key: cord-301183-k39e12cq authors: pham, tho d.; huang, chunhong; wirz, oliver f.; röltgen, katharina; sahoo, malaya k.; layon, arlene; pandey, suchitra; foung, steven k.; boyd, scott d.; pinsky, benjamin a. title: sars-cov-2 rnaemia in a healthy blood donor 40 days after respiratory illness resolution date: 2020-07-17 journal: ann intern med doi: 10.7326/l20-0725 sha: doc_id: 301183 cord_uid: k39e12cq nan than 1 month after symptom resolution is concerning in light of current guidelines, which do not recommend sars-cov-2 screening in the general allogeneic donor population (5) . in this case, plasma viral rna was reproducibly detected at a time point that exceeded recommendations for deferral based on time since symptom resolution (14 days). of importance, these results are unlikely to be false-positive given that 2 different regions of the sars-cov-2 genome were detected in separate specimens collected on the day of donation and that quality control passed on all runs, including the absence of amplification in the negative controls. of note, however, the infectivity of sars-cov-2 from blood remains unknown and, to date, we are not aware of cases of transfusion-transmitted covid-19. furthermore, the risk for transmission of other transfusion-transmitted viral infections, such as hiv-1, is correlated with virus load, indicating that if bloodborne transmission is possible, the low level of coronavirus disease 2019: coronaviruses and blood safety severe acute respiratory syndrome coronavirus 2 rna detected in blood donations sample pooling as a strategy to detect community transmission of sars-cov-2 comparison of a laboratorydeveloped test targeting the envelope gene with three nucleic acid amplification tests for detection of sars-cov-2 aabb's resources for: fda's updated information for blood establishments regarding the novel coronavirus (covid-19) outbreak. accessed at www.aabb.org/advocacy/regulatorygovernment/documents/covid-19-tool kit key: cord-335003-7ae0galy authors: kussmaul, william g. title: covid-19 and angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker therapy date: 2020-05-15 journal: ann intern med doi: 10.7326/m20-3047 sha: doc_id: 335003 cord_uid: 7ae0galy mackey and colleagues reported a systematic review that found high-certainty evidence that angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers are not associated with greater illness severity in patients with covid-19. the editorialist discusses the findings and emphasizes that, unless further data show otherwise, clinicians should continue to prescribe these drugs for their standard indications in patients with covid-19. • the epidemic broke out widely in january and february. • early reports showed that common comorbid conditions, including hypertension, were statistically linked to worse illness severity. • many hypertensive persons take aceis or arbs. • previous studies of a related coronavirus, the causal agent of the 2003-2004 severe acute respiratory syndrome epidemic, had shown that the ace-2 membrane receptor is key to the ability of the virus to infect cells. • both aceis and arbs may upregulate the ace-2 receptor. a cogent line of reasoning (1) therefore led to the following question (2): could these drugs be magnifying the risk for covid-19 or contributing to its severity? we now have abundant data from italy, china, the united kingdom, and the united states to suggest otherwise. these reports are summarized in a systematic review by mackey and colleagues (3) . the authors present data from 3 studies that found, with moderate certainty of evidence, no relationship of acei or arb use with testing positive for the virus or becoming ill from it. on the basis of further data from 14 observational studies encompassing more than 23 000 adults with covid-19, they found high-certainty evidence that the drugs are not associated with greater illness severity. in addition, common sense tells us that common comorbid conditions, such as hypertension and cardiovascular disease, are likely to be common in any population assessment. and it is a clinical truism that people with any chronic condition are more ill than those without. in the hallway vernacular, "what's common is common" and "the sicker you are, the sicker you are." initial fears that hypertension or its therapy uniquely contribute to covid-19 illness seem now to have been unfounded. as a result of this progression from fear and theory through data and multiple analyses from different continents, we now have reasonable reassurance that drugs that alter the renin-angiotensin system (ras) do not pose substantial threats as either covid-19 risk factors or severity multipliers. and although there were reasons that ras-related drugs might have been harmful, there are other reasons that they could be helpful (4) . furthermore, withdrawing these drugs if they are prescribed for evidence-based indications could harm patients, especially those with heart failure (5) . at this time, professional societies and expert editorialists agree: until further data show otherwise, these drugs should continue to be used for their standard indications (6) . one might also add that there are currently insufficient outcomes data to show that they provide specific benefit during covid-19 illness. mackey and colleagues' review is one of a new class of "living systematic reviews." the conclusions reached on the basis of research available as of the publication date can of course change at any time. the analysis in their article will accordingly be updated whenever new data become available. readers are referred to a recent annals editorial explaining how these updates may be easily accessed (7). the covid-19 pandemic has placed the nation and the world under more stress than usual. stress magnifies things; it can make fears loom larger and spawn hopes that may eventually prove illusory. such has been the brief saga of covid-19 and the ras to this point. in any case, it comes as a welcome relief that we have clarification on at least 1 aspect of this pandemic. renin-angiotensinaldosterone system inhibitors in patients with covid-19 can angiotensin receptor-blocking drugs perhaps be harmful in the covid-19 pandemic? risks and impact of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers on sars-cov-2 infection in adults. a living systematic review drugs, covid-19' working group of the french society of pharmacology clinical consequences of angiotensin-converting enzyme inhibitor withdrawal in chronic heart failure: a double-blind, placebo-controlled study of quinapril. the quinapril heart failure trial investigators inhibitors of the renin-angiotensin-aldosterone system and covid-19 keeping up with emerging evidence in (almost) real time key: cord-325643-nszsf0nu authors: tan, benjamin y.q.; chew, nicholas w.s.; lee, grace k.h.; jing, mingxue; goh, yihui; yeo, leonard l.l.; zhang, ka; chin, howe-keat; ahmad, aftab; khan, faheem ahmed; shanmugam, ganesh napolean; chan, bernard p.l.; sunny, sibi; chandra, bharatendu; ong, jonathan j.y.; paliwal, prakash r.; wong, lily y.h.; sagayanathan, renarebecca; chen, jin tao; ying ng, alison ying; teoh, hock luen; ho, cyrus s.; ho, roger c.; sharma, vijay k. title: psychological impact of the covid-19 pandemic on health care workers in singapore date: 2020-04-06 journal: ann intern med doi: 10.7326/m20-1083 sha: doc_id: 325643 cord_uid: nszsf0nu nan of 500 invited health care workers, 470 (94%) participated in the study; baseline characteristics are shown in table 1 . sixty-eight (14.5%) participants screened positive for anxiety, 42 (8.9%) for depression, 31 (6.6%) for stress, and 36 (7.7%) for clinical concern of ptsd. the prevalence of anxiety was higher among nonmedical health care workers than medical personnel (20.7% versus 10.8%; adjusted prevalence ratio, 1.85 [95% ci, 1.15 to 2.99]; p = 0.011), after adjustment for age, sex, ethnicity, marital status, survey completion date, and presence of comorbid conditions. similarly, higher mean dass-21 anxiety and stress subscale scores and higher ies-r total and subscale scores were observed in nonmedical health care workers ( table 2) . discussion: overall mean dass-21 and ies-r scores among health care workers were lower than those in the published literature from previous disease outbreaks, such as the severe acute respiratory syndrome (sars). a previous study in singapore found higher ies scores among physicians and nurses during the sars outbreak, and an almost 3 times higher prevalence of ptsd, than those in our study (4) . this could be attributed to increased mental preparedness and stringent infection control measures after singapore's sars experience. of note, nonmedical health care workers had higher prevalence of anxiety even after adjustment for possible confounders. our findings are consistent with those of a recent covid-19 study demonstrating that frontline nurses had significantly lower vicarious traumatization scores than non-frontline nurses and the general public (5) . reasons for this may include reduced accessibility to formal psychological support, less first-hand medical information on the outbreak, less intensive training on personal protective equipment and infection control measures. as the pandemic continues, important clinical and policy strategies are needed to support health care workers. our study identified a vulnerable group susceptible to psychological distress. educational interventions should target nonmedical health care workers to ensure understanding and use of infectious control measures. psychological support could include counseling services and development of support systems among colleagues. our study has limitations. first, data obtained from selfreported questionnaires were not verified with medical records. second, the study did not assess socioeconomic status, which may be helpful in evaluating associations of outcomes and tailoring specific interventions. finally, the study was performed early in the outbreak and only in singapore, which may limit the generalizability of the findings. follow-up studies could help assess for progression or even a potential rebound effect of psychological manifestations once the imminent threat of covid-19 subsides. in conclusion, our study highlights that nonmedical health care personnel are at highest risk for psychological distress during the covid-19 outbreak. early psychological interventions targeting this vulnerable group may be beneficial. dass-21 = depression, anxiety, and stress scales; ies-r = impact of events scale-revised; ptsd = posttraumatic stress disorder. * the dass-21 is a 21-item system that provides independent measures of depression, stress, and anxiety with recommended severity thresholds. cutoff scores >9, >7, and >14 indicate a positive screen for depression, anxiety, and stress respectively. the ies-r is a 22-item self-report instrument that measures the subjective distress caused by traumatic events. it has 3 subscales (intrusion, avoidance, and hyperarousal), which are closely affiliated with ptsd symptoms. a total ies-r cutoff score of 24 is used to classify ptsd as a clinical concern. † adjusted for age, sex, ethnicity, marital status, presence of comorbid conditions, and survey completion date. the adjusted prevalence ratio was derived from logistic regression models by calculating marginally adjusted prevalence for each group. the 95% cis were derived by using the delta method. the adjusted mean difference was obtained by using linear regression. updates on covid-19 (coronavirus disease 2019) local situation. ministry of health manual for the depression anxiety stress scales psychometric properties of the impact of event scale -revised psychological impact of the 2003 severe acute respiratory syndrome outbreak on health care workers in a medium size regional general hospital in singapore vicarious traumatization in the general public, members, and non-members of medical teams aiding in covid-19 control key: cord-309207-n8u8ddv7 authors: lechien, jerome r.; chiesa-estomba md, carlos m.; hans, stephane; barillari md, maria rosaria; jouffe, lionel; saussez, sven title: loss of smell and taste in 2013 european patients with mild to moderate covid-19 date: 2020-05-26 journal: ann intern med doi: 10.7326/m20-2428 sha: doc_id: 309207 cord_uid: n8u8ddv7 nan april 2020, we identified 2153 consecutive ambulatory and hospitalized patients with positive results on reverse transcriptase polymerase chain reaction (rt-pcr) testing at 18 european hospitals. patients had mild to moderate covid-19, defined as an infection not requiring intensive care, and those who were hospitalized were discharged during the study period. of the 2153 patients, 2013 (93.5%) provided informed consent and participated in the study ( figure) , which was approved by the ethics committee at each institution. using a standardized online questionnaire, we collected clinical and epidemiologic data from hospitalized patients on discharge day and from ambulatory patients after the resolution of key symptoms (such as cough, fever, dyspnea, headache, myalgia, and arthralgia) (figure) . we assessed general and otolaryngologic symptoms believed to be associated with covid-19 (by using a 4-point scale, from 0 for no symptoms to 4 for severe symptoms). the olfactory and gustatory assessment was based on 8 questions on the smell and taste component of the national health and nutrition examination survey (3). objective evaluations for olfactory dysfunction were performed in a subset of patients who reported total loss of smell at 1 of the study sites (epicura hospital, hainaut, belgium) at the time of the questionnaire. we used a standard olfactory identification test (sniffin' sticks [medisense]) (4), in which we presented 16 scented pens to each patient to smell every 30 seconds. patients were asked to choose the best term among 4 options to describe the aroma. the test was scored on the basis of a 16-point total. according to the results, patients were classified as normosmic (12 to 16 points), hyposmic (9 to 11 points), or anosmic (<9 points). findings: of 2013 patients, 161 (8%) were hospitalized ( figure) ; the remainder were ambulatory patients not previously hospitalized for covid-19. the table presents characteristics of our study participants. loss of smell and headache were the most prevalent symptoms. a total of 1754 patients (87%) reported loss of smell, whereas 1136 (56%) reported taste dysfunction. mean time from the end of the disease to the evaluation was 7.8 days (sd, 6.8); mean duration of general symptoms (excluding loss of smell and taste) was 11.5 days (sd, 6.0). most patients had loss of smell after other general and otolaryngologic symptoms (table) . at the time of evaluation, 573 of 1754 patients regained their sense of smell, 60.9% of them between 5 and 14 days after the onset of smell loss; mean duration of olfactory dysfunction was 8.4 days (sd, 5.1). in the subset of 93 patients who were eligible to have an objective olfactory evaluation, 86 (92.5%) completed the assessment; anosmia and hyposmia were confirmed in more than half the patients (table) , but more than a third showed no objective signs of dysfunction. taste disorder, defined as partial or total loss of the 4 taste types-salty, sweet, bitter, and sour (3)-affected 56.4% of patients. additional aroma disorder (3) occurred in 82.5% of patients. characteristics of patients with loss of taste and smell are shown in the table. two main categories of patients with total loss of smell were observed: those with and those without nasal obstruction (table) . no significant association was found between loss of smell and the otolaryngologic symptoms of nasal obstruction, rhinorrhea, and postnasal drip in the entire cohort or among subgroups with anosmia, hyposmia, or normosmia. discussion: the prevalence of self-reported smell and taste dysfunction in our study is higher than previously reported and may be characterized by different clinical forms. our results suggest that anosmia may not be related to nasal obstruction or inflammation. future studies are needed to understand the pathophysiologic mechanisms underlying loss of smell and taste in covid-19, including potential viral spread through the olfactory neuroepithelium and invasion of the olfactory bulb and central nervous system (5) . our study has limitations. hospitalized patients were assessed at discharge, which may have biased our assessment of symptom duration. the study population was limited to patients with mild to moderate symptoms. because patients were asked about taste and smell after they received their diagnosis, they may have been influenced by news reports of smell and taste dysfunction in covid-19 and overreported these symptoms: only two thirds of patients reporting olfactory symptoms and who had objective olfactory testing had abnormal results. nonetheless, these findings highlight the importance of considering loss of smell and taste in the diagnosis of mild to moderate covid-19. covid-19 task force of yo-ifos. clinical and epidemiological characteristics of 1,420 european patients with mild-to-moderate coronavirus disease 2019 lancovid-19). clinical, laboratory and imaging features of covid-19: a systematic review and meta-analysis prevalence and risk factors of self-reported smell and taste alterations: results from the 2011-2012 us national health and nutrition examination survey (nhanes) normative data for the "sniffin' sticks" including tests of odor identification, odor discrimination, and olfactory thresholds: an upgrade based on a group of more than 3,000 subjects non-neuronal expression of sars-cov-2 entry genes in the olfactory system suggests mechanisms underlying covid-19-associated anosmia epicura and other centers for the collaboration, as well as the physicians who collected the data. key: cord-330916-s99ayg1j authors: hernandez, adrian v.; roman, yuani m.; pasupuleti, vinay; barboza, joshuan j.; white, c. michael title: update alert: hydroxychloroquine or chloroquine for the treatment or prophylaxis of covid-19 date: 2020-07-15 journal: ann intern med doi: 10.7326/l20-0945 sha: doc_id: 330916 cord_uid: s99ayg1j nan published reports of 3 studies previously available as preprints became available (2-4), enabling more thorough assessment for risk of bias. the risk of bias is now determined to be serious for yu and colleagues' study (4) , remains high for tang and colleagues' study (2), and changed from moderate to serious for mahé vas and colleagues' study (3) . we found 1 new randomized controlled trial (rct) with high risk of bias (5), 1 new cohort study with moderate risk of bias (6) , and 4 cohort studies that each had serious risk of bias (7) (8) (9) (10) . an additional large cohort study was published and subsequently retracted due to concerns about the veracity of the data (11, 12) and was not considered further. press releases reported 3 large rcts (recovery, solidarity-who, and orchid-nih) that ceased enrollment for the hydroxychloroquine versus control comparison early because of lack of efficacy in preliminary analyses (13) (14) (15) . these trials had strong study designs, but other than press releases, no reports were available to assess. the only new data on chloroquine came from chen and colleagues' aforementioned rct, which contained a chloroquine group that was compared with a control group (5). this rct had high risk of bias and observed no deaths or severe disease progression, and all patients in both groups cleared the virus from the upper respiratory tract by day 10 (5). however, clinical recovery took fewer days in the chloroquine group than the control group. supplement tables 1 and 2 (available at annals.org) provide updated unadjusted outcomes data (1-28). given the risk of bias for individual studies and the conflicting direction and magnitude of results, the evidence from both rcts and cohort studies remains insufficiently strong to support a benefit of hydroxychloroquine or chloroquine for treatment of covid-19 in hospitalized patients. we were unable to identify a pattern by which risk of bias, dosage, duration of therapy, or other factors explained the conflicting findings. the strength of evidence remains insufficient for all safety outcomes. this update identified 1 new rct, several new cohort studies, and more complete published reports of studies previously available as preprints; the conclusions are un-changed from the initial review. the newly available evidence has high risk of bias. there is insufficient evidence to support the effectiveness or safety of hydroxychloroquine or chloroquine for the treatment of covid-19 in hospitalized patients. the results of the recovery, solidarity-who, and orchid-nih trials could help to more definitively determine the role of this therapy for covid-19. clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data low dose of hydroxychloroquine reduces fatality of critically ill patients with covid-19. sci china life sci efficacy and safety of chloroquine or hydroxychloroquine in moderate type of covid-19: a prospective open-label randomized controlled study. medrxiv. preprint posted online 22 hydroxychloroquine with or without azithromycin and in-hospital mortality or discharge in patients hospitalized for covid-19 infection: a cohort study of 4,642 inpatients in france. medrxiv. preprint posted online 16 association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with covid-19 in new york state hydroxychloroquine and tocilizumab therapy for covid-19 patients -an observational study. medrxiv. preprint posted online 21 outcomes of hydroxychloroquine treatment among hospitalized covid-19 patients in the united states-real-world evidence from a federated electronic medical record network. medrxiv. preprint posted online 12 henry ford covid-19 task force. treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with covid-19 retraction-hydroxychloroquine or chloroquine with or without a macrolide for treatment of covid-19: a multinational registry analysis 2 papers about drug therapy for covid-19 retracted from prestigious journals /article/05-20/2-papers-aboutdrug-therapy-in-covid-19-retracted-from -prestigious-journals/58677 on 6 no clinical benefit from use of hydroxychloroquinein hospitalised patients with covid-19 accessed at www.who .int/news-room/detail/04-07-2020-who-discontinues-hydroxychloroquine -and-lopinavir-ritonavir-treatment-arms-for-covid-19 on 6 a randomized trial of hydroxychloroquine as postexposure prophylaxis for covid-19 preliminary study of hydroxychloroquine sulfate in treating common coronavirus disease (covid-19) patients in 2019 clinical outcomes of hydroxychloroquine in hospitalized patients with covid-19: a quasi-randomized comparative study. accessed at www.dropbox.com/s/urzapkyij542qx5/nejm_clinical %20outcomes%20of%20hydroxychlorquine%20in%20patients%20with %20covid19 outcomes of hydroxychloroquine usage in united states veterans hospitalized with covid-19. medrxiv. preprint posted online 23 hydroxychloroquine is associated with slower viral clearance in clinical covid-19 patients with mild to moderate disease: a retrospective study. medrxiv. preprint posted online 2 early hydroxychloroquine is associated with an increase of survival in covid-19 patients: an observational study observational study of hydroxychloroquine in hospitalized patients with covid-19 no evidence of clinical efficacy of hydroxychloroquine in patients hospitalized for covid-19 infection with oxygen requirement: results of a study using routinely collected data to emulate a target trial. medrxiv. preprint posted online 14 efficacy of hydroxychloroquine in patients with covid-19: results of a randomized clinical trial. medrxiv. preprint posted online hydroxychloroquine and azithromycin as a treatment of covid-19: results of an open-label non-randomized clinical trial chloroquine diphosphate in two different dosages as adjunctive therapy for hospitalized patients with severe respiratory syndrome in the context of coronavirus (sars-cov-2) infection: preliminary safety results of a randomized, double-blinded, phase iib clinical trial (clorocovid-19 study). medrxiv. preprint posted online 16 effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection: a randomized clinical trial preliminary evidence from a multicenter prospective observational study of the safety and efficacy of chloroquine for the treatment of covid-19. medrxiv key: cord-263549-hmdyb7hi authors: dewitt, dawn e. title: fighting covid-19: enabling graduating students to start internship early at their own medical school date: 2020-04-07 journal: ann intern med doi: 10.7326/m20-1262 sha: doc_id: 263549 cord_uid: hmdyb7hi this perspective proposes one way to ensure enough doctors, nurses, and pharmacists during the covid-19 pandemic: enable graduating students to start internship early at their own medical school. tems affiliated with their medical school. first, medical schools could point students toward existing "readiness for internship" content. many medical schools have a "capstone" course in the final weeks before graduation that prepares students for internship, with content geared toward meeting common patient care challenges. most schools could deliver much of that content online now or via specific programs (3) (4) (5) . in addition, some commonly required certificate courses, such as advanced cardiac life support and pediatric advanced life support, can be completed online in less than a week (6) . the united states could provide loan repayment or other federal payment programs for any senior students willing (and competent, as judged by their medical school) to begin early. the average u.s. medical student graduates with approximately $200 000 of debt (7), so generous repayment programs would be welcome-and fitting-with potentially less bureaucracy than officially hiring students through health care systems short term. an alternative would be to pay the students a stipend equal to a tuition rebate plus the equivalent of a resident's salary funded by medicare (8) . further, delays in transition to residency for this year's students due to chaos, credentialing, and other barriers might generate more problems for graduating students and short-staffed health care systems. we should urgently prepare these all-but-graduated students to help us address the looming workforce shortage as junior physicians during the next few weeks. however, they also should get credit for the experience they will gain and the service they will provide. the last big advantage of this plan is that the new junior interns would be working on home turf rather than adjusting to a different hospital or place, as happens for many interns who move across states, or across the country, to start in different health systems. starting at their home institutions would vastly decrease credentialing and barriers to electronic health record access. we would have to rapidly address financial and logistic issues. potential guarantees for loan repayment and tuition refunds would be key to success. health profession schools would have to signal which students have the competency to begin working with more independence and agree to supervision requirements similar to those for residents. supervision might be expanded to appropriate recently retired physicians or this article was published at annals.org on 7 april 2020. those whose health risks due to covid-19 make them unable to work on the front lines. health systems would need to authorize access so that competent students could write orders and access electronic medical records from home. graduate medical education (gme) leaders would need to discuss potentially giving participating students "credit" toward residency completion. these are bold but relatively straightforward requests, which i am certain academic medicine could tackle nationally in concert with gme leadership. breaking down bureaucratic barriers must be a priority-a national effort could save many thousands of lives, not to mention being a substantial uplift for exhausted health care providers. despite the logistic challenges, definitive and organized collective action now may give the united states an edge that we desperately need in this fight. italy rushes to promote new doctors to relieve coronavirus crisis accessed at www .ama-assn.org/delivering-care/public-health/covid-19-states-call-early -medical-school-grads-bolster-workforce on 5 accessed at www.wisemed .org/wise-oncall the key role of a transition course in preparing medical students for internship advanced cardiovascular life support (acls) course options house of representatives committee on small business. the doctor is out. rising student loan debt and the decline of the small medical practice medicare payments for graduate medical education: what every medical student, resident, and advisor needs to know. accessed at www.aamc.org/data -reports/faculty-institutions/report/medicare-payments-graduate -medical-education-what-every-medical-student-resident-and -advisor key: cord-309650-6xz9gjq0 authors: chou, roger; dana, tracy; buckley, david i.; selph, shelley; fu, rongwei; totten, annette m. title: update alert 4: epidemiology of and risk factors for coronavirus infection in health care workers date: 2020-09-11 journal: ann intern med doi: 10.7326/l20-1134 sha: doc_id: 309650 cord_uid: 6xz9gjq0 nan 48% 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the netherlands serological prevalence of antibodies to sars cov-2 amongst cancer centre staff comparing hospitalised, community and staff covid-19 infection rates during the early phase of the evolving covid-19 epidemic covid-19 cluster study at a teaching hospital at the height of the storm: healthcare staff's health conditions and job satisfaction and their associated predictors during the epidemic peak of covid-19 analysis of the infection status of the health care workers in wuhan during the covid-19 outbreak: a cross-sectional study covid-19 in wuhan: immediate psychological impact on 5062 health workers deaths from covid-19 in healthcare workers in italy -what can we learn? epidemiological, clinical characteristics and outcome of medical staff infected with covid-19 in wuhan, china: a retrospective case series analysis clinical characteristics of 30 medical workers infected with new coronavirus pneumonia epidemiology of covid-19 in a long-term care facility in king county, washington association between 2019-ncov transmission and n95 respirator use psychological symptoms among frontline healthcare workers during covid-19 outbreak in wuhan study on health-related quality of life and influencing factors of pediatric medical staff during the covid-19 outbreak mental health survey of medical staff in a tertiary infectious disease hospital for covid-19 factors associated with mental health outcomes among health care workers exposed to coronavirus disease mental health of young physicians in china during the novel coronavirus disease mental distress among frontline healthcare workers outside the central epidemic area during the novel coronavirus disease (covid-19) outbreak in china: a cross-sectional study psychological status of medical workforce during the covid-19 pandemic: a cross-sectional study the evaluation of sleep disturbances for chinese frontline medical workers under the outbreak of covid-19 a study on mental health status among the staff in a designated hospital for covid-192020 mental health status among family members of health care workers in ningbo, china during the coronavirus disease 2019 (covid-19) outbreak: a cross-sectional study prevalence and impact of burnout, secondary traumatic stress and compassion satisfaction on hand hygiene of healthcare workers in medical aid team during covid-19 pandemic risk of symptomatic covid-19 among frontline healthcare workers sars-cov-2 infection among healthcare workers in a hospital in covid-19 and the risk to health care workers: a case report seroprevalence of sars-cov-2 among frontline healthcare personnel during the first month of caring for covid-19 patients healthcare workers & sars-cov-2 infection in india: a casecontrol investigation in the time of covid-19 ----11.8% (38/323) 19 key: cord-339509-4ezt6o0o authors: fox, sharon e.; lameira, fernanda s.; rinker, elizabeth b.; vander heide, richard s. title: cardiac endotheliitis and multisystem inflammatory syndrome after covid-19 date: 2020-07-29 journal: ann intern med doi: 10.7326/l20-0882 sha: doc_id: 339509 cord_uid: 4ezt6o0o nan background: endotheliitis and microangiopathy have been identified as key features of the pathophysiology of severe coronavirus disease 2019 (covid-19) (1, 2) . in addition, a multisystem inflammatory syndrome (mis) similar to kawasaki disease has been increasingly reported in association with covid-19 in children and young adults (3) (4) (5) . although vascular damage seems to be a component of both of these presentations, the pathologic features of mis remain elusive. objective: to provide what we believe to be the first report on the pathologic findings of vasculitis of the small vessels of the heart, which likely represents mis, leading to death in a young adult after presumed resolution of severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection. case report: the patient was a 31-year-old african american woman with a body mass index of 36.1 kg/m 2 , hypertension controlled with lisinopril, and diabetes with poor adherence to metformin and glipizide (hemoglobin a 1c level, 13.9%). she was admitted for fever, dry cough, and abdominal discomfort of 5 days. she was positive for sars-cov-2 by reverse transcriptase polymerase chain reaction testing of a nasopharyngeal swab specimen and was treated with a course of azithromycin and 2 days of hydroxychloroquine. at discharge, she was afebrile and her oxygen saturation was 95% on room air. the patient returned 12 days later with sudden fever; throbbing, left-sided neck pain; nausea; and vomiting. she had a fever of 39.8°c, with sinus tachycardia of approximately this article was published at annals.org on 29 july 2020. letters 120 beats/min on electrocardiography. her physical examination was remarkable for parotitis. a computed tomography scan of her neck showed bilaterally enlarged parotid glands and swelling in the posterior nasopharynx to oropharynx, and a computed tomography scan of her chest showed interval improvement of bibasilar ground-glass opacities, with cervical and anterior mediastinal lymphadenopathy. reverse transcriptase polymerase chain reaction of a new nasopharyngeal swab was negative for sars-cov-2. laboratory results at the time showed an elevated leukocyte count of 17.7 x10 9 cells/l, a d-dimer level of 2.48 nmol/l, and c-reactive protein levels trending upward (table) . while she was being evaluated for hospital admission, she developed hemodynamic instability and ventricular fibrillation and could not be resuscitated. permission for autopsy was granted by the next of kin, and this study was determined to be exempt by the institutional review board at louisiana state university health sciences center. gross abnormalities noted at autopsy (4 hours after death) were conjunctival injection, enlarged cervical and mediastinal lymph nodes, and vascular thrombi with focal surrounding hemorrhage in the left lower lung, which probably contributed to illness but were not likely the primary cause of death. pulmonary microscopic examination showed focal acute hemorrhage and numerous megakaryocytes, consistent with our previously reported findings (2) . most of the lung showed predominantly reparative changes. flow cytometry of an enlarged cervical lymph node revealed reactive changes, with a ratio of cd4 to cd8 t cells of 3:1. the heart had a grossly normal appearance, without evidence of coronary artery aneurysm, atherosclerosis, or stenoimmunostain showing reduced numbers of cd8 + compared with cd4 + lymphocytes. g. a similar neutrophilic vasculitis was seen in occasional portal triads of the liver, involving small arteries and veins with surrounding congestion and no direct inflammation of hepatocytes. levels of aspartate aminotransferase and alanine aminotransferase became elevated just before death (table). sis. microscopically, however, endotheliitis and vasculitis were present, diffusely involving the small cardiac vessels and extending into the surrounding epicardial fat and interstitial spaces ( figure, a and b) . there was no lymphocytic infiltrate of the myocardium (2, 3) . the vasculitis was composed of numerous neutrophils (figure, c) , as well as cd4 + >cd8 + lymphocytes ( figure, e and f) . inflammation was not present in the coronary arteries or larger blood vessels (figure, d) . similar inflammation was noted in occasional portal triad vessels within the liver (figure, g) . discussion: multisystem inflammatory syndrome is currently defined as fever, systemic inflammation, end-organ dysfunction, or symptoms similar to kawasaki disease or toxic shock syndrome (4, 5) . the clinical picture in this adult patient of sudden lymphadenopathy and parotitis combined with small-vessel cardiac vasculitis after covid-19 is strongly suggestive of a similar systemic inflammatory process. of note, the coronary arteries were spared, and neutrophils were identified along with cd4 + >cd8 + lymphocytes. the appearance was not that of a lymphocytic or eosinophilic myocarditis, and cardiac myocytes did not seem to be the target of the inflammatory process. the autopsy was also significant for the presence of new pulmonary thrombi in a background of otherwise reparative changes in the lungs. these thrombi indicate a potential for hypercoagulability affecting the pulmonary vasculature beyond the initial course of covid-19, as well as the need for continued monitoring of laboratory markers and possible anticoagulation. our report highlights the potential for serious complications due to endothelial damage and describes potential pathologic characteristics of mis after covid-19, a possible mimicker of true myocarditis. careful monitoring of laboratory markers of inflammation, as well as therapeutic intervention to target this inflammatory process, may improve patient outcomes. endothelial cell infection and endotheliitis in covid-19 pulmonary and cardiac pathology in african american patients with covid-19: an autopsy series from new orleans unexpected features of cardiac pathology in covid-19 infection multisystem inflammatory syndrome related to covid-19 in previously healthy children and adolescents in new york city kawasaki-like disease: emerging complication during the covid-19 pandemic key: cord-273192-r1wt1oyg authors: blackburn, justin; yiannoutsos, constantin t.; carroll, aaron e.; halverson, paul k.; menachemi, nir title: infection fatality ratios for covid-19 among noninstitutionalized persons 12 and older: results of a random-sample prevalence study date: 2020-09-02 journal: ann intern med doi: 10.7326/m20-5352 sha: doc_id: 273192 cord_uid: r1wt1oyg nan background: because many cases of coronavirus disease 2019 (covid-19) are asymptomatic, generalizable data on the true number of persons infected are lacking. mortality rates therefore are calculated from confirmed cases, which overestimates the infection fatality ratio (ifr). to calculate a true ifr, population prevalence data are needed from large geographic areas where reliable death data also exist. most previous ifr estimates came from non-u.s. populations, including a cruise ship, or were calculated by using simulation techniques (1) (2) (3) . previous estimates also are not age specific, are relatively ungeneralizable, and are unsuitable for making clinical or policy decisions. objective: to estimate ifrs among noninstitutionalized (that is, community-dwelling) populations by age, race, ethnicity, and sex by using the first u.s. statewide random-sample study of severe acute respiratory syndrome coronavirus 2 (sars-cov-2) prevalence. methods and findings: we combined prevalence estimates from a statewide random sample with indiana vital statistics data of confirmed covid-19 deaths (4). in brief, our stratified random sample consisted of state residents aged 12 years and older. known decedents and incarcerated persons were excluded. because nursing homes were limiting residents' ability to leave and re-enter the facilities, their participation was unlikely. participants were tested from 25 april to 29 april 2020 for active viral infection and sars-cov-2 antibodies, which would indicate prior infection. demographic information was collected. we accounted for nonresponse by weighting prevalence estimates for age, race (dichotomized as white or non-white), and hispanic ethnicity to reflect state demographics. estimated prevalence included all current and past infections with bootstrapped 95% cis. the prevalence of each demographic stratum was multiplied by the stratum-specific state population estimate to determine the number of cumulative infections by group. we calculated the ifr by age, race, sex, and ethnicity on the basis of the cumulative number of confirmed covid-19 deaths as of 29 april 2020, divided by the number of infections. although nursing home residents were not tested, they represented 54.9% of indiana's deaths. thus, we excluded nursing home residents from all calculations (that is, deaths and infections). to account for all infections, we added the number of patients hospitalized with covid-19 during the testing period and noninstitutionalized covid-19 deaths into the denominator. as of 29 april 2020, indiana had recorded 1099 covid-19 deaths, 495 of which occurred in noninstitutionalized persons. our random-sample study estimated 187 802 cumulative infections, to which 180 hospitalizations were added. the average age among all covid-19 decedents was 76.9 years (sd, 13.1). the overall noninstitutionalized ifr was 0.26%. in order of magnitude, the demographic-stratified ifr varied most by age, race, ethnicity, and sex (table) . persons younger than 40 years had an ifr of 0.01%; those aged 60 or older had an ifr of 1.71%. whites had an ifr of 0.18%; non-whites had an ifr of 0.59%. discussion: by using sars-cov-2 population prevalence data, we found that the risk for death among infected persons increased with age. indiana's ifr for noninstitutionalized persons older than 60 years is just below 2% (1 in 50). in comparison, the ratio is approximately 2.5 times greater than the es-this article was published at annals.org on 2 september 2020. timated ifr for seasonal influenza, 0.8% (1 in 125), among those aged 65 years and older (5) . of note, the ifr for non-whites is more than 3 times that for whites, despite covid-19 decedents in that group being 5.6 years younger on average. we are unaware of any similar ifr estimates by demographic group but recognize several limitations of our analysis. first, despite random selection and weighting for nonresponse, the potential for response bias remains. second, imperfections in tests have the potential for false-positives, which may bias estimated infections upward. separately, use of confirmed covid-19 deaths may undercount the true number of deaths; both issues might result in lower ifrs. third, because children and non-state tax filers were excluded, our estimates may lack generalizability to persons who were not studied. fourth, we could not account for disease severity among random-sample participants with positive test results. although participants represented persons with less severe illness, some with positive test results may have later died of covid-19, resulting in a potential underestimation of the ifr. however, accounting for right-censoring bias also might overestimate the ifr, because we cannot distinguish deaths among persons we randomly tested from those among patients who were hospitalized during the testing period. race and ethnicity data for confirmed covid-19 deaths may have been inaccurate, thus biasing these ifr estimates. lastly, ifr is a population-based measure and should be interpreted cautiously as a measure of individual risk. a systematic review of covid-19 epidemiology based on current evidence estimating the infection and case fatality ratio for coronavirus disease (covid-19) using age-adjusted data from the outbreak on the diamond princess cruise ship estimating the infection fatality rate among symptomatic covid-19 cases in the united states. health aff (millwood) population point prevalence of sars-cov-2 infection based on a statewide random sample -indiana estimated influenza illnesses, medical visits, hospitalizations, and deaths in the united states-2018 -2019 influenza season correction: this article was corrected on 3 september 2020 to fix inaccurate values within the male and female categories in the table. key: cord-307717-vf85qt8j authors: dewey, charlene; hingle, susan; goelz, elizabeth; linzer, mark title: supporting clinicians during the covid-19 pandemic date: 2020-03-20 journal: ann intern med doi: 10.7326/m20-1033 sha: doc_id: 307717 cord_uid: vf85qt8j the covid-19 pandemic has upended clinicians' sense of order and control, creating the potential for stress in the short term and burnout over the long term. this commentary offers suggestions to encourage a culture that will sustain the clinician workforce during the pandemic. t he coronavirus disease 2019 (covid-19) pandemic has upended clinicians' sense of order and control. such disruption may lead to substantial stress in the short term and higher risk for burnout over the long term. while natural disasters, such as hurricane katrina, demonstrated the effectiveness of short-term emergency planning (1), the covid-19 pandemic poses unique long-term stressors and risks to clinicians' physical, mental, spiritual, and emotional well-being. leaders and front-line clinicians need to proactively protect the well-being of themselves and their colleagues to avoid adverse outcomes for clinicians and adverse effects on quality of patient care (2) . we provide practical suggestions to encourage a culture that will sustain the clinician workforce during the pandemic. regardless of practice location or size, everyone must commit to supporting the well-being of those involved in patient care. first and foremost, organizational leaders should provide clear messages that clinicians are valued and that managing the pandemic together is the goal. front-line clinicians must individually and collectively identify concerns that arise while facing the reality of the pandemic. leaders must communicate current best practices clearly and compassionately, manage expectations, clarify work hours, and provide sufficient resources and effective personal protective equipment. to better enable clinicians to maintain personal wellbeing and resilience throughout the pandemic, leaders should aim to monitor clinician wellness and proactively address concerns related to the safety of clinicians and their families. leaders should aim for work schedules that promote physical resilience by enabling adequate sleep and providing access to call rooms for hospital-based clinicians working long or multiple shifts. leaders should also take initiatives to provide basic provisions during work hours, such as easy access to water, healthy snacks, chargers for phones and other devices, and toiletries. leaders must also designate times for clinicians to take breaks, eat, and take medications. it may also be helpful to advise clinicians working such shifts to bring at least 3 days of their own medications to work and designate a source for emergency refills. clinicians should also continue using wellness activities that have worked for them in the past and make efforts to support each other during this challenging time. reduction of noncritical work activities may help to promote mental well-being. examples include rescheduling preventive and routine patient follow-up visits and eliminating nonessential administrative tasks. anxiety can be reduced by providing a central source for updated information and clear communication of