infections, point out evidence gaps and make a case for consideration of nipvv as a possible alternative to early intubation in patients with covid-19. aims to limit intubations are mainly based on concerns about ventilator-induced lung injury and the recognition that the pathophysiological and anatomical features of covid-19 related lung infection are different from classic ards, for which invasive mechanical ventilation is considered the standard of care. covid-19 is primarily causing injury to the capillary endothelium instead of essential injury to the alveolar epithelium. 1 lungs affected by covid-19 show marked ventilation-perfusion mismatch but preserved compliance, 2 making the recruitment maneuver and the use of high positive end-expiratory pressure potentially deleterious. the risk of ventilator-induced lung injury in patients with covid-19 is further increased by the lack of specialized personnel (e.g. shortage in respiratory therapists and intensivists) and the lack of appropriate equipment (e. g. use of devices used for chronic mechanical ventilation, use of a single device for several patients). j o u r n a l p r e -p r o o f nippv includes treatment with continuous positive airway pressure (cpap) and bilevel positive airway pressure (bipap). 3 cpap is useful in ahrf, as it recruits collapsed alveoli, improves ventilation-perfusion matching, and therefore oxygenation. bipap is useful for the treatment of hypercapnic respiratory failure, as it supports ventilation by using a different level of in-and expiratory continuous airway pressure, thus increasing tidal volume and minute ventilation. patients with covid-19 pneumonia and ards typically have severe hypoxemia and relatively well preserved lung mechanics. 2 it is therefore reasonable to assume that patients with covid-19 will benefit from cpap therapy. however, as many patients with covid-19 and severe respiratory failure are obese and may therefore have risk factors for hypercapnia including obstructive sleep apnea and obesity hypoventilation syndrome, bipap therapy should be considered on a case-by-case basis. guideline recommendations on the use of nippv in covid-19 vary widely (table 1) prone positioning has been shown to reduce mortality in severe ards. 13 there is emerging evidence that prone positioning is beneficial in patients with ards due to covid-19, and that nippv can be provided to these patients in the prone position in a general ward. 14 nippv has been widely used in china and some european countries during the current pandemic, but to date there is insufficient evidence to support this use. an italian retrospective chart review study of patients with covid-19 found that of 71 patients on helmet cpap, 26 (37%) were intubated and 54 (76%) died (before or after intubation). the availability of ventilators was limited in the study setting, thus not allowing for a comparison between cpap use and early intubation. nippv was commonly used during the severe acute respiratory syndrome (sars) epidemic in china that emerged in 2002, but only four small observational studies that mention nippv are available, 17 one of which focused on the nosocomial infection risk and included only two patients on bipap. 18 another study did not specify the ventilation type that was used and did not evaluate outcomes in patients on nippv. 19 in the two remaining studies, both from hong kong, bipap treatment was used in all patients on nippv. 20, 21 intubation was avoided in 14 out of 20 (70%) patients on bipap and was associated with a shorter icu stay (3.1 days vs 21.3 days, p < 0.001) compared with intubated patients in one study. 20 it was, however, j o u r n a l p r e -p r o o f unclear if early intubation as opposed to bipap use would have resulted in better outcomes, especially for the patients who required intubation despite treatment with bipap. the other study assessed the outcomes in patients with sars in one hospital that used bipap as initial ventilatory support compared with outcomes in 13 hospitals in which only invasive mechanical ventilation was used. 21 patients in the hospital using bipap did not significantly differ from the patients in the hospitals not using any nippv in terms of demographic characteristics, co-morbidities and disease severity on admission apart from significantly higher lactate dehydrogenase levels in the patients admitted to the nippv hospital. patients in the nippv hospital had lower adjusted odds ratios (ors) for intubation (or 0. 36; 95% ci 0.16 -0.79) and death (or 0. 24; 95% ci 0.08 -0.72) compared with patients in the hospitals only using mechanical ventilation. a systematic review identified 22 studies conducted on the use of nippv during the 2009 influenza a pandemic caused by the swine influenza (h1n1) virus, of which the majority were case series and none were randomized trials. 17 in a spanish registry study of 685 patients with h1n1 pneumonia 177 patients were treated with nippv (specific type of ventilation not specified), which was successful in 72 patients (41%); the remainder of patients required intubation. when nippv treatment failed, the delay in intubation was not associated with increased mortality compared with patients who were intubated without a trial of nippv (26.5% versus 24.2%, p <0.001). 22 the lack of randomization introduces selection bias. patients who were directly intubated were likely sicker than those treated with nippv initially, and it is therefore unclear whether in comparable patients failure of nippv would not increase mortality compared with early intubation. in summary, there is insufficient evidence about the effectiveness of nippv in ahrf due to viral pneumonia. observational studies suggest that the use of nippv has the potential to reduce the need for intubation. it is unclear whether patients in whom nippv treatment fails would have had better outcomes if they would have been intubated earlier without a trial of nippv. patients who can overcome severe covid-19 without requiring intubation will benefit from avoiding sedation, inability to communicate, potential delirium and posttraumatic stress disorder. table 2 gives an overview of potential benefits and disadvantages of different breathing support strategies in acute respiratory failure. high flow nasal cannula (hfnc) is an emerging therapy for ahrf that can warm and humidify gas, which can decrease airway inflammation, improve mucus clearance and enhance patient comfort. hfnc can deliver a 21% to 100% fraction of inhaled oxygen at flow rates of up to 60 liters/min and generates a positive end-expiratory pressure which prevents alveolar collapse. there is currently no available evidence to assess the effectiveness of hfnc compared with standard oxygen or cpap. a european multicenter trial of 310 patients with ahrf (caused by pneumonia in 84% of the patients) found that treatment with hfnc, standard oxygen, or nippv did not result in significantly different intubation rates. hfnc was associated with lower 90-day mortality j o u r n a l p r e -p r o o f than either standard oxygen or nippv. 23 this could potentially suggest a role for hfnc in patients with ahrf due to covid-19. recommendations against the use of nippv and/or hfnc in patients with ahrf due to covid are at least partially based on concerns about virus spread in aerosols produced by these procedures. however, very little is known about the risk of viral transmission associated with different aerosol generating procedures. a systematic review found that tracheal intubation had a significantly higher risk of transmission of acute respiratory infections to healthcare professionals (or 6.6, 95% confidence interval [ci] 2.3 to 18.9, 4 cohort studies) than nippv (pooled or 3.1, 95% ci 1.4 to 6.8, 2 cohort studies). 24 a study that used laser smoke visualisation to assess dispersion distances during aerosol producing procedures using a human patient simulator found that the maximum exhaled air dispersion distance was greatest (100 cm) using a nasal cannula at an oxygen flow rate of 5litres/min while there was only negligible air dispersion with the use of cpap via oronasal mask at a pressure of 20 cmh 2 o. 25 the risk of viral transmission with nippv can be significantly reduced with the use of a filter on the expiratory circuit and the automatic measurement and quantification of a leak at the interface (which allows prompt leak correction and reduction of virus dispersion). although intubation is associated with a high risk of viral transmission, the risk can be reduced by techniques of apneic oxygenation and rapid sequence intubation with paralysis. invasive mechanical ventilation has a reduced risk of viral transmission compared with nippv once a closed ventilation circuit is established. in summary, there is insufficient evidence to determine whether cpap and hfnc are associated with a higher viral transmission risk than standard oxygen delivered via nasal cannula or different mask types, especially when relatively high oxygen flow rates are used. the use of filters on the expiratory circuit of nippv may indeed result in lower viral transmission rates with nippv than with the use of standard oxygen or hfnc. precautions to minimize transmission from aerosol-generating procedures in covid-19 patients are warranted, including the use of negative-pressure rooms, personal protective equipment including a respirator that ensures a level of protection equal or greater than n95/ffp2 and the use of viral/bacterial filters with any devices. on july 1, 2020, only 12 studies (including five randomized trials) that investigate nippv in covid-19 were registered on clinicaltrials.gov. this compares to a total of 2447 registered studies using the term "covid". the table in the supplement provides an overview of all identified studies and their characteristics. a us randomized trial assesses the effectiveness of cpap treatment at home compared with no intervention in patients with presumed or confirmed covid-19 who are sent home from the emergency room with mild pneumonia or respiratory illness. one randomized trial from the us and sweden respectively compares helmet cpap with hfnc; whereas an italian trial compares helmet cpap with no intervention. a french trial compares the effectiveness of standard oxygen, cpap, hfnc, and invasive ventilation while also assessing the effectiveness of dexamethasone versus placebo using a factorial design. in the absence of sufficient evidence and pending trial results, nippv should be considered as an alternative to early intubation, and the type of nippv should be based on case-by-case decision making that takes into account a patient's characteristics (e.g. the ability to independently move into a prone position) and co-morbidities (e.g. obstructive sleep apnea or chronic obstructive pulmonary disease). there is currently insufficient evidence to assess the effectiveness of hfnc compared with nippv in covid-19. safety concerns around aerosol spread of sars-cov-2 during nippv treatment make such trials difficult to conduct. nevertheless, evidence from large well-conducted randomized trials is urgently needed because future pandemics with other viral pneumonias are likely. these trials should address the effectiveness of nipvv compared with early intubation and hfnc, and the risk of viral transmission to health care workers when patients are using different breathing support strategies. the authors have no conflicts of interests to disclose. , intubation with sedation may better facilitate patient undergoing certain procedures or transporting to a different medical facility (e.g. patient cannot lie flat for a computed tomography scan) • requires specialist care in the intensive care unit (physician, nurses, respiratory therapists) • often requires sedation, inability for patient to communicate and may have increased association with delirium and posttraumatic stress disorder • may be associated with longer hospitalization and higher mortality compared to patients who have avoided intubation on nippv d • risk of vocal cord damage, procedural hypotension, and other adverse effects directly associated with placement of an endotracheal tube • potential for lung injury associated with positive endexpiratory pressure • high risk of viral transmission during intubation (can be limited by techniques of apneic oxygenation and rapid sequence intubation with paralysis) and also during pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid-19 covid-19 does not lead to a "typical" acute respiratory distress syndrome association of home noninvasive positive pressure ventilation with clinical outcomes in chronic obstructive pulmonary disease: a systematic review and meta-analysis surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (covid-19) guidance for the role and use of non-invasive respiratory support in adult patients with covid19 (confirmed or suspected) national institutes of health (nih). covid-19 treatment guidelines. oxygenation and ventilation clinical management of severe acute respiratory infection (sari) when covid-19 disease is suspected. interim guidance covid-19: interim guidance on management pending empirical evidence. from an american thoracic society-led international task force infectious diseases society of america guidelines on the treatment and management of patients with covid-19 use of non-invasive ventilation for patients with covid-19: a cause for concern? the lancet respiratory medicine prone positioning in severe acute respiratory distress syndrome respiratory parameters in patients with after using noninvasive ventilation in the prone position outside the intensive care unit severity of respiratory failure and outcome of patients needing a ventilatory support in the emergency department during italian novel coronavirus sars-cov-2 outbreak: preliminary data on the role of helmet cpap and non-invasive ventilation (3/30/2020) severity of respiratory failure and outcome of patients needing a ventilatory support in the emergency department during italian novel coronavirus sars-cov2 outbreak: preliminary data on the role of helmet cpap and non-invasive positive pressure ventilation noninvasive mechanical ventilation in high-risk pulmonary infections: a clinical review transmission of severe acute respiratory syndrome during intubation and mechanical ventilation a retrospective study on clinical features of and treatment methods for 77 severe cases of sars effectiveness of noninvasive positive pressure ventilation in the treatment of acute respiratory failure in severe acute respiratory syndrome non-invasive versus invasive mechanical ventilation for respiratory failure in severe acute respiratory syndrome early non-invasive ventilation treatment for severe influenza pneumonia high-flow oxygen through nasal cannula in acute hypoxemic respiratory failure aerosol generating procedures and risk of transmission of acute respiratory infections to healthcare workers: a systematic review protecting healthcare workers from sars-cov-2 infection: practical indications. european respiratory review : an official journal of the for adults with covid-19 f and acute hypoxemic respiratory failure despite conventional oxygen therapy, we suggest using over conventional oxygen therapy (weak recommendation, low quality evidence). in adults with covid-19 f and acute hypoxemic respiratory failure, we suggest using hfnc g over nippv i (weak recommendation, low quality evidence). in adults with covid-19 f and acute hypoxemic respiratory failure, if hfnc g is not available and there is no urgent indication for endotracheal intubation, we suggest a trial of nippv i with close monitoring and short-interval assessment for worsening of respiratory failure (weak recommendation, very low-quality evidence). key: cord-303747-o09canse authors: bennett, courtney e.; anavekar, nandan s.; gulati, rajiv; singh, mandeep; kane, garvan c.; sandoval, yader; foley, thomas a.; jaffe, allan s.; sandhu, gurpreet s.; bell, malcolm r.; askew, j. wells title: st-segment elevation, myocardial injury, and suspected or confirmed covid-19 patients: diagnostic and treatment uncertainties date: 2020-04-11 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.04.005 sha: doc_id: 303747 cord_uid: o09canse nan coronavirus disease 19 (covid-19) is caused by severe acute respiratory syndrome coronavirus 2 (sars-cov-2) and has resulted in a global pandemic with considerable morbidity and mortality. 1-3 multiple studies have noted both increased susceptibility in patients with underlying cardiovascular disease to covid-19, as well as severe cardiovascular sequelae in covid-19 infected patients including acute myocardial injury, arrhythmias, and shock. 3, 4 in addition, there have been several reports of stsegment elevation (ste) in patients with covid-19 who do not have evidence for obstructive coronary artery disease (cad) on invasive coronary angiography. 5, 6 the impact of "false" catheterization laboratory activation includes multiple inherent risks arising from the following: an invasive arterial procedure and adjunctive antithrombotic administration for these patients; the exposure of personnel during transfers; and possible respiratory failure in patients with covid-19 and subsequent aerosolized generating procedures during resuscitation and intubation. the downstream effects of inadvertent exposure and contamination may not be trivial and could result in critical isolation of exposed staff. the potential effects may result in staffing shortages leading to slowed or even closed cardiac catheterization or other cardiac imaging services, especially in smaller facilities. conversely, it remains critically important to provide timely, emergent reperfusion therapy in patients experiencing an acute myocardial infarction due to acute coronary occlusion. 7 thus there is an urgent need for an april 7, 2020 st-segment elevation, myocardial injury, and covid-19 algorithm that facilitates triage of suspected or proven covid-19 patients with ste toward initial invasive or noninvasive pathways. the reported experiences, published and unpublished (correspondence, ad hoc webinars and social media), from countries in which significant exposure to covid-19 has occurred highlight the enormous challenges with regard to the evaluation and treatment of patients with covid-19 and ste on the electrocardiogram. these experiences emphasize the need for health care facilities to rapidly prepare and configure their own stemi systems of care in anticipation of treating increasing numbers of covid-19 patients whose clinical course is complicated by the appearance of ste on their electrocardiogram. it is within this context that we offer this background information and proposal of algorithms for the evaluation and treatment of these patients. acute myocardial injury (rise and/or fall of troponin with at least one value >99 percentile upper reference limit) 8 is common among patients with acute respiratory infections and correlated with disease severity. 9, 10 abnormal high sensitivity troponin (hs-ctn) values are common in patients with covid-19 and are significantly higher in non-survivors. 3, 11 the mechanisms for these ctn elevations are incompletely understood, but likely reflect underlying cardiac comorbidities and potentially, acute myocardial injury due to direct, toxic ("non-coronary") myocardial damage, critical illness, cytokine storm, heat shock proteins or stress cardiomyopathy. all of these mechanisms can occur in patients with april 7, 2020 st-segment elevation, myocardial injury, and covid-19 acute respiratory failure and/or systemic infections from a variety of etiologies. 8, 12 marked alterations in myocardial oxygen consumption and supply-demand mismatch, with or without bystander concomitant atherosclerotic coronary artery disease, can lead to type 2 myocardial infarction. 8, 12 type 2 mi is typically treated with non-invasive medical management. 12 however, on occasion, type 1 myocardial infarction related to atherosclerotic plaque disruption can be triggered by the inflammatory milieu caused by a respiratory infection, [13] [14] [15] typically necessitating invasive stabilization. in the absence of ste or hemodynamic instability, many of these events probably can be managed medically. the incidence of acute myocardial infarction (including mi subtypes) in covid-19 is unknown, although the sparse ecg data that are available suggests that acute ischemic events are uncommon. it is critical to understand that increased ctn concentrations are common in patients with acute illnesses such as covid-19, particularly when using hs-ctn assays in whom modest elevations exist in many adults with comorbidities for varied reasons. 4, 8, 11 the recent diagnostic guidelines for acute myocardial infarction emphasize that a significant change in ctn is insufficient for the diagnosis of mi. the significant change in troponin must be accompanied by clinical evidence of overt myocardial ischemia. 8 the subsequent pathways emphasize the critical importance of clinical assessment of patients presenting with ste and the necessity of establishing clinical evidence of myocardial ischemia before rushing such patients to the catheterization laboratory. april 7, 2020 st-segment elevation, myocardial injury, and covid-19 the approach to ste in patients with suspected or confirmed covid-19 can be challenging for the previous reasons we have described. ste may occur from atherothrombotic type 1 mi or type 2 mi including vasospasm, but recent reports suggest that ste can occur from covid-19 related myopericarditis. 6 to facilitate diagnosis and management, we created a multi-disciplinary working group of experts in cardiac acute critical care, ischemic heart disease, invasive cardiology and cardiac imaging to propose an algorithm delineated in figure 1 . this algorithm seeks to achieve the following objectives: 1) the accurate identification of patients with type 1 or type 2 mi who would benefit from reperfusion therapy and revascularization; 2) the minimization/avoidance of unnecessary exposure of covid-19 patients to invasive care and pharmacological management that may result in clinical harm; and 3) a strategy to wisely utilize resources and avoid unnecessary exposure to a potentially fatal infectious agent. the proposed algorithm (figure 1 ) is a basic, high-level decision aid for acute management of ste in patients with suspected or proven covid-19. an important aspect of care in managing covid-19 patients is to minimize the patient's footprint in the inpatient environment in order to reduce risks to both the patient and to others including health care workers, hospital patients and physicians. this approach, however, must be balanced against the need for a rapid and precise diagnosis in covid-19 patients with ste due to an acute myocardial infarction in order for timely and appropriate reperfusion therapy including coronary revascularization to be implemented when appropriate. we recommend considering an approach that takes april 7, 2020 st-segment elevation, myocardial injury, and covid-19 into account severity of illness coupled with risk stratification utilizing cardiac imaging in select cases to assess the potential benefit from coronary revascularization rather than a blanket policy of proceeding with diagnostic catheterization, often triggered by prehospital ecg testing, for all ste patients with suspected or known covid-19. we recognize that strategies will vary depending on the specifics and capabilities/resources at any given institution and may reflect some ethical concerns for health care staff. our current approach in patients with a high suspicion for acute coronary occlusion who are candidates for coronary angiography with an expected benefit from coronary artery revascularization is to continue with the standard pre-hospital or emergency department (ed)-triggered stemi activation of the cardiac catheterization laboratory (ccl) for anticipated primary percutaneous coronary intervention. protection of the ccl team is of paramount importance and rigorous covid-19 ccl protocols should be followed to protect individuals from airborne, droplet, and contact infectious sources, given the potential high risk of aerosolized generating procedures. 