welldefined protocols, expectations, and such resources as childcare via e-mails, tweets, and automated calls. when an individual clinician feels well but cannot be present in the clinical setting because of mandatory isolation or childcare, hospitals and practices should aim to redistribute work and have these clinicians participate in computer-and phone-based care while home. during the pandemic, clinicians should be encouraged to openly discuss vulnerability and the importance of protecting one's emotional strength. health care organizations can provide information on managing stress, reducing burnout, and identifying mental health professionals available to support clinicians (3). deploy designated wellness champions in health care systems and practices to field clinicians' concerns, advocate for clinicians, and distribute messages of gratitude and support. we also suggest fostering spiritual resilience through distribution of positive messaging that emphasizes appreciation for clinicians' dedication and altruism. disseminating strategies for connecting with colleagues to share stories of success, rather than focusing on failures and stresses, can help clinicians find joy amidst chaos (4). helping clinicians recognize what they can and cannot control helps to balance expectations with realities. a supportive work culture is vital to maintaining the resilience of clinicians during a crisis such as covid-19. we suggest developing an evidence-based menu of interventions, to be carefully selected from, and tailored to various workplace settings. for larger health systems, wellness committees and employee assistance programs are the logical resources to organize these interventions. in smaller settings, appointing a wellness champion could help to elucidate colleagues' needs and implement solutions. surveys to assess stress points, fears, and concerns can inform leaders and provide insight into areas requiring attention. we also suggest developing plans to back up, cross-train, and rotate leadership to avoid leader burnout. sharing challenges and successes will help to meet urgent needs during the evolving pandemic. examples of settings for such sharing include the american college of physicians physician well-being and discussion forum (5), the society of general internal medicine gimconnect (6) , and the american medical association physician health (7) resources that members can access. other professional organizations, or organizations with access to community discussion boards, could develop similar venues for highlighting best practices in wellness. emphasizing clinician wellness during the covid-19 pandemic (8) is necessary to enable them to provide high-quality care. we propose some preliminary, common sense steps toward this goal and encourage colleagues to share strategies they find successful. how we this article was published at annals.org on 20 march 2020. meet the wellness needs of our clinicians may determine how well we survive the covid-19 pandemic and future public health crises. new orleans rises anew: community health after katrina evidence relating health care provider burnout and quality of care: a systematic review and metaanalysis a cluster randomized trial of interventions to improve work conditions and clinician burnout in primary care: results from the healthy work place (hwp) study forty-five good things: a prospective pilot study of the three good things well-being intervention in the usa for healthcare worker emotional exhaustion, depression, worklife balance and happiness american college of physicians. physician well-being and discussion forum. accessed at www.acponline.org/forums/physician-well -being-and-professional-satisfaction on accessed at www.ama-assn.org/practice-management/physician-health on 18 sustaining the wellbeing of healthcare personnel during coronavirus and other infectious disease outbreaks. accessed at www.cstsonline.org/assets /media/documents/csts_fs_sustaining_well_being_healthcare _personnel_during key: cord-298632-xu1sgguh authors: tyan, kevin; cohen, pieter a. title: investing in our first line of defense: environmental services workers date: 2020-05-01 journal: ann intern med doi: 10.7326/m20-2237 sha: doc_id: 298632 cord_uid: xu1sgguh environmental services personnel are a critical first line of defense against the spread of covid-19. this commentary discusses the importance of environmental cleaning during the pandemic and the essential role of environmental services personnel in patient safety. d uring the height of the pandemic in new york city, thousands of residents leaned out their windows every evening to cheer and celebrate the physicians, nurses, and other professionals on the frontline of combating covid-19. employees at groceries, pharmacies, and other essential businesses have also received welldeserved recognition. largely absent from national attention, however, are the hundreds of thousands of workers devoted to disinfecting our hospitals. these environmental services (evs) personnel are among those most likely to be exposed to the virus and most essential to combating its spread. these staff perform the arduous tasks of wiping down beds, cleaning bathrooms, and decontaminating hospital equipment. they are the unnoticed sinews of a well-functioning hospital. these essential personnel are still often called "housekeepers"-a relic from a time when their role was regarded as purely janitorial rather than fundamental to patient safety. in the face of this pandemic, they are among the unsung heroes, the critical first line of defense against infection. yet their task of hospital cleaning and their stature in the health care hierarchy have long been underappreciated (1) (2) (3) . this is despite extensive evidence that environmental contamination places patients and health care personnel at risk for life-threatening disease. when a hospitalized patient suffers an infection, the next patient to occupy their room has a 6-fold greater risk of acquiring the same pathogen (4). in intensive care units, dirty objects and failure to remove surface bioburden correlate with increased acquisition of infections (2) . across hospital systems, cost-cutting to reduce evs staff and cleaning hours has been associated with increased nosocomial infections (1) (2) (3) . in light of evidence that severe acute respiratory syndrome coronavirus 2 (sars-cov-2) can survive on surfaces for up to 3 days (5), along with studies demonstrating that viral shedding contaminates over 80% of the interior of hospital rooms (6) and aerosolization of sars-cov-2 causes extensive surface contamination (7), it is now more urgent than ever to emphasize the importance of environmental cleaning. unfortunately, evs personnel have been a target for cost-cutting since the mid 1990s. cleaning staff have been whittled down by 25% during this time, and more than one third of hospitals have disbanded their own evs teams to outsource this work to contractors, shedding valuable institutional experience while exacerbating high turnover and inadequate training (1). some new hires receive only 3 days of training, forcing 83% of evs staff to train new recruits on the job, furthering the notion that their work is menial and unskilled rather than vital to patient outcomes. meanwhile, stagnant low wages condemn over three quarters of workers below the poverty line (1) . a recent analysis found that 30.5% of health workers at risk for poor covid-19 outcomes lack paid sick leave, and support workers remain uninsured at rates above the national average (8) . it is no accident that many evs workers feel invisible to the rest of the hospital team-they are systemically devalued, ignored, and relegated to the bottom of the socioeconomic hierarchy. now, as the surge of covid-19 cases threatens to overwhelm our hospitals, evs workers are being asked to do more with less. even before the covid-19 pandemic, two thirds of evs staff reported working under chronically understaffed conditions, and over 80% worry that this impedes high-quality work (1). to thoroughly disinfect a hospital room, evs workers need sufficient time, proper technique, and effective tools. each worker must methodically work their way through each room, removing soiled linens, discarding trash, and mopping floors. to eliminate potential reservoirs for disease, they must meticulously wipe down all of the high-touch surfaces of a room, including bed rails, tables, intravenous poles, and door knobs (2) . in deploying their arsenal of disinfectants ranging from bleach to ethanol, they must be trained on the different contact times necessary to kill different pathogens (2) . the presence of high-risk pathogens complicates their work. they must garb themselves in personal protective equipment (ppe) to render these spaces safe for their colleagues and patients, and many evs staff now find themselves deprioritized in the distribution of scarce protective gear against covid-19 (9). this is a daunting set of tasks for anybody to accomplish, yet hospitals are asking their evs workers to perform it all in less than 15 minutes for up to 36 rooms a day (1) . many are pressured to cut corners and rushed to turn over rooms for waiting patients. the inevitable result: a study of more than 1000 patient rooms across 23 hospitals revealed that less than 50% of surfaces are properly cleaned (10) . there are alternatives. a culture of agency and responsibility could be instilled in every hospital employee. airplane mechanics and parachute packers are recognized for their critical work, as each tightened bolt and each untangled line represents crises averted, lives saved. we should afford the same respect to our evs workers and take steps to support their efforts on the frontline of infection prevention (table) . we can start by properly acknowledging their role as valuable members of the patient care team. hospitals need to embrace evs employees as a core investment in improving patient outcomes. further research and innovation should be directed toward enhancing their efforts. crucially, evs employees need sufficient ppe to protect themselves as they endeavor to protect others. cleaning up: how hospital outsourcing is hurting workers and endangering patients controlling hospital-acquired infection: focus on the role of the environment and new technologies for decontamination superbugs versus outsourced cleaners: employment arrangements and the spread of health careassociated infections association between healthcareassociated infection and exposure to hospital roommates and previous bed occupants with the same organism aerosol and surface stability of sars-cov-2 as compared with sars-cov-1 air, surface environmental, and personal protective equipment contamination by severe acute respiratory syndrome coronavirus 2 (sars-cov-2) from a symptomatic patient aerodynamic analysis of sars-cov-2 in two wuhan hospitals health insurance status and risk factors for poor outcomes with covid-19 among u.s. health care workers: a cross-sectional study accessed at www.reuters.com /article/us-health-coronavirus-housekeepers/in-fight-for-masks -hospital-janitors-sometimes-come-last-iduskbn21o2jf on 28 identifying opportunities to enhance environmental cleaning in 23 acute care hospitals key: cord-303420-3jlqx83u authors: kiser, stephanie b.; bernacki, rachelle e. title: when the dust settles: preventing a mental health crisis in covid-19 clinicians date: 2020-06-09 journal: ann intern med doi: 10.7326/m20-3738 sha: doc_id: 303420 cord_uid: 3jlqx83u this essay describes timely and targeted actions that clinicians can take during the covid-19 pandemic to support fellow clinicians. tients with coronavirus disease 2019 in new york city, emergency room physician lorna breen took her own life. her grieving family recounts days of helplessness leading up to this as dr. breen described how covid-19 upended her emergency department and left her feeling inadequate despite years of training and expertise. the clinical experience of dr. breen during this pandemic has not been unique. during the past 5 months, covid-19 has caused an upheaval of medical systems around the world, with more than 4 million cases and 300 000 deaths worldwide so far (1). unfortunately, we've also seen that the experience in caring for patients with the virus may have profound effects on clinicians' mental health (2) . a recent study conducted at the center of the outbreak in china reported that more than 70% of frontline health workers had psychological distress after caring for patients with covid-19 (3). understanding and addressing these effects starts with naming the problem. watching patients die alone, constant worry about inadequate resources, and paranoia about our own health are all deeply distressing and unprecedented experiences that cannot be described as anything other than trauma. much of what we are facing daily is uncharted territory, but history tells us that this trauma, like other types, may have profound implications for the mental health of clinicians. in a study of health care workers involved in the 2003 sars (severe acute respiratory syndrome) outbreak in toronto, one third of those surveyed reported posttraumatic stress symptoms at levels similar to those of victims of a large-scale natural disaster (4). furthermore, the risk for this secondary trauma comes for clinicians who already have a higher burden of mental health disease than the average population (5). many institutions have established resources, such as employee assistance programs, offering counseling and debriefing groups. these institution-wide approaches are crucial, but from our work in palliative care, where death is experienced daily, we know they will not be enough. we have learned the value of finding meaning in times of intense grief and sorrow-a new skill for many clinicians outside palliative care. as we have struggled to adapt our own coping mechanisms during this time, we have also observed our colleagues throughout the health care system in despair, often without the support, structure, and skills to process these events. with that in mind, we share a foundational set of principles to use as guidance for building internal support for the trauma caused by the pandem-ic: looking past the illness, fostering community, promoting vulnerability, and establishing boundaries and limitations. the practice of health care often dehumanizes our patients, reducing them to a list of symptoms and diagnoses. as we grieve over the restrictions currently limiting family members' presence at the bedside in our hospitals, we lose our most valuable connection to remembering who the patient is outside of their illness. during these times, we seek out ways to grasp small pieces of what that family presence often provides us. we spend a few extra minutes on the phone listening to a patient's wife tell us about the time they first met. we ask about an intubated patient's favorite song and play it at their bedside. these humanizing moments are desperately needed now. they sustain us and allow us to process our experiences as part of the complex narrative of illness. for many persons, the first response to trauma is self-isolation (4). although personal processing and reflection are certainly needed, healing requires community. topics that are challenging to discuss often are not talked about transparently in our work culture. in palliative care, these challenges bring us together and we make time to talk about them in groups; 1 example is weekly bereavement rounds to share grief about the death of our patients. these groups promote and honor each other's strengths to further build resiliency and help us process the grief and ensure that we protect ourselves. throughout the pandemic, the community has praised health care workers. from posters of support to donated meals, these gestures are a warm embrace. in much of this, health care workers are cast as "superheroes." although the sentiment is honored, the disconnect it creates cannot be ignored. many health care workers may not feel they are "flying" but instead barely keeping their heads above water. clinicians are not superheroes. we make mistakes, and we have limits. leaders of our departments and institutions must broadcast this message. senior clinicians can acknowledge the reality of the situation and encourage questioning of ourselves and our systems during this period of uncertainty. in palliative care, these thoughts are of-this article was published at annals.org on 9 june 2020. ten shared during structured weekly reflection rounds. although some may worry that this approach promotes weakness, we have seen the strength and support it provides. the calling to the medical profession may feel even stronger during these times of intense need. this comes at the risk of throwing ourselves into the work without considering our own needs and protection. leaders must protect their clinicians by carefully considering appropriate time off in scheduling and ensuring that colleagues, superiors, and trainees use this time. a need will always exist to do more, but this need cannot be met without ensuring that clinicians are well. for our palliative care department, incorporating all these supports means making dedicated time with intentional activities and, more importantly, fostering a cohesive community of constant reflection. the strength of our program in honoring these principles comes from our leaders, who have made them a priority and have led by example. we do this together and have learned the power of community and how diversity within community can provide perspective. as we offer these thoughts, we remain hopeful. the time for us to do more is now. if we take timely and targeted action, we will provide the support our fellow clinicians desperately need. we challenge leaders to act and make this a priority in the culture of their institutions. today, we honor dr. breen and we grieve with her family. as we continue to mourn the catastrophic mortality from this pandemic, we must recognize that some outcomes can be prevented. authors have disclosed no conflicts of interest. forms can be viewed at www.acponline.org/authors/icmje /conflictofinterestforms.do?msnum=m20-3738. epidemiology of and risk factors for coronavirus infection in health care workers factors associated with mental health outcomes among health care workers exposed to coronavirus disease 2019 the experience of the 2003 sars outbreak as a traumatic stress among frontline healthcare workers in toronto: lessons learned suicide rates among physicians: a quantitative and gender assessment (meta-analysis) current author addresses: dr. kiser: 450 author contributions: conception and design: s.b. kiser. analysis and interpretation of the data: r.e. bernacki. drafting of the article key: cord-301852-9nza3po0 authors: sears, david; ahalt, cyrus; augustine, dallas; williams, brie title: occupational health: a key to the control of covid-19 in correctional facilities date: 2020-07-27 journal: ann intern med doi: 10.7326/m20-4543 sha: doc_id: 301852 cord_uid: 9nza3po0 coronavirus disease 2019 has swept through prisons in much the same way it has nursing homes: after being introduced by staff or newly arrived residents, it spreads efficiently, including to many with medical vulnerabilities. yet, many correctional workers lack basic protections. the authors believe that ensuring community-standard occupational health for correctional staff during covid-19 will protect prison residents, staff, and their communities. c orrectional facilities (prisons and jails) are the second largest source of coronavirus disease 2019 (covid-19) outbreaks in the united states, surpassing all other non-nursing home congregate settings combined (1) . the disease has swept through prisons in much the same way it has devastated nursing homes: after being introduced by staff or newly arrived residents, it spreads efficiently, including to many with medical vulnerabilities. as covid-19 transmission continues unabated in these settings, protecting the health and safety of correctional workers is a moral imperative and an underappreciated requirement to mitigate the pandemic's effect on incarcerated persons and surrounding communities. public health experts agree that the most critical action governments can take to reduce the risk for catastrophic prison outbreaks is to immediately and dramatically address overcrowding through depopulation (via release) (2, 3) . although few correctional systems have followed this guidance, most have taken secondary precautions to ensure that facilities are occupied almost exclusively by full-time staff and a stable resident population (for example, by limiting in-person visitation; decreasing population movements between facilities; reducing new admissions; and suspending activities of volunteers and nonessential, part-time, or transient staff) (3, 4) . what has been too often lost in this conversation is the need for enhanced measures to safeguard the occupational health of correctional staff in ways that are commensurate with the risk they face while carrying out their duties. tens of thousands of correctional workers interact with incarcerated persons and each other every day. this workforce includes correctional officers; clinicians; social workers; and janitorial, food service, administrative, and clerical staff. most notably, uniformed correctional officers may come into close contact with hundreds of colleagues and incarcerated persons every day and are at disproportionately high risk for severe complications from covid-19 because of high rates of chronic and behavioral health conditions (5) . although occupational health interventions should focus primarily on correctional officers given their numbers and close, sustained contact with incarcerated persons, interventions should be adapted to reduce risk for infection for all staff. at the end of every shift, each of these workers risks introducing covid-19 into their homes, families, and communities if infected at work. furthermore, incarcerated persons have a constitutional right to health care that meets community standards (6) . community-standard infection control in con-gregate living and health care facilities includes efforts to ensure that those providing care, including nonmedical staff, are not ill and capable of spreading covid-19 to their patients (7) . patients in the community expect health care workers to be screened for infection, granted sick leave if infected, offered personal protective equipment, and evaluated for infection if they show symptoms. yet, this community standard of occupational health is not met in many correctional facilities. correctional officers are not universally guaranteed medical benefits or paid sick leave, and most access occupational health services via outside organizations. as a result, strategic workplace testing of asymptomatic correctional staff has not been the norm. in some states, labor agreements between correctional officer unions and departments of corrections even preclude correctional departments from requiring basic health screenings on facility entry or knowing the results of testing among these essential workers, some of whom come to work despite being infected if they have no sick leave available (8) . the patchwork of policy and practice that is failing to meet the urgent occupational health crisis that covid-19 presents in correctional systems should be of particular concern to correctional officers because their unique duties, coupled with the severe overcrowding of u.s. prisons, place them at a level of risk unmatched by an appropriate policy response to protect them. officers escort patients with suspected or confirmed covid-19 to medical appointments, implement housing movements for medical isolation or quarantine, help distribute medications, accompany hospitalized patients, and act as first responders to medical emergencies. each of these activities may bring officers into close contact with the novel coronavirus, and none can be accomplished while physically distancing. in addition, because testing in correctional systems has thus far been extremely limited relative to the risk, staff members often return home at the end of each shift without knowledge of the extent of risk they or their families are facing. a growing number of covid-19related deaths among u.s. correctional officers underscores the health perils and outsized risk for covid-19 complications many face (9) . fortunately, effective policy to safeguard the health of staff working in comparably high-risk settings, particularly in health care, can guide departments of corrections and correctional officer unions faced with similar challenges. to protect correctional staff and ensure that community standards of care are afforded to incarcerated populations during the covid-19 pandemic, prisons must: this article was published at annals.org on 27 july 2020. 