16 the strategy at our institution is to continue primary pci for most patients, with occasional fibrinolytic therapy as per our normal ste pathways, 17 rather than adopt a strategy of preferential fibrinolytic therapy in suspected or known covid-19 patients. we recognize that revascularization strategies may evolve based on the covid-19 impact on the ccl availability. on the other end of the spectrum, there will be covid-19 positive patients with severe respiratory and multisystem organ failure who are less likely to derive substantial benefit from emergent coronary angiography and revascularization because of the potentially higher likelihood of myopercarditis. we acknowledge it will be difficult not to activate the april 7, 2020 st-segment elevation, myocardial injury, and covid-19 ccl team in these patients, despite the identification of ste. we recommend a multidisciplinary team review acutely if there is any doubt about the likelihood of type 1 mi. a similar approach should be considered for those with cardiac arrest and/or cardiogenic shock in whom clinical history is ambiguous. there may be uncertainty regarding the likelihood of acute coronary occlusion in covid-19 patients with ste within that spectrum because of any one of the following considerations: (1) the clinical presentation is not consistent with acute ischemic symptoms; (2) the only cardiopulmonary symptom is dyspnea in the setting of a presumptive respiratory infection with or without radiographic findings consistent with covid-19; or (3) there is a paucity of traditional risk factors for cad. in these scenarios, taking additional time to consider the value of upstream (pre-ccl stemi activation) adjunct cardiac imaging including echocardiography or coronary ct angiography (ccta) may reduce unnecessary ica and thus ccl exposure to a highly contagious virus. the selection of the particular imaging modality should be chosen based upon patient factors such as age, renal function, body habitus, hemodynamics, and prior surgical and/or pci history. the decision on using a focused and rapid goal-directed transthoracic echocardiogram and/or a ccta in patients admitted to the ed or the icu will be predicated on multiple factors apart from the estimated likelihood of a primary acute ischemic event; these include patient symptoms, hemodynamic stability, availability and proximity of the april 7, 2020 st-segment elevation, myocardial injury, and covid-19 imaging studies to the ed, as well as time to image acquisition, study completion and interpretation. a goal-directed echocardiogram focusing on left ventricular systolic function and regional wall motion analysis performed in the ed or icu can be instrumental in the decision of ccl activation for ste, assuming the study can be efficiently completed. if regional wall motion abnormalities in a coronary distribution are present, then expedited ccl activation should be considered if the expected benefit from revascularization is estimated to outweigh the risk of deterioration from other non-cardiac related illness. importantly, if there is concern for progressive respiratory failure, we suggest early intubation in a setting that minimizes risks of aerosolized material with subsequent exposure to hospital staff should occur and mechanical ventilation initiated in the emergency department or intensive care unit as opposed to the ccl. if there is profound diffuse left ventricular or biventricular systolic dysfunction, it may be reasonable to consider ccta to further delineate coronary anatomy versus continued supportive care. in many healthcare systems the role of ccta in the immediate evaluation of ste in suspected or confirmed covid-19 will be limited due to patient factors as well as constraints on time to study completion and interpretation. however, there are hospitals with a robust ccta practice which are located in close proximity to the ed practice and can be expeditiously performed and interpreted by a cardiac radiologist or cardiologist. the role of ccta is likely to be limited in the evaluation of ste, but in specific cases april 7, 2020 st-segment elevation, myocardial injury, and covid-19 may add tremendous value in assessing coronary anatomy and determining the radiographic extent of lung involvement. however, the availability of ccta needs to be considered in this context and may not be suitable in older patients who may have significant coronary calcification, for those who have severe tachycardia or tachypnea, and for those who are hemodynamically unstable. on balance a goal-directed echocardiogram may be clinically and logistically easier to obtain and result in less exposure to hospital staff. the value of a focused echocardiogram is highly dependent on the skills of both the sonographer and the interpreting echocardiographer as accurate evaluation of left ventricular regional wall motion abnormalities can be challenging even for an expert level echocardiographer. while point-of-care ultrasound (pocus) it an excellent tool in the management of the acutely ill including those with covid-19 infection, we do not recommend its use in this setting as the characterization of regional wall motion abnormalities is typically beyond the scope of most pocus users. however, we strongly advise that the choice of echocardiography should be predicated upon the availability of this service on a very rapid basis, and upon the presence of an advanced sonography/physician team who can perform and interpret myocardial enhancement +/-perfusion echo imaging as a way to better evaluate wall motion and ventricular function. 18 myocardial injury in the setting of covid-19 should be expected as there are observed cases of type 1 or 2 myocardial infarction in the setting of acute infectious viral illnesses. april 7, 2020 st-segment elevation, myocardial injury, and covid-19 of ste without obstructive coronary disease, which creates diagnostic and management challenges . 5 although the frequency of ste in covid-19 remains unclear, it is important for institutions to define acute cardiac care pathways which balance the risks of complicating covid-19 patients from invasive therapies and unnecessary contrast exposure versus the potential benefit if the patient is experiencing a mi from acute coronary occlusion. the principle of "first, do no harm" should apply to patient care and to the workplace in the ccl and hospital. the potential risk of a false positive ste with ccl activation and exposure of ccl staff to a highly infectious agent must be taken in consideration as institutions and hospitals grapple with the need for patientcentered, ethical care. we believe that the strategy we propose will create slight delays in low probability patients, which reduce risks to patients and hospital staff, while allowing for invasive care if the diagnosis of a stemi or type 1 mi is rapidly established. clinical course and outcomes of critically ill patients with sars-cov-2 pneumonia in wuhan, china: a single-centered, retrospective, observational study characteristics and outcomes of 21 critically ill patients with covid-19 in washington state clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan association of cardiac injury with mortality in hospitalized patients with covid-19 in wuhan, china coronavirus fulminant myocarditis saved with glucocorticoid and human immunoglobulin cardiac involvement in a patient with coronavirus disease 2019 (covid-19) accf/aha guideline for the management of stelevation myocardial infarction: a report of the american college of cardiology foundation/american heart association task force on practice guidelines significance of elevated cardiac troponin t levels in critically ill patients with acute respiratory disease clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study cardiac troponin i in patients with coronavirus disease 2019 (covid-19): evidence from a meta-analysis type 2 myocardial infarction: jacc review topic of the week acute myocardial infarction and influenza: a meta-analysis of case-control studies role of acute infection in triggering acute coronary syndromes influenza as a trigger for acute myocardial infarction or death from cardiovascular disease: a systematic review considerations for cardiac catheterization laboratory procedures during the covid-19 pandemic perspectives from the society for cardiovascular angiography and interventions emerging leader mentorship (scai elm) members and graduates regional systems of care to optimize timeliness of reperfusion therapy for st-elevation myocardial infarction: the mayo clinic stemi protocol. circulation american society of echocardiography guidelines update the authors would like to thank gayle flo, aprn, cnp for her contributions to our perspective. april 7, 2020 st-segment elevation, myocardial injury, and covid-19 april 7, 2020 st-segment elevation, myocardial injury, and covid-19 kwong, j.c., k key: cord-319023-ucm8frol authors: nuzzo, andrea; tan, can ozan; raskar, ramesh; desimone, daniel c.; kapa, suraj; gupta, rajiv title: universal shelter-in-place vs. advanced automated contact tracing and targeted isolation: a case for 21st-century technologies for sars-cov-2 and future pandemics date: 2020-06-22 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.06.027 sha: doc_id: 319023 cord_uid: ucm8frol abstract objective to model and compare effect of digital contact tracing versus shelter-in-place on sars-cov-2 spread. methods using a classical epidemiologic framework, and parameters estimated from literature published between february 1, 2020 and may 25, 2020, we modeled two non-pharmacologic interventionsshelter-in-place and digital contact tracingto curb spread of sars-cov-2. for contact tracing, we assumed an advanced, automated contact tracing (aact) application that sends alerts to individuals advising self-isolation based on individual exposure profile. model parameters included percentage population ordered to shelter-in-place, adoption rate of aact, and percentage individuals who appropriately follow recommendations. under influence of these variables, number of individuals infected, exposed, and isolated were estimated. results without any intervention, a high rate of infection (>10 million) with early peak is predicted. shelter-in-place results in rapid decline in infection rate at the expense of impacting a large population segment. the aact model achieves reduction in infected and exposed individuals similar to shelter-in-place without impacting a large number of individuals. for example, a 50% aact adoption rate mimics a shelter-in-place order for 40% of the population and results in >90% decrease in peak number of infections. however, as compared to shelter-in-place, with aact significantly fewer individuals would be isolated. conclusion wide adoption of digital contact tracing can mitigate infection spread similar to universal shelter-in-place, but with considerably fewer individuals isolated. in the absence of a vaccine or cure, non-pharmacological interventions are critical to reducing spread of severe acute respiratory syndrome-coronavirus-2 (sars-cov-2). this is primarily accomplished through containment and isolation, such as the universal shelter-in-place order used in many cities and states across the united states. the need for such orders is due to the exponential growth of cases that occur during an outbreak, which generally needs to be countered by a fast, coordinated and widespread response. transmission of sars-cov-2 during asymptomatic infectious periods further complicates this response. 1 asymptomatic infected individuals may not see the need to self-isolate, and it is difficult for public health infrastructure to identify such cases and enforce isolation during this period. 2 contact tracing has the potential to limit spread of infectious diseases. this has been proven in epidemics such as sars, bird flu, middle east respiratory syndrome (mers), and others. 3, 4 traditional contact tracing suffers from the problem of scalability as they are based on phone interviews and record keeping. on the other hand, current technologies permit constant tracking of individuals and locations via mobile phones, global positioning systems (gps), wifi, and bluetooth. a system that leverages these technologies to track and record movement of individuals, and monitor proximity to others for potential exposure, can help overcome difficulties posed by manual contact tracing. many app-based systems -for example, private kit: safepaths (http://safepaths.mit.edu/), covid symptom tracker (https://covid.joinzoe.com/us), and the apple/google collaborative venture (https://www.apple.com/covid19/contacttracing) -are currently being tested. such advanced automated contact tracing (aact) systems -which could infer exposure risk and propagate warnings to people at risk -may help curb disease spread by facilitating targeted self-isolation rather than universal mandates such as shelter-inplace. in this paper, we compare universal shelter-in-place with targeted self-isolation envisioned in aact. with available data pertaining to sars-cov-2 we model strategies for the united states available at https://github.com/andreanuzzo/aact_simulation. our disease model is based on the seir (susceptible, exposed, infected, recovered) model assuming a constant susceptible population. [5] [6] [7] using these data, two separate models were created -aact and universal shelter-in-place. in both, computational methods were used to determine impact in terms of infected individuals and proportion of population impacted by isolation/quarantine orders. modeling and study was performed based on data regarding the pandemic published between february 1, 2020 and may 25, 2020. for the model, we assumed the following: • t inc = incubation period (~5.1 days) 8 ; • t lat = latency period before development of symptoms (~ 11.5 days) 8 ; • basic r 0 = 3.02 9 . preliminary death rate µ = 0.057 (with case fatality ratio of 1.5018%, as estimated by recent global data). 10 further details are summarized in supplemental material. several variables were considered in model development and summarized in figure 1 . compartments included: s (susceptible individuals), e (exposed to infection, unclear symptomatic conditions, potentially infectious), i (infected, confirmed symptomatic and infectious), r (recovered, immune from further infection), and d (death due to sars-cov-2). in aact, an additional compartment sq (traced contacts that are exposed and under selfisolation) was used while for shelter-in-place, the compartment q (individuals isolated through universal enforcement measures) was used. the basic difference between the models is that isolation/quarantine is based solely on exposure history in aact, while isolation orders apply to the entire population in universal shelter-in-place. we assumed that through the aact app, it is possible to inform exposed (asymptomatic/noninfected) individuals of exposure risk. once warned, they may self-isolate and prevent second-order spreading. therefore, self-isolated contacts will depend on penetrance p of the aact app in infected and exposed populations. the equations and details used to build the model are summarized in the supplemental section. two key elements that fall into aact include percentage of individuals adopting (ie, downloading) the app, and percentage who selfisolate in response to an exposure alert. our model assumes that for the fraction of individuals who heed the warning, there is no transmission of sars-cov-2 from exposed individuals to other susceptible individuals. universal shelter-in-place model ( figure 1 , right panel) measures that limit public gatherings or mandate full lockdown uniformly impact the susceptible population. they are successful in isolating a fraction of the population, with the unquarantined transitioning through exposure, infection, recovery or death. such measures, depending on duration of enforcement (assumed to be constant in our model), are independent of percentage of infected population or percentage exposed. the key variable considered is percentage of population that is under shelter-in-place orders. for example, if 100% of the population (including essential personnel) is ordered to stay at home, nobody will be allowed outside and disease transmission will be halted. in real life, percentages far below 100% would be expected. in the current model, we assume shelter-in-place measures will be released after 50 days. all models were created using r (version 3.6.1, 2019), and tidyverse (2017) and stats packages (https://cran.r-project.org). all graphs were created using r. both models agree with each other when adoption of digital contact tracing and universal shelterin-place mandate are close to zero (i.e., p=0 and g=0, where p is adoption rate of aact and g is both shelter-in-place and aact achieve reductions in number of infected cases (table 1) . for example, with 20% adoption and 100% compliance, aact would lower peak number of infected individuals by 49% and cumulative deaths by 23%. enforcing shelter-in-place measures for 30% of the population would almost completely halt sars-cov-2 spread. however, such a measure would quarantine, at peak, more than 71 million people as opposed to isolating approximately 12 million in aact to achieve similar reduction. as can be seen in panels (e) and (f) of figure 2 , the main difference between the models is in societal burden imposed in terms of number of individuals expected to be quarantined or isolated. both adoption of aact (i.e., how many people downloaded the application), and percentage of people who heed the advice of the application (i.e., self-isolate when a warning is issued) are critical to success of digital contact tracing. for example, if 100% of users respond to an exposure alert by self-isolating, lower adoption rates would be sufficient; conversely, lower response rates to alerts require a higher adoption rate in the general population. figure 3a and the supplementary video (https://youtu.be/h6crrfdek4i) summarize this tradeoff for different adoption rates and user response rates over the course of the pandemic. figure 3b offer a graphical representation of percentage of the population impacted at peak as a function of the application adoption rate and user response rate. sars-cov-2 is a global pandemic with variable approaches implemented to address its spread. past experience with spanish flu, sars and mers shows that interventions that limit contact, increase social distance, and reduce exposure risk are essential to "flattening the curve". governments around the world have instituted isolation measures such as shelter-in-place or stay-at-home to achieve these goals. however, universal isolation measures disrupt the fabric of society by hindering social interactions, limiting support for people with disabilities, and exacerbating mental health political discourse refers to the pain and suffering associated with these measures. contact tracing is routinely used for controlling infectious diseases. 11 stochastic mathematical models, and past experience in the swine flu pandemic of 2009 and ebola outbreak of 2014, have shown contact tracing can reduce r 0 by as much as 90%. 11 preliminary studies have shown that, accounting for heterogeneity of social interactions, it may be sufficient to trace 36 contacts per infected person to reduce r 0 for sars-cov-2 from 3.11 to 0.21. 12 contact tracing is not novel, but the exponential nature of the ever-enlarging tree of exposures makes conventional manual contact tracing cumbersome. 13 especially in later stages of an epidemic, an automated or semi-automated solution is required in order to be scalable-a solution that we have dubbed aact. in this paper we compared universal containment against aact, a version of automated contact tracing that is able to recursively enumerate all persons who came into contact with an infected person. aact envisions a system that can instantaneously trace individuals in the exposure network of an index case, and issue warnings to everyone in this network. aact coupled with targeted self-isolation has several advantages over universal containment measures. the obvious advantage is society can still function with a select number of individuals in isolation. this approach also attempts to halt disease spread at the earliest time point after identification of infected individuals. aact enables first or second order exposures to isolate and limit further disease spread even when not showing symptoms. therefore, it enables remedies that may work in the pre-symptomatic stage. from the point of view of public health officials, aact may provide an early estimate of exposure risk and disease burden that the healthcare system will face. such information can be used to increase readiness. it may also facilitate patient surveillance and streamline flow and distribution through the healthcare system. finally, with the envisioned pandemic control system, aact and targeted isolation can be quickly deployed at first signs of an outbreak with the goal of limiting disease spread without resorting to measures such as shelter-in-place. spread while impacting fewer individuals. success of aact hinges not only on user adoption, but also on users' willingness to abide by recommendations. if individuals do not universally respond to alerts by self-isolating, impact of aact on disease spread would be minimal. similarly, at lower adoption rates, exposures could not be tracked, thus undercutting benefits. aact would be most successful with universal adoption and universal response. nonetheless, we have demonstrated even at modest adoption and response rates, it is feasible to significantly mitigate disease spread while limiting number of individuals isolated. in a real-world context, several countries have started introducing aact to help reopen societies and mitigate continued disease spread. data from singapore suggested that digital contact tracing carries higher sensitivity and specificity for identifying contacts than traditional approaches. 14 the data on the efficacy of these measures, however, is limited and requires rigorous analysis before conclusions from models can be made. thus, recommendations have been proposed to achieve this and hopefully will result in more rigorous analysis. 15 the need for real-world context is especially important given that several factors, including technological literacy, infrastructure, governmental regulations, user adoption based on culture, and factors such as regional population flow may impact efficacy. for example, likelihood of broad user adoption and compliance would likely be lower in the absence of governmental support, depending on the population. furthermore, populations with high frequency of exchange with surrounding countries, states, or regions in which aact is not used may overcome any value of aact. additionally, without appropriate infrastructure (wireless systems to transmit data, centralized databases that can aggregate data, etc), the viability of aact would be limited. there are several limitations to our models. first, we initialized our models with fixed parameters; in reality, parameters have been dynamic and evolved as the pandemic progressed. however, the intent of this paper was to compare strategies for mitigating disease spread assuming a common disease model. it is fair to assume comparative outcome of aact and universal stay-at-home would be similar regardless of their initialization. second, success of aact may depend on type of technology used. for example, gps systems have lower location accuracy than bluetooth or wifi. thus, systems that predict exposure based on proximity between an infected individual and an app user would be more accurate (and thus impact fewer people) when technology has higher location accuracy. also, we assumed adoption of aact is uniformly distributed throughout the population. diffuse uptake evenly throughout a society would be expected to have more benefit than uptake in dense pockets. finally, our modeling doesn't account for transmission from exposed individuals to other susceptible individuals (eg, household members) between the time of exposure and the time they self-quarantine. such third order exposures were not accounted for by the model and thus skew the data in favor of aact. however, with comprehensive use, near real-time results, and application of self-quarantine rules to household exposures, such deviations could be reduced. contact tracing can mitigate disease spread through a curated approach of identifying and isolating exposed individuals, as opposed to shelter-in-place orders. applications that can be implemented through available smart phones and other devices may offer an opportunity to facilitate contact tracing and alert individuals to self-isolate after exposure. these efforts afford the ability to mitigate disease spread in similar rates to universal shelter-in-place when adopted at sufficient rates, assuming a high percentage of users respond to exposure alerts issued by the system. figure 3a summarizes curves for different levels of adoption and response rates over the course of the pandemic. in this figure, the right panel summarizes response rates, and inset numbers are adoption rates. figure 3b offers a graphical representation of number of individuals expected to be isolated at difference adoption and response rates. approach in this framework we analyze two possibilities to implement non-clinical procedures to stop the spread of the epidemic: • advanced contact tracing: through aact, it is possible to inform exposed (asymptomatic/non-infected) members of the community of the exposure risk. once warned, they would ideally self-isolate themselves and prevent second-order spreading of the contagion. therefore, self-isolated contacts will depend on the aact penetrance p in both the infected and the exposed population. we are assuming efficacy 100% (or rather, traced contacts receiving warnings and not self-isolating would pose as much risk as nontraced contacts). self-isolated members might still develop symptoms. the percentage of aact penetration will also limit the further exposure, thus reducing the transition between susceptible and exposed. • traditional measures: in order to stop the contagion, authorities might recur to enforce social distancing through different measures, going from limitation of public gathering to full lockdown. we use the variable g to model these interventions which will act aspecifically on susceptible, exposed and infected population. this measure does not depend on the percentage of infected patients, but will still limit the of the susceptible population. quarantine will last for a time of 50 days (assumed reasonable in the current scenario) we assume the following initial parameters: • t inc = incubation period (~5.1 days) • t lat = latency period before development of symptoms (~ 11.5 days) • basic r 0 = 3.02 preliminary death rate µ = 0.057 (with case fatality ratio of 1.5018%, as estimated by recent global data). imputed from the definition of = compartment functional definition s susceptible individuals e exposed to infection, unclear symptomatic conditions, potentially infectious i infected, confirmed symptomatic and infectious sq traced contacts, thus exposed but (self-)isolated r recovered, immune from further infection d case fatality (death due to covid-19, not other causes) here we will consider as the percentage of adoption of the contact tracing digital solution among the whole population and $$ the percentage of population with the app that would eventually follow the recommendation and self-isolate. we are assuming that percentage of responsible use corresponds to efficacy and tempestivity of isolation moreover, we do not model the second and third-grade exposure risks from the first contacts for simplicity. here we will consider as the strength of intervention, hard to quantify numerically, but can be assumed to increase from limiting big gathering events up to full lockdown, and as the rate of intervention (assumint time of intervention 50 days). here will have effect on the susceptible population. quarantined people will decrease after the intervetion time (and ideally assigned to the recovered, not the susceptible population for simplicity purposes). the incidence of intervention does not depend on the i compartment. presumed asymptomatic carrier transmission of covid-19 substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (sars-cov2) epidemic models of contact tracing: systematic review of transmission studies of severe acute respiratory syndrome and middle east respiratory syndrome the effectiveness of contact tracing in emerging epidemics contributions to the mathematical theory of epidemics contributions to the mathematical theory of epidemics -ii the problem of endemicity contributions to the mathematical theory of epidemics -iii further studies of the problem of endemicity the incubation period of coronavirus disease covid-19) from publicly reported confirmed cases: estimation and application early in the epidemic: impact of preprints on global discourse about covid-19 transmissibility first-principles machine learning modelling of covid-19 contact tracing the efficacy of contact tracing for the containment of the 2019 novel coronavirus (covid-19) 773 people are under quarantines in new york city. the new york times. 3/5/2020 use of a real-time locating system for contact tracing of health care workers during the covid-19 pandemic at an infectious disease center in singapre: validation study digital health and the covid-19 epidemic: an assessment framework for apps from an epidemiological and legal perspective key: cord-322714-s0wge7o4 authors: joyner, michael j.; bruno, katelyn a.; klassen, stephen a.; kunze, katie l.; johnson, patrick w.; lesser, elizabeth r.; wiggins, chad c.; senefeld, jonathon w.; klompas, allan m.; hodge, david o.; shepherd, john r.a.; rea, robert f.; whelan, emily r.; clayburn, andrew j.; spiegel, matthew r.; baker, sarah e.; larson, kathryn f.; ripoll, juan g.; andersen, kylie j.; buras, matthew r.; vogt, matthew n.p.; herasevich, vitaly; dennis, joshua j.; regimbal, riley j.; bauer, philippe r.; blair, janis e.; van buskirk, camille m.; winters, jeffrey l.; stubbs, james r.; van helmond, noud; butterfield, brian p.; sexton, matthew a.; diaz soto, juan c.; paneth, nigel s.; verdun, nicole c.; marks, peter; casadevall, arturo; fairweather, delisa; carter, rickey e.; wright, r. scott title: safety update: covid-19 convalescent plasma in 20,000 hospitalized patients date: 2020-07-19 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.06.028 sha: doc_id: 322714 cord_uid: s0wge7o4 abstract objective to provide an update on key safety metrics after transfusion of convalescent plasma in hospitalized covid-19 patients, having previously demonstrated safety in 5,000 hospitalized patients. patients and methods from april 3 to june 2, 2020, the us fda expanded access program for covid-19 convalescent plasma transfused a convenience sample of 20,000 hospitalized patients with covid-19 convalescent plasma. results the incidence of all serious adverse events was low; these included transfusion reactions (n=89; <1%), thromboembolic or thrombotic events (n=87; <1%), and cardiac events (n=680, ∼3%). notably, the vast majority of the thromboembolic or thrombotic events (n=55) and cardiac events (n=562) were judged to be unrelated to the plasma transfusion per se. the seven-day mortality rate was 8.6% (8.2%, 9.0%), and was higher among more critically-ill patients relative to less ill counterparts, including patients admitted to the intensive care unit vs. not admitted (10.5% vs. 6.0%), mechanically ventilated vs. not ventilated (12.1% vs. 6.2%), and with septic shock or multiple organ dysfunction/failure vs. those without dysfunction/failure (14.0% vs. 7.6%). conclusion these updated data provide robust evidence that transfusion of convalescent plasma is safe in hospitalized patients with covid-19, and support the notion that earlier administration of plasma within the clinical course of covid-19 is more likely to reduce mortality. coronavirus disease 2019 continues to be a world-wide pandemic, and the number of deaths attributed to covid-19 in the us at the time of this writing (~110,000) exceed that of any other nation in the world 1 . the overall case fatality rate for diagnosed covid-19 ranges from about 4% to greater than 50% 2-6 , with higher mortality rates observed in more critically ill patients. in response to the covid-19 outbreak in the us and reportedly high case-fatality rates, the us food and drug administration (fda) in collaboration with the mayo clinic and national blood banking community developed a national expanded access program (eap) to collect and distribute covid-19 convalescent plasma. historical precedent indicates that human convalescent plasma is a viable option for mitigation and treatment of covid-19 7, 8 . the premise of human convalescent plasma therapy is that plasma of recently-infected and currently-recovered covid-19 patients contains anti-viral antibodies and other bioactive elements that can be used to treat patients with covid-19. convalescent plasma has a strong historical record of some efficacy during acute infectious pandemics 7, 9 . as recently summarized 7 , convalescent plasma represents a promising treatment strategy with strong historical precedence, biological plausibility, and limited barriers for rapid development and deployment of this investigational therapy. recently, our investigation of key safety indicators in 5,000 patients transfused with covid-19 convalescent plasma demonstrated an incidence of transfusion-related serious adverse events (sae) of less than 1% and a mortality rate of 14.9% 10 . these early indicators suggest that transfusion of convalescent plasma is safe in hospitalized adults with covid-19. because an additional 15,000 hospitalized patients have been transfused with convalescent plasma under the purview of the eap, a subsequent safety update is warranted. these new data may provide novel insights into the incidence of emerging adverse events associated with covid-19, including thromboembolic 11, 12 and cardiac events 13 . further, these data may provide better understanding of the clinical features contributing to the seven-day mortality rate among transfused patients with covid-19. thus, we analyzed key safety metrics following transfusion of convalescent plasma in 20,000 hospitalized adults with severe or life-threatening covid-19. these data represent a deeper and larger analysis relative to our initial report of 5,000 transfused patients under the eap. we hypothesized that both the seven-day mortality rate and the number of serious adverse events related to the transfusion of convalescent plasma would continue to be low. additionally, we hypothesized that higher mortality rates would be observed in more critically-ill patients. as described previously 10 , the program is a fda-initiated, national, multicenter, open-label eap in hospitalized adults that had (or were judged to have high risk of progression to) severe or life-threatening covid-19. the us covid-19 convalescent plasma eap was conducted as a pragmatic treatment study, empowering local acute care facilities to use the emerging best evidence for care while allowing for administration of convalescent plasma. it was conducted within a modified clinical trial framework: all participants were allowed access to convalescent plasma per the discretion of the treating physician/ principal investigator given the nature of the pandemic and the lack of any effective therapies at the time of design. it was the intent a priori to create a control comparator group to determine potential efficacy using patients hospitalized with covid-19 infections during the same time period. this decision was made after collaboration with the us fda. this report is only on safety of the cp for the initial 20,000 subjects. a future publication will discuss potential efficacy. between the date of initial institutional review board (irb) approval of the eap (april 1 st 2020) and june 11 2020, more than 20,000 patients were transfused with covid-19 convalescent plasma, figure 1 . the mayo clinic irb served as the central irb and empaneled an independent data and safety monitoring board (dsmb) to oversee the safety analyses. written informed consent was obtained from the participant or a legally-authorized representative prior to enrollment, or with use of emergency consent procedures recommended by the us fda and approved by the mayo clinic irb. the protocol was modified to allow inclusion of incarcerated participants once it became clear that this group was especially vulnerable and at risk. eligible patients were aged 18 years or older, hospitalized with a laboratory confirmed diagnosis of infection with severe acute respiratory syndrome coronavirus 2 (sars-cov-2), and had (or were judged by a healthcare provider to be at high risk of progression to) severe or life-threatening covid-19. the clinical symptoms defining severe or life-threatening covid-19 are outlined in table 1 . as described previously 10 , abo-compatible covid-19 convalescent plasma had no minimum neutralizing-antibody titer level and was donated by recently-recovered, covid-19 survivors. approximately 200 -500 ml of convalescent plasma was administered intravenously according to institutional transfusion guidelines. web-based, standardized data reporting surveys were completed to assess clinical status of patients at regular time intervals (four-hours and seven-days after convalescent plasma transfusion) using the research electronic data capture system (redcap, v.9.1.15 vanderbilt university, nashville, tn) 14, 15 . serious adverse event reporting. separate redcap data collection forms were used to report each sae that occurred within seven days following the convalescent plasma transfusion. two primary data capture forms were used to report saes: a transfusion form and a sae form. serious adverse events which occurred during the time window beginning at the onset of the plasma transfusion and including the four-hour time-period following the transfusion were reported on the transfusion form. by definition, the primary saes related to transfusion (including transfusion associated circulatory overload [taco] and transfusion-related acute lung injury [trali]) occurred within six hours of the transfusion. all transfusion-related saes occurred within four hours of the transfusion and thus, were all reported on the transfusion form. all other saes were reported on the sae form. the attribution scale used by treating physicians for evaluating sae relatedness to convalescent plasma transfusion included unrelated, possibility related, probably related, or definitely related. all transfusion-related saes were independently adjudicated over the course of the study by the ind sponsor (mjj) and trained designee (amk) using the national healthcare safety network biovigilance component hemovigilance module surveillance protocol as a conceptual framework 16 . statistics. data presented in this safety report may undergo additional data quality control measures as the study continues. the cumulative incidence of each of a series of saes was summarized using a point estimate and 95% score confidence interval (ci), as outlined in table 2 . to assess mortality, time (in days) between transfusion and mortality was examined using the kaplan meier product limit estimator. participants were censored at their last known vital status and all reported mortalities through seven days were used to estimate the survival function. data were censored at 0.25 days for patients who did not have follow-up beyond the initial report at four hours post transfusion at time of the analysis. for patients who expired within 24 hours, a survival time of 0.5 days was assigned. precise time of day for key events was not recorded in the data collection system; thus, these imprecise time estimates were used. the point estimate and 95% ci for mortality were estimated at day seven based on the estimated survival function. all analyses and graphics were produced with r version 3.6.2 (vienna, austria). from april 3 to june 11, 2020, a total of 30,117 patients were enrolled in the eap and a total of 21,987 enrolled patients received a covid-19 convalescent plasma transfusion (figure 1) . data from the first 5,000 transfused patients have been reported previously 10 . this update reports data from 20,000 patients including the initial 5,000 and subsequent 15,000 transfused patients. by june 2, 2020, a total of 20,000 patients had been transfused with covid-19 convalescent plasma, thus, 7-day mortality data is presented for all 20,000 patients. table 1 . the patient enrollment indicates a wide age range of hospitalized patients with covid-19, consistent with prior cdc published data 17 . the study population was diverse, with 20% of patients being african american, nearly 35% hispanic and 5% asian. the recruitment of a diverse population has improved over the time course of the study. nearly 40% of our subjects were women. most of the patients enrolled were overweight or obese, consistent with early reports of risk 18 . nearly all of the patients had severe or life-threatening covid-19, by design of the investigational protocol. nearly two-thirds had respiratory failure as well as dyspnea as a primary symptom. most were hypoxic and nearly half had pulmonary infiltrates. at least one-third had severe respiratory compromise. equal numbers appeared to have multi-organ failure or septic shock, but these were a small percentage of the total population. table 2 . our report is not a comprehensive summary of all risks associated with hospitalization of covid-19 but did assume that convalescent plasma potentially could cause life-threatening cardiac events and thrombotic events, so these were collected with an underlying assumption of attribution. within four hours of completion of the covid-19 convalescent plasma transfusion, 146 saes classified as transfusion reactions were reported (<1% of all transfusions). of these saes, there were 83 non-mortality events reported, with 37 reports of transfusion-associated circulatory overload (taco), 20 reports of transfusionrelated acute lung injury (trali), and 26 reports of severe allergic transfusion reaction. of the saes reported within four hours of plasma transfusion, there were 63 mortalities (0.3% of all transfusions) and 13 of these mortalities were judged as related (possibly, n=12; probably, n=1; definitely, n=0) to the transfusion of covid-19 convalescent plasma. within seven days of completion of the covid-19 convalescent plasma transfusion, 1,136 other saes were reported. of these saes, 87 thromboembolic or thrombotic events were reported, 406 sustained hypotensive events requiring intravenous pressor support were reported, and 643 patients suffered a cardiac event. notably, the vast majority of the thromboembolic or thrombotic complications (n=55) and cardiac events (n=569) were judged to be unrelated to the plasma transfusion. table 2 . over the first seven days after the covid-19 convalescent plasma transfusion, a total of 1,711 deaths were observed. the overall seven-day mortality rate was 8.56% (95% ci: 8.18%, 8.95%), figure 2 . the seven-day mortality rate was higher among the sickest of our critically-ill patients, including patients admitted to the intensive care unit (icu) vs. not admitted to the icu (10.5% vs. 6.0%), mechanically ventilated vs. not mechanically ventilated (12.1% vs. 6.2%), and those with septic shock or multiple organ dysfunction/failure vs. without septic shock or multiple organ dysfunction/failure (14.0% vs. 7.6%). in this safety update of the us convalescent plasma expanded access program of 20,000 hospitalized patients in the us with severe or life-threatening covid-19, the overall frequency of saes classified as attributable or likely secondary to convalescent plasma transfusion continued to be low (<1% of all transfusions) and the seven-day mortality rate in this extremely high risk cohort was 8.6%. despite the potential risks associated with plasma transfusion in critically-ill patients 16, 19 , these data provide continued optimism for the safety of covid-19 convalescent plasma. although thrombotic and thromboembolic events are emerging clinical complications of covid-19 11, 12, 20 , our data demonstrate a low rate (<1%) of these events within the first seven days after covid-19 convalescent plasma transfusion. cardiac events represent another novel clinical concern of covid-19 13 , particularly in the context of open-label use of experimental treatments such as hydroxychloroquine 21 . in aggregate, adverse cardiac events occurred in ~3% of patients transfused with covid-19 convalescent plasma. the vast majority of adverse cardiac events of interest were deemed unrelated to the plasma transfusion (88%) by the treating physicians. collectively, these data suggest that transfusion of covid-19 convalescent plasma per se does not demonstrably increase the risk of adverse cardiac events. we note that the incidence of trali and taco reported in this study of 0.18% and 0.10%, respectively is significantly lower than those reported in previous studies, which ranged from 5-8% and 1-4%, respectively 22 , despite the fact that many of the covid-19 patients receiving plasma were critically ill and likely at risk for clinical conditions which mimic taco. limitations. although this study was not designed to evaluate efficacy of convalescent plasma, we note with optimism that after 20,000 transfused patients the seven-day mortality rate (8.6%) is lower than the mortality rate observed in the first 5,000 transfused patients (12.0%), table 2 . while the mortality rate has fallen (figure 2) , we note that the clinical characteristics of the transfused patients in the eap have shifted toward less critically-ill patients and lower proportions of apparent "rescue therapy". no therapy has been introduced into clinical use during this time period which reduces (to our knowledge) mortality in hospitalized patients with covid-19. we postulate that several potential explanations may explain the observed decline in mortality. the ability and success of the us healthcare community at managing hospitalized covid-19 patients is likely improving. second, the blood banking communities have enhanced the availability of convalescent plasma such that more patients received plasma earlier in their hospital course compared to the initial cohort of 5000 participants. the more expeditious delivery of plasma to patients reflects improved logistics for the collection, deployment and use of convalescent plasma, and a larger covid-19 recovered population that may be potential plasma donors. in this regard it is remarkable that there was no system in place for convalescent plasma use in march 2020 and yet within months the nation is now able to meet most of the demand, despite complex logistics 23 . given the historical experience that antibody therapies are most effective when given earlier and that convalescent plasma has reduced mortality in prior epidemics 7 , the lower mortality in more recently treated patients would be consistent with greater efficacy from earlier use. finally, as recovered covid-19 patients were more quickly recruited for convalescent plasma donation, the plasma may contain higher levels of neutralizing antibodies or other bioactive elements. however, additional data are required to evaluate these potential explanations for the observed trends. data from the first 20,000 patients transfused with covid-19 convalescent plasma demonstrate that use of convalescent plasma is safe and carries no excess risk of complications. indeed, convalescent plasma may be associated with improvement in survival, however, this report does not establish efficacy. additionally, our data demonstrate that the us health care system is improving in its care for those hospitalized for covid-19 including managing those critically-ill patients with multiple comorbidities included in these analyses. overall, the mortality observed has fallen with our observations and continued use of convalescent plasma. given the accelerating deployment of this therapy, these emerging data provide early safety indicators of convalescent plasma for covid-19 treatment and suggest research should shift focus from safety toward determining the efficacy of convalescent plasma. for disease control and prevention. coronavirus disease 2019 (covid-19): cases in us the many estimates of the covid-19 case fatality rate 15-day mortality and associated risk factors for hospitalized patients with covid-19 in wuhan, china: an ambispective observational cohort study clinical course and outcomes of critically ill patients with sars-cov-2 pneumonia in wuhan, china: a single-centered, retrospective, observational study presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with covid-19 in the covid-19 in critically ill patients in the seattle region -case series the convalescent sera option for containing covid-19 a serological survey on neutralizing antibody titer of sars convalescent sera meta-analysis: convalescent blood products for spanish influenza pneumonia: a future h5n1 treatment? early safety indicators of covid-19 convalescent plasma fibrinolysis shutdown correlates to thromboembolic events in severe covid-19 infection autopsy findings and venous thromboembolism in patients with covid-19 cardiac involvement in a patient with coronavirus disease 2019 (covid-19) research electronic data capture (redcap)--a metadata-driven methodology and workflow process for providing translational research informatics support the redcap consortium: building an international community of software platform partners centers for disease control and prevention. the national healthcare safety network (nhsn) manual: biovigilance component v2.5 hospitalization rates and characteristics of patients hospitalized with laboratoryconfirmed coronavirus disease 2019-covid-net, 14 states clinical characteristics of covid-19 in new york city covid-19 convalescent plasma: now is the time for better science confirmation of the high cumulative incidence of thrombotic complications in critically ill icu patients with covid-19: an updated analysis urgent guidance for navigating and circumventing the qtc-prolonging and torsadogenic potential of possible pharmacotherapies for coronavirus disease 19 (covid-19) taco and trali: biology, risk factors, and prevention strategies deployment of convalescent plasma for the prevention and treatment of covid-19 6%) 80 years or older 650 (10.5%) 1,858 (13.9%) 60 (14.1%) 2,568 (12.8%) gender women 2,254 (36.3%) 5,360 (40.1%) 163 (38.2%) 7,777 (38.9%) men 3,935 (63.3%) 7,953 (59.5%) 264 (61.8%) 12,152 (60.8%) 17.6%) 2,356 (17.8%) 62 (14.6%) 3,246 (17.7%) overweight 1,413 (30.1%) 3,695 (28.0%) 120 (28.2%) 5,228 (28.5%) obese 2%) lung infiltrates > 50% the ratio of partial pressure of arterial oxygen to fraction of inspired oxygen ratio 56% (8.18%, 8.95%) clinical status no icu admission 17% (5.75%, 6.61%) mechanical ventilation (n = 6,337) 767 12.10% (11.32%, 12.93%) clinical symptoms no mof or septic shock (n = 17,081) 62% (7.23%, 8.03%) mof or septic shock abbreviations: icu, intensive care unit; mof, multiple organ failure or dysfunction. a point estimate of related serious adverse event incidence relative to 20,000 transfusions. b sustained hypotension included events requiring intravenous pressor support. c cardiac events included ventricular or atrial fibrillation or arrhythmia requiring treatment, and cardiac arrest. d these data were previously published 10 and reported for comparison with current data. key: cord-334708-lbmktall authors: putman, michael s.; ruderman, eric; niforatos, joshua d. title: publication rate and journal review time of covid-19 related research date: 2020-08-31 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.08.017 sha: doc_id: 334708 cord_uid: lbmktall nan the academic community has responded swiftly to the novel coronavirus 2019 pandemic. anecdotally, academic researchers have noticed a reduction in the amount of time journals require to review covid-19 manuscripts. in this letter we describe the growth of this literature and the review time of covid-19 related manuscripts. bibliographic data were extracted from all articles in the dedicated covid-19 research sections of the preprint databases medrxiv and biorxiv (https://connect.medrxiv.org/relate/content/181) and the ncbi section litcovid (https://www.ncbi.nlm.nih.gov/research/coronavirus/). bibliographic data were also extracted from all non-covid-19 articles published by the journals listed in litcovid. articles were included if posted between november 1st, 2019 and may 26th, 2020. for published articles, the difference between the date of submission and the date of acceptance ("review time") was compared using the independent samples t-test. see supplemental appendix for detailed methodology. reporting errors have also occurred 2 and might be more frequent in an expedited process. finally, the reduction in review time may in part be attributable to an abridged process of peer review. the recent experience with hydroxychloroquine in covid-19 may illustrate the consequences of expedited or inadequate peer review. initially, a small cohort study with substantive methodologic flaws was accepted after one day of peer review. 3 public acquisition, medication shortages, and widespread adoption in clinical practice followed. subsequent large observational cohorts and randomized controlled trials (rcts) have not verified these results. more recently, rcts of hydroxychloroquine in covid-19 halted enrollment after a study by mehra et al suggested an association between hydroxychloroquine use and increased mortality. 4 substantive concerns about the validity of these data could not be addressed, and the study has been retracted. 5 our approach has limitations. the types of published articles could not be assessed and many journals did not list submission or acceptance dates in bibliographic metadata. however, our data highlight important threats to the validity of the evolving covid-19 literature, which may be particularly acute in the current climate. while our response to this crisis should be swift, it must also be scientifically rigorous. editorial concern-possible reporting of the same patients with covid-19 in different reports clarification of mortality rate and data in abstract, results, and table 2 hydroxychloroquine and azithromycin as a treatment of covid-19: results of an open-label non-randomized clinical trial hydroxychloroquine or chloroquine with or without a macrolide for treatment of covid-19: a multinational registry analysis. the lancet key: cord-331754-4cssullk authors: shakshouk, hadir; lehman, julia s. title: purple fingers and toes date: 2020-05-20 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.02.025 sha: doc_id: 331754 cord_uid: 4cssullk nan hadir shakshouk, mbbs; and julia s. lehman, md a 34-year-old female patient presented with painful erythematous papules on both hands and feet. the lesions appeared in late december and were increasing in number by the time she was evaluated in early spring. she was at 19 weeks of pregnancy, with no other new symptoms or relevant medical or drug history. on dermatologic examination, multiple mildly tender violaceous papules were noted bilaterally on tips of acral surfaces ( figure 1 ). no ulceration or necrosis was observed. the clinical differential diagnosis was broad and included chilblains, chilblains lupus, vasculitis, or occlusive vasculopathy. laboratory investigations for antinuclear antibody (ana), antineutrophil cytoplasmic antibody (anca), homocysteine, cardiolipin, and hepatitis virology were negative. also, results of the complete blood count (cbc), erythrocyte sedimentation rate (esr), c-reactive protein (crp), coagulation profile, and urinanalysis were normal. punch biopsy from the left great toe revealed papillary dermal edema with superficial and deep perivascular lymphocytic inflammation and endothelial cell swelling ( figure 2 ). red blood cell extravasation was noted in upper dermis. vacuolar interface changes typically present in lupus were absent, as were fibrinoid degeneration of vessel walls or intravascular occlusive changes. direct immunofluorescence was unremarkable. taken together, clinical, histopathologic, and serologic findings led to a diagnosis of idiopathic perniosis. perniosis, also known as chilblains, is a cold-induced inflammatory disorder commonly affecting acral sites and is frequently accompanied by a sensation of itching, burning, or pain. 1 perniosis can be categorized as primary or secondary perniosis. primary perniosis has been linked to abnormal neurovascular responses of dermal vessels in reaction to cold. affected patients develop vasoconstriction in acral sites instead of the protective vasodilatory response. 