1. provide staff with universal screening for covid-19 symptoms and exposures before entry into the facility at each shift and recurrent universal testing in hot spots with widespread community transmission or in facilities with outbreaks (these measures will bring screening in line with guidelines for other congregate settings, such as nursing homes); 2. reorganize staff and residents into assigned cohorts that practice physical distancing from each other and comprise as few persons as is feasible on the basis of facility resources (10); 3. institute policies that promote a culture of health, including sick leave that requires workers to stay home when they are sick or have been exposed to infection; 4. provide access to and training in appropriate use of hand sanitizer, soap, and personal protective equipment, including universal masking and enhanced protection when in contact with infected residents or those suspected of being infected (such as n95 masks, face shields, gloves, and gowns); and 5. streamline workplace-based, no-cost clinical evaluation and diagnostic testing for staff who have covid-19 symptoms, high-risk exposures, or known infection and are being evaluated for a return to work. many correctional workers lack these basic protections and continue to do their jobs, in some cases playing an essential role in ensuring that incarcerated patients receive prompt access to adequate care themselves. prison residents and staff should not fear that each encounter is needlessly putting the other at risk, nor should the staff's families or those in their communities be subject to increased risk for infection because of inadequate occupational health protections. ensuring community-standard occupational health for correctional staff during covid-19 will protect us all. latest map and case count. the new york times covid-19 in correctional settings: immediate population reduction recommendations flattening the curve for incarcerated populations-covid-19 in jails and prisons responses to the covid-19 pandemic. prison policy initiative mission critical: correctional employee health and wellness preparing for covid-19 in nursing homes union files national grievance over alleged safety violations at federal prisons during coronavirus pandemic. government executive the marshall project. a state-by-state look at coronavirus in prisons limiting covid-19 transmission and mitigating the adverse consequences of a covid-19 outbreak in correctional settings: release: cohort: test key: cord-287191-e8073l9p authors: klompas, michael title: coronavirus disease 2019 (covid-19): protecting hospitals from the invisible date: 2020-03-11 journal: ann intern med doi: 10.7326/m20-0751 sha: doc_id: 287191 cord_uid: e8073l9p coronavirus disease 2019 (covid-19) is optimized to spread widely: its signs and symptoms are largely indistinguishable from those of other respiratory viruses. this commentary specifically addresses best ways to protect our hospitals against covid-19. i t is increasingly apparent that severe acute respiratory syndrome coronavirus 2 (sars-cov-2) is optimized to spread widely. it causes mild but prolonged disease, infected persons are contagious even when minimally symptomatic or asymptomatic, the incubation period can extend beyond 14 days, and some patients seem susceptible to reinfection (1) (2) (3) . these factors make it inevitable that patients with respiratory viral syndromes that are mild or nonspecific will introduce the virus into hospitals, leading to clusters of nosocomial infections. the signs and symptoms of coronavirus disease 2019 (covid-19) are largely indistinguishable from those of other respiratory virus infections. less than one half of patients with confirmed disease have fever on initial presentation (4) . the sensitivity of a single nasopharyngeal swab early in the course of disease is only 70% (5) . multiple reports already exist of delayed diagnoses leading to nosocomial transmissions. how bad will it be? characterizing the morbidity rate of covid-19 is challenging because case detection in the early stages of an outbreak is biased toward severe disease. an initial series reported a mortality rate of 15% (6) . a subsequent analysis that included patients who were less sick reported a mortality rate of 2.3% (7), but this is still likely an overestimate. mortality rates are substantially lower outside than inside hubei province, where the outbreak began (114 deaths among 13 152 patients [0.9%] vs. 2986 deaths among 67 707 patients [4.4%] as of 8 march 2020). this is presumably because of hubei's initial focus on patients with severe disease, constraints on the province's testing and care capacity, and the passage of more time since the outbreak began in hubei versus other provinces allowing more time for patients to declare themselves (8) . more to the point, current mortality estimates minimally account for patients with mild or asymptomatic infections, an important aspect of this epidemic (9) . case detection is still primarily focused on identifying patients with fever, cough, or shortness of breath; this focus leads to underestimation of the number of infected persons, overestimation of the mortality rate, and ongoing spread of disease. what can we do to prevent further spread of infection? we have to be more aggressive about case detection. current screening is still focused on identifying patients with foreign travel or contacts with known cases. both of these foci no longer reflect the current status of this epidemic given increasing evidence of community spread. we need to be able to test patients with milder syndromes regardless of travel or contact history. the u.s. centers for disease control and pre-vention has updated its "person under investigation" criteria to permit this, but there is still a severe shortage of readily available tests. more broadly, however, the best way to protect hospitals against covid-19 is to bolster our approach to routine respiratory viruses (that is, influenza, respiratory syncytial virus, parainfluenza, adenovirus, human metapneumovirus, and "conventional" coronaviruses). this will simultaneously improve care for current patients, make work safer for clinicians, and help prevent the incursion of occult covid-19 into hospitals. we underestimate the contagiousness and seriousness of routine respiratory viruses. we underappreciate that 30% to 50% of cases of community-acquired pneumonia are caused by viruses, that nosocomial transmission of respiratory viruses is common, and that "routine" respiratory viruses cause substantial morbidity and mortality that may not differ much from those caused by sars-cov-2 once minimally symptomatic covid-19 is accounted for. respiratory viruses infect millions of persons each year (about 10% of the population) and cause tens of thousands of deaths in the united states alone (10) . they can cause severe pneumonia, predispose patients to bacterial superinfection, and exacerbate cardiac and pulmonary conditions up to and including death. most hospitals, however, manage respiratory viruses passively. we rely on signs alone to deter visitors with upper respiratory tract infections from visiting, we isolate patients in private rooms only if they test positive for influenza virus (even though many other viruses can cause influenza-like syndromes that are equally morbid), we discontinue precautions in patients with acute respiratory tract syndromes if they test negative for viruses (even though viral tests have variable and imperfect sensitivity), we consider masks alone to be adequate protection (even though viruses can be transmitted via fomites and eye contact as well as mouth and nose contact), and we tolerate health care workers coming to work with upper respiratory tract infections so long as they are not febrile. our halfhearted approach to endemic respiratory viruses is a source of harm to our patients and puts us at increased risk for covid-19 infiltration. to cause a nosocomial outbreak, it will take just 1 patient with occult covid-19 who is hospitalized, tests negative for influenza virus, and is taken off precautions despite persistent respiratory symptoms. or just 1 visitor with covid-19 and mild respiratory symptoms who is permitted free access to the hospital because it does not have an active screening and exclusion policy for visi-this article was published at annals.org on 11 march 2020. tors with respiratory tract symptoms. or just 1 infected health care worker who decides to soldier through a shift despite a sore throat and runny nose. we need to be more aggressive about respiratory hygiene and placing restrictions on patients, visitors, and health care workers with even mild symptoms of upper respiratory tract infection. potential policies to consider include the following: 1) screening all visitors for any respiratory symptoms that may be related to a virus, including fever, myalgias, pharyngitis, rhinorrhea, and cough, and excluding them from visiting until they are better; 2) restricting health care workers from working if they have any upper respiratory tract symptoms, even in the absence of fever; and 3) screening all patients, testing for all respiratory viruses (including sars-cov-2) in those with positive screening results regardless of illness severity, and using precautions (single rooms, contact precautions, droplet precautions, and eye protection) for patients with respiratory syndromes for the duration of their symptoms regardless of viral test results. a collateral benefit is that if a patient is subsequently diagnosed with covid-19, staff who used these precautions will be considered minimally exposed and will be able to continue working. none of these measures will be easy. restricting visitors will be psychologically difficult for patients and loved ones, maintaining respiratory precautions for the duration of patients' symptoms will strain supplies in all hospitals and bed capacity in hospitals that depend on shared rooms, and preventing health care providers with mild illness from working will compromise staffing. but if we are frank about the morbidity and mortality of all respiratory viruses, including sars-cov-2, this is the best thing we can do for our patients and colleagues regardless of covid-19. disclosures: disclosures can be viewed at www.acponline.org /authors/icmje/conflictofinterestforms.do?msnum=m20-0751. washington state 2019-ncov case investigation team. first case of 2019 novel coronavirus in the united states transmission of 2019-ncov infection from an asymptomatic contact in germany positive rt-pcr test results in patients recovered from covid-19 china medical treatment expert group for covid-19. clinical characteristics of coronavirus disease 2019 in china sensitivity of chest ct for covid-19: comparison to rt-pcr clinical features of patients infected with 2019 novel coronavirus in wuhan the novel coronavirus pneumonia emergency response epidemiology team. vital surveillances: the epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (covid-19) -china covid-19): situation report -48 evidence of sars-cov-2 infection in returning travelers from wuhan annual estimates of the burden of seasonal influenza in the united states: a tool for strengthening influenza surveillance and preparedness. influenza other respir viruses protecting hospitals from the invisible key: cord-337482-imxkpfrn authors: koplan, jeffrey; ostroff, samuel m.; mokdad, ali h. title: maxims for a pandemic: time, distance, and data date: 2020-10-27 journal: ann intern med doi: 10.7326/m20-6934 sha: doc_id: 337482 cord_uid: imxkpfrn in their article, alagoz and colleagues explored the effect of covid-19–related public health mandates in 3 u.s. locations. the editorialists discuss lessons from this analysis and the role of modeling to inform decision making related to the covid-19 pandemic and future public health crises. i n their article, alagoz and colleagues explored the effect of coronavirus disease 2019 (covid-19)-related public health mandates in 3 u.s. locations-dane county, wisconsin; the milwaukee metropolitan area; and new york city-using agent-based simulation models (1) . they modeled variations in adherence to social distancing mandates, time of intervention, and population density. mask mandates are notably absent from the model because the authors focused on early periods of the pandemic before recommendations that the general population wear masks. the findings corroborate the growing scientific consensus that social distancing mandates (for example, limiting the size of group gatherings and closing schools and nonessential businesses) limit community spread of respiratory viruses, such as severe acute respiratory syndrome coronavirus 2. moreover, we learn that the challenge of controlling covid-19 is magnified in urban locations where factors like higher population densities and greater reliance on public transportation increase transmission rates. alagoz and colleagues' study provides an opportunity to pause and assess how modeling can and should inform covid-19 decision making. although alagoz and colleagues' methods are sound, some of the assumptions about public health interventions are questionable. authorities imposed social distancing mandates to decrease population mobility and reduce in-person contacts, but the effects of these mandates varied. cellular mobility data show that many people began to stay home before the mandates, and steeper decreases in mobility were seen when the orders went into effect. in wisconsin, mobility decreased to ϫ7% below baseline averages 5 days before social distancing mandates were issued. when the orders went into effect on 18 march, mobility rates plummeted to ϫ28% below average, reaching a nadir of ϫ66% on 11 april before increasing again (2) . similar patterns were seen in new york city. many states saw upticks in mobility in early april as officials signaled the relaxation of mandates (2) . the researchers did not account for these fluctuations and based assumptions about contacts per person on pre-covid-19 data rather than capturing pandemic-era behavioral changes. one of the hard truths revealed by the pandemic is that demography is destiny and population density is a contributor. black americans are about twice as likely as white americans to die of covid-19 (3) (4) (5) . not only are many "essential workers" low income and persons of color, but the very nature of work in many essential fields makes quarantine infeasible because of financial precarity, in-person work requirements, reliance on public transport, and dense living arrangements. at the same time, many white-collar professionals transitioned to at-home work rather seamlessly. there is no onesize-fits-all community solution. to control the spread of the virus, we must localize our responses. however, while tending to local contexts, there must be some consistency. a commitment to transparency and scientific integrity should guide all policies and practices. alagoz and colleagues' analysis shows the variability of the pandemic across geographic locations. a pandemic model must carefully consider local conditions and account for a range of variables. rigorous modeling requires an analytic structure with clear and defensible assumptions, varying scenarios, appreciation of a myriad of contributory factors, and attention to sensitivity analysis. modeling and forecasting are increasingly common features of epidemiologic studies and have become especially prominent in academic, policy, and media circles during the current pandemic (6) . forecasting models are a dynamic science based on moving variables and are indispensable tools when faced with a virus that we are only starting to understand. it is imperative that the scientific community improve our forecasting capacity because this will not be the last crisis. there will be other global pandemics, and we must prepare for future health scenarios. this burgeoning area of research and policy should be a focus for researchers and funders. having the capacity for rigorous modeling analyses will improve decision making during future public health crises. we need massive investment to build a national disease surveillance system similar to our advanced weather-tracking infrastructure. three salient lessons related to the current model have been learned. first, early interventions save lives. second, social distancing mandates are an effective policy intervention. third, tracking cases and deaths deepens our knowledge of the virus and can inform decision making. timing, distance, and data are critical during a pandemic. unfortunately, the federal response to covid-19 fell short on all 3 of these issues. the absence of an adequate national plan undermined our ability to curb the pandemic at its beginning, and this continues to impede progress. from a scientific standpoint, when the highest levels of government ignored nearly 2 decades of pandemic planning (7-9) and evidence-based messaging from the nation's top disease experts, it served to sow confusion and foment discord. even while many americans were battling covid-19, some influential voices perpetuated a misleading narrative about the virus and quite literally infected the body politic. downplaying the severity of covid-19 as nothing more serious than the common flu is an insult to the 210 000 grieving families of persons who died so far and the many more who have had the illness. the american public has paid dearly for this recklessness. the united states is home to 4% of the world's population, yet it accounts for more than 20% of both cases and deaths (10) . by year's end, covid-19 will be the second-leading cause of death in the united states. other high-income and asian countries have fared far better. alagoz and colleagues' study makes a strong case for recognizing the threat of a disease outbreak as early as possible and taking decisive action. with mass vaccination months, if not years, away and few effective therapies, the timely use of nonpharmaceutical public health interventions will reduce morbidity and mortality from covid-19. future pandemics may tie our hands in different knots. commonly accepted truths about the nature of a viral disease or expectations about human behavior may prove elusive for any model to capture, no matter how technically impressive. as a result, our ability to forecast must be nimble and quick to be recalibrated, modified, or even reversed. alagoz and colleagues' analysis contributes to an emergent body of science on pandemic modeling that is certain to prove useful. effect of timing of and adherence to social distancing measures on covid-19 burden in the united states. a simulation modeling approach covid-19 scenarios for the united states. medrxiv. preprint posted online 14 covid-19 hospitalization and death by race/ethnicity the association of race and covid-19 mortality hospitalization and mortality among black patients and white patients with covid-19 pandemic surge models in the time of severe acute respiratory syndrome coronavirus-2: wrong or useful? national strategy for pandemic influenza. homeland security council the importance of reestablishing a pandemic preparedness office at the white house executive orderadvancing the global health security agenda to achieve a world safe and secure from infectious disease threats covid-19 map key: cord-253196-et1ekgdl authors: yazdany, jinoos; kim, alfred h.j. title: use of hydroxychloroquine and chloroquine during the covid-19 pandemic: what every clinician should know date: 2020-03-31 journal: ann intern med doi: 10.7326/m20-1334 sha: doc_id: 253196 cord_uid: et1ekgdl two medications often used for treatment of immune-mediated conditions, hydroxychloroquine and chloroquine, have recently attracted widespread interest as potential therapies for coronavirus disease 2019. the authors of this commentary provide guidance for clinical decision making for patients with coronavirus disease 2019 as well as for patients with rheumatologic conditions, such as systemic lupus erythematosus and rheumatoid arthritis i n the desperate search to find effective treatments for coronavirus disease 2019 (covid-19), 2 generic drugs, used largely by rheumatologists and dermatologists to treat immune-mediated diseases, have entered the spotlight. the antimalarials hydroxychloroquine (hcq) and chloroquine (cq) have demonstrated antiviral activity against severe acute respiratory syndromecoronavirus 2 (sars-cov-2) in vitro and in small, poorly controlled or uncontrolled clinical studies (1) (2) (3) . normally, such research would be deemed hypothesisgenerating at best. a tweet by president trump on 21 march 2020 claiming that the combination of hcq and azithromycin "ha[s] a real chance to be one of the biggest game changers in the history of medicine" accelerated a worldwide run on the drugs, with pharmacies reporting shortages within 24 hours. here, we try to provide guidance regarding clinical decision making both for patients with covid-19 and those with immune-mediated conditions, such as systemic lupus erythematosus (sle) and rheumatoid arthritis (ra), and strategies to mitigate further harm to these patients. data to support the use of hcq and cq for covid-19 are limited and inconclusive. the drugs have some in vitro activity against several viruses, including coronaviruses and influenza, but previous randomized trials in patients with influenza have been negative (4, 5) . in covid-19, one small nonrandomized study from france (3) (discussed elsewhere in annals of internal medicine [6] ) demonstrated benefit but had serious methodological flaws, and a follow-up study still lacked a control group. yet, another very small, randomized study from china in patients with mild to moderate covid-19 found no difference in recovery rates (7) . sadly, reports of adverse events have increased, with several countries reporting poisonings and at least 1 death reported in a patient who drank fish tank cleaner because of its cq content. antimalarial drugs can cause ventricular arrhythmias, qt prolongation, and other cardiac toxicity, which may pose particular risk to critically ill persons. given these serious potential adverse effects, the hasty and inappropriate interpretation of the literature by public leaders has potential to do serious harm. at this time of crisis, it is our ethical obligation as physicians and researchers to organize and refer patients to expedited, well-performed randomized trials that can clarify if, when, and for whom antimalarial medications are helpful in covid-19. as of this writing, 10 such trials are under way, and information should be forthcoming within weeks. whereas the evidence supporting the use of antimalarial medications for covid-19 is equivocal, the evidence for the use of these drugs to treat immune-mediated diseases is not. for example, hcq is a cornerstone of therapy for sle. hydroxychloroquine can effectively treat disease manifestations, such as joint pain and rashes; reduce thrombotic events; and prolong survival. of note, landmark clinical trials have demonstrated that the withdrawal of hcq can lead to flares of disease, including