2 several criteria have been proposed for diagnosis, including 1 major criterion of localized erythema and swelling involving acral sites that persists for >24 hours, in addition to 1 of the following minor criteria: onset and/or worsening in cooler months (between november and march in the northern hemisphere), histopathologic findings of skin biopsy consistent with perniosis, without findings of lupus erythematosus, and response to conservative treatments (warming and drying). 3 secondary perniosis has been linked to several systemic etiologies including cryoglobulinemia, autoimmune connective tissue diseases, leukemia, hyperviscosity syndrome, and antiphospholipid syndrome. in addition, reports of perniosislike skin changes in association with infection by the novel coronavirus sars-cov-2 are emerging. however, the association between pernio and lupus erythematosus (chilblains lupus) is the most well established. 4 given these associations, it is of paramount importance to exclude other diseases in cases of perniosis. primary perniosis is a self-limited condition. conservative treatment by keeping the acral sites warm and dry, as well as maintaining core body temperature and avoiding smoking is usually adequate to control disease. for resistant cases, nifdepine and pentoxyphylline may be considered. 5 epidemiological patterns of perniosis, and its association with systemic disorder idiopathic chilblains clinical characteristics, etiologic associations, laboratory findings, treatment, and proposal of diagnostic criteria of pernio (chilblains) in a series of 104 patients at mayo clinic a histologic and immunohistochemical study of chilblains nifedipine vs placebo for treatment of chronic chilblains: a randomized controlled trial key: cord-298094-ctikhqvr authors: elias, pierre; poterucha, timothy j.; jain, sneha s.; sayer, gabriel; raikhelkar, jayant; fried, justin; clerkin, kevin; griffin, jan; defilippis, ersilia m.; gupta, aakriti; lawlor, matthew; madhavan, mahesh; rosenblum, hannah; roth, zachary b.; natarajan, karthik; hripcsak, george; perotte, adler; wan, elaine y.; saluja, deepak; dizon, jose; ehlert, frederick; morrow, john p.; yarmohammadi, hirad; kumaraiah, deepa; redfors, bjorn; gavin, nicholas; kirtane, ajay; rabbani, leroy; burkhoff, dan; moses, jeffrey; schwartz, allan; leon, martin; uriel, nir title: the prognostic value of electrocardiogram at presentation to emergency department in patients with covid-19 date: 2020-08-15 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.07.028 sha: doc_id: 298094 cord_uid: ctikhqvr abstract background rapid risk stratification is essential during the covid-19 pandemic. we aimed to study whether combining vital signs and electrocardiogram (ecg) analysis can improve early prognostication. methods 1,258 adults with covid-19 seen at three hospitals in new york in march and april 2020 were analyzed. ecgs at presentation to the emergency department were systematically read by electrophysiologists. the primary outcome was a composite of mechanical ventilation or death 48 hours from diagnosis. the prognostic value of ecg abnormalities was assessed in a model adjusted for demographics, comorbidities, and vital signs. results at 48 hours, 73 patients (6%) had died and 174 (14%) were alive but receiving mechanical ventilation with 277 (22%) patients dying by 30 days. early development of respiratory failure was common, with 53% of all intubations occurring within 48 hours of presentation. in a multivariable logistic regression, atrial fibrillation/flutter (or 2.5, 95% ci [1.1-6.2]), right ventricular strain (or 2.7, 95% ci [1.3-6.1]), and st segment abnormalities (or 2.4, 95% ci [1.5-3.8]) were associated with death or mechanical ventilation at 48 hours. in 108 patients without these ecg abnormalities and with normal respiratory vitals (rate <20 and saturation >95%), only 5 (5%) died or required mechanical ventilation by 48 hours versus 68 of 216 patients (31%) having both ecg and respiratory vital sign abnormalities. conclusions the combination of abnormal respiratory vital signs and ecg findings of atrial fibrillation/flutter, right ventricular strain, or st segment abnormalities accurately prognosticates early deterioration in patients with covid-19 and may assist with patient triage. with severe acute respiratory syndrome coronavirus-2 (sars-cov-2). 1 in the united states, covid-19 has infected more than 3.4 million people, leading to over 138,000 deaths. 1, 2 severe cases can result in respiratory failure with acute respiratory distress syndrome (ards), shock, and death. 3 some patients remain stable with mild symptoms, and others develop rapid deterioration after a period of stability lasting up to a week or more. 1, 4, 5 known markers of poor prognosis include age, comorbidities, and high sequential organ failure assessment (sofa) score. 5 in patients with severe infection, numerous laboratory findings have been associated with adverse outcomes including hematological disturbances and inflammatory biomarkers. 5 however, there is a limited understanding of how presenting vital signs relate to final outcome from covid-19, hampering the development of effective approaches for triaging patients early in their clinical course. additionally, there is increasing evidence of the prognostic capacity of cardiac involvement in covid-19. 6 electrocardiographic (ecg) abnormalities have been described but there have been no large studies of ecg abnormalities in covid-19 patients nor their correlation with clinical outcomes. 8, 9 early triage of patient that will required higher level of care is crucial due to the high volume of patients admitted with the disease. in this study, we sought to determine if data available early in a patient's emergency department presentation (demographics, comorbidities, vital signs, and ecg) could prognosticate the composite outcome of mechanical ventilation or death by 48 hours after covid-19 diagnosis. we hypothesized that abnormalities on ecg done at presentation would add additional prognostic capacity after adjusting for the above data in a from march 1 st to april 3 rd , 5,587 individuals were tested for covid-19 with 2,421 (43%) having positive results. a total of 1,258 patients who were admitted to the hospital were included in the study. demographics, comorbidities, presentation vital signs, and outcomes are displayed in table 1 . the mean age was 61.6 years (sd 18.4) and 563 (46%) patients were female. the most common comorbidities were hypertension (57%), diabetes (37%), obesity (34%), primary lung disease (17%), and chronic kidney disease (16%). prior known cardiovascular disease included coronary artery disease (11%), hfref (7%), and hfpef (4%). the most common symptoms reported at the time of triage were fever (39%), cough (32%), shortness of breath (29%), gastrointestinal complaints (10%), weakness (7%), and chest pain (3%). at 48 hours, 1,011 (80%) patients were alive without receiving mechanical ventilation, 174 (14%) received mechanical ventilation but had not died, and 73 (6%) had died ( figure 1 ). during the 14-day period a total of 287 patients (23%) were intubated, of which 16 (6%) were extubated and discharged, 36 (13%) were extubated but remained hospitalized, 121 (42%) remained intubated, and 115 (40%) died. the rate of early clinical decompensation was high, with a median time from hospital arrival to mechanical ventilation of 1 day (iqr 0-4) and a median time of hospital arrival to death of 6 days (iqr 3-10). mortality increased from 231 (18%) patients at 14 days to 277 (22%) patients at 30 days. patients who met the primary outcome tended to be older (mean age 66.3 versus 60.4), male (62% vs 52%), have hypertension (67% vs 55%), diabetes (47% vs 34%), and ckd (20% j o u r n a l p r e -p r o o f elias 10 vs 15%). on presentation they were more likely to have a respiratory rate >20 (50% vs 22%) and oxygen saturation <=95% (67% vs 55%). there were differences noted in earliest creatinine (median 1.3 vs 1.0 mg/dl) and crp (184.7 vs 89.6 mg/l) but differences in esr (73 vs 63 mm/hr) and absolute lymphocyte count (0.88 vs 1.06x10 3 cells/µl) were less pronounced. laboratory results are further detailed in the supplement. vital sign abnormalities on presentation are shown in table 1 . the median temperature was 37.4° c (iqr 36.8-38.2) and 361 patients (29%) had a temperature ≥ 38.0. the median heart rate was 98 (iqr 86-110) and median systolic blood pressure was 124 mmhg (iqr 111-142). the median respiratory rate was 20/min (iqr 18-22) and the median oxygen saturation was 94% (iqr 90-97%). a total of 682 (54%) patients met criteria for abnormal respiratory vitals (respiratory rate >20, saturation <=95%, or oxygen therapy via nrb or ffm). a total of 850 initial ecgs were available for analysis. the most common rhythm was sinus rhythm (66%) followed by sinus tachycardia (25%), and atrial fibrillation or flutter (5%). we then combined the two vital sign abnormalities and three ecg abnormalities into two binary variables (abnormal respiratory vitals and abnormal ecg findings). at 48 hours after diagnosis, 4.6% of patients with none of the three ecg abnormalities and normal respiratory vital signs received mechanical ventilation or died, compared to 31.5% of patients with any ecg abnormality and any abnormal respiratory vital sign. the presence of any of the three ecg abnormalities increased the rate of mechanical ventilation or death from 4.6% to 12.3% in patients with normal respiratory vital signs, and from 16.8% to 31.5% in patients with abnormal respiratory vital signs ( figure 2 ). looking at 14-day and 30-day outcome, these five variables (two respiratory vitals and three ecg abnormalities) continued to all be significant in multivariable regression. the pathway to outcome at 14 days for all patients is detailed in figure 3 . j o u r n a l p r e -p r o o f elias 12 we analyzed 1,258 patients with covid-19 seen at three hospitals in new york city during the peak of the covid-19 pandemic. the principal findings of this study include: (1) rapid clinical deterioration is common in admitted patients, with 53% of intubations occurring within 48 hours, (2) 33% of admitted patients either died or required mechanical ventilation within fourteen days of covid-19 diagnosis, and (3) combining abnormal ecg and abnormal respiratory vital signs quickly identifies a group of patients at high risk for mechanical ventilation or death. myocardial injury is an important marker for severe covid-19. 8 ecg remains the simplest assessment for myocardial involvement. to our knowledge, no study on covid-19 has had a majority of patients with ecgs done at presentation and assessed its prognostic capacity. while triage and management during a patient's admission evolves when additional information such as laboratory values and imaging become available, it is important to be able to quickly screen patients upon arrival to the ed to plan for the level of care they may need. abnormalities in initial vitals and presentation ecg can be detected rapidly in a range of clinical settings. more studies are needed to determine how initial presentation affects outcome beyond the most acute phase of covid-19. understanding risk factors for covid-19 severity remains critical due to a need for rapid triage as well as potentially guiding resource allocation. studies have reported age, hypertension, diabetes, sofa score, neutrophilia, elevated ldh, and d-dimer as prognostic factors for patients with covid-19. 5, 9 a study from new york described male gender, obesity, elevated j o u r n a l p r e -p r o o f elias 13 liver function tests, ferritin and c-reactive protein as predictors of mechanical ventilation. 9 in addition, cardiac injury, as measured by elevated troponin levels, carries a particularly poor prognosis. [10] [11] [12] the brescia-covid respiratory severity scale is the most easily applied decision tool developed to date, basing risk on presenting vital signs and chest radiograph, but lacks input variables that point to extra-pulmonary involvement which we believe is critical for effective triage. 13 unfortunately, the majority of risk factors identified so far are laboratory values that will not be immediately available upon presentation. utilizing data immediately available such as vital signs and ecg provides a quick, simple and effective assessment of the patient's prognosis. herein, we reported a significant increase in event rate when abnormal ecg was incorporated into multivariable regression, with higher prognostic value than every other variable in the model except for abnormal respiratory vitals. we propose that in the setting of triaging covid-19 patients in the ed, ecg be treated as a sixth vital sign. during this study period the new york department of health found 962 deaths at home were from confirmed or suspected covid-19 accounting for 9.3% of total covid-19 deaths in new york city. 14 given these sobering statistics, our analysis of hospitalized patients may underestimate illness severity on presentation and raising concern that some patients may be seeking or receiving medical attention too late in their disease course. in the wuhan experience, the median time of symptom onset to dyspnea was 5 days, symptom onset to hospital admission 7 days, and symptom onset to ards 8 days. 15 a study including 655 of our patients found a median of 5 days of symptoms before presentation to the ed. 16 j o u r n a l p r e -p r o o f once respiratory symptoms develop in covid-19, rapid clinical decline appears to be quite common. in addition to disease specific factors, there are patient and medical system features that likely contribute to critical illness of presentation. the news media has highlighted hospital overcrowding and the importance of social distancing which may make patients more likely to wait before contacting the medical system. when patients call their physicians with possible covid-19 related symptoms, they are often encouraged to avoid medical attention due to concerns about either disseminating the virus or receiving a nosocomial infection. considering more intubations occurred within the first 24 hours than any other day, patients who had respiratory symptoms for many days may have benefited from earlier assessment. it remains unclear if earlier presentation would have changed clinical outcome. the american college of emergency physicians among others has noted lack of evidence as the key hurdle to devising criteria for safe triage from the ed. 17 amongst those patients planned for admission, it remains a challenge to determine who is likely to decompensate requiring intensive care in the following days. our study found that amongst a cohort of covid-19 patients slated for admission, normal respiratory vitals and no evidence of atrial fibrillation/flutter, right ventricular overload, or st segment deviation meant there was <5% chance of poor outcome in the next 48 hours. considering this population only included patients sick enough for admission, we feel these criteria can quickly and effectively determine who is safe for lower acuity settings. as a retrospective analysis during an ongoing pandemic, this study has multiple limitations. first, at the time of data abstraction many patients remained hospitalized with their final outcomes unclear. to ensure equal exposure time, outcome was assessed at 48 hours and j o u r n a l p r e -p r o o f elias 15 again at 14 days. it is likely that additional adverse outcomes will accumulate in these patients as their course progresses. to mitigate for this, we reassessed mortality two weeks past censoring at 30 days. second, data were abstracted from the medical record, and it is probable that comorbidities were incompletely characterized. third, this analysis begins at the time of presentation to the hospital. the timing of symptom onset was only captured in about half of these patients. lastly, our institution only tested patients who were planned to be admitted so this cohort does not reflect all patients presenting to the hospital with symptoms concerning for covid-19. j o u r n a l p r e -p r o o f no funding sources were utilized for conducting this research. authors have no conflicts of interest to disclose. (8) 43 (6) 12 (9) 9 (21) abbreviations: sd indicates standard deviation, copd indicates chronic obstructive pulmonary disease, ckd indicates stage 3 or greater chronic kidney disease, hfref indicates heart failure with reduced ejection fraction which was defined as a clinical diagnosis of systolic heart failure or a baseline echocardiogram with left ventricular ejection fraction < 50%, hfpef indicates heart failure with preserved ejection fraction, cad indicates obstructive coronary artery disease. ecg indicates electrocardiogram. mm indicates millimeters, ms indicates milliseconds. right ventricular overload was defined as the presence of right ventricular hypertrophy or s1q3t3. any st segment elevation/depression includes sub-millimeter changes from baseline, but st elevations and depressions must have occurred in two contiguous leads to be considered positive. early triage of patient that will required higher level of care is crucial due to the high volume of patients admitted with the disease. in this study, we sought to determine if data available early in a patient's emergency department presentation (demographics, comorbidities, vital signs, and ecg) could prognosticate the composite outcome of mechanical ventilation or death by 48 hours after covid-19 diagnosis. we hypothesized that abnormalities on ecg done at presentation would add additional prognostic capacity after adjusting for the above data in a abstracted laboratory data included white blood cell count, absolute lymphocyte count, hemoglobin, creatinine, c-reactive protein (crp), and erythrocyte sedimentation rate (esr). for each lab assay, the first laboratory test that was performed during the encounter was defined as "initial" test. in addition, the most abnormal result (peak or nadir depending on clinical relevance) of each lab any point during the 14-day period was recorded. analysis of clinical outcomes was assessed by chart review. patients were grouped into one of 3 mutually exclusive groups: (1) alive, never required mechanical ventilation, (2) patients who met the primary outcome tended to be older (mean age 66.3 versus 60.4), male (62% vs 52%), have hypertension (67% vs 55%), diabetes (47% vs 34%), and ckd (20% j o u r n a l p r e -p r o o f vs 15%). on presentation they were more likely to have a respiratory rate >20 (50% vs 22%) and oxygen saturation <=95% (67% vs 55%). there were differences noted in earliest creatinine (median 1.3 vs 1.0 mg/dl) and crp (184.7 vs 89.6 mg/l) but differences in esr (73 vs 63 mm/hr) and absolute lymphocyte count (0.88 vs 1.06x10 3 cells/µl) were less pronounced. laboratory results are further detailed in the supplement. vital sign abnormalities on presentation are shown in table 1 . the median temperature was 37.4° c (iqr 36.8-38.2) and 361 patients (29%) had a temperature ≥ 38.0. the median heart rate was 98 (iqr 86-110) and median systolic blood pressure was 124 mmhg (iqr 111-142). the median respiratory rate was 20/min (iqr 18-22) and the median oxygen saturation was 94% (iqr 90-97%). a total of 682 (54%) patients met criteria for abnormal respiratory vitals (respiratory rate >20, saturation <=95%, or oxygen therapy via nrb or ffm). a total of 850 initial ecgs were available for analysis. the most common rhythm was sinus rhythm (66%) followed by sinus tachycardia (25%), and atrial fibrillation or flutter (5%). all variables in table 1 figure 2 ). looking at 14-day and 30-day outcome, these five variables (two respiratory vitals and three ecg abnormalities) continued to all be significant in multivariable regression. the pathway to outcome at 14 days for all patients is detailed in figure 3 . myocardial injury is an important marker for severe covid-19. 8 ecg remains the simplest assessment for myocardial involvement. to our knowledge, no study on covid-19 has had a majority of patients with ecgs done at presentation and assessed its prognostic capacity. while triage and management during a patient's admission evolves when additional information such as laboratory values and imaging become available, it is important to be able to quickly screen patients upon arrival to the ed to plan for the level of care they may need. abnormalities in initial vitals and presentation ecg can be detected rapidly in a range of clinical settings. more studies are needed to determine how initial presentation affects outcome beyond the most acute phase of covid-19. understanding risk factors for covid-19 severity remains critical due to a need for rapid triage as well as potentially guiding resource allocation. studies have reported age, hypertension, diabetes, sofa score, neutrophilia, elevated ldh, and d-dimer as prognostic factors for patients with covid-19. 5, 9 a study from new york described male gender, obesity, elevated j o u r n a l p r e -p r o o f liver function tests, ferritin and c-reactive protein as predictors of mechanical ventilation. 9 in addition, cardiac injury, as measured by elevated troponin levels, carries a particularly poor prognosis. [10] [11] [12] the brescia-covid respiratory severity scale is the most easily applied decision tool developed to date, basing risk on presenting vital signs and chest radiograph, but lacks input variables that point to extra-pulmonary involvement which we believe is critical for effective triage. 13 unfortunately, the majority of risk factors identified so far are laboratory values that will not be immediately available upon presentation. utilizing data immediately available such as vital signs and ecg provides a quick, simple and effective assessment of the patient's prognosis. herein, we reported a significant increase in event rate when abnormal ecg was incorporated into multivariable regression, with higher prognostic value than every other variable in the model except for abnormal respiratory vitals. we propose that in the setting of triaging covid-19 patients in the ed, ecg be treated as a sixth vital sign. during this study period the new york department of health found 962 deaths at home were from confirmed or suspected covid-19 accounting for 9.3% of total covid-19 deaths in new york city. 14 given these sobering statistics, our analysis of hospitalized patients may underestimate illness severity on presentation and raising concern that some patients may be seeking or receiving medical attention too late in their disease course. in the wuhan experience, the median time of symptom onset to dyspnea was 5 days, symptom onset to hospital admission 7 days, and symptom onset to ards 8 days. 15 a study including 655 of our patients found a median of 5 days of symptoms before presentation to the ed. 16 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 (6) 12 (9) 9 (21) abbreviations: sd indicates standard deviation, copd indicates chronic obstructive pulmonary disease, ckd indicates stage 3 or greater chronic kidney disease, hfref indicates heart failure with reduced ejection fraction which was defined as a clinical diagnosis of systolic heart failure or a baseline echocardiogram with left ventricular ejection fraction < 50%, hfpef indicates heart failure with preserved ejection fraction, cad indicates obstructive coronary artery disease. ecg indicates electrocardiogram. mm indicates millimeters, ms indicates milliseconds. right ventricular overload was defined as the presence of right ventricular hypertrophy or s1q3t3. any st segment elevation/depression includes sub-millimeter changes from baseline, but st elevations and depressions must have occurred in two contiguous leads to be considered positive. variables from table 1 with p-values under .05 in univariable logistic regression were included in multivariable logistic regression and reported above. clinical features of patients infected with 2019 novel coronavirus in wuhan, china an interactive web-based dashboard to track covid-19 in real time first case of 2019 novel coronavirus in the united states covid-19 in critically ill patients in the seattle region -case series clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study coronavirus disease 2019 (covid-19) and cardiovascular disease the variety of cardiovascular presentations of covid-19 association of cardiac injury with mortality in hospitalized patients with covid-19 in risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (covid-19) risk factors of fatal outcome in hospitalized subjects with coronavirus disease 2019 from a nationwide analysis in china. chest 2020. 12 presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with covid-19 in the new york city area. jama 2020. 14. confirmed and probable covid-19 deaths weekly report. nyc health clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan, china characterization and clinical course of 1000 patients with covid-19 in new york: retrospective case series acep covid-19 field guide clinical features of patients infected with 2019 novel coronavirus in wuhan, china an interactive web-based dashboard to track covid-19 in real time first case of 2019 novel coronavirus in the united states covid-19 in critically ill patients in the seattle region -case series clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study coronavirus disease 2019 (covid-19) and cardiovascular disease the variety of cardiovascular presentations of covid-19 association of cardiac injury with mortality in hospitalized patients with covid-19 in risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (covid-19) risk factors of fatal outcome in hospitalized subjects with coronavirus disease 2019 from a nationwide analysis in china. chest 2020. 12 presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with covid-19 in the new york city area. jama 2020. 14. confirmed and probable covid-19 deaths weekly report. nyc health clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan, china characterization and clinical course of 1000 patients with covid-19 in new york: retrospective case series acep covid-19 field guide we would like to thank vijay rajaram, who provided invaluable assistance with the development and debugging of data visualization in the manuscript. we would also like to thank andrea kim who was essential in data abstraction. we would like to thank vijay rajaram, who provided invaluable assistance with the development and debugging of data visualization in the manuscript. we would also like to thank andrea kim who was essential in data abstraction.j o u r n a l p r e -p r o o f no funding sources were utilized for conducting this research. authors have no conflicts of interest to disclose. 1011 we assessed the ability to prognosticate 48 hour outcome utilizing the first electrocardiogram and vital signs recorded in the emergency department. ecg abnormality was defined as the presence of atrial fibrillation or flutter, right ventricular hypertrophy or s1q3t3, or any st elevation or depression in two contiguous leads. respiratory vital sign abnormality was defined as a respiratory rate >20, saturation <= 95%, or requiring oxygen therapy by non-rebreather or full face mask. the absence of any of these ecg abnormalities and any respiratory abnormality made the likelihood of intubation or death at 48 hours < 5%. key: cord-337172-vgw8uz83 authors: kaltenboeck, anna; rajkumar, s. vincent title: the case for masks – health care workers can benefit, too date: 2020-04-20 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.04.014 sha: doc_id: 337172 cord_uid: vgw8uz83 nan as the coronavirus crisis in the united states evolves, states and healthcare organizations are meeting the limits of their preparedness for surging cases that require critical care. evidence to guide practice is scant. four months into the pandemic, there are models of possible trajectories of the disease but there are still no clear, national recommendations to guide practice that could reduce the spread of infection in hospitals facing limited availability of personal protective equipment (ppe) including surgical masks and n95 masks. this confusion complicates the tradeoff decisions hospitals must now make between conserving supply for the immediate future, and limiting spread of infection now. anticipating even greater need as the virus spreads in communities across the country, many have opted to limit the use of ppes, especially n95 masks, to only certain clinical procedures and patient encounters. as the new york times reported recently, doctors, nurses, and staff at hospitals across the country are sounding the alarm about risk of exposure. 1 but one solution may be hiding in plain sight, and it's rooted in basic high school physics. the largest respiratory droplets, which are expelled by coughing, sneezing, or speaking, come from the pharynx and upper respiratory tract. 2 this is also where the virus replicates the most. 3 volume is a cubic function, so these large droplets can hold exponentially more copies of the virus than small ones. the large ones quickly succumb to gravity due to their size, while the smaller aerosols, generated in the lower respiratory tracts of infected patients, can remain suspended in the air for several hours. 4 this makes n95 respirators indispensable for protecting healthcare workers treating critically ill patients; it also raises the question of whether more humble alternatives could block the large droplets outside critical care settings. as dr. sui huang lays out in a brilliant exposition of the problem, even makeshift masks create a physical barrier that limits where these droplets can land. 5 while wearing them doesn't stop all exposure, it is curtailed, and studies of crude masks made from basic consumer materials suggest that they can make a difference. perhaps more importantly, masks drastically reduce the number of droplets that make it beyond the wearer's mask and into their surroundings. this insight may be critical for coronavirus. preliminary analysis of nasals swabs from asymptomatic and symptomatic individuals indicate that they appear to have similar viral loads. 6 using a mask allows even those who do not suspect that they are infected to reduce the probability of transmission. added to social distancing, this barrier could reduce the number of viral copies making contact with others and coming to rest on surfaces, waiting for the unwitting brush of a hand that later meets the face. countries that have adopted uniform mask requirements, such as the czech republic, have benefitted from a more notable flattening of their epidemic curves than their counterparts. 7 the cdc recently followed suit, recommending that the general public wear makeshift masks in public areas where social distancing is difficult. 8 however, some healthcare organizations have remained slow to consider them for all employees coming into work. while current rationing helps preserve the supply of n95s and procedural masks, it comes at the risk of adding to the problem by infecting those working in hospitals. the same healthcare workers trying to avoid transmission from patients are susceptible to another sourceeach other. one study suggests that physicians spend around a quarter of their time caring for patients. 9 though that measure likely varies by specialty and may be far higher under current circumstances, it highlights the fact that healthcare involves significant interaction outside of patient care. even with rapid advances in the use of telemedicine and remote work policies for non-essential workers, this still leaves plenty of opportunities to unwittingly pass the virus among unprotected colleagues. reports from other countries indicate that, relative to other groups, healthcare workers are over-represented among confirmed cases. estimates from several us states suggests that as many as 20% of covid-19 cases may be among healthcare workers. 10 the high numbers suggest that exposure beyond patient care is responsible for at least some transmission. 11 adding to the problem is that higher inoculating doses of certain pathogens are hypothesized to result in more severe disease, 12, 13 and clinics and hospitals are the most likely places to encounter highly concentrated doses of the coronavirus. initial analyses and anecdotal reports indicate that healthcare workers are indeed becoming more ill than the general population. 14, 15 the joint commission, which accredits hospitals, has endorsed allowing workers to use their own, privately owned masks and respirators. 16 but even these resources run dry quickly. some groups are already sewing masks for donation to hospitals that are critically short of ppe. we suggest that hospitals treat makeshift masks not only as substitute but also as a complement to ppe, where none is currently being used due to rationing. requiring that anyone on the premises of a patient care organization, whether in clinical or non-clinical workspaces, cover their nose and mouth with a mask -homemade if necessary -is a valuable measure in its own right. some hospitals have already adopted this policy. we urge that this become a universal policy across the country in all health care institutions and nursing homes. the math of coronavirus hasn't worked in our favor, but it isn't set in stone. even if we cannot completely prevent transmission, we can take simple steps to reduce its spread. asking that the general public wear homemade masks was a step in the right direction. we recommend that all persons entering clinics and hospitals, in clinical settings as well as any other non-clinical areas where healthcare workers convene, should wear a mask. this can be a surgical mask if possible, but a makeshift homemade mask should be permitted if surgical masks are unavailable or are in short supply another. we must consider it as a small investment that pays compound interest by safeguarding healthcare workers, and flattening the curve by reducing the likelihood of spreading the virus among themselves, their patients, and families. frightened doctors face off with hospitals over rules on protective gear. the new york times relative contributions of four exposure pathways to influenza infection risk sars-cov-2 entry genes are most highly expressed in nasal goblet and ciliated cells within human airways aerosol and surface stability of sars-cov-2 as compared with sars-cov-1 covid-19: why we should all wear masks -there is a new scientific rationale the early phase of the covid-19 outbreak in simple diy masks could help flatten the curve. we should all wear them in public recommendation regarding the use of cloth face coverings, especially in areas of significant community-based transmission. ceners for disease control and prevention allocation of physician time in ambulatory practice: a time and motion study in 4 specialties health care workers see wave of coronavirus coming in their ranks. nbc news virus knocks thousands of health workers out of action in europe. the new york times coronavirus infections: epidemiological, clinical and immunological features and hypotheses how does the coronavirus behave inside the patient? the new yorker 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 professional and home-made face masks reduce exposure to respiratory infections among the general population key: cord-345058-jfzzngce authors: baughn, linda b.; sharma, neeraj; elhaik, eran; sekulic, aleksandar; bryce, alan h.; fonseca, rafael title: targeting tmprss2 in sars-cov-2 infection date: 2020-07-19 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.06.018 sha: doc_id: 345058 cord_uid: jfzzngce abstract sars-coronavirus 2 (sars-cov-2) has rapidly caused a global pandemic associated with a novel respiratory infection now termed coronavirus disease-19 (covid-19). ace2 is necessary to facilitate sars-cov-2 infection, but due to its essential metabolic roles, it may be difficult to target it in therapies. tmprss2, which interacts with ace2, may be a better candidate for targeted therapies. using publicly-available expression data, we show that both ace2 and tmprss2 are expressed in many host tissues, including lung. the highest expression of ace2 is found in the testes, whereas the prostate display the highest expression of tmprss2. given the increased severity of disease among older males with sars-cov-2 infection, we address the potential roles of ace2 and tmprss2 in their contribution to the sex differences in disease severity. we show that expression levels of ace2 and tmprss2 are overall comparable between males and females in multiple tissues suggesting that differences in the expression levels of tmprss2 and ace2 in the lung and other non-sex-specific tissues may not explain the gender disparities in sars cov-2 severity. however, given their instrumental roles for sars-cov-2 infection and their pleiotropic expression, targeting the activity and expression levels of tmprss2 is a rational approach to treat covid-19. in december 2019, a novel member of the coronaviridae family, sars-coronavirus 2 (sars-cov-2), has spread rapidly throughout the world, probably from wuhan, hubei province, china resulting in an infectious respiratory infection termed coronavirus disease-19 (covid-19) [1] [2] [3] . as of may 1, 2020, over 3.2 million individuals are confirmed to have contracted sars-cov-2, and nearly 250,000 have died from this global pandemic 4 . this global public health emergency requires a rapid and effective response to mitigate covid-19-related morbidity and mortality 2 . elucidating the mechanism of sars-cov-2 infection is necessary for the rational design of therapeutics, the use of novel or re-purposed therapeutics, effective vaccine development and understanding the clinical course of covid-19. infections by the sars coronaviruses, sars-cov and sars-cov-2, are dependent on host proteins angiotensin converting enzyme 2 (ace2) receptor, which has been the subject of multiple investigations in the literature 5, 6 . however, viral entry requires not only binding to the ace2 receptor but also priming of the virus's spike (s) protein by the transmembrane protease serine 2 (tmprss2) protease by cleavage of the s proteins at the s1/s2 and s2' sites. this cleavage step is necessary for the virus-host cell membrane fusion and cell entry 6, 7 . one striking observation made across most countries is the increased severity of disease among older males with sars-cov-2 infection 8 , although there might also be differences in infectivity. while early data of 140 sars-cov-2 patients from wuhan, china demonstrated a nearly equal male to female ratio for infection 9 , subsequent studies of hospitalized and/or deceased patients have identified an increased male prevalence from about 55% to 85% in china 1, 10-16 , to 82% in italy 17 and about 63% in new york city of hospitalized patients 18 . interestingly, this skewed sex difference in disease severity was also reported in studies of respiratory infections caused by related coronaviruses, sars-cov and mers-cov, suggesting a potentially shared underlying mechanism responsible for the high disease severity among infected males [19] [20] [21] [22] . host susceptibility to severe covid-19 disease is also associated with older age, hypertension, heart failure, chronic kidney disease, diabetes, obesity and the use of ace inhibitors 22-24 . while gender can be associated with these additional comorbidities, male sex remains an independent variable associated with severe covid-19 infection in multiple studies 22, 23 . it is possible that expression differences in ace2 and tmprss2 explain the increased severity of disease among males. ace2 is located at xp22.2 within the non-pseudoautosomal portion of the x chromosome (15,561,033-15,602,069, grch38). it displays incomplete x-chromosome inactivation and shows a male-biased expression pattern in several tissues 25 . tmprss2 is located at 21q22.3 within chromosome 21 (41,464,305-41,508,158, grch38) and its expression is modulated by androgen signaling via multiple androgen receptor elements upstream of the gene's transcriptional start site 26, 27 . in this study, we evaluate the expression levels of both ace2 and tmprss2 in many host tissues, including lung. given the increased severity of disease among older males with sars-cov-2 infection, we also address the potential roles of ace2 and tmprss2 in their contribution to the sex differences in disease severity. ace2 and tmprss2 expression data were obtained directly from the genotype-tissue expression (gtex) project (https://gtexportal.org) or from the human protein atlas gtex data (rnaseq based on rsemv1.2.22 (v7). expression from all tissue samples available were plotted using the box plots available from the gtexportal website with plots shown as median and 25 th and 75 th percentiles and dots displayed as outliers if they are above or below 1.5 times the interquartile range. comparison of ace2 and tmprss2 expression was performed using gtex tool multigenequerypage. from the human protein atlas gtex data (rnaseq based on rsemv1.2.22 (v7), box plots were created using spss software (ibm) and extreme outliers in each type of sample were identified (data not shown). if extreme outliers were present in the sample population, then the significance of the difference was calculated using the mood's median test. for all other samples without extreme outliers, kruskal wallis was used to calculate the significance. allele frequency of two missense variants rs75603675 and rs12329760 in tmprss2 gene were calculated using the geography of genetic variants browser 28 . given the necessity of ace2 and tmprss2 genes for sars cov-2 infection, we evaluated their expression in human tissues using data from the genotype-tissue expression (gtex) project (https://gtexportal.org). expression of ace2 and tmprss2 was detectable in multiple tissues. since the common symptoms of covid-19 involve cough, sore throat, gastrointestinal issues, anosmia and dysgeusia 14, 29 , we analyzed the levels of ace2 and tmprss2 in tissues associated with these sequelae. both ace2 and tmprss2 were expressed in the lung, with expression levels of tmprss2 higher than ace2 ( figure 1 ). tissues associated with the gastrointestinal system with elevated ace2 expression include small intestine (terminal ileum), colon (transverse), esophagus (mucosa), minor salivary gland and pancreas, esophagus, liver, colon (sigmoid) and stomach ( figure 1a ). tmprss2 expression was also detected in gastrointestinal tissues, including stomach, colon (transverse), pancreas, small intestine (terminal ileum), minor salivary gland, esophagus (mucosa), liver and colon (sigmoid) ( figure 1b ). some patients with covid-19 experience anosmia and dysgeusia, findings that may be a result of olfactory nerve abnormalities 29 . while gtex does not have expression data specifically from olfactory tissues, the overall expression levels of both (table 2) ; however, these findings were not considered significant. no significant differences in ace2 or tmprss2 expression were observed in lung tissue (table 2 ). the rapid development of novel approaches or re-purposing of existing therapies is critical in mitigating the coronavirus pandemic. due to the centrality of ace2 and c.589g>a p.val197met) whose frequencies vary by ancestry and geography ( figure 4 ). targeting tmprss2 protease activity through protease inhibitors or indirectly through adt will require additional studies to determine the role of rs75603675 and rs12329760 on tmprss2 expression, protease activity and in response to protease inhibition. our observations are consistent with previous studies evaluating tmprss2 expression in lung tissue using gtex data 45 , although, due to the limitation of the data, they do not consider age, menopausal status, or ancestry. while a very slight increase in tmprss2 expression was observed in the bronchial epithelial cells of males compared to females using gse66499 microarray data; 45 , it is unclear whether this small increase in tmprss2 expression explains the increase in disease severity in males. our results are also consistent with previous studies supporting no significant differences in ace2 expression in lung tissue in association with age (>60 and <60 years), race (caucasian and asian) and sex using rnaseq, microarray and gtex datasets 46 . combined, these findings suggest that differences in the expression levels of tmprss2 and ace2 in the lung and other non-sex-specific tissues likely do not explain the gender disparities in sars cov-2 severity. however, the observation of high ace2 expression in the testes is an intriguing observation, and a recent study hypothesized that the testes could serve as a reservoir for sars-cov-2 30 . however, the expression of genes in the testes has been associated with "leaky expression" without evidence of a functional consequence of the expressed genes 47 . therefore, the expression of ace2 in the testes warrants additional investigation, including demonstration of sars-cov-2 in semen. additional studies are also needed to evaluate whether androgens (or even estrogens) contribute to sex-associated disease severity independently of ace2 or tmprss2 functions. sars-cov-2 has rapidly caused a global pandemic. both ace2 and tmprss2 are expressed in many host tissues, but the expression levels of ace2 and tmprss2 are overall comparable between males and females in multiple tissues. this suggests that expression differences of tmprss2 and ace2 in the lung and other non-sex-specific tissues may not explain the gender disparities in sars cov-2 severity. however, targeting the activity and expression levels of tmprss2 is a rational approach to treat covid-19 and should be explored further. the genotype-tissue expression (gtex) project was supported by the common clinical features of patients infected with 2019 novel coronavirus in wuhan a novel coronavirus outbreak of global health concern a novel coronavirus from patients with pneumonia in china an interactive web-based dashboard to track covid-19 in real time a pneumonia outbreak associated with a new coronavirus of probable bat origin sars-cov-2 cell entry depends on ace2 and tmprss2 and is blocked by a clinically proven protease inhibitor enhanced isolation of sars-cov-2 by tmprss2-expressing cells clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study clinical characteristics of 140 patients infected with sars-cov-2 in wuhan epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive study key: cord-343227-6n5el4hz authors: fischer, philip r.; bostwick, j michael title: intentionality in medical school admissions in the covid-19 era date: 2020-09-24 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.09.026 sha: doc_id: 343227 cord_uid: 6n5el4hz nan in only months, sars-cov-2 has irrevocably changed our world. previous social norms are no longer normal. personally, we isolate ourselves from our fellow humans as much as possible, and when we absolutely need to have contact with others, we keep a six-foot distance while wearing masks that hide all but our yearning eyes. as healthcare workers, when we must cross the six-foot social chasm, we supplement our masks with goggles and gloves for routine interactions, more elaborate protective costumes when risking exposure to body fluids. as medical educators, we teach what we can virtually and mitigate risk by arranging for students to don appropriate ppe when learning requires them to lay on hands. in this issue of mayo clinic proceedings, bhatt and bhatt highlight practical difficulties medical school applicants confront in the covid-19 era. 1 we sympathize with the disruptions they face -altered mcat schedules, restricted volunteering opportunities, closed campuses, shuttered laboratories -as the familiar route to medical school veers into uncharted territory. and yet we wish to gently challenge a tendency towards solipsism-a propensity for self-absorption -as aspiring medical students face what bhatt and bhatt describe as "an increased sense of stress as carefully charted paths to medical school become so utterly disrupted." 1 that is, we want to remind applicants this season that they are not alone in having to deal with disruptions. as admissions deans, we share in their struggles. we know that the future of medicine depends on our adapting assessment processes to ensure that qualified applicants continue to receive fair and just evaluations. a recent new york times op-ed by frank bruni focuses on the ideas of jeffrey selingo, author of the recently published who gets in and why: a year inside college admissions. selingo calls out "application bloat", which he defines as "the flamboyant multiplicity of clubs, causes, hobbies, and other material that applicants assemble and showcase." 2,3 this bloat has also infected medical school applications. bhatt and bhatt note how it may be harder for candidates to demonstrate their fitness in the usual, hyperinflated ways. this may not be a bad thing. "the pandemic,"bruni writes, "put many of those activities on hold, creating a pause in which [selingo] believes some schools and some students will recognize the lunacy of this overkill." 2 admissions committees have the opportunity to recalibrate their criteria to emphasize quality over quantity in selecting what truly matters in building the best future doctors. atop the pandemic, the united states has been riven by social unrest that exploded in the aftermath of george floyd's death. as a nation we have been forced to face up to deep social and economic inequities that continue to restrict access to the american dream for people of color. we know that these inequities also limit opportunities in our profession for members of many groups underrepresented in medicine, including students of color, students with disabilities, lgbtq students, students from lower socioeconomic backgrounds, and other. these are applicants for whom "flamboyant multiplicity" may not be possible, let alone expected. we -applicants and admissions personnel alike -are called to be flexible and improvisatory, even while wracked with unfamiliarity and uncertainty. nowhere is this more apparent than in the virtual environment in which we now meet one another for the first -and maybe only -time. we -applicants and admissions personnel alike -fear that remote interviews compromise adequately getting to know j o u r n a l p r e -p r o o f applicants' personalities and interests adequately. we --applicants and admissions personnel alikefear that the dearth of in-person interactions with current students, faculty, and even the brick and mortar itself interferes with applicants discerning what a given school really has to offer them. if getting into medical school is a dance, it is as if we have been perfecting our plies and jetes for the ballet recital for years, only to be told just before the performance that we will be expected to show off our jazz and hip-hop moves instead. there goes our "carefully charted" choreography out the window. yet it's all dance. we must all flex and improvise. in recent years, "change management" has become key in shaping how business communities adapt to new and shifting realities. change has always been inevitable, but both the pandemic and social unrest prompt us to manage it even more assiduously than usual. we begin with the obvious: things are different, but that doesn't have to mean worse. we don't want merely to figure out how to "do interviews" with technology. we want to discover ways to harness technology to help us get to know one another virtually as effectively as we used to do in person. the goal of achieving meaningful human connection must drive innovation. we must not settle for substituting something new but inferior for the old. online dating has been around for years, with many finding life partners in ways that were unthinkable not that long ago. as virtual meetings and telehealth visits have become commonplace and surprisingly effective, we have no reason to believe that remote interview experiences cannot be tailored to provide authentic engagement between applicants, faculty, and students. innovative use of chat rooms and guided video tours can supplement formal interviews. embracing technology can facilitate staying in touch throughout the season as applicants and committees proceed with narrowing their picks. engagement is communication's bedrock. it is no longer enough to say, "we've always been adaptable and we'll get through this," or, "yes, black lives have always mattered to us and still do." applicants appreciate our transparency as we honestly acknowledge the institutional racism existing within organized medicine. they want to know how our school is responding to the critical issues of our time. we must be prepared not only to profess our values but also to respond to questions about how we live them out in our teaching and patient care. we have come to realize that our admissions committee has long prepared for this moment in a seemingly incongruous way: book club. each admissions season for the past half-dozen years, we have collectively read a book chosen to open our minds and guide our thoughts as we sift through thousands of applications, extend invitations to hundreds of interviewees, and select applicants to receive offers of admission to the 96 md seats in our national medical school. we have read excellent sheep, 4 and tackled the reality that some pre-medical students have based their lives on becoming a perfect -and too often perfectly non-descript -applicant at the expense of themselves. we have come to realize we favor real people who retain their individualities and don't just "check off boxes". as bhatt and bhatt state, students this season have had "novel opportunity" to help out in "unprecedented" situations, even while potentially finding it harder to achieve excellent sheepness. 