life-threatening manifestations, such as lupus nephritis (8) . the current shortages of hcq have therefore alarmed rheumatologists and patients. offices across the country report fielding calls from concerned patients who are having difficulty obtaining their medication. given the likelihood that shortages will continue in the near term, we propose that manufacturers, clinicians, pharmacies, health systems, and governmental health agencies continue to coordinate an aggressive response to ensure that antimalarial drug use is appropriately managed during the covid-19 pandemic. first, it is important to prioritize available supply for clinical trials evaluating important questions, such as dosing, prophylaxis, and treatment in covid-19. second, treatment interruptions for those with sle and other rheumatic diseases must be prevented, because lapses in therapy can result in disease flares and strain already stretched health care resources. third, stakeholders should work together to see whether dispensation of remaining supply to patients with covid-19 makes sense as evidence rapidly changes. fourth, clear messages that reflect the proper interpretations of available data must be disseminated with high frequency to counteract misinformation, including misleading statements or articles with "clickbait" material. finally, safeguards should be put into place to discourage overutilization by health professionals who are depleting supply by prescribing antimalarials for preexposure prophylaxis. hoarding by health professionals for themselves and their friends or family is already occurring, but state governments and pharmacy boards have started to institute strict utilization policies to prevent further hcq overutilization. meanwhile, multiple manufacturers have already made critical commitments to initiate or increase production of hcq. what advice should clinicians give to patients with sle or ra who have difficulty securing hcq? the pharmacokinetics of hcq are an important consideration in answering this question. with long-term use of hcq, peak plasma levels occur 3 to 4 hours after each dose, with a terminal half-life of 40 to 50 days (9) . the long half-life means that brief gaps in therapy, on the order of 1 to 2 weeks, are less concerning. however, longer treatment lapses put patients at risk for disease exacerbations, given studies showing that lower plasma con-this article was published at annals.org on 31 march 2020. centrations of hcq correlate with more sle disease activity (10) . in addition, in a well-designed clinical trial, a higher incidence of sle flares was seen as soon as 2 weeks after the drug was stopped (8) . patients may also wonder whether rationing their supply by halving their current dose is a good approach. studies show significant heterogeneity in plasma concentrations of hcq, even when standard doses of approximately 5 mg/kg are used (9) . therefore, some patients may do better than others with this approach. the looming public health crisis for people with rheumatic diseases who will be unable to obtain hcq is the result of a perfect storm of fear and dissemination of overpromised data. however, there is still time to mitigate the damage. physicians should educate themselves about the strength of available data regarding hcq and cq in treating covid-19. they should avoid misuse of hcq and cq for the prophylaxis of covid-19, because there are absolutely no data to support this. public figures should refrain from promoting unproven therapies to the public, and instead provide clear messages around the uncertainties we face in testing and using experimental treatments during the current pandemic, including the risk for serious adverse events. well-done, randomized clinical trials should be performed urgently to test potential therapies, including hcq. in the meantime, physicians should remember that first, we must do no harm to the patients with rheumatic disease for whom high-quality evidence shows that hcq improves health. hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting sars-cov-2 infection in vitro in vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus hydroxychloroquine and azithromycin as a treatment of covid-19: results of an open-label nonrandomized clinical trial chloroquine for influenza prevention: a randomised, double-blind, placebo controlled trial in vitro inhibition of human influenza a virus replication by chloroquine covid-19 global rheumatology alliance. a rush to judgment? rapid reporting and dissemination of results and its consequences regarding the use of hydroxychloroquine for covid-19 a pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (covid-19) a randomized study of the effect of withdrawing hydroxychloroquine sulfate in systemic lupus erythematosus mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology low blood concentration of hydroxychloroquine is a marker for and predictor of disease exacerbations in patients with systemic lupus erythematosus the authors thank the members of the key: cord-275601-9y5zj9an authors: boutron, isabelle; chaimani, anna; meerpohl, joerg j.; hróbjartsson, asbjørn; devane, declan; rada, gabriel; tovey, david; grasselli, giacomo; ravaud, philippe title: the covid-nma project: building an evidence ecosystem for the covid-19 pandemic date: 2020-09-15 journal: ann intern med doi: 10.7326/m20-5261 sha: doc_id: 275601 cord_uid: 9y5zj9an these authors propose an “evidence ecosystem” for covid-19–related studies that minimizes multiple low-quality reviews and helps connect evidence generation, synthesis, and decision making. pandemic, the ability of the evidence synthesis model to meet the needs of stakeholders was challenged (1, 2) . there are too many low-quality systematic reviews that mainly address pairwise comparisons and are rarely updated, resulting in redundancies and gaps. producing high-quality, up-to-date systematic reviews requires substantial time and resources. in addition, although evidence synthesis is directly affected by the quality of primary research, interaction is limited between the evidence generation and synthesis communities. these issues have been highlighted and exacerbated by the covid-19 pandemic, where stakeholders urgently need relevant, accessible, up-to-date, and trustworthy syntheses of high-quality evidence to inform their decisions. thousands of randomized controlled trials (rcts) have been initiated during the pandemic, and their results are frequently rushed to publication or communicated through non-peer-reviewed preprints. the situation is further complicated by changes in the questions of interest and trial components (such as standard of care) as the pandemic develops (3). to tackle covid-19, we developed and implemented a previously proposed model (4, 5) to address the challenges and help to connect evidence generation, synthesis, and decision making. rather than focusing on 1 specific treatment or comparison, the covid-nma project provides a living mapping of all trials and a comprehensive living synthesis of all available trial evidence evaluating the effect of interventions for the prevention or treatment of covid-19 ( figure) . we developed a master protocol (6) and subprotocols dedicated to specific questions, which are discussed and agreed on by a steering committee. every week, we screen the covid-19 database produced by the world health organization's international clinical trials registry platform to identify eligible rcts. the living mapping produced provides a description of all registered rcts. the data retrieved and extracted can be explored through interactive data visualizations to identify research gaps and help prioritize and improve future trials. we are also conducting a living systematic review based on a living protocol (6) that is scalable to stakeholders' evolving needs. all changes in the protocol (for example, primary study design and outcomes) are discussed by a steering committee and reported transparently. as part of the living process, we do a systematic search daily, collect data as soon as we identify any trial that has published results or is available in preprint, and assess risk of bias fully using the cochrane risk of bias tool, version 2.0 (7). we provide the descriptive data online and produce forest plots of appropriately pooled data with grade (grading of recommendations assessment, development and evaluation) summary-of-findings tables and evidence profiles. we have developed a tool to automatically identify new versions or publication of preprints. we contact trialists at the outset (that is, trial registration) to request information (protocol) and inform them of the outcomes (consistent with the core outcome sets developed by the comet [core outcome measures in effectiveness trials] initiative [8, 9] ) that should be reported to enable their trial to be incorporated into the meta-analyses. when results are available, we systematically request from trial authors any missing data and update the reviews accordingly. we have established robust quality control processes in collaboration with the cochrane bias methods group. collectively, covid-nma data are used to conduct systematic reviews on specific questions, meta-analyses of individual participant data (ipd), and network meta-analyses and to support the guideline development process and health decision making. our databases can also be shared to allow guideline developers to do their own analyses. to improve research planning, we monitor trials' quality related to outcomes, completeness of reporting (that is, adherence to some consort [consolidated standards of reporting trials] items), risk of bias, and data sharing (intended and realized). as a feedback loop, we provide trialists and funders the results of this monitoring to increase the value of covid-19 trials research. we also send automatic e-mails to investigators of completed trials to encourage them to post results on registries (10) and share ipd, and we have developed a secure process to enable them to do this at no cost. our collaborative project involves an international consortium of 85 persons, including methodologists, clinicians, and statisticians. on 31 august 2020, our research mapping identified 1686 registered rcts, of which 944 are recruiting. overall, 54% have fewer than 100 participants. we have screened more than 42 000 records and reported detailed data for 45 rcts, with forest plots for all comparisons. we have contacted this article was published at annals.org on 15 september 2020. * for members of the covid-nma consortium, see the appendix (available at annals.org). about 1000 investigators of ongoing trials and requested missing data from 45 authors. this new approach is creating challenges and threats. first, sustainability is an issue as the crisis continues. we developed covid-nma with the support of many volunteers from various countries who were available during the containment period but must now return to normal activities. as the amount of data increases, we need to move to a long-term and sustainable structure with a website that is more accessible and useful to end users. the resources necessary to maintain this model are critical because the volume of evidence is increasing, the scope is expanding at end users' request (for example, new focus on vaccine trials), and new sources (clinical study reports) or new types of data (such as ipd) are becoming available. we need funders to provide long-term funding for this platform. this would be far more cost-effective than funding a disparate and uncoordinated series of systematic reviews on narrow research questions. second, some cultural issues exist. the success of this approach depends entirely on the acceptance of and engagement with this model by stakeholders, in particular funders and trialists. some may be reluctant to add new outcomes, adhere to reporting guidelines, or share ipd because this involves change in culture, as well as time and effort. we hope that the urgency associated with the covid-19 pandemic, combined with external pressure, may help to overcome these barriers. governance of the project is an important consideration. we must ensure that volunteers and researchers involved in the platform receive the appropriate reward and recognition for their contributions. we are developing transparent processes for both the researchers involved and the users of the data, and our work is overseen by an independent steering committee. overall, the present crisis unmasks the shortcomings of the current synthesis model and provides a strong impetus for change and improvement. we hope covid-nma plays a role in this work. the protocol can be accessed at https://zenodo.org /record/3744599. all data are shared on our website, https: //covid-nma.com. future of evidence ecosystem series: 1. introduction evidence synthesis ecosystem needs dramatic change meta-analysis and the science of research synthesis china medical treatment expert group for covid-19. clinical characteristics of coronavirus disease 2019 in china future of evidence ecosystem series: 2. current opportunities and need for better tools and methods future of evidence ecosystem series: 3. from an evidence synthesis ecosystem to an evidence ecosystem interventions for preventing and treating covid-19: protocol for a living mapping of research and a living systematic review who working group on the clinical characterisation and management of covid-19 infection. a minimal common outcome measure set for covid-19 clinical research centre of research in epidemiology and statis-tics (cress umr1153), methods team laboratoire bordelais de recherche en informatique (labri) epistemonikos foundation center for health regulatory policies, istituto di ricerche farmacologiche mario negri irccs centre of research in epidemiology and statis-tics (cress umr1153), eren team cochrane germany foundation laboratoire d'informatique, de modé lisation et d'optimisation des systè mes (limos) who collaborating centre for guideline implementation and knowledge translation & chinese grade centre laboratoire d'informatique en image et systè mes d'information (liris) key: cord-338757-fsid4a39 authors: bibbins-domingo, kirsten title: this time must be different: disparities during the covid-19 pandemic date: 2020-04-28 journal: ann intern med doi: 10.7326/m20-2247 sha: doc_id: 338757 cord_uid: fsid4a39 african americans and latinos are overrepresented among cases of and deaths from covid-19 nationally and in many of the u.s. regions hardest hit by the pandemic. the editorialist discusses lessons that we should have learned from prior experiences and strategies to reduce observed disparities. a fter reports of racial and ethnic disparities in the u.s. pandemic, a large, nationally representative survey provided empirical evidence regarding the sources of these disparities (1) . the authors found that increased likelihood of exposure to the virus, increased susceptibility to severe consequences of the infection, and lack of health care access were all important contributors, and they concluded with pointed, domainspecific recommendations to mitigate these disparities. the clarity of this path forward would be alluring and reassuring were the historical nature of these observations not so alarming. these data are not based on the coronavirus disease 2019 (covid-19) pandemic; rather, they describe the nation's experience of the 2009 h1n1 influenza pandemic. unfortunately, things have not changed for the better. african americans and latinos are overrepresented among cases of and deaths from covid-19, both nationally and in many of the areas hardest hit by the pandemic (2, 3) . in new york city, african american and latino residents have the highest age-adjusted rates of hospitalized and nonhospitalized covid-19, and age-adjusted death rates for african americans are more than twice those for white and asian residents (4) . throughout the united states, data by race and ethnicity are incomplete and highly dependent on what information is collected at the local level-a glaring omission in data collection that was highlighted for remediation during the 2009 h1n1 pandemic (1). the likely causes of the disparities are also distressingly similar. minority communities are more likely to be exposed to the virus because they are overrepresented in the low-wage, essential workforce at the front lines, including low-wage health care workers who often move between clinics, hospitals, and nursing homes to make a living, thereby magnifying their risk (5) . poor communities may face challenges implementing social distancing because of housing density and overcrowding, and minority populations are overrepresented in congregate settings, such as homeless shelters and prisons, that increase exposure risk. minority communities may be more susceptible to severe forms of covid-19 because of existing disparities in underlying conditions known to be associated with covid-19 mortality, including hypertension, cardiovascular disease, kidney disease, and diabetes. although largely preventable or amenable to medical management, these chronic conditions are more common, less likely to be controlled, and more likely to occur at younger ages in these communities. health care access is also a probable contributor to covid-19 mortality given the limited availability of both testing and treatments. much of the testing for severe acute respiratory syndrome coronavirus 2 (sars-cov-2) has occurred in the context of a health care evaluation, resulting in barriers for those without insurance. although data are not yet available, concerns about the equitable distribution of ventilators and treatments have also been raised. we simply cannot afford to bear witness to yet another manifestation of health inequities. this time must be different because we are living in a global pandemic of massive proportion and uncertain duration, the management of which will require ongoing, effective, and equitable attention to the areas of greatest need if we are to avoid even more devastating consequences. this time must be different because the increasing diversity of the u.s. population and our essential workers reminds us of our interdependence and means that focusing on minority communities is essential both to relieve suffering in these communities and to effectively manage this crisis. this time must be different because the economic underpinning of these disparities has worsened over the past decade and threatens to deteriorate further in the face of the anticipated global depression, likely exacerbating the covid-19 disparities we are already witnessing. it is time to learn from the lessons of past epidemics and their disproportionate effect on minority communities. we need robust data to guide these efforts, but better information must be coupled with urgent and effective action to decrease exposure, susceptibility, and limitations in health care to achieve the desired results. for our public health efforts at mitigation and containment to be most effective, resources must be invested in the communities hardest hit by covid-19 to redress past underinvestment and the ongoing impact of the economic crisis. our clinical and public health sectors that have been relentlessly focused on addressing the acute issues of covid-19 over the past months must refocus to also address prevention and treatment of the underlying cardiovascular and metabolic conditions that are the major contributors to morbidity and mortality in these communities. as we plan for a sars-cov-2 vaccine, we must heed the lessons from past vaccination campaigns. during the 1970s, the gap in measles vaccination rates between minority and white children was as high as 18 percentage points. consequently, the u.s. measles epidemic of 1989 to 1991 that resulted in more than 55 000 cases included 4-to 7-fold higher rates among minority children than white children. today, gaps in measles vaccination rates by race and ethnicity are nonexistent thanks in part to a dual strategy of boosting universal childhood vaccination and implementing targeted measures in minority communities. these targeted approaches have included increased funding to urban health departments; development of local action this article was published at annals.org on 28 april 2020. plans; linkage of vaccination to other programs like the special supplemental nutrition program for women, infants, and children; increased reimbursement for medicaid providers; reduced vaccine prices for medicaid programs; adjustment of hours in public health clinics to meet the local needs of populations; ongoing monitoring and surveillance through annual surveys; and broad engagement with community organizations with specific targeted messages to minority communities (6) . unfortunately, influenza vaccinations and most other adult vaccinations have not seen similar success. although influenza vaccination rates improved in the 2018 to 2019 season compared with prior years, the rate overall was only 45.3% (far short of the 70% goal of healthy people 2020), and rates were substantially lower among african american, latino, and american indian/alaska native adults (7) . achieving the desired population benefit of a sars-cov-2 vaccine will require an implementation strategy that addresses the current gaps in overall rates of adult vaccination, as well as specific issues in minority communities. establishing and nurturing trust and partnerships within affected communities will be critical because diminished trust in health care borne from a legacy of unethical experimentation, including the tuskegee study, has been identified as an important contributor to vaccine hesitancy among african americans (8, 9) . to borrow the words of dr. martin luther king jr., "we are now faced with the fact that tomorrow is today. we are confronted with the fierce urgency of now. in this unfolding conundrum of life and history, there is such a thing as being too late. this is no time for apathy or complacency. this is a time for vigorous and positive action" (10). can we eschew our collective amnesia, acknowledge the persistence and pervasive nature of our health and health care disparities, and draw on our experience to overcome? or will the failure of our collective will define us as a generation that refused to care and refused to act? racial disparities in exposure, susceptibility, and access to health care in the us h1n1 influenza pandemic cases of coronavirus disease (covid-19) in the u.s. accessed at www.cdc.gov/corona virus/2019-ncov/cases-updates/cases-in-us provisional death counts for coronavirus disease (covid-19): weekly state-specific data updates by select demographic and geographic characteristics covid-19: data. accessed at www1.nyc.gov /site/doh/covid/covid-19-data labor force statistics from the current population survey elimination of measles and of disparities in measles childhood vaccine coverage among racial and ethnic minority populations in the united states determinants of trust in the flu vaccine for african americans and whites exploring racial influences on flu vaccine attitudes and behavior: results of a national survey of white and african american adults the author thanks ms. amy markowitz for helpful edits to earlier drafts of this manuscript. the author has disclosed no conflicts of interest. the form can be viewed at www.acponline.org/authors/icmje /conflictofinterestforms.do?msnum=m20-2247. author contributions: conception and design: k. bibbins-domingo. drafting of the article: k. bibbins-domingo. critical revision of the article for important intellectual content: k. bibbins-domingo. final approval of the article: k. bibbins-domingo. administrative, technical, or logistic support: k. bibbins-domingo. key: cord-355805-ajlf5je4 authors: qaseem, amir; yost, jennifer; etxeandia-ikobaltzeta, itziar; miller, matthew c.; abraham, george m.; obley, adam jacob; forciea, mary ann; jokela, janet a.; humphrey, linda l. title: should clinicians use chloroquine or hydroxychloroquine