1 we have read black man in a white coat 5 in tandem with implicit bias training to help us uncover and acknowledge the biases we hold. we have read quiet, 6 a text that encourages us to look beyond the shiny, carefully curated personas many candidates present for the thoughtful and observant introverts we believe medicine needs more of. keeping a holistic approach always in mind, we have sought to identify societal inequities and do what we can to address them by attracting students from groups historically blocked from medical education. educated, 7 hillbilly elegy, 8 and there will be no miracles here 9 have facilitated our committee recognizing and recruiting applicants from all sorts of socioeconomic and cultural backgrounds in hopes of crafting truly diverse classes. this season, we are reading caste 10 as we seek to understand, identify, and remediate the ways in which hundreds of years of baked-in assumptions about who is up and who down continue to privilege some at the expense of others. as universities like yale and harvard engage in ongoing legal battles over their admissions policies, we realize we must tread gingerly: the courts will not tolerate overcompensating for past wrongs by applying new power imbalances. we must consider each applicant thoughtfully as we carefully thread the needle between conflicting approaches on how best to go about assembling classes that fairly represent america's diversity. maybe, just maybe, the intentionality with which we have been forced to approach our admissions work in this time of covid, social distancing, and societal unrest will foster greater justice in how we identify future physicians. aspiring to that outcome amid a virally induced revolution is a worthy goal. applying to medical school in the covid-19 era the coronavirus may change college admissions forever who gets in and why: a year inside college admissions excellent sheep: the miseducation of the american elite and the way to a meaningful life black man in a white coat: a doctor's reflections on race and medicine the power of introverts in a world that can't stop talking educated: a memoir hillbilly elegy: a memoir of a family and culture in crisis there will be no miracles here: a memoir caste: the origins of our discontents key: cord-258307-nsdhvc8w authors: maki, dennis g. title: sars revisited: the challenge of controlling emerging infectious diseases at the local, regional, federal, and global levels date: 2011-10-20 journal: mayo clin proc doi: 10.4065/79.11.1359 sha: doc_id: 258307 cord_uid: nsdhvc8w nan i n 1992, a blue-ribbon panel was commissioned by the institute of medicine of the national academy of sciences to advise the us government on emerging infectious diseases that posed a threat or potential threat to the health of people living in the united states and assist in the federal allocation of public health resources. 1,2 emerging infections were defined as infections caused by newly identified human pathogens-such as the legionella bacillus, 3 the reemergence of previously controlled pathogens-such as measles, 4 or the appearance of anti-infective resistancesuch as methicillin-resistant staphylococcus aureus, 5 the incidence of which had increased significantly within the past 2 decades or threatened to increase in the near future. since the outbreak of severe pneumonia in us veterans attending a convention at the bellevue-stratford hotel in 1976, found 6 months later to have been caused by a previously unknown and remarkably ubiquitous waterborne bacterium, legionella pneumophila, 3 more than 3 dozen human pathogens have been identified as agents of emerging infectious diseases in the united states (table 1) . the most recent and perhaps most fearsome emerging infections are the appearance of west nile virus encephalitis in new york city in 1999 and its rapid spread westward 6 ; inhalation anthrax, deriving from use of bacillus anthracis spores as a biologic weapon against the us civilian population in 2001 7 ; the global outbreak of severe acute respiratory syndrome (sars) in 2003 8 ; and the looming threat of pandemic influenza, especially global disease caused by the highly virulent avian subtype a (h5n1). [9] [10] [11] during the past 16 months, mayo clinic proceedings has published reviews of diseases caused by 3 of these emerging pathogens, west nile virus, 12 the sars coronavirus (sars-cov), 13 and avian influenza virus. 14 efforts to better inform readers about the consequences of emerging infectious diseases continue in this issue of the proceedings, in which chiang et al 15 report a study of 14 cases of nosocomial sars acquired in 3 taipei hospitals during 2003. most of the 14 patients, 13 of whom were followed up for at least 8 months, were health care workers, and because few had underlying diseases, all except 1 survived; thus, this study provides some of the best data on the long-term effects of sars on the lung. the clinical features and natural history of sars encountered by chiang et al are similar to those reported in much larger cohorts. 16, 17 all their patients had fever, and most had cough and dyspnea as well; however, 79% had diarrhea, and 64% had myalgias, indicative of the severe systemic immunoinflammatory response to this unique new human infection. 18, 19 similarly, all their patients had lymphopenia, and most had elevated levels of lactate dehydrogenase, now well-defined surrogate laboratory markers for patients presenting with sars. 16, 17 however, chiang et al also found that patients with a very high c-reactive protein or lactate dehydrogenase level at the outset were far more likely to have progression to a severe stage of disease requiring mechanical ventilatory support, information of value to clinicians who might be called on to manage patients with sars in the not-too-distant future. most interestingly, chiang et al show that whereas bilateral fibrotic changes were demonstrable by high-resolution computed tomographic imaging 6 to 8 months after the acute infection, most of the survivors showed near-normal spirometric lung volumes (forced vital capacity, forced expiratory volume in 1 second), albeit one third with reduced diffusion capacity, but none required home oxygen. it is likely that most of these individuals will have recovery of normal lung function. these findings are very similar to the well-documented long-term pulmonary effects of garden-variety acute respiratory distress syndrome, stemming from overwhelming pneumonia, gastric aspiration, near drowning, trauma, pancreatitis, or systemic sepsis, in which most survivors have gratifying recovery of lung function in the early years after the acute episode. [20] [21] [22] because sars is such a unique human viral infection and induces such an unusually severe systemic inflammatory response, 18, 19 it will be important to closely follow survivors of severe sars for considerably longer to be certain that latently expressed progressive pulmonary fibrosis does not occur. between the first reports from the world health organization and the centers for disease control and prevention (cdc) that defined sars as a global threat in march 2003 23,24 and control of the epidemic in southeast asia and north america 5 months later, more than 8000 persons in the republic of china, hong kong, singapore, vietnam, taiwan, and canada became infected, and 774 (9.6%) died of the infection 8 ; mortality exceeded 50% in patients older than 60 years. 16, 17 since the last communication on sars in the proceedings in april 2004, there have been extraordinary advances in our understanding of the disease in terms of its pathogenesis, epidemiology, management, and control: editorial • like many of the emerging human pathogens such as borrelia burgdorferi (mice, deer), us hantavirus (mice), west nile virus (wild birds), variant creutzfeldt-jakob prions (cattle, potentially free-ranging cervids), monkeypox virus (exotic african rodents and primates, us prairie dogs), and avian influenza virus a (h5n1) (edible birds), infection by sars-cov can legitimately be considered a zoonosis, and wild mammals formed the initial reservoir of the virus-sars-cov has been isolated from palm-top civets and raccoon dogs in the live animal markets in southern china, 25 and purveyors of these animals commonly show asymptomatic sars-cov seropositivity. 25, 26 the genomic evidence that sars-cov is an animal-human recombinant is compelling, [27] [28] [29] [30] and sars-cov appears to have had a biologic origin remarkably similar to the human influenza a viruses and human immunodeficiency virus. although the sars virus originated in animals and made the leap to humans, once established in the human population, the virus has spread rapidly person-toperson, and the major reservoir of human disease is humans in the early stage of infection, before they have been diagnosed as having the virus and placed in respiratory and barrier isolation. 31 • elegant molecular epidemiology has traced the origins of sars-cov to foshan in guangdong province, southern china, from whence it spread to beijing, then to hong kong, and from hong kong to vietnam, singapore, and canada. 32,33 a 65-year-old chinese physician who traveled to hong kong on march 21, 2003 , where he spent only 1 day, appears to have been the source of sars-cov that ultimately resulted in thousands of cases of sars in 26 countries and 5 continents. 34 • sars-cov is a new human pathogen to most of the world. studies by the cdc have shown no serologic evidence of past infection in more than 400 specimens from us residents collected long before the sars epidemic. 35 • as a new human pathogen, there is, understandably, little if any natural immunity. virtually all persons who became infected by sars-cov became symptomatic, 31 and studies of exposed health care workers show that less than 1% to 2% of those infected experience mild or subclinical infection. 36 • sars spreads almost exclusively person-to-person by respiratory droplets, rarely by the airborne route 31 ; the roles of contact or fecal-oral transmission are less clear but probably occur. 16, 37 the puzzling large outbreak in amoy gardens in hong kong was recently traced to virus-laden aerosols generated from sewage, using sophisticated airflow-dynamic studies and computational fluid-zone modeling. 38 however, whereas the outbreak in the amoy gardens complex represents distant airborne spread, distant spread is probably rare, as evidenced by the very low risk of infection in patients with no plausible face-to-face exposure to a patient with symptomatic sars, by the effectiveness of simple isolation measures in hospitals that did not have sophisticated negative-pressure air-controlled rooms with separate roofline exhaust, and by the relatively few secondary cases on commercial airliners. 31, [39] [40] [41] in an investigation of 3 flights in which an airliner transported 1 or more symptomatic infected passengers, 16 laboratory-confirmed cases of secondary sars were detected on 1 flight, with the greatest risk to other passengers close to the index case (seated within 3 rows, relative risk 3.1); on 1 flight carrying 4 symptomatic infected persons, possible transmission occurred to only 1 other passenger, and no secondary illness was documented on another flight that carried 1 person with early sars. 39 • simple control measures, most importantly the use of a high-quality filtration mask, ideally an n-95-type mask but even a surgical mask, 42 combined with full-barrier precautions in a single room were highly effective in preventing spread to other patients and health care workers where it was most carefully studied, in hong kong, singapore, and canada. 16, 17, 31, 42 • patients with early sars do not pose a risk to others until they become symptomatic and start to cough, 31 but there is considerable variability in contagiousness, probably based on the quantity of virus in the respiratory secretions 43 and the degree of coughing. very close proximity to an infected patient who is coughing heavily poses the greatest risk. 16 it appears that most spread of the virus can be linked to "super spreaders," and most infected persons are probably not very contagious. 31, 34, [44] [45] [46] [47] understandably, the risk of acquisition of sars-cov is far higher in the hospital than in the community. 31, 46 • the mean incubation period of sars is approximately 6 days 48 (range, 2-10 days) and is considerably longer than that for most other human respiratory viral infections, such as the common cold or influenza a, which permits case-contact investigations and quarantine of exposed contacts before those destined to become infected and contagious can spread the disease to others. • because so few persons develop clinical sars more than 10 days after exposure, there is no need to extend quarantine of exposed persons beyond 10 days. 31 • fever is so ubiquitous in sars that monitoring the body temperature of quarantined contacts and health care workers caring for patients with sars is a sensitive and specific method for detection of early infection, especially for health care workers before they become symptomatic and contagious. 49 all health care workers caring for patients with suspected or proven sars should be monitored 3 to 4 times daily; fever constitutes grounds for quarantine and diagnostic studies. 50,51 for personal use. mass reproduce only with permission from mayo clinic proceedings. • to control sars, early diagnosis is essential. clinical predictors for sars, based on study of large cohorts of patients in hong kong, 52 suggest that fever, myalgia, malaise, an abnormal chest radiograph, lymphopenia, thrombocytopenia, and, most importantly, previous contact with a patient with sars are each associated with a greatly increased likelihood of sars. in contrast, in a newly symptomatic patient older than 65 years or younger than 18 years without a plausible face-to-face exposure who has a cough productive of sputum, abdominal pain, sore throat, rhinorrhea, or leukocytosis, sars is unlikely. • modern-day virology has shifted rapidly during the past decade, from tissue cultures and serologic techniques to detection of the viral genome in clinical specimens by nucleic acid amplification techniques, such as polymerase chain reaction (pcr) or, for rna viruses, reverse transcriptase-pcr (rt-pcr). 53 highly sensitive and specific rt-pcr assays were developed in most of the countries afflicted by sars, most notably in hong kong, singapore, and canada, and were invaluable in early confirmation of sars-cov infection. the sensitivity of second-generation assays has been as high as 80% in the first 3 days of illness. [54] [55] [56] [57] whereas a pcr assay developed at the cdc was given immediate investigational device exemption approval by the food and drug administration, no commercial pcr assay has yet been licensed for clinical use in the united states. if sars returns and spreads in the united states, it will be essential that reliable real-time pcr assays are available in us hospitals. public health laboratories are not clinical service laboratories and are unlikely to be able to meet the need if sars reappears on a major scale. private companies should be given access to clinical strains of sars-cov and, if available, clinical specimens from infected patients in order to test and validate commercial assays that hopefully will be as accurate as, perhaps more accurate than, the current cdc assay. • ribavirin was used empirically in many patients with sars in southeast asia with the impression that it was effective therapeutically; however, in vitro studies have shown that sars-cov is not susceptible to ribavirin at concentrations achievable clinically. 58 hence, it is unlikely that the drug is active therapeutically. uncontrolled trials suggest that interferon alfa may be of benefit. 59, 60 there are a number of compounds and antiviral drugs with in vitro activity against sars-cov, including interferon alfa, interferon beta, and glycyrrhizin (licorice-root extract). theoretical rna virus targets, such as protease inhibitors and fusion inhibitors, also need to be assessed for efficacy. if sars returns on a major scale, it will be essential that the efficacy of antiviral drugs, such as commercial interferons, is tested in randomized, double-blind trials. • whereas uncontrolled studies of treated cohorts in asia have suggested that using moderate doses of corticosteroids, 1 to 2 mg/kg of a prednisone-equivalent daily, at the first evidence of severe sars, specifically hypoxemia, may improve survival, 59,61,62 corticosteroid therapy for sars has had serious adverse effects, 63 and a single randomized trial of preemptive pulse corticosteroid therapy did not show benefit. 64 if sars returns, it will also be essential that efforts are made to determine the efficacy of corticosteroids in a large prospective, randomized, doubleblind trial. • advancing age (>50 years) and coexisting illnessespecially diabetes or heart failure-greatly increase the likelihood of severe sars (requiring mechanical ventilatory support) and the risk of death. 16, 17, 43 inexplicably, sars is usually very mild in children, 65 who do not appear to be very contagious. 31 also, maternal-fetal transmission does not appear to occur. 66 • while coronaviruses are more resistant than most other respiratory viruses, 67 sars-cov appears to be susceptible to the commercial microbicides used for surface decontamination in hospitals. 31 • most importantly, outbreaks in hong kong, singapore, vietnam, canada, and elsewhere in the world were successfully controlled, but only by an intensive, coordinated effort in which the national public health authorities worked very closely with the regional public health agencies and, especially, hospital infection control officers and clinicians caring for patients with sars. [68] [69] [70] [71] the measures needed for control of sars are clear 31, 50, 51 : (1) earliest detection of cases, having at-risk individuals isolated and queried about their face-to-face contacts during the 10 to 14 days before the onset of illness; (2) expeditious contact tracing, with uncompromising home quarantine for all contacts of suspect and proven cases; and (3) stringent isolation of symptomatic suspect and proven cases, focusing most heavily on techniques to prevent droplet and airborne spread (eg, single negative-pressure rooms, ideally with separate roofline exhaust or filtration of outlet air; fit-tested high-filtration mask respirators and a face shield or goggles or a powered air-purifying system for all health care workers and others entering the room of the case, as well as the use of nonsterile gloves and gowns to prevent contact transmission). 50,51 the value of border screening and temperature monitoring of travelers is questionable. 71 the resources needed to control an outbreak in a city or a country are huge. in north america, the toronto outbreak consisted of 246 documented cases in 4 hospitals. 70 to control sars in toronto required home quarantine of more than 23,000 contacts and an informational hotline that handled more than 300,000 calls; the economic cost of the epidemic to the city and the city and provincial governments was estimated at $1.13 billion (canadian). the longterm psychological impact of sars on patients, families, and health care workers was also very substantial. [72] [73] [74] • efforts are now under way to test candidate sars vaccines. 75 the national tragedy of september 11, 2001, was followed by the most serious instance of bioterrorism involving the us civilian population in history, the spread of anthrax through the us mail. 7 these events coincided with growing awareness that weaponized smallpox virus almost certainly yet exists in the world, with strong suspicion that the former soviet union, 76 as well as countries that have sponsored international terrorism, such as iran and north korea, 77,78 retained smallpox virus as a potential weapon. the unthinkable has become plausible: weaponized smallpox virus in the hands of international terrorist groups. as a consequence, the federal government has undertaken major steps to greatly improve emergency preparedness at all levels, especially the capacity to respond to the use of biologic agents such as smallpox or anthrax as weapons against the civilian population as well as our military (table 2) . 79,80 billions of dollars have been appropriated to improve the capacity of public health and clinical laboratories to reliably detect infectious agents that might represent biologic weapons; to improve the likelihood that emergency department physicians and all primary care providers could recognize anthrax, smallpox, and other infectious diseases that might denote bioterrorism; to establish and coordinate surveillance programs at the regional, state, and federal levels; and to train more than a million public protection personnel and greatly improve preparedness of the 7000 us hospitals. 81 at my center, we have spent hundreds of person-hours identifying and retrofitting a 35bed patient-care unit for the potential accommodation of patients with smallpox or other highly contagious infections such as sars or pandemic influenza caused by a new strain. this local effort has focused on air control and negative-pressure isolation rooms, which have the capacity for supporting mechanical ventilation, and developing comprehensive guidelines for health care workers who would staff the unit. for the first time in our generation, there has been a major injection of federal dollars into the public health sector at the state, regional, and municipal levels. 81 the challenge will be to provide sustained support, rather than a limited bolus of supplemental funding. hopefully all this effort will never be needed to control smallpox-or an even more terrifying engineered pathogen 76, 82 -that might be used as a biologic weapon. if it is not, the effort will not have been wasted because it is likely that all the planning and resource allocation will prove invaluable for controlling the spread of natural emerging pathogens, such as sars-cov or a new strain of influenza virus, which are probably far more likely to pose a serious threat to human and animal health in the united states and worldwide. the greatest and most immediate threat is the longoverdue reappearance of pandemic influenza a. the leading and most dreaded candidate for the new pandemic subtype is avian influenza a (h5n1), recently reviewed in this journal, 14 which was first recognized in a large poultry outbreak in the live-animal markets of hong kong in 1997, where the virus had acquired the capacity to spread from infected birds to humans and killed 6 of 18 infected persons. 83 to control the outbreak, authorities killed nearly 2 million chickens to eliminate the reservoir of infection. since that time there have been contained outbreaks of different subtypes of avian influenza-h9n2, h7n2, and h7n7-that have caused disease in poultry, with secondary infections reported among pigs and humans, but infrequent and mild human disease, such as conjunctivitis or mild influenza-like illness. 14 there was only 1 human death among 89 cases in a large h7n7 outbreak in the netherlands in 2003. 84 in january 2003, a highly pathogenic strain of avian influenza a (h5n1) was identified in south korea and spread rapidly over the succeeding months to 7 other asian countries, cambodia, china and hong kong, indonesia, japan, laos, thailand, and vietnam. [9] [10] [11] to date, there have been 43 confirmed cases in humans, nearly all in children or young adults; 31 (72%) have proved fatal. 11 more than 100 million edible birds have been slaughtered by governmental authorities. all species of domestic birds appear to be susceptible to the h5n1 strain, which is probably transmissible to all species of wild birds, some of which migrate transcontinentally. the epidemic a (h5n1) strain appears to be gaining virulence 85 and was recently shown to have acquired the capacity of infecting mammalian species, domestic cats and wild felines within zoos 86 and pigs. most alarmingly, there is growing evidence that person-to-person spread can occur, 87 albeit yet rarely. the epidemic strain further shows high-level resistance to amantadine and rimantadine but is thus far susceptible to neuraminidase inhibitors, such as oseltamivir or zanamivir. 14 if the strain acquires recombinant genes that facilitate human infection and person-to-person transmission, pandemic disease could prove more catastrophic than the great h1n1 influenza epidemic of 1918. even more concerning has been the challenge of developing an avian influenza vaccine. current influenza vaccines are unlikely to provide any protection against the new h5n1 avian strain. the standard method for manufacturing influenza vaccines, growing the vaccine strain in chicken embryos, does not work because the avian a (h5n1) strain is so virulent that it kills the embryo before there is sufficient virus to harvest. novel genetic techniques, under way in the united kingdom, 88 will be needed to alter the strain's phenotypic features so that it can be grown in sufficient quantities in fertilized eggs and an effective vaccine can be constructed. vaccine manufacturers are understandably reluctant to make the investment to develop and manufacture a new vaccine, particularly in large quantities, when there is uncertainty whether the avian strain will indeed spread and necessitate administration of hundreds of millions of doses. 89 similarly, the sole manufacturer of the only oral neuraminidase inhibitor likely to be effective against avian influenza (oseltamivir) has very limited production capacity, and less than 2 million doses are currently available in us pharmaceutical stocks; the director of the cdc has stated that it would be desirable to have at least 100 million doses available. 89 in summary, 22 cases of cutaneous or inhalation anthrax traced to domestic bioterrorism and the global sars outbreak represent ill winds that have blown considerable good. the greatly expanded us federal effort to improve national preparedness for bioterrorism has strengthened public health at every level, and whereas we are far from being able to consider the united states as fully prepared, we are better prepared than only 3 years ago. 90 the recent us epidemic of monkeypox, 91 traced to importation of infected exotic african rodents and the burgeoning domestic trade in us prairie dogs, could be considered a live tabletop exercise-with a relatively innocuous pathogen-for the recognition and containment of smallpox. similarly, the global sars emergence has proved the enormous power of modern-day molecular biology to identify and characterize new pathogens, to detect clinical infections far more rapidly than in the past, and to quickly unravel the epidemiology of new infectious diseases-the scientific foundation for strategic control. the sars outbreak was contained only by unprecedented international cooperation under the leadership of the world health organization 68 and successful coordination within the affected countries between national and regional public health agencies and health care providers. controlling the next influenza pandemic, especially if it is caused by a highly virulent subtype such as the current a (h5n1) avian influenza virus, will require even greater international collaboration and vertical coordination in public health within the involved countries. it will also require an unprecedented commitment by the industrialized countries of the world to meet the needs of afflicted developing countries with limited public health resources. we are all in this together: it is in every country's self-interest to work collaboratively toward a common goal-the prevention of communicable disease and improvement of health of every citizen of the world. methicillin-resistant staphylococcus aureus: interstate spread of nosocomial infections with emergence of gentamicin-methicillin resistant strains update: investigation of bioterrorism-related anthrax and adverse events from antimicrobial prophylaxis world health organization. summary of probable sars cases with onset of illness from 1 world health organization international avian influenza investigative team world health organization. cumulative number of confirmed human cases of avian influenza a (h5n1) since 28 west nile virus: epidemiology, clinical presentation, diagnosis, and prevention sars: epidemiology, clinical presentation, management, and infection control measures avian influenza: a new pandemic threat? eight-month prospective study of 14 patients with hospital-acquired severe acute respiratory syndrome clinical features and short-term outcomes of 144 patients with sars in the greater toronto area plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome analysis of serum cytokines in patients with severe acute respiratory syndrome pulmonary function and health-related quality of life in a sample of long-term survivors of the acute respiratory distress syndrome canadian critical care trials group. one-year outcomes in survivors of the acute respiratory distress syndrome world health organization. severe acute respiratory syndrome (sars)-multi-country outbreak-update isolation and characterization of viruses related to the sars coronavirus from animals in southern china prevalence of igg antibody to sars-associated coronavirus in animal traders characterization of a novel coronavirus associated with severe acute respiratory syndrome the genome sequence of the sars-associated coronavirus mosaic evolution of the severe acute respiratory syndrome coronavirus phylogenomics and bioinformatics of sars-cov comparative full-length genome sequence analysis of 14 sars coronavirus isolates and common mutations associated with putative origins of infection coronavirus genomic-sequence variations and the epidemiology of the severe acute respiratory syndrome severe acute respiratory syndrome (sars) in singapore: clinical features of index patient and initial contacts sars working group. a novel coronavirus associated with severe acute respiratory syndrome prevalence of asymptomatic infection by severe acute respiratory syndrome coronavirus in exposed healthcare workers [abstract cluster of severe acute respiratory syndrome cases among protected health care workers-toronto evidence of airborne transmission of the severe acute respiratory syndrome virus low risk of transmission of severe acute respiratory syndrome on airplanes: the singapore experience assessment of in-flight transmission of sars-results of contact tracing expert sars group of hospital authority. effectiveness of precautions against droplets and contact in prevention of nosocomial transmission of severe acute respiratory syndrome (sars) clinical progression and viral load in a community outbreak of coronavirusassociated sars pneumonia: a prospective study transmission dynamics of the etiological agent of sars in hong kong: impact of public health interventions transmission dynamics and control of severe acute respiratory syndrome modeling the sars epidemic epidemiological determinants of spread of causal agent of severe acute respiratory syndrome in hong kong nosocomial transmission of the severe acute respiratory syndrome (sars) [abstract abstract k-1313. 50. world health organization. severe acute respiratory syndrome (sars): who guidelines/recommendations/descriptions. available at: www.who.int/csr/sars/guidelines/en. accessibility verified hospital authority sars collaborative group. a clinical prediction rule for diagnosing severe acute respiratory syndrome in the emergency department molecular and diagnostic clinical virology in real time early diagnosis of sars coronavirus infection by real time rt-pcr detection of sars coronavirus in plasma by real-time rt-pcr detection of sars coronavirus in patients with suspected sars centers for disease control and prevention. severe acute respiratory syndrome (sars) and coronavirus testing--united states description and clinical treatment of an early outbreak of severe acute respiratory syndrome (sars) in guangzhou, pr china preliminary results on the potential therapeutic benefit of interferon alfacon-1 plus steroids in severe acute respiratory syndrome :11. abstract k-1315e development of a standard treatment protocol for severe acute respiratory syndrome high-dose pulse versus nonpulse corticosteroid regimens in severe acute respiratory syndrome fatal aspergillosis in a patient with sars who was treated with corticosteroids the use of corticosteroids in sars clinical presentations and outcome of severe acute respiratory syndrome in children sattar sa. microbicides and the environmental control of nosocomial viral infections world health organization. a multicentre collaboration to investigate the cause of severe acute respiratory syndrome the international response to the outbreak of sars in 2003 public health measures to control the spread of the severe acute respiratory syndrome during the outbreak in toronto world health organization working group on prevention of international and community transmission of sars. public health interventions and sars spread the immediate psychological and occupational impact of the 2003 sars outbreak in a teaching hospital post-traumatic stress disorder and quality of life in patients diagnosed with sars [abstract severe acute respiratory syndrome-related psychiatric and posttraumatic morbidities and coping responses in medical staff within a primary health care setting in singapore canadian researchers testing sars vaccine in china the chilling true story of the largest covert biological weapons program in the world, told from the inside by the man who ran it the looming threat of bioterrorism available at: www.bt.cdc.gov/planning/tprstrategy/index.asp. accessibility verified october 8, 2004. 81. public health security and bioterrorism preparedness and response act of expression of mouse interleukin-4 by a recombinant ectromelia virus suppresses cytolytic lymphocyte responses and overcomes genetic resistance to mousepox human influenza a h5n1 virus related to a highly pathogenic avian influenza virus transmission of h7n7 avian influenza a virus to human beings during a large outbreak in commercial poultry farms in the netherlands the evolution of h5n1 influenza viruses in ducks in southern china avian h5n1 influenza in cats. science [serial online thais suspect human spread of bird flu uk 'developing bird flu vaccine experts confront major obstacles in containing virulent bird flu hospital preparedness for severe acute respiratory syndrome in the united states: views from a national survey of infectious diseases consultants the detection of monkeypox in humans in the western hemisphere key: cord-330104-wgo4pml6 authors: farrugia, gianrico; plutowski, roshelle w. title: innovation lessons from the covid-19 pandemic date: 2020-06-06 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.05.024 sha: doc_id: 330104 cord_uid: wgo4pml6 abstract on december 31, 2019, chinese authorities reported the first case of what would become known as covid-19 to the world health organization (who), which declared a public health emergency of international concern one month later. in the ensuing weeks, health care organizations, industry partners, and government agencies worldwide have quickly come together to address pandemic challenges such as scaling high-quality laboratory tests, conducting treatment research, and enabling virtual health care in a time of social distancing. what we have accomplished together to date demonstrates the opportunity for future cross-sector partnerships in science and technology to fight the disease, while simultaneously creating the new digital health care solutions that our world greatly needs. on december 31, 2019, chinese authorities reported the first case of what would become known as covid-19 to the world health organization (who), which declared a public health emergency of international concern one month later. 1 at the time of this publication, the virus has spread to all six who regions, infecting several million people and killing more than a 280,000 worldwide, with numbers that continue to grow. 2 to stem pandemic-related deaths and prevent health care systems from being overwhelmed with sick patients, governments responded by limiting travel, closing schools, issuing stay-at-home orders, making emergency investments in health care, scaling testing, and using data and technology to trace contacts. 3 in the interim, health care organizations ramped up molecular and serologic testing, initiated triage systems to reduce exposure, and prepared facilities and staff for a surge of covid-19 cases. 4 to identify effective tools to fight the disease, biotech, pharma, it, and academia quickly turned their attention and resources to research vaccines, antivirals, and immune response to the virus. now, a few months into the pandemic, people worldwide continue to suffer from both the health and economic fallout of covid-19. as the crisis wears on and experts predict additional waves of infection, 5 we must strongly resist the natural urge to retreat to our safe zones to ride out the storm. instead, we must seize the opportunity for cross-sector partnerships in science and technology to fight the disease, while simultaneously deploying new digital health care solutions that our world greatly needs. with science guiding every step, we must adopt an urgent, short-term strategy to save lives, but always with an eye toward the long-term. public-private partnership facilitates innovation, and we've seen significant collaboration from many levels of the u.s. government over the last months. we and other health care providers have advocated for many years for more flexibility in licensing and telehealth regulations to enable virtual care. the pandemic catalyzed these changes. the federal communications commission (fcc) facilitated expanding access with the covid-19 telehealth program, fasttracking application processes and funding to help health care providers quickly establish telehealth services for remote patients. 6 to date, the centers for medicare and medicaid services has agreed to pay in-person visit rates for virtual visits for several office and hospital telehealth appointments with a variety of providers, including physicians, nurse practitioners, and psychologists. 7 to meet the demand for virtual services, mayo clinic has expanded video appointments from about 200 to 35,000 virtual visits per week. many if not close to all other medical centers also are ramping up quickly. 8 mayo clinic patients' response to virtual care has been positive, and we intend to build on this model in the future -not to replace face-to-face visits but rather to increase patient convenience and make in-person care more efficient when needed. we also must ensure that the regulatory changes that have made virtual services scalable are refined but not rolled back. the response to the pandemic has produced partnerships that are impressive in scale and that reimagine traditional organizational boundaries. one initiative, the covid-19 healthcare coalition, has garnered the expertise and resources from large health care organizations, private industries, academic institutions, and startups. coordinating the use of data and advanced analytics, the collaboration-which includes mayo clinic, the university of california health care system, amazon web services, microsoft, and epic, among others -aims to flatten the infection and mortality curves, improve outcomes, and enable clinics and hospitals to continue to respond to patient needs. the initiative's guiding principles stipulate no participants receive pay or preferential advantage. 9 while international collaboration has long been common practice in research, the pandemic has shown the ability to achieve clinical results at an unprecedented pace through data sharing with trusted partners. initiatives such as the global initiative on sharing all influenza data, which gather sequenced viral covid-19 genomes from labs all over the world, have proven to be essential open-access tools so investigators can learn more about the virus and its spread. 10 to study four potential covid-19 therapeutics, a new international consortium of researchers rose up immediately to form the solidarity trial, which is being conducted in more than a dozen countries. 11 in addition, our collaborations have also enabled us to massively scale-up innovation. we have collaborated with investigators across the country to initiate a national effort to procure convalescent plasma from eligible donors who have recuperated from covid-19. to date, more than 8,000 patients have been treated with convalescent plasma, and there are more than 2,000 participating sites across the u.s. 13 when sars-cov2 tests were in very short supply from the cdc, our mayo clinic laboratories developed pcr testing within three weeks, and our partnership with roche diagnostics increased capacity and relieved testing backlogs in several states. mayo clinic laboratories also developed a serology test as the next critical tool for health care providers. simultaneously, we are working with the state of minnesota, the university of minnesota, and other minnesota health care providers to accelerate state-wide testing using both types of tests, while also working with other u.s. states including florida and arizona. all of these efforts provide a view of an even more robust and nimble approach to medical science and application that needs to carry forward beyond this era. meanwhile, we are observing first-hand the power of engaging industries with diverse, even seemingly unrelated, capabilities. medical device makers and car manufacturers have joined forces to mass produce ventilators and streamline ventilator design. 14 the partnerships may demonstrate new avenues for device development that will set us in better stead to address future pandemics. the covid-19 outbreak also has vaulted collaborative opportunities to apply artificial intelligence (ai) and machine learning to new medical problems. researchers in china have used ai to reveal distinctions between the ct scans of patients with covid-19 and those with other pneumonias. 15 other research teams are using ai to identify new treatment pathways. 16 tech companies are working with hospitals in new york city to use ai platforms to assess the risk profiles of non-hospitalized patients. to help with diagnosis and risk stratification even before infection occurs, mayo clinic researchers are using ai to study whether data from ecg can help predict who is infected with and susceptible to covid-19. overall, the new challenges posed by the pandemic are sharpening our skills and quickly teaching us the ways ai can enhance care. before the outbreak, mayo clinic had established a partnership with boston-based company nference to use ai to match potential treatments to diseases. through the pandemic, our partnership has greatly expanded its ai applications to a variety of covid-related questions, from keeping track of testing in real-time to predicting hot spots. in fact, efforts to track and trace the virus, particularly using big data and ai, reveal health care organizations, industry partners, and government agencies will be engaged together in matters of epidemiology well into the future. some governments, as in china and south korea, are deploying tracking initiatives, using combinations of smartphones and other tools that gather information regarding location and activities, such as credit cards. 17 these and future efforts will have to balance the imperative for large-scale, rapidly acquired epidemiological datacollection with individual privacy. large networks and resources to solve complex problems simultaneously instead of solving them one at a time in isolation. this will accelerate the digital platform model in health care and help more people. now is the time to build upon new digital care options to address urgent needs for the crisis we face today, but also to form the foundation for how we deliver care tomorrow. through our united efforts, the pandemic will eventually come under control, and, in the process, we will have achieved a more nimble, consumer-friendly digital health care system that can better stand up to future challenges. considering everyone and everything we have lost to covid-19, we should fight determinedly for this thin but essential silver lining. world health organization who coronavirus disease (covid-19) dashboard variation in government responses to coivid-19 world health organization. responding to community spread of covid-19 federal communications commission. fcc approves first set of covid-19 telehealth program applications delivering more care remotely will be critical as coid-19 races through communities enabling rapid and open access to epidemic and pandemic virus data who launches global megatrial of the four most promising coronavirus treatments accelerating research on covid-19 in resource-limited settings mayo clinic named national site for convalescent plasma expanded access program ford and gm are undertaking a warlike effort to produce ventilators. it may fall short and come too late a deep learning algorithm using ct images to screen for corona virus disease (covid-19) health care of tomorrow, today: how artificial intelligence is fighting the current, and future, covid-19 pandemic after 9/11, we gave up privacy for security. will we make the same trade-off after covid-19? health tech screening for cardiac contractile dysfunction using an artificial intelligence-enabled electrocardiogram the authors thank kate ledger for her contributions to this editorial. key: cord-346607-1mewok8l authors: oesterle, tyler s.; kolla, bhanuprakash; risma, cameron j.; breitinger, scott a.; rakocevic, daniela b.; loukianova, larissa l.; hall-flavin, daniel k.; gentry, melanie t.; rummans, teresa a.; chauhan, mohit; gold, mark s. title: substance use disorders and telehealth in the covid-19 pandemic era: a new outlook date: 2020-10-21 journal: mayo clin proc doi: 10.1016/j.mayocp.2020.10.011 sha: doc_id: 346607 cord_uid: 1mewok8l during the current covid-19 epidemic many outpatient chemical dependency treatment programs and clinics are decreasing the number of in-person patients contact. this has widened an already large gap between patients with substance use disorders (sud) that need treatment and those that actually received treatment. for a disorder where group therapy is the mainstay treatment option for decades, social distancing, shelter in place and treatment discontinuation have created an urgent need for alternative approaches to addiction treatment. in an attempt to continue some care for patients in need, many a medical interventions have transitioned to a virtual environment in order to promote safe social distancing. although there is ample evidence to support tele-medical interventions, these can be difficult to implement especially in sud populations. this article reviews current literature for the use of tele/virtual interventions in the treatment of suds and offers recommendations on safe an effective implementation strategies based on the current literature. we live in an extraordinary time. the covid-19 (novel coronavirus disease of 2019) pandemic is a global public health crisis not seen since the influenza pandemic of 1918. 1 social distancing and rigorous infectious disease prevention strategies are the new normal and driving rapid changes in clinical practice. rapid changes and extreme uncertainty resulting from covid-19 have driven individual fears, grief, and apprehension and a near omnipresent struggle to cope with social isolation, economic tumult and displacement, all of which are all associated with an increase in mental health concerns worldwide. 2 prior to the international public health crisis of covid-19, in the united states an epidemic of substance use disorders (sud) had been contributing to an unprecedented rise in deaths of despair from suicide and drug overdoses. 3 in 2018, 164.8 million people reported using addictive substances within the past month (1 in 5 people or 19.4 % of the population) and 21.2 million people needed sud treatment. however, only 1 in 10 of those individual (11.1 %) received treatment due to a significant lack of access to sud providers. 4 there is emerging evidence that the pandemic has worsened substance use and mental health symptoms in the most vulnerable populations. 5 while the need for support is growing, the access to help is diminishing. self-help support options like alcoholics anonymous (aa) and narcotics anonymous (na) have become even less accessible, as most us states have restricted group gathering and social distancing has become the mainstay of infectious disease prevention. many formal group-based sud programs are less accessible in an attempt to mitigate the spread of infection. there is also evidence that with health systems concentrating on covid-19 patients, access to care for people with sud can be further diminished. 6 emergency rooms, previously, a common first stop for patients seeking help with their sud patients have become less accessible and despite the severity of their condition, patients hesitate to come to the emergency room due to fear of infection. 7 it is now more important than ever j o u r n a l p r e -p r o o f to provide chemical dependency assessment and care through modalities that are safe for the provider and the patient. telehealth, also sometime called telemedicine, is defined as the delivery of health care across a distance using telecommunications technology. telehealth has been shown to improve access to care (especially for rural populations). 8 it can produce similar results to in-person treatment, reduce the burden of travel, and help reduce the perception of stigma. it has been shown to provide substantial patient and provider satisfaction with the delivery of care . 9, 10 there is also a growing evidence base to support the benefit of telehealth in access to sud related care. 11 although research shows a rapid (approximately 20-fold), increase in the use of this intervention for sud in the years from 2010 to 2017, it still remains underutilized, representing just a fraction of overall tele-psychiatry visits. 12 multiple barriers to the acceptance of tele-mental health services have been identified. these include both patient-based and provider-based factors. however, regulatory barriers have been one of the biggest hindrances so far, including insurance reimbursement and state licensure requirements. 13 in the midst of the pandemic, most of these impediments have been, at least temporarily, removed. on january 31, 2020, the secretary of health and human services (hhs) declared a public health state of emergency, which included immediate (although temporary) regulatory changes at the federal level. 