alone or in combination with azithromycin for the prophylaxis or treatment of covid-19? living practice points from the american college of physicians (version 1) date: 2020-05-13 journal: ann intern med doi: 10.7326/m20-1998 sha: doc_id: 355805 cord_uid: ajlf5je4 nan using chloroquine or hydroxychloroquine, with or without azithromycin, to prevent coronavirus disease (covid-19) after infection with novel coronavirus (sars-cov-2) or to treat covid-19 began to receive attention following preliminary reports from in vitro (1) and human (2) studies. while multiple studies are planned or under way (3, 4) , it is imperative to continually synthesize the results from the best available evidence to inform point-of-care decisions about the use of chloroquine or hydroxychloroquine. these practice points are based on a rapid and living systematic evidence review conducted by the university of connecticut health outcomes, policy, and evidence synthesis group and will be updated as new evidence becomes available. the practice points development and update methods are included in the appendix, available at annals.org. this version of the practice points, based on an evidence review conducted on 17 april 2020, was approved by the american college of physicians board of regents on 4 may 2020 and submitted to annals of internal medicine on 6 may 2020. the efficacy of chloroquine or hydroxychloroquine alone or in combination with azithromycin to prevent covid-19 after infection with sars-cov-2 or to treat patients with covid-19 is not established and future clinical trials are needed to answer these questions. there are known harms of these medications when used to treat other diseases (5, 6) . current evidence about efficacy and harms for use in the context of covid-19 is sparse, conflicting, and from low quality studies, increasing the uncertainty and lowering our confidence in the conclusions of these studies when assessing the benefits or understanding the balance when compared with harms. these interim practice points are based on best available evidence. we will maintain these practice points as a living guidance document, updated as new evidence becomes available. (9). the evidence is very uncertain about the effect of hydroxychloroquine alone compared with standard treatment on the conversion to negative on day 3 (50% vs. 6%), day 4 (60% vs. 25%), day 5 (65% vs. 19%), and day 6 (70% vs. 13%) via nasopharyngeal pcr in 1 cohort study (11) . pulmonary radiologic assessment the evidence is very uncertain about the effect of hydroxychloroquine alone compared with standard treatment on the progression or exacerbation of pulmonary lesions on ct scan in 2 rcts (33.3% vs. 46.7% [7] and 6.5% vs. 29% [8] ) and radiologic improvement of pneumonia (80.6% vs. 54.8%) in 1 rct (8). resolution of fever, respiratory symptoms, and oxygenation the evidence is very uncertain about the effect of hydroxychloroquine alone (50%) compared with standard treatment (43.6%) in 1 rct (9). the evidence is very uncertain about the effect of hydroxychloroquine alone compared with standard treatment in 2 rcts; median, 1 day vs. 1 day in 1 rct (7), and mean, 2.2 days vs. 3.2 days in another rct (8) . the evidence is very uncertain about the effect of hydroxychloroquine alone compared with standard treatment (mean 2.0 days vs. 3.1 days) in 1 rct (8) . progression to severe disease the evidence is very uncertain about the effect of hydroxychloroquine alone compared with standard treatment in 2 rcts; 6.7% vs. 0% (7) and 0% vs. 12.9% (8). all-cause mortality 1 rct the evidence is very uncertain about the effect of hydroxychloroquine alone compared with standard treatment (0% vs. 0%) in 1 rct (7). the evidence is very uncertain about the effect of hydroxychloroquine alone compared with standard treatment in 2 cohort studies; 12.9% vs. 3.13% (10) and 2.8% vs. 4.6% (12) . continued on the following page the evidence is very uncertain about the effect of hydroxychloroquine alone compared with standard treatment on adverse effects in 3 rcts; 26.7% vs. 20% (7), 6.5% vs. 0% (8), and 30% vs. 8.8% (9) . prolonged qtc interval the evidence is very uncertain about the effect of hydroxychloroquine alone compared with standard treatment (8.3% vs. 0%) in 1 cohort study (12) . the evidence is very uncertain about the effect of hydroxychloroquine alone compared with standard treatment; 13.3% vs. 0% (7) and 10% vs. 0% (9). abnormal liver function the evidence is very uncertain about the effect of hydroxychloroquine alone (6.7%) compared with standard treatment (6.7%) in 1 rct (7). the evidence is very uncertain about the effect of hydroxychloroquine alone (3.2%) compared with standard treatment (0%) in 1 rct (8). the evidence is very uncertain about the effect of hydroxychloroquine alone (3.2%) compared with standard treatment (0%) in 1 rct (8). the evidence is very uncertain about the effect of hydroxychloroquine alone (0%) compared with standard treatment (6.7%) in 1 rct (7). elevated serum creatinine the evidence is very uncertain about the effect of hydroxychloroquine alone (0%) compared with standard treatment (6.7%) in 1 rct (7). hydroxychloroquine in combination with azithromycin for treatment of covid-19 diarrhea 1 obs the evidence is very uncertain about the effect of hydroxychloroquine in combination with azithromycin in 1 case series study (14) ; 5.0% patients experienced diarrhea. any adverse event series study; 8.7% of patients treated with hydroxychloroquine alone experienced adverse effects (14) . the evidence is very uncertain about the effect of hydroxychloroquine in combination with azithromycin. in 2 case series studies, 9% (15) and 11% (13) of patients showed a prolonged qtc. the qtc interval significantly increased (435 6 24 ms at baseline to a maximal value of 463 6 32 ms) in 1 case series study (13) ; however, a prolonged qtc interval was not reported for any patients in another case series study (16) . evidence gaps for covid-19 clinical considerations • the use and extent of parallel treatment interventions, in addition to hydroxychloroquine alone or in combination with azithromycin, is difficult to determine. • known harms of chloroquine in patients without covid-19 include (but not limited to): cardiovascular (cardiomyopathy, ecg changes), hematologic (aplastic anemia, thrombocytopenia), nervous system (seizures, psychosis, extrapyramidal disorders), ophthalmic macular degeneration) (5). • known harms of hydroxychloroquine in patients without covid-19 include (but not limited to): cardiovascular (cardiomyopathy, cardiac failure, ventricular arrhythmias, torsade de pointes), endocrine (hypoglycemia), hematologic (aplastic anemia, thrombocytopenia), nervous system (seizures, psychosis, extrapyramidal disorders), ophthalmic macular degeneration) (6). • shared and informed decision making with a patient (and/or families) should include a discussion of potential harms of chloroquine and hydroxychloroquine and lack of known benefits in patients with covid-19. • in the evidence reviewed, hydroxychloroquine doses did not exceed 600 mg daily for 5 to 10 days. • chloroquine and hydroxychloroquine are used to manage other major ailments, such as rheumatic diseases, with a known benefit and are in short supply in the united states. • inappropriate and overuse of antibiotics (e.g., azithromycin) is an important contributor to the antibiotic resistance, an immediate public health threat (17) . ct = computed tomography; ecg = electrocardiography; ecmo = extracorporeal membrane oxygenation; icu = intensive care unit; obs = observational study; pcr = polmerase chain reaction; rct = randomized controlled trial. evidence search conducted by the university of connecticut health outcomes, policy, and evidence synthesis group. * efficacy cannot be evaluated in case-series studies (16, 18) . † certainty: insufficient, when confidence is inadequate to assess the likelihood of benefit (benefit minus harm) of an intervention or its impact on a health outcome; low, confidence in the effect is limited as the true effect may be substantially different from the estimated effect; moderate, confidence in the effect is moderate as the true effect is likely close to the estimated effect, but there is a sizable possibility that it is substantially different; high, confident that the true effect is close to the estimated effect. financial support: financial support for the development of the practice points comes exclusively from the acp operating budget. disclosures: all financial and intellectual disclosures of interest were declared and potential conflicts were discussed and managed. a record of disclosures of interest and management of conflicts of is kept for each scientific medical policy committee meeting and conference call and can be viewed at https://www.acponline.org/about-acp/who-we-are/leadership/ boards-committees-councils/scientific-medical-policy-committee/ disclosure-of-interests-and-conflict-of-interest-managementsummary-for-scientific-medical-policy. disclosures can also be viewed at www.acponline.org/authors/icmje/conflictofinterest forms.do?msnum=m20-1998. remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-ncov) in vitro breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of covid-19 associated pneumonia in clinical studies a brief review of antiviral drugs evaluated in registered clinical trials for covid-19 accessed at www.accessdata.fda.gov/drugsatfda_ docs/label/2013/006002s043lbl plaquenil hydroxychloroquine prescribing information a pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (covid-19) efficacy of hydroxychloroquine in patients with covid-19: results of a randomized clinical trial hydroxychloroquine in patients with covid-19: an open-label, randomized, controlled trial. preprint. posted online 14 clinical outcomes of hydroxychloroquine in hospitalized patients with covid-19: a quasi-randomized comparative study. nejm submission hydroxychloroquine and azithromycin as a treatment of covid-19: results of an open-label non-randomized clinical trial no evidence of clinical efficacy of hydroxychloroquine in patients hospitalized for covid-19 infection with oxygen requirement: results of a study using routinely collected data to emulate a target trial the qt interval in patients with sars-cov-2 infection treated with hydroxychloroquine/ azithromycin clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 covid-19 patients with at least a six-day follow up: a pilot observational study no evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe covid-19 infection the latest hydroxychloroquine data high value care task force of the american college of physicians and for the centers for disease control and prevention. appropriate antibiotic use for acute respiratory tract infection in adults: advice for high-value care from the american college of physicians and the centers for disease control and prevention the hierarchy of evidence: levels and grades of recommendation special article current author addresses: dr. qaseem: american college of physicians, 190. n independence mall west etxeandia-ikobaltzeta: 1, santa margarita hospital street, ground floor 123 summer street obley: 3030 sw moody dr. jokela: 1405 west park, #207, champaign, il 61801. dr. humphrey: 3710 sw u.s. veterans hospital road critical revision for important intellectual content administrative, technical, or logistic support: a. qaseem the scientific medical policy committee (smpc), in collaboration with staff from acp's department of clinical policy, developed these practice points based on a rapid systematic evidence review conducted by the university of connecticut health outcomes, policy, and evidence synthesis group. the smpc comprises 11 internal medicine physicians representing various clinical areas of expertise and 1 public (nonclinician) member and includes members with expertise in epidemiology, healthy policy, and evidence synthesis. in addition to contributing clinical, scientific, and methodological expertise, clinical policy staff provided administrative support and liaised among the smpc, evidence review funding entity and evidence team, and the journal. clinical policy staff and the smpc reviewed and prioritized potential topic suggestions from acp members, smpc members, and acp governance. a committee subgroup, including the chair of smpc, worked with staff to draft the key questions and lead the development of the practice points. clinical policy staff worked with the subgroup and the evidence review team to refine the key question(s) and determine appropriate evidence synthesis methods for each key question. via conference calls and e-mail, clinical policy staff worked with the committee subgroup to draft the practice points based on the results of the rapid systematic evidence review. the full smpc reviewed and approved the final practice points. before publication, acp's executive committee of the board of regents also reviewed and approved the practice points on behalf of the acp board of regents. the evidence review will be continually updated by the evidence review team. acp will update the practice points based on the evidence review using the same process as for version 1 (described above). key: cord-312125-j9l6l3dx authors: pau, alice k.; aberg, judith; baker, jason; belperio, pamela s.; coopersmith, craig; crew, page; glidden, david v.; grund, birgit; gulick, roy m.; harrison, carly; kim, arthur; lane, h. clifford; masur, henry; sheikh, virginia; singh, kanal; yazdany, jinoos; tebas, pablo title: convalescent plasma for the treatment of covid-19: perspectives of the national institutes of health covid-19 treatment guidelines panel date: 2020-09-25 journal: ann intern med doi: 10.7326/m20-6448 sha: doc_id: 312125 cord_uid: j9l6l3dx in the united states, the efficacy and safety of convalescent plasma for treating coronavirus disease 2019 (covid-19) is currently being tested in randomized placebo-controlled clinical trials. treatment of individual patients with covid-19 with convalescent plasma outside such trials is also now permitted through u.s. food and drug administration emergency use authorization. here, members of the national institutes of health covid-19 treatment guidelines panel provide their views regarding use of convalescent plasma for treating covid-19. c urrently, no food and drug administration (fda)approved therapeutics exist for coronavirus disease 2019 . in this context, the pandemic has put considerable pressure on health care providers to prescribe treatments despite limited information about their safety and efficacy. this pressure has exacerbated the tension between the importance of practicing evidence-based medicine and the urgency of providing access to promising therapies before their safety and efficacy are established. as members of the national institutes of health covid-19 treatment guidelines panel (the panel) (1), we are charged with providing guidance for u.s. clinicians on the treatment of covid-19 by reviewing current scientific evidence and providing real-time recommendations based on the strength and quality of the data. on 23 august 2020, the fda issued an emergency use authorization (eua) for convalescent plasma for treating covid-19 (2). an eua does not constitute drug approval by the fda. rather, an eua allows the fda to facilitate the availability and unapproved uses of medical products during a public health emergency (3). the criteria for issuing an eua for medical products include the following: the public health concern must be serious or life threatening; sufficient evidence must exist that the product "may be effective"; the known and potential benefits of the product, when used to diagnose, prevent, or treat the identified disease or condition, outweigh the known and potential risks of the product; and no adequate, approved alternatives to the product are available (3). a strong scientific rationale and historical precedents exist for the study of passive immunotherapeutic approaches for viral infections (4). concentrated, virusspecific immunoglobulin preparations are fda approved for the postexposure prophylaxis of such viral infections as hepatitis b, varicella, and rabies (5). recently, a randomized controlled trial (rct) demonstrated the efficacy of 2 different monoclonal antibody products for treating ebola virus disease (6). the situation is less clear regarding the safety and efficacy of convalescent plasma, which has been used to treat viral infections from the 1918 influenza pandemic to the recent epidemics of severe acute respiratory syndrome (sars), h1n1 influenza, middle east respiratory syndrome, and ebola virus disease (7-10). the only rct demonstrating efficacy of convalescent plasma for an infectious disease was conducted more than 40 years ago, for treating argentine hemorrhagic fever (11). early in the covid-19 pandemic, convalescent plasma was used in china to treat hospitalized patients with covid-19 (7). shortly thereafter, rcts evaluating convalescent plasma in patients with covid-19 began in several countries, including the united states (12) . in march 2020, the fda authorized expanded access to convalescent plasma for treating severe or life-threatening covid-19 under individual-patient emergency investigational new drug applications. the mayo clinic's expanded access program (eap) was developed in parallel to provide broader access to convalescent plasma; however, it was not designed to generate definitive data on safety or to evaluate efficacy (13) . one of the requirements for an eap is that it not interfere with pivotal trials (14) . adequately powered rcts of convalescent plasma in the united states have been slow to enroll patients. given the lack of data from properly powered rcts, and the need to inform regulatory decision making regarding continued access to convalescent plasma, both the fda and the mayo clinic performed retrospective, indirect evaluations of efficacy by using eap data, hypothesizing that patients who received plasma units with higher titers of neutralizing antibodies would have better clinical outcomes. the results of the analyses were used as supporting evidence for the eua. the fda analysis included 4330 patients, and donor neutralizing antibody titers were measured by the broad institute, using a sars coronavirus 2 (sars-cov-2) neutralization assay (15) . the analysis revealed no difference in 7-day mortality between the patients who received high-titer and those who received lowtiter plasma in the overall population or in the subset of patients who were intubated. however, among nonintubated patients (approximately two thirds of those analyzed), 11% of those who received high-titer plasma died within 7 days of transfusion compared with 14% who received low-titer plasma (p = 0.03) (16) . in a post hoc analysis of nonintubated patients who were younger than 80 years and treated within 72 hours of diagnosis, 7-day mortality for those who received high-versus lowtiter plasma was 6.3% and 11.3%, respectively (p = 0.0008) (15) . a similar efficacy analysis by the mayo clinic included 3082 participants who had received a single unit of plasma among the 35 322 participants who had received plasma through the eap by 4 july 2020 (17) . antibody titers were measured by using the vitros anti-sars-cov-2 igg assay (ortho clinical diagnostics), and outcomes were compared among patients receiving low-(lowest 18%), medium-, and high-titer (highest 17%) plasma. after adjusting for baseline characteristics, the 30-day mortality rate was 29.1% in the low-titer group and 24.7% in the high-titer group. this difference did not reach statistical significance. the mayo clinic post hoc subgroup analyses also suggested a benefit of high-titer plasma in patients who received plasma within 3 days of covid-19 diagnosis (17) . the fda concluded that the totality of data, including additional data from small randomized trials and nonrandomized, observational, and animal studies, met the criteria for eua issuance. despite clearly meeting the "may be effective" criterion for eua issuance, the analyses of the eap data are not sufficient to establish the efficacy or safety of convalescent plasma because of the lack of an untreated control group. for example, the possibility that differences in outcomes are attributable to harm from low-titer plasma rather than benefit from high-titer plasma cannot be excluded. in addition, the eap data may be subject to several confounders, including regional differences and temporal trends in covid-19 management. there is no widely available and generally agreed-upon best test for measuring neutralizing antibodies, and the antibody titers in convalescent plasma from patients who have recovered from covid-19 are highly variable. in addition, the analyses focused on early mortality, which may not be clinically meaningful in the context of the prolonged disease course of covid-19. the efficacy analyses rely on a subset of eap patients and thus represent only a fraction of patients who received plasma through the eap (17) . in this regard, additional analyses of the eap cohort and completion of the current rcts will be of critical importance. taking everything into account, the panel has determined that currently the data are insufficient to recommend for or against convalescent plasma for treating covid-19 (18) . prospective, well-controlled, and adequately powered rcts are needed to determine whether convalescent plasma and other passive immunotherapies are effective and safe for covid-19 treatment. although providers have access to this therapy, the panel cannot recommend it as a standard of care for treating covid-19 at this time. this is consistent with the language of the convalescent plasma eua fact sheet (19) . the covid-19 pandemic has intensified the tension between providing rapid access to promising therapies and generating the scientific evidence needed to establish whether those therapies are safe and effective. this tension was also noted during the west african ebola outbreak in 2014 to 2016, when several therapies, including convalescent plasma, were claimed to be of benefit. a national academies of sciences, engineering, and medicine review of that response noted that rcts are critical during an outbreak, because they are the quickest way to identify effective therapies (20) . experience with convalescent plasma, hydroxychloro-quine, and other interventions has taught us that large observational cohorts, eaps, and euas can have a profound impact on our ability to conduct the properly designed rcts necessary to provide definitive evidence of safety and efficacy. conversely, the lack of access to large rcts at many health care centers during the covid-19 pandemic may exacerbate issues of equity in access to care. expanded access programs continue to be an important mechanism to provide promising therapies for patients who do not otherwise have access to them (that is, through clinical trials). balancing this tension is challenging but imperative to maintaining the ability to generate rigorous and convincing evidence during a public health crisis. despite the challenges of the covid-19 pandemic, conducting well-controlled, adequately powered rcts is possible. two such trials, actt (adaptive covid-19 treatment trial) and recovery (randomized evaluation of covid-19 therapy), recently demonstrated the efficacy of remdesivir and dexamethasone, respectively, for treating covid-19 (21, 22) . collaboration and partnership among governmental agencies, industry, academia, and the public are needed to establish and carry out a robust and coordinated emergency research response, including the rapid development, deployment, and analysis of high-caliber rcts. this approach is the quickest and most efficient way to generate the answers needed to provide the best evidence-based patient care. covid-19 treatment guidelines list of randomized trials of convalescent plasma. clinicaltrials.gov. accessed at www.clinicaltrials.gov /ct2/results? expanded accesss to convalescent plasma for the treatment of patients with covid-19 [protocol]. version 10.0. accessed at www.uscovidplasma.org/physicians-protocol on food and drug administration expanded access to investigational drugs for treatment use. section 312 eua 26382: emergency use authorization (eua) request. accessed at www.fda.gov/media /141481/download on 6 food and drug administration. decisional memo. accessed at www.fda.gov/media/141480/download on 6 effect of convalescent plasma on mortality among hospitalized patients with covid-19: initial three-month experience. medrxiv national institutes of health. the covid-19 treatment guidelines panel's statement on the emergency use authorization of convalescent plasma for the treatment of covid-19. accessed at www .covid19treatmentguidelines.nih.gov/statement-on-convalescent -plasma fact sheet for health care providers. emergency use authorization (eua) of covid-19 convalescent plasma for treatment of covid-19 in hospitalized patients integrating clinical research into epidemic response: the ebola experience. national academies pr remdesivir for the treatment of covid-19 -preliminary report dexamethasone in hospitalized patients with covid-19 -preliminary report author contributions: conception and design analysis and interpretation of the data critical revision for important intellectual content obtaining of funding: h.c. lane. administrative, technical, or logistic support key: cord-313345-zwe3tmq0 authors: chou, roger; dana, tracy; jungbauer, rebecca; weeks, chandler; mcdonagh, marian s. title: update alert: masks for prevention of respiratory virus infections, including sars-cov-2, in health care and community settings date: 2020-07-20 journal: ann intern med doi: 10.7326/l20-0948 sha: doc_id: 313345 cord_uid: zwe3tmq0 nan . masks for prevention of respiratory virus infections evidence map -july 2020 update masks for prevention of respiratory virus infections, including sars-cov-2, in health care and community settings: a living rapid review reduction of secondary transmission of sars-cov-2 in households by face mask use, disinfection and social distancing: a cohort study in beijing, china probable secondary infections in households of sars patients in hong kong sars transmission in vietnam outside of the health-care setting risk factors for sars among persons without known contact with sars patients face mask use and control of respiratory virus transmission in households surgical mask to prevent influenza transmission in households: a cluster randomized trial facemasks and hand hygiene to prevent influenza transmission in households: a cluster randomized trial preliminary findings of a randomized trial of non-pharmaceutical interventions to prevent influenza transmission in households impact of non-pharmaceutical interventions on uris and influenza in crowded, urban households cluster randomised controlled trial to examine medical mask use as source control for people with respiratory illness findings from a household randomized controlled trial of hand washing and face masks to reduce influenza transmission in the role of facemasks and hand hygiene in the prevention of influenza transmission in households: results from a cluster randomised trial mask use, hand hygiene, and seasonal influenza-like illness among young adults: a randomized intervention trial facemasks, hand hygiene, and influenza among young adults: a randomized intervention trial facemask versus no facemask in preventing viral respiratory infections during hajj: a cluster randomised open label trial march 8 pilot randomised controlled trial to test effectiveness of facemasks in preventing influenza-like illness transmission among australian hajj pilgrims in 2011 risk factors for sars infection among hospital healthcare workers in beijing: a case control study sars among critical care nurses a case-control study on the risk factors of severe acute respiratory syndromes among health care workers rapid awareness and transmission of severe acute respiratory syndrome in hanoi french hospital, vietnam risk factors for sars infection within hospitals in hanoi, vietnam beijing da xue xue bao yi xue ban risk factors for sars transmission from patients requiring intubation: a multicentre investigation in toronto effectiveness of precautions against droplets and contact in prevention of nosocomial transmission of severe acute respiratory syndrome (sars) factors associated with transmission of severe acute respiratory syndrome among health-care workers in singapore effectiveness of personal protective measures in prevention of nosocomial transmission of severe acute respiratory syndrome illness in intensive care staff after brief exposure to severe acute respiratory syndrome association between 2019-ncov transmission and n95 respirator use risk factors for middle east respiratory syndrome coronavirus infection among healthcare personnel sars transmission among hospital workers in hong kong surgical mask vs n95 respirator for preventing influenza among health care workers: a randomized trial a cluster randomized clinical trial comparing fit-tested and non-fit-tested n95 respirators to medical masks to prevent respiratory virus infection in health care workers. influenza other respir viruses a randomized clinical trial of three options for n95 respirators and medical masks in health workers intubation of sars patients: infection and perspectives of healthcare workers a cluster randomised trial of cloth masks compared with medical masks in healthcare workers n95 respirators vs medical masks for preventing influenza among health care personnel: a randomized clinical trial key: cord-284694-bk6bnox0 authors: wang, changsong; kang, kai; gao, yan; ye, ming; lan, xiuwen; li, xueting; zhao, mingyan; yu, kaijiang title: cytokine levels in the body fluids of a patient with covid-19 and acute respiratory distress syndrome: a case report date: 2020-05-12 journal: ann intern med doi: 10.7326/l20-0354 sha: doc_id: 284694 cord_uid: bk6bnox0 nan during this patient's illness to see whether they could help us decide how to modify his treatment as the disease progressed. we found high and fluctuating levels of these cytokines in his peripheral blood, bronchoalveolar lavage fluid, and pleural fluid. however, these levels correlated only inconsistently with the treatments we administered, even for plasmapheresis, which was intended to dilute circulating cytokines, and for a dialysis filter that was designed to adsorb cytokines ( figure) . in addition, these cytokine levels correlated inconsistently with his clinical course, except that the levels increased dramatically in the last days before he died. we suspect that this patient's immune system was partially suppressed due to his advanced age and multiple chronic conditions, which might have contributed to the virus's continued replication and the disease's progress. in addition, the time from symptom onset to confirmation of covid-19 diagnosis was relatively long, the patient's hospital course was longer, and we wonder whether this long duration of viral replication contributed to the high cytokine levels we measured. other studies have reported that patients with covid-19 have evidence of local damage, which includes diffuse alveolar injury with cellular fibrous mucus-like exudates (2). we measured il-6 levels in bronchoalveolar lavage fluid that were higher than the corresponding serum levels. on one occasion (7 march), the il-6 level was approximately 10 times higher. this difference is even more remarkable because the process of collecting bronchoalveolar fluid dilutes the specimen. in addition, the level of il-6 in pleural effusion was higher than the corresponding serum levels on the 2 times we measured it. if these observations indicate a cytokine storm, we propose that the local storm may be worse than the systemic storm. interleukin-6 blockers have been used to treat cytokine storm in patients with other causes of cytokine storm (3), and tocilizumab has been suggested for immunotherapy for severe patients with extensive lung lesions and elevated il-6 levels (3). as a result, we wonder whether tocilizumab would have affected the il-6 levels we observed and whether it might have improved this patient's disease course, especially because others have reported that as covid-19 progresses to its middle and late stages, the expression of inflammatory cytokines is related to the severity of the disease (4). on the basis of our experience, we encourage additional research to determine whether inflammatory cytokines in the lungs predict the clinical course of covid-19 and whether these cytokines should be a target for intervention and treatment. in summary, this case suggests an increased inflammatory response in the lung tissues of critically ill patients with covid-19, and it suggests that future research should include examinations of local inflammation in the lungs. continued on the following page epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive study pathological findings of covid-19 associated with acute respiratory distress syndrome toxicity management for patients receiving novel t-cell engaging therapies clinical features of patients infected with 2019 novel coronavirus in wuhan key: cord-300474-r5gms09p authors: mackey, katherine; kansagara, devan; vela, kathryn title: update alert 2: risks and impact of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers on sars-cov-2 infection in adults date: 2020-07-23 journal: ann intern med doi: 10.7326/l20-0969 sha: doc_id: 300474 cord_uid: r5gms09p nan in this second monthly update of our living review (1), we searched medline (ovid) weekly from 9 june 9 to 6 july 2020 using the same search strategy as described in the original review. we did not limit by language. this search update yielded 91 results (de-duplicated). after an independent dualreview process, we identified 3 new meta-analyses, 5 new observational studies, and 1 in-progress trial for inclusion. results of 3 new meta-analysis (2-4) evaluating the association of angiotensin-converting enzyme inhibitor (acei) or angiotensin-receptor blocker (arb) use with coronavirus disease 2019 (covid-19) illness severity are consistent with the findings that we reported in the original manuscript. five new observational studies also examine this association. four of these studies found that use of aceis or arbs is not associated with more severe covid-19 illness (5) (6) (7) (8) . in a retrospective study of 113 patients hospitalized with covid-19 in turkey, use of acei/arbs was associated with higher inhospital mortality (9). however, a major limitation of the study is that the group of patients taking acei/arbs were older and more likely to have coronary artery disease than the non-acei/arb group. overall, inclusion of these 3 new meta-analyses and 5 new observational studies does not change the certainty of evidence rating we reported in the original manuscript for key question 2-high-certainty evidence that acei or arb use is not associated with more severe covid-19 disease. we identified 1 randomized controlled trial that is currently in progress in the netherlands comparing arb therapy (valsartan) with placebo on intensive care unit admission, mechanical ventilation, and death among hospitalized adults with covid-19 (10). the estimated study completion date is december 2021. a study by yang and colleagues (11) that was included in our original manuscript as a preprint has now been published. risks and impact of angiotensinconverting enzyme inhibitors or angiotensin-receptor blockers on sars-cov-2 infection in adults treatment with ace inhibitors or arbs and risk of severe/lethal covid-19: a meta-analysis. heart a systematic review and meta-analysis to evaluate the clinical outcomes in covid-19 patients on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. eur heart j cardiovasc pharmacother estimation of renin-angiotensin-aldosterone-system (raas)-inhibitor effect on covid-19 outcome: a meta-analysis predictors of severe or lethal covid-19, including angiotensin converting enzyme inhibitors and angiotensin ii receptor blockers, in a sample of infected italian citizens clinical characteristics and disease progression in early-stage covid-19 patients in south korea use of raas inhibitors and risk of clinical deterioration in covid-19: results from an italian cohort of 133 hypertensives association of angiotensinconverting enzyme inhibitor or angiotensin receptor blocker use with covid-19 diagnosis and mortality is the use of ace inb/arbs associated with higher in-hospital mortality in covid-19 pneumonia patients? rationale and design of the praetorian-covid trial: a double-blind, placebocontrolled randomized clinical trial with valsartan for prevention of acute respiratory distress syndrome in hospitalized patients with sars-cov-2 infection disease effects of angiotensin ii receptor blockers and ace (angiotensin-converting enzyme) inhibitors on virus infection, inflammatory status, and clinical outcomes in patients with covid-19 and hypertension: a single-center retrospective study this article was published at annals.org on 23 annals of internal medicine 1 key: cord-309633-1cd74xdl authors: rogers, julia h.; link, amy c.; mcculloch, denise; brandstetter, elisabeth; newman, kira l.; jackson, michael l.; hughes, james p.; englund, janet a.; boeckh, michael; sugg, nancy; ilcisin, misja; sibley, thomas r.; fay, kairsten; lee, jover; han, peter; truong, melissa; richardson, matthew; nickerson, deborah a.; starita, lea m.; bedford, trevor; chu, helen y. title: characteristics of covid-19 in homeless shelters: a community-based surveillance study date: 2020-09-15 journal: ann intern med doi: 10.7326/m20-3799 sha: doc_id: 309633 cord_uid: 1cd74xdl background: homeless shelters are a high-risk setting for severe acute respiratory syndrome coronavirus 2 (sars-cov-2) transmission because of crowding and shared hygiene facilities. objective: to investigate sars-cov-2 case counts across several adult and family homeless shelters in a major metropolitan area. design: cross-sectional, community-based surveillance study. (clinicaltrials.gov: nct04141917) setting: 14 homeless shelters in king county, washington. participants: a total of 1434 study encounters were done in shelter residents and staff, regardless of symptoms. intervention: two strategies were used for sars-cov-2 testing: routine surveillance and contact tracing (“surge testing”) events. measurements: the primary outcome measure was test positivity rate of sars-cov-2 infection at shelters, determined by dividing the number of positive cases by the total number of participant encounters, regardless of symptoms. sociodemographic, clinical, and virologic variables were assessed as correlates of viral positivity. results: among 1434 encounters, 29 (2% [95% ci, 1.4% to 2.9%]) cases of sars-cov-2 infection were detected across 5 shelters. most (n = 21 [72.4%]) were detected during surge testing events rather than routine surveillance, and most (n = 21 [72.4% {ci, 52.8% to 87.3%}]) were asymptomatic at the time of sample collection. persons who were positive for sars-cov-2 were more frequently aged 60 years or older than those without sars-cov-2 (44.8% vs. 15.9%). eighty-six percent of persons with positive test results slept in a communal space rather than in a private or shared room. limitation: selection bias due to voluntary participation and a relatively small case count. conclusion: active surveillance and surge testing were used to detect multiple cases of asymptomatic and symptomatic sars-cov-2 infection in homeless shelters. the findings suggest an unmet need for routine viral testing outside of clinical settings for homeless populations. primary funding source: gates ventures. shelters, and self-reported new or worsening cough alone or 2 or more new or worsening ari symptoms with onset in the past 7 days. eligible ari symptoms included subjective fever, cough, sore throat, shortness of breath, myalgia, headache, and rhinorrhea. data on chills, sweats, ear pain or discharge, nausea or vomiting, diarrhea, and rash were also collected, although these alone were not sufficient to meet ari criteria. once a month, study eligibility was extended to shelter residents aged 3 months or older regardless of symptoms. study staff recruited participants 6 days a week during this period ( figure 1) . in response to sars-cov-2 in washington state, onsite testing and treatment of influenza (that is, the trial intervention) were discontinued on 1 april 2020. we reduced study staff to 3 onsite days per week at each shelter and recruited persons regardless of symptoms. shelter staff were also eligible for study participation at this time. individual participants were not followed longitudinally, but eligible persons could have multiple encounters throughout the study period. study participation was limited to once weekly unless new or worsening ari symptoms developed, in which case a person was permitted to reenroll within 7 days. this study was approved by the human subjects division of the university of washington institutional review board (study00007800). participants were recruited in person using 2 mechanisms: routine surveillance and surge testing events. routine surveillance, as detailed earlier, involved selfselected participation at staffed kiosks in shelters during standardized days and times. surge testing was initiated on 30 march 2020 (and continued through 24 april) in collaboration with public health-seattle & king county's communicable disease epidemiology team to conduct contact tracing at 6 shelters where cases of sars-cov-2 were previously detected ( figure 2 ). during these 1-day events, we offered sars-cov-2 testing to all residents and staff. in addition to 3 shelters participating in routine surveillance, we did surge testing at 3 other shelters where a case of sars-cov-2 was detected. these 3 additional shelters had residents or staff members that had sought services from or worked at 1 of the routine surveillance sites in the prior month. sampling strategies for asymptomatic versus symptomatic study participants were the same at these sites. the 9 original participating shelters included those serving women (shelter a), mixed-sex adults (shelters b and c), mixed-sex adults aged 18 to 25 years (shelter d), families (shelters e, f, and g), men aged 50 years or older (shelter h), and men aged 18 years or older (shelter i). private or shared rooms were available as sleeping accommodations at shelters e, f, and g. shelters b symptomatic encounters include those with ≥1 self-reported symptom. characteristics of covid-19 in homeless shelters and g were closed in early april, and to reduce crowding, residents were moved to shelters j and k, which had private or shared rooms. we did routine surveillance at these new sites. altogether, 11 shelters (shelters a through k) were sites for routine surveillance, and 3 additional shelters (shelters l, m, and n) were sites for surge testing alone. maximum nightly capacity ranged from 45 to 275 persons. supplement table 1 (available at annals.org) shows shelter site characteristics and participant encounter metrics. all questionnaire data were collected electronically in research electronic data capture (redcap) on a tablet (supplement, available at annals.org). participants chose to complete the questionnaire themselves or with the assistance of study staff. telephonic interpretation services were available for non-english-speaking participants. mid-nasal samples were obtained using a sterile nylon flocked nasal swab (copan diagnostics). until 6 march, study staff collected these swabs. thereafter, because of heightened infection control precautions, participants were instructed to self-collect a mid-nasal swab while observed by study staff. visual guides were shared with participants before sample collection to demonstrate self-swabbing. questionnaire data included participant age, race, sex, smoking status, underlying conditions, flu vaccine status, sleeping arrangements, and symptom profiles and duration. smoking status was determined by asking participants if they used tobacco products, e-cigarettes, or vape pens. underlying conditions included asthma, blood disorders, cancer, chronic obstructive pulmonary disease or emphysema, chronic bronchitis, immunosuppression, liver disease, heart disease, diabetes, neurologic conditions, or aspirin therapy. flu vaccine status was determined by self-reported receipt of influenza vaccine since 1 july 2019. sleeping arrangements were reported only by shelter residents and categorized as communal or private room/shared family room. communal included sleeping in a congregate space with bunk beds, bed mats, or rooms shared with more than 1 family. participant encounters with 1 or more new or worsening symptoms with onset in the past 7 days were defined as symptomatic, and those without any new or worsening symptoms in the past 7 days were defined as asymptomatic. participants with ari symptoms also had symptom duration data collected in response to the question, "when did the symptoms you mentioned in the beginning of this survey become new or worsening?" viral co-infection was defined as the presence of 2 or more viral pathogens (supplement table 2 , available at annals.org). influenza-like illness was defined as having a fever and cough or sore throat. coronavirus disease 2019 -like illness was defined as fever and cough or increased difficulty breathing. samples were transported to the university of washington laboratory in universal viral transport medium (becton dickinson) in ice-packed coolers and stored at 4°c before testing. testing was done at the brotman baty institute for precision medicine. total nucleic acids were extracted (magna pure [roche]) and tested for the presence of 27 respiratory pathogens using taqman reverse transcriptase polymerase chain reaction (rt-pcr) on the openarray platform (thermo fisher scientific) as well as sars-cov-2 using a laboratory-developed test or research assay (supplement table 2 ). for the laboratorydeveloped test, sars-cov-2 detection was done using real-time rt-pcr with probe sets targeting orf1b and s with fam fluor (life technologies 4332079 assays #apgzjkf and #apxgvc4apx) multiplexed with a ribonuclease p (rnase p) probe set with vic or hex fluor (life technologies a30064 or idt custom), each in duplicate on a quantstudio 6 instrument (applied biosystems). the research assay uses only the orf1b and rnase p multiplexed rt-pcr in duplicate. shelter specimens collected between 25 february and 18 march 2020 were tested for sars-cov-2 using the research assay in real time. specimens collected after 19 march were tested for sars-cov-2 using the laboratory-developed test under an emergency use authorization issued by washington state. specimens collected before 25 february were tested retrospecasymptomatic symptomatic symptomatic encounters include those with ≥1 self-reported symptom. annals.org annals of internal medicine tively using a single replicate orf1b and rnase p multiplexed rt-pcr research assay to detect sars-cov-2 orf1b. we used cycle threshold (ct) values as a semiquantitative measure of viral load in a sample. cycle threshold values are inversely related to the viral load. three or 4 replicates for rnase p and sars-cov-2 were required to have a ct value less than 39 for a sample to be considered positive for the laboratory-developed test, and both replicates had to be positive for the research assay. the primary outcome of this study was sars-cov-2 infection, defined as detection of sars-cov-2 from a nasal swab, regardless of symptoms. we calculated the test positivity rate of sars-cov-2 infection at shelters by dividing the number of positive cases by the total number of participant encounters in the study period. all data in this analysis are presented by participant encounter, defined as each time an eligible person, either with or without symptoms, completed a nasal swab and survey with an onsite study staff member. we used participant encounters as the primary unit of analysis in this study rather than unique participants because of difficulties in matching names at different encounters in a transient population. (we estimated that there were 925 unique participants identified in this study population, but this number is uncertain.) we used descriptive statistics to evaluate the sociodemographic and clinical characteristics, virologic factors, and symptom profiles of all participant encounters. the 95% cis for study measures of disease occurrence are provided in the results section. responses of "do not know" and "prefer not to say" were coded as missing observations and dropped from the analysis. descriptive statistics comparing demographic characteristics of unique participants versus participant encounters were similar overall. most persons had only 1 encounter during the study period (n = 696 [75.2%]), and all sars-cov-2 cases included in this study involved unique participants. this study was funded by gates ventures. the funder was not involved in the design of the study and does not have any ownership over the management and conduct of the study, the data, or the rights to publish. a total of 1434 participant encounters occurred between 1 january and 24 april 2020 at 14 shelters. of these encounters, 601 (41.9%) involved asymptomatic persons, and 833 (58.1%) involved symptomatic persons. the median age of participants was 46 years (range, 0 to 82 years) ( table 1) . most encounters involved males (67.9%). the predominant racial groups were white (40.9%) and black or african american (30.5%). more than half of the encounters involved smokers (57.7%), and 39.4% involved participants with at least 1 underlying condition. among the 833 symptomatic participant encounters, the mean number of symptoms was 2 (sd, 2.2) ( table 2) . rhinorrhea (43.0%), cough (37.3%), and myalgia (23.7%) were the most common symptoms. of the 725 participant encounters with symptom duration data available, 40.3% had ari symptoms for less than 2 days at the time of testing. the proportion of encounters that met the case definition for influenza-like illness was 13.2%, and the proportion for covid-19 -like illness was 12.7%. samples from 28 (2.1%) participant encounters were positive for 2 or more of 17 respiratory pathogens (plus sars-cov-2) (supplement table 2 ). samples from 201 (15%) encounters were positive for streptococcus pneumoniae. we identified 29 (2.0% [95% ci, 1.4% to 2.9%]) participant encounters with sars-cov-2 infection involving 29 unique persons. four (13.8%) of these persons were shelter staff. the positivity rate among encounters with shelter staff compared with shelter residents was similar (2.5% vs. 2.0%, respectively). approximately half of encounters with sars-cov-2 detected involved persons aged 60 years or older (44.8%), and only 3 involved persons younger than 35 years (10.3%) ( table 1) table 2) . one positive encounter met both the influenza-like illness (3.4%) and covid-19 -like illness (3.4%) case definition. of the 6 positive encounters with symptom duration data available, 5 (83.3%) reported symptoms developing less than 48 hours before study participation. among encounters that were negative for sars-cov-2, 1.9% of persons tested positive for at least 1 other respiratory virus, compared with 10.3% among encounters with positive sars-cov-2 results. mean sars-cov-2 ct values among samples collected from symptomatic (n = 8) and asymptomatic (n = 21) persons were 27.9 (sd, 5.0) and 29.6 (sd, 6.1), respectively. in total, participating shelters had 1482 beds, of which 1183 (80.0%) were at routine surveillance sites. a total of 1119 (78%) participant encounters occurred at routine surveillance sites ( table 1) . shelter h, which served older men, represented the greatest number of participant encounters (18%) from a single site, whereas 21.7% of encounters were in family shelters (supplement table 1 ). between 30 march and 24 april, we held 8 surge testing events at 6 sites, resulting in 315 participant encounters, ranging from 12 to 97 during each event. cases of sars-cov-2 were detected at 5 shelters. the first case was detected on 11 march at shelter h, with a subsequent case on 30 march at shelter i ( figure 2 ). most positive cases were detected during surge testing events (n = 21 [72.4%]) compared with routine surveillance (n = 8 [27.6%]). site-specific positivity rates original research characteristics of covid-19 in homeless shelters ranged between 1% and 20%. overall, 85.7% of positive cases were in participants who had slept in a communal space in the past week, compared with 78.2% of negative encounters ( table 1) . of sars-cov-2 cases, 5 were detected at shelter f (4.6% of total site encounters), which had both private and communal sleeping spaces. three sars-cov-2 cases from this site were among persons sharing the same private room. the remaining 24 sars-cov-2 cases were at shelters serving adult men with only communal sleeping spaces available. most sars-cov-2 cases (79.3%) were detected at shelters serving older male residents, with shared day center services, showering facilities, and a rotating staff (figure 3 ). our findings show detection of sars-cov-2 in homeless shelters during 4 months of active surveillance and surge testing. overall, 2% of participant encounters involved positive sars-cov-2 results, with most cases detected through surge testing events. encounters with positive results were more frequent in older persons and nonsmokers. most sars-cov-2 in-fections were asymptomatic, with similar mean ct values in cases with and without symptoms. in our study, most positive cases reported no or mild symptoms. this may in part be from early detection of presymptomatic cases or identification of persons with mild illness episodes who would not have sought care or testing services. an outbreak investigation at a boston-based shelter serving only men reported a substantially higher positivity rate (36%) among all residents tested at a single time point. however, testing at this shelter was done at a time when the community incidence of sars-cov-2 in massachusetts was higher than that in washington state (14, 15) . similar to our study, the boston group noted that a large proportion of persons with sars-cov-2 were asymptomatic, with only 7.5% reporting cough and 1.4% reporting shortness of breath (13) . although the exact role of presymptomatic and asymptomatic sars-cov-2 transmission remains unclear, recent publications have linked outbreaks to asymptomatic index cases (16 -18) . recent studies have shown that ct values from positive rt-qpcr results may relate to viral transmissibility and may inform clinical decision making about isolation annals.org annals of internal medicine precautions (19) . cycle threshold values were similar in persons with and without symptoms, suggesting that viral load may not be associated with symptoms. prior studies have implicated asymptomatic and presymptomatic persons as a source of infection, but the duration of sars-cov-2 infectivity is unknown (16 -18) . this has major implications for public health and shelter service providers developing guidelines for isolation of residents who are positive for sars-cov-2 and reintroduction into a general shelter population. further research is needed to understand the effect of temporal dynamics in viral shedding on transmissibility of sars-cov-2 in communal settings and the role of asymptomatic cases. shelter characteristics, particularly resident density and sleeping arrangements, may play a role in sars-cov-2 transmission. the outbreak seen in shelters h, l, and m may have been related to the use of floor mats in a communal sleeping space without temporary dividers and less than 6 feet apart (12) . we observed only 1 positive sars-cov-2 result in shelters with bunk beds rather than floor mats in congregate sleeping areas. the family shelters adhered to the centers for disease control and prevention recommendations of using curtains as a temporary barrier between familial bed clusters in congregate sleeping areas (20) . these shelters also implemented social distancing and handwashing protocols in late march, with daily temperature checks and symptom assessments by staff, which were indepen-dent from voluntary participation in this study. these measures may have curtailed further transmission within shelter f. shelters h, l, and m, where more cases were detected, had limited staff-conducted screening and a shortage of hygiene resources. we sampled both staff and residents and found sars-cov-2 test positivity rates to be similar between the groups. future analyses will focus on transmission dynamics within shelters, with sampling from both groups. our positivity rate was lower than the 8.8% rate seen in the university of washington clinical laboratory during that same period (21) . this may be because most clinical samples were obtained from persons seeking medical care. public health and other groups did additional testing at 2 shelters in this study during an outbreak investigation between 31 march and 8 april. interestingly, only 2 of 41 confirmed cases (4.9%) from this investigation were identified through routine symptom-based screening, and only 3 (7.3%) were identified after health care was sought (12) . in addition, our study identified nearly a third of sars-cov-2 cases through routine surveillance, which may have resulted from study eligibility expansion to asymptomatic persons. we speculate that with earlier asymptomatic testing, additional outbreaks may have been detected at study sites. this study's findings may be subject to selection bias because all participation was voluntary. high levels characteristics of covid-19 in homeless shelters of distrust of health care providers and low rates of health care use in homeless populations have been documented (9, 22, 23) . this may account for more asymptomatic cases of sars-cov-2 having been detected through surge testing events when shelter management actively encouraged all residents and staff to participate. in addition, reducing onsite testing from 6 to 3 days per week may have decreased our ability to detect additional positive cases at participating sites. another limitation is the lack of robust follow-up data on participants. we had very low response rates to a follow-up survey sent via text message or e-mail to asymptomatic participants 7 days after onsite study participation to evaluate for new or worsening symptoms; thus, it was excluded from our analysis. therefore, it is unclear what proportion of the asymptomatic sars-cov-2 cases detected in this study were presymptomatic. in addition, the small numbers of sars-cov-2 cases and unmeasured shelter-level covariates limit the extent to which we can draw conclusions about how sleeping arrangements may mitigate transmission. finally, this study was not able to track unique participants and could not reliably identify encounters in the same participant. the sensitivity of self-sampling for sars-cov-2 detection may also be a problem. however, a recent study shelter l was a temporary homeless service site opened on 14 march when half of the residents at shelter h were moved to reduce crowding. residents at shelter h shared day center services, showering facilities, and a rotating staff with shelters g and m during this period. residents were men aged ≥50 y that slept on communal floor mats in 2 separate rooms. participant recruitment was done through surge testing only at shelter l; routine surveillance was never available as a sampling mechanism. characteristics of covid-19 in homeless shelters annals.org annals of internal medicine of self-collected mid-turbinate nasal swabs for influenza detection found rnase p in 100% of nasal swab specimens, but with higher mean ct values among positive results in self-collected swabs compared with cliniciancollected nasopharyngeal swabs (24) . additional studies have found that self-swabbing results in viral positivity rates similar to those of sentinel physician networks and has excellent diagnostic yield (25-27). in conclusion, this study provides key insights into detection strategies for sars-cov-2 in a vulnerable, hard-to-reach population. passive sentinel surveillance for respiratory viruses may only detect symptomatic cases severe enough to prompt health-seeking behavior and may miss milder ones, delaying the recognition of outbreaks and further viral spread (28, 29) . results of this study's combined active surveillance and surge testing strategy suggest an unmet need for routine viral testing outside of clinical settings in homeless shelters and other congregate living facilities. secretary carson certifies annual data: homelessness ticked up in 2019, driven by major increases in california utilization of mental health and substance abuse services among homeless adults in los angeles influenzalike illness among homeless persons respiratory syncytial virus infection in homeless populations homelessness and the response to emerging infectious disease outbreaks: lessons from sars covid-19: a potential public health problem for homeless populations utilization of health care services among subgroups of urban homeless and housed poor high utilizers of emergency health services in a population-based cohort of homeless adults factors associated with the health care utilization of homeless persons infections in the homeless respiratory viruses within homeless shelters in marseille, france covid-19 outbreak among three affiliated homeless service sites-king county, washington institute for health metrics and evaluation. covid-19 projections: massachusetts. accessed at https://covid19.healthdata.org /united-states-of-america/massachusetts on 19 may 2020. 15. institute for health metrics and evaluation. covid-19 projections: washington screening of healthcare workers for sars-cov-2 highlights the role of asymptomatic carriage in covid-19 transmission presumed asymptomatic carrier transmission of covid-19 evidence supporting transmission of severe acute respiratory syndrome coronavirus 2 while presymptomatic or asymptomatic to interpret the sars-cov-2 test, consider the cycle threshold value interim guidance for homeless service providers to plan and respond to coronavirus disease 2019 (covid-19) uw virology covid-19 dashboard a comprehensive assessment of health care utilization among homeless adults under a system of universal health insurance health care for the homeless: what we have learned in the past 30 years and what's next results of a pilot study using self-collected mid-turbinate nasal swabs for detection of influenza virus infection among pregnant women. influenza other respir viruses feasibility study for the use of self-collected nasal swabs to identify pathogens among participants of a population-based surveillance system for acute respiratory infections (grippeweb-plus)-germany population-based active surveillance cohort studies for influenza: lessons from peru characteristics of covid-19 in homeless shelters original research annals.org annals of internal medicine current author addresses: ms department of biostatistics 35-7232 critical revision of the article for important intellectual content appendix: members of the seattle flu study investigators members of the seattle flu study investigators who authored this work: principal investigators washington), louise e. kimball, phd (vaccine and infectious disease division characteristics of covid-19 in homeless shelters key: cord-339459-z22a5yzo authors: mackey, katherine; king, valerie j.; gurley, susan; kiefer, michael; liederbauer, erik; vela, kathryn; sonnen, payten; kansagara, devan title: risks and impact of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers on sars-cov-2 infection in adults: a living systematic review date: 2020-05-15 journal: ann intern med doi: 10.7326/m20-1515 sha: doc_id: 339459 cord_uid: z22a5yzo background: the role of angiotensin-converting enzyme inhibitors (aceis) and angiotensin-receptor blockers (arbs) in covid-19 disease susceptibility, severity, and treatment is unclear. purpose: to evaluate, on an ongoing basis, whether use of aceis or arbs either increases risk for severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection or is associated with worse covid-19 disease outcomes, and to assess the efficacy of these medications for covid-19 treatment. data sources: medline (ovid) and cochrane database of systematic reviews from 2003 to 4 may 2020, with planned ongoing surveillance for 1 year; the world health organization database of covid-19 publications and medrxiv.org through 17 april 2020; and clinicaltrials.gov to 24 april 2020, with planned ongoing surveillance. study selection: observational studies and trials in adults that examined associations and effects of aceis or arbs on risk for sars-cov-2 infection and covid-19 disease severity and mortality. data extraction: single-reviewer abstraction confirmed by another reviewer, independent evaluation by 2 reviewers of study quality, and collective assessment of certainty of evidence. data synthesis: two retrospective cohort studies found that acei and arb use was not associated with a higher likelihood of receiving a positive sars-cov-2 test result, and 1 case–control study found no association with covid-19 illness in a large community (moderate-certainty evidence). fourteen observational studies, involving a total of 23 565 adults with covid-19, showed consistent evidence that neither medication was associated with more severe covid-19 illness (high-certainty evidence). four registered randomized trials plan to evaluate aceis and arbs for treatment of covid-19. limitation: half the studies were small and did not adjust for important confounding variables. conclusion: high-certainty evidence suggests that acei or arb use is not associated with more severe covid-19 disease, and moderate-certainty evidence suggests no association between use of these medications and positive sars-cov-2 test results among symptomatic patients. whether these medications increase the risk for mild or asymptomatic disease or are beneficial in covid-19 treatment remains uncertain. primary funding source: none. (prospero: registration number pending) c oncerns exist that angiotensin-converting enzyme inhibitors (aceis) and angiotensin-receptor blockers (arbs) increase susceptibility to severe acute respiratory syndrome coronavirus 2 (sars-cov-2, the viral agent that causes the disease covid-19) and the likelihood of severe covid-19 illness (1). early reports from wuhan, china, showed that hypertension and diabetes were common among patients with covid-19 and were associated with worse outcomes (2) . although these early studies did not specify whether patients were using aceis or arbs before becoming infected, these medications are widely used to treat hypertension and diabetes (3, 4) . the proposed mechanism by which aceis and arbs may play a role in covid-19 is through upregulation of angiotensin-converting enzyme 2 (ace2), which is presumed to act as a functional receptor for sars-cov-2 to gain entry to host cells (5) (figure 1 ). angiotensin-converting enzyme 2 exists primarily as a membrane-bound monocarboxypeptidase with robust expression in such tissues as lung, vasculature, intestine, and kidney (5) . a soluble or circulating form of ace2 (sace2) has cardiovascular effects in the reninangiotensin system (6 -8) . related to viral pathogenesis, sace2 was shown to block sars viral entry into cells (9) and is now being considered as a potential therapy (10) . angiotensin-converting enzyme 2 is distinct and not directly related to the clinical use of aceis or arbs, or to their mechanisms of action. angiotensinconverting enzyme inhibitors target angiotensinconverting enzyme 1 (ace) to inhibit conversion of angiotensin i to angiotensin ii, thereby reducing levels of angiotensin ii available to bind and activate the type 1 angiotensin receptor (at 1 ), which mediates most of the vasopressor effects of angiotensin ii (11) . angiotensinreceptor blockers work by binding to at 1 receptors and directly blocking the actions of angiotensin ii. in contrast to ace, which acts to generate angiotensin ii, ace2 degrades angiotensin ii into angiotensin (1-7) and is thus a negative regulator of the renin-angiotensin system ( figure 1 ) (12) . although postulated as a mechanism for increased susceptibility to sars-cov-2 (13) , upregulation of ace2 due to aceis or arbs has not been consistently demonstrated in human and animal studies (14) . in addition to acei and arb exposure, several other mechanisms of ace2 upregulation are being explored, including exposure to nonsteroidal anti-inflammatory agents (2) and thiazide diuretics (15) , tobacco use (16) , diabetes (17) , and cytokines produced by the body in response to viral infections (18). finally, polymorphisms in the ace2 gene in humans previously were associated with hypertension and diabetes, suggesting that there is some genetic determination of ace2 levels and function (19) . paradoxically, mechanisms by which aceis and arbs may be protective in sars-cov-2 infection are also being proposed (12, 20) . animal studies have found that direct angiotensin ii suppression with aceis and at 1 receptor antagonism with arbs may promote and stabilize cell membrane complexes between ace2 and at 1 receptors (21). in theory, these complexes may reduce the ability of the virus to enter host cells (14) . suppression of angiotensin ii may also prevent virus-mediated acute lung injury (22) and other organ dysfunction, which is another proposed mechanism by which use of aceis and arbs may be beneficial in covid-19. uncertainty regarding the role of aceis and arbs in the covid-19 disease course has generated several questions for clinicians. the aims of this living systematic review are to synthesize evidence related to the following questions: does use of aceis or arbs among adults before infection with sars-cov-2 increase the risk for covid-19? is the use of these medications before infection associated with more severe covid-19 disease and worse outcomes? what are the benefits and harms of initiating these drugs as treatment for patients with covid-19? this is a living systematic review with ongoing literature surveillance and critical appraisal. it was originally conducted in response to a request from the world health organization. we registered the review with prospero (registration number pending) and followed standard methods and reporting guidelines for systematic reviews (23, 24) . key questions were developed by world health organization staff and revised with input from authors (d.k., v.j.k., and k.m.). methods of the review included searches and review of data related to sars-cov-2 and 2 other coronaviruses associated with earlier pneumonia outbreaks: sars-cov-1, causing severe acute respiratory syndrome (sars), and mers-cov, causing middle east respiratory syndrome (mers). this report and the ongoing surveillance focus on questions and data related to sars-cov-2 and disease from sars-cov-2 (covid-19). we searched, without language restrictions, the following databases: medline (ovid) and the cochrane database of systematic reviews from 1 january 2003 to 4 may 2020, the world health organization database of covid-19 publications (25) and medrxiv.org from inception to 17 april 2020, and clinicaltrials.gov to 24 april 2020. (see the supplement, available at annals.org, for search strategy and terms.) we also identified additional citations through hand-searching of reference lists. angiotensin (1-7) as part of the ras, ace2 (green) regulates the levels of angiotensin ii. as the functional receptor for sars-cov-2, ace2 may facilitate viral entry into cells. this figure illustrates the role of ace2 in the ras and how pharmacologic ras blockade with aceis or arbs (red) could theoretically increase the amount of ace2 available for viral binding. ace2 = angiotensin-converting enzyme 2; acei = angiotensin-converting enzyme inhibitor; arb