14 many state legislatures declared similar states of emergency orders which included various measures to loosen restrictions on telehealth. [15] [16] [17] furthermore, department of health and human services office for civil rights (hhs ocr) waived potential penalties for health insurance portability and accountability act (hipaa) violations against health care providers that serve patients in good faith using virtual care technologies, such as facetime or skype. the hhs also announced an easing of practice regulations across state lines "to meet the needs of hospitals that arise in adjoining areas" during the covid-19 health emergency. the covid-19 pandemic makes it imperative for clinical practice to adapt rapidly in order to meet patient needs for sud treatment while reducing risk of covid-19 infection; hence, many providers are now using telehealth for the first time. this manuscript intends to focus on the evidence base for of telehealth services and provides recommendations for evidenced based safely delivered sud focused telehealth visits. the general evidence base for telehealth in medical settings is characterized by significant heterogeneity of study designs, populations, interventions, and outcome measures. 18, 19 the four most common modes of telehealth in sud treatment programs are computerized assessments (45%), telephone-based recovery support (29%), telephone-based therapy (28%), and video-based therapy (20%). 20, 21 less utilized tools include texting, smartphone apps, and virtual reality interventions. evidence for each tool will be discussed below. computerized/web-based assessments and treatments with no "live" interaction are the most commonly utilized form of sud virtual intervention; they offer improved ease of access to assessments. these interventions are considered asynchronous (i.e. patients may access them at any time), with the advantage that patients may use them at critical moments in recovery. although there is significant variation in the format, function, and aim of these tools, common features include: screening assessments (e.g. the audit), cognitive behavioral (cbt) modules, motivational therapy sessions, psychoeducation, behavioral skill-building, links to self-help recovery groups, and computerized brief interventions. the majority of studies consistently demonstrate positive effects of these tools in addiction treatment when they focus on the electronic delivery of evidence based strategies . furthermore, these tools demonstrated very few adverse outcomes. 22 for example, in a study of eighty four alcoholic patients, (assessed at 3, 6, and 12 months), improvement was noted in the percentage of j o u r n a l p r e -p r o o f days abstinent (14.5% to 27.2%), reduced mean drinks per drinking day (5.7 to 3.7), and reduced alcohol-related problems. results were similar to traditional face-to-face interventions. notably no safety concerns were identified. 23 however, several reviews of asynchronous online smoking cessation resources show that most programs were of mediocre quality and that the highest quality websites attracted few visitors. 24 this may create risk if individuals are attempting to apply mediocre tools without consulting a physician for advice on quality. further work is needed to determine adequate length (i.e. dose) of treatment, degree of integration needed with traditional treatment, and the sustainability of effects.) [25] [26] [27] telephone-based recovery supports and therapy are the next most commonly used forms of telemedicine. they are labeled as synchronous, requiring real-time contact between patient and clinician. phone calls offer support, link patients to resources, and deliver brief interventions. they are considered minimally resource intensive, in that apart from the capacity to deliver effective brief intervention, cost of infrastructure is low. cost-efficiency however, is limited by lower reimbursement rates which may vary geographically and by payer type. when compared to treatment as usual for alcohol use disorder, the addition of telephone-based services has been shown to improve abstinence rates and reduce binge drinking in the short term but not after the cessation of the interventions examined with no increase in adverse outcomes. current evidence only supports the use of telephonebased telemedicine in continuing care after completion of traditional addiction treatment and may be alcohol specific. 28, 29 as smartphones and tablets have become ubiquitous over the past decade, the use of synchronous videoconferencing in medical treatment has expanded. 12 according to a 2018 systematic review, studies have repeatedly demonstrated that, compared to in-person treatment, videoconferencing for similar modality treatment of suds is no less effective and is associated with significant patient satisfaction and j o u r n a l p r e -p r o o f safety. 11 indeed, the use of videoconferencing for the treatment of alcohol use disorder is associated with reduced drop out, reduced alcohol consumption, higher abstinence rates, and high patient satisfaction compared to treatment as usual. [30] [31] [32] similar results for videoconferencing have been demonstrated for the treatment of opioid use disorder with buprenorphine and methadone. (30) (31) (32) videoconferencing for smoking cessation has also shown similar 12-month abstinence rates (25%) compared to in-person treatment (21%). 33 several studies support improved one-year retention with videoconferencing compared to in-person treatment, owed partially to the ease of access, perception of reduced stigma, and reduced burden of traveling to appointments. 32, 34 also owing to the proliferation of smartphones, health care organizations are increasingly utilizing text messages to support health care delivery. most often used as appointment reminders, text messaging has been shown to decrease the frequency of missed appointment. 35 additional texting interventions include craving helplines, automated cbt, relapse prevention skills support, personalized messages delivery based on stage of change, and personalized motivational reminders. importantly, texting interventions can be utilized in vivo at moments of critical decision making. when used for smoking cessation, either as stand-alone treatment or combined with traditional treatment, texting interventions demonstrated improved long-term abstinence rates in 11 rcts with nearly 13,000 combined participants. 36 furthermore, a stand-alone texting intervention after an emergency room visit, when compared to controls, demonstrated a reduction in alcohol intake: 3.4 fewer heavy drinking days per month and 2.1 fewer drinks per drinking day over a three month period. 37 as a simple and cost-effective tool, text messaging is an often underutilized method of supporting sud treatment. smartphone apps and virtual reality are promising new technologies to further improve sud treatment options. rarely out of arm's reach, smartphones represent a nearly continuous opportunity for patients to engage in virtual addiction treatment. smart phone apps represent a rapidly emerging market j o u r n a l p r e -p r o o f attracting the attention of patients, clinicians, and third-party payers. in addition to sharing features with web-based tools (discussed above), apps offer features such as personalized push notifications, direct connections to support persons (i.e. sponsor, family, etc.), in vivo assessments, real-time interventions for cravings, contingency management based rewards and gps-tracking alerting the patient when they approach a high-risk location. 38 such apps have been shown to reduce hazardous drinking and drinks per day. 39 some use predictive modeling to identify patients at high risk for relapse and to deliver personalized interventions. 40 in addition, aa and na have developed free apps that provide a one stop repository for local entities to provide information on location, daily reflections, local meeting guidelines, news etc. although most commonly used as augmentation stratagems to traditional, treatment they appear to be safe ways to enhance skills conducive to maintaining sobriety. virtual reality for sud treatment offers the possibility of both asynchronous and synchronous environments. asynchronous virtual environments are primarily designed to simulate reality for patients to test reactions to environmental cues. by contrast, synchronous virtual worlds allow patients to create digital avatars to interact in real time with peers and clinicians. studies have demonstrated that virtual reality can reliably recreate cravings, although no studies to date have evaluated the effects of a synchronous virtual world in sud treatment. apart from the lack of evidence, these virtual worlds can cost up to $100,000-a prohibitive cost for most treatment centers. 41 despite evidence supporting its safe use of all the a for mentioned modalities , there remain limitations many patients with suds have relied upon intrapersonal, face-to-face interactions that may be disrupted by the fluidity of virtual interactions; many may not have reliable phone service or internet access and some lack basic necessities. a 2012 analysis showed that <1% of sud treatment centers had adopted telemedicine technologies. 20 surveys show clinicians tend to be most concerned about patient outcomes, work efficiency due in part to the implementation of new technology, and reimbursement. widespread implementation of telemedicine has also been hindered by complex reimbursement and regulatory barriers at the state and federal levels. 42 many telemedicine products are now being marketed directly to third-party payers in order to alleviate reimbursement concerns. additionally, patients remain concerned about their privacy in a digital world, and health care organizations must carefully evaluate prospective technology to ensure products meet privacy/security requirements. although most physicians do not provide or facilitate psychosocial interventions, it is important to understand that these treatments are perhaps even more important during viral pandemic restrictions. there is a substantial body of literature supporting the efficacy of both individual and group-based behaviorally oriented treatment components and self-help group intervention in patients with sud. 43 understandably, many patients and providers have concerns about whether video based interactions can provide the same quality of interaction as in person treatment. a number of studies have shown group based treatment by videoconference, both support groups and treatment groups, including those targeting tobacco, alcohol and opioid use disorders have been shown to provide safe intervention, high patient satisfaction and appear to have similar outcomes to in person treatments. 11, 44 a few studies of group treatment by videoconference (in ptsd and with inmates) have indicated there may be a reduction in patient reported group cohesion and treatment alliance. 44 unfortunately, few studies of group based video treatment have directly assessed specific group therapy process outcomes. nonetheless, virtual groups are a practical alternative to face-to-face treatment limited due to social distancing. patients should be encouraged to participate in virtual 12-step and other self-help meetings, obtain an on-line sponsor or maintain a virtual connection with their current sponsors. 56 additional care and preparation should be taken regarding safety planning for medical or psychiatric emergencies j o u r n a l p r e -p r o o f during the course of group treatment. 10, 45 additional research is needed to explore potential limitations of video group treatment, particularly in the area of sud treatment. there is a substantial body of literature supporting the efficacy of face-to-face treatment modalities in helping improve addiction related outcomes and overall symptom burden in patients with sud. general recommendations for a mental health focused primary care telehealth visit based on best practice guidelines include: a quiet space with good lighting, an uncluttered and professional looking environment (home or office). perhaps most importantly an adequate transmission speed and bandwidth of (at least 384 kbps) are needed for videoconferencing. good transmission speed is especially important in behavioral health visits in order to support the detection of facial cues and to prevent fragmented movement because decreased ability of a provider to recognize nonverbal cues can adversely affect rapport building. 13 if possible, the camera should be positioned at eye level as this will what standard of care may mean in this setting, and require creative thinking to address. vital signs and physical exams are difficult to do virtually but despite these limitations even predominantly physical medical complaints like sore throats can be safely assessed without these portions of the visit. 47 observational parts on the physical exam certainly could still be performed and recorded. for a rough assessment of vital signs, patients could procure and use home-based tools (for example, automated electronic blood pressure monitoring cuff, thermometer etc.) at some addition cost. the main goal of the urine drug screen is to objectively assess for substance use. even during restrictions related to the pandemic, most patients are able to access labs where they could provide a urine sample. however, there are also many remote options for monitoring substance use that could be utilized, including oral j o u r n a l p r e -p r o o f fluid and hair analysis in select cases. 48 however, there is high risk for tampering with unobserved collection methods outside of the clinic. observed oral fluid testing for example has been integrated into apps where the patients are observed placing their fluids into the testing cups; other methods of monitoring have been utilized within the criminal justice system. 49, 50 all of these have their relative strengths and weaknesses and considering urine drug screens performed in certified labs are likely to be the only option reimbursed by most insurance companies, they remain the modality of choice. intoxication/withdrawal during the interview can be assessed by clinical observation and utilizing instruments such as ciwa for alcohol or cows for opioids. home monitoring kits (for example bluetooth enabled breathalyzer) can also be utilized to assess for acute intoxication but these are not widely available for most patients. intoxication with the potential for overdose can be particularly challenging and sometimes difficult to assess remotely. if this is at all suspected then immediate use of emergency services (i.e., local to the patient) would be extremely important. while the covid-19 public health emergency lasts, urine testing for buprenorphine treatment does not have to be a mandatory part of the treatment. 51 in areas where access to laboratory services are difficult the clinician can consider pausing urine drug testing in clinical practice if they consider the patient at low risk for substance use and restart when patients are able to access laboratory services again. some strategies for risk reduction in a situation where frequent and optimal urine drug monitoring is not feasible include: patient education regarding the risks of overdosing, more frequent clinical encounters, prescribing smaller quantities of medications, prescribing naloxone for individuals on opioid agonist medications and training the patient and any family members engaged with the patient's care to use naloxone. there are many unique features and considerations for providing effective telehealth j o u r n a l p r e -p r o o f visits to sud patients (see table 2 ) and an important research opportunity exists to build a deeper evidence base for best practices in this domain. conducting telehealth medication assisted treatment visits for opioid use disorders represents a unique challenge. prescribing controlled substances like buprenorphine for patients seen exclusively via virtual visits was previously restricted but is possible with temporary emergency legislative changes during the covid-19 pandemic. however, methadone still requires in-person visits for induction. 52 medications for opioid use disorder (oud) require the greatest supervision and observation due to the risk of misuse and diversion. 10, 45, 53, 54 for new patients seen via telehealth with oud, buprenorphine has advantages over methadone or injectable naltrexone. buprenorphine allows greater prescribing flexibility, and a better safety profile than methadone (greater risk of overdose early in induction, concern for stacking with other opioids, need for lab workup and ecg monitoring). injectable naltrexone requires an office visit which can pose difficulty because of social distancing recommendations but typically can be done quite safely with the appropriate protective equipment. as noted previously, outpatient induction of controlled substances like buprenorphine is currently permissible even if the patient does not have a face-to-face evaluation with the provider. similarly, it became possible to refill a buprenorphine prescription for a patient that has previously not been seen in office, but only via telehealth. .52 home induction of buprenorphine via a telehealth visit should follow most of the steps that this process would entail during an in office visit (see table 3 )(55) (56) j o u r n a l p r e -p r o o f to-face evaluation is still needed for methadone induction, however in light of the covid 19 pandemic more flexible take home dosing is possible. 52 the covid-19 pandemic has brought on unprecedented challenges for the health care system generally, as well as specific challenges for patients coping with suds. fortunately, for patients with internet and wifi access, federal and state agencies have rapidly responded to the crisis by loosening restrictions on telehealth to provide much needed medical care. this has been a necessary and vital step in providing needed services, but presents many challenges for patients and providers. we do not yet fully understand the ramifications of the rapid switch to virtual medical visits. some patients may benefit tremendously by coming to the clinic, meeting with the counseling staff, sharing experiences with other patients in treatments, taking mats, giving a urine test, and getting encouragement and feedback, while other patients may appreciate the convenience of virtual options. many providers have been ill prepared to launch a telehealth practice, often over the course of just a few days leading to a significant delay or potentially even termination in their patient contact. although there are many available resources to guide clinicians in providing a safe and effective video based practice, this is not a substitute for more organized and well-designed training programs. furthermore, these landmark regulatory changes may well be temporary which fuels further uncertainty. this time of crisis has forced a tremendous leap forward in the use of technology to improve quality of care and access to services for patients with suds. telemedicine is a good and required response to the crisis, but its value in the provision of clinical care in post-pandemic healthcare systems will be different depending on unique features of the health systems where it is applied. telemedicine is one means of delivering healthcare and must be contextualized-and perhaps used in conjunction with in-person j o u r n a l p r e -p r o o f and/or asynchronous care delivery-to solve specific care delivery challenges. more randomized trials of in-clinic vs telemedicine will be necessary to evaluate short and long-term outcomes for patients with suds, evaluating retention, overdose, concurrent illness, emergency room visits, urine test results, and return to premorbid function. treatment of suds without independent evaluation of outcomes such a urine testing or interviews with employer, partner, and friends is difficult to evaluate. many longitudinal outcome studies have allowed researchers to look at which aspects of sud treatment patient have deemed most helpful to their recovery. of the various components, group treatment and sharing, was at the top of the list. it is possible but hard to imagine virtual meetings being as compelling over the long term where in-person care may be a viable option. greater implementation experimentation with potential combinations of in-person, asynchronous, and telemedicine options may help define optimal structure of care delivery and clinical communication. telehealth during the covid-19 crisis is reimbursed at the same rates as in-person care, but may not be reimbursed at these rates going forward. it remains unclear whether the broad capability to provide telehealth without previous restrictions imposed by government and private payers and state licensure will continue beyond the immediate covid crisis period. however, as patients and providers quickly adapt to these new options for treatment, it is likely that telehealth will only continue to be a large component of the health care system overall. it is essential that all health care providers become competent in the use of telehealth including video visits. tele-behavioral health competencies have been developed and should be systematically implemented in training programs across medical disciplines. health care systems and regulatory agencies will need to continue to work together to solve challenges in using telehealth to optimize treatment for individuals with substance use disorders. table 2 j o u r n a l p r e -p r o o f updating the accounts: global mortality of the 1918-1920" spanish" influenza pandemic generalized anxiety disorder, depressive symptoms and sleep quality during covid-19 outbreak in china: a web-based cross-sectional survey covid-19: the hidden impact on mental health and drug addiction facing addiction in america: the surgeon general's report on alcohol, drugs, and health [internet]: us department of health and human services mental health, substance use, and suicidal ideation during the covid-19 collision of the covid-19 and addiction epidemics the role of alcohol, drugs, and deaths of despair in the us's falling life expectancy. missouri medicine the new england journal of medicine best practices in videoconferencing-based telemental health a framework for telepsychiatric training and e-health: competency-based education, evaluation and implications telemedicine-delivered treatment interventions for substance use disorders: a systematic review how is telemedicine being used in opioid and other substance use disorder treatment? health aff (millwood) online recovery resources provided by hpsp 2020 trump administration releases covid-19 medicare tele-medicine healthcare provider fact sheet the role of technology-based interventions for substance use disorders in primary care: a review of the literature telemedicine interventions for substance-use disorder: a literature review use of telemedicine in addiction treatment: current practices and organizational implementation characteristics trends in telemedicine use in addiction treatment mobile technology-based interventions for adult users of alcohol: a systematic review of the literature a web application for moderation training: initial results of a randomized clinical trial a list of the most popular smoking cessation web sites and a comparison of their quality computerized behavior therapy for opioiddependent outpatients: a randomized controlled trial overcoming addictions, a web-based application, and smart recovery, an online and in-person mutual help group for problem drinkers, part 2: six-month outcomes of a randomized controlled trial and qualitative feedback from participants the drinker's check-up: 12-month outcomes of a controlled clinical trial of a stand-alone software program for problem drinkers extending residential care through telephone counseling: initial results from the betty ford center focused continuing care protocol extended telephonebased continuing care for alcohol dependence: 24-month outcomes and subgroup analyses a brief behavioral telehealth intervention for veterans with alcohol misuse problems in va primary care. drug and alcohol dependence metelemedicine: a pilot study with rural alcohol users on community supervision effectiveness of optional videoconferencing-based treatment of alcohol use disorders: randomized controlled trial telehealth-delivered group smoking cessation for rural and urban participants: feasibility and cessation rates the effectiveness of telemedicine-delivered opioid agonist therapy in a supervised clinical setting. drug and alcohol dependence the effectiveness of mobile-health technologies to improve health care service delivery processes: a systematic review and meta-analysis text messaging for addiction: a review text-message-based drinking assessments and brief interventions for young adults discharged from the emergency department examining perceptions of a smartphone-based intervention system for alcohol use disorders results of a pilot test of a self-administered smartphonebased treatment system for alcohol use disorders: usability and early outcomes predictive modeling of addiction lapses in a mobile health application center for connected health policy. state telehealth laws and reimbursement policies report the asam principles of addiction medicine evidence for telehealth group-based treatment: a systematic review a framework of interprofessional telebehavioral health competencies: implementation and challenges moving forward the effectiveness of residential treatment services for individuals with substance use disorders: a systematic review. drug and alcohol dependence variation in quality of urgent health care provided during commercial virtual visits extended-release injectable naltrexone for opioid use disorder: a systematic review validity of transdermal alcohol monitoring: fixed and self-regulated dosing sweat testing for heroin, cocaine, and metabolites caring for patients during the covid-19 pandemic. asam covid-19 task force recommendations telehealth tip sheet. pcss faq-treating opioid use disorder via telehealth tips for primary care providers alcoholics anonymous and other 12-step programs for alcohol use disorder home buprenorphine/naloxone induction in primary care unobserved "home" induction onto buprenorphine â�¢ start with a visit to establish â�¢ dsm 5 diagnosis â�¢ complete history of substance use â�¢ full medical, social and psychiatric history â�¢ evaluate for current depression or suicidal thoughts (si) â�¢ pmp review â�¢ provide medications for breakthrough withdrawal symptoms targeting insomnia, nausea, muscle aches, abdominal cramping â�¢ warn patient of precipitated withdrawal â�¢ the initial prescription should be sufficient for the patient to complete the induction phase, stabalize and return in 1 week or less â�¢ most patients will stabilize on 8-16 mg of buprenorphine â�¢ after hours clinical contact information must be provide to address questions or concerns â�¢ it is always a good practice to provide patients with oud a prescription for naloxone kit. table 3 j o u r n a l p r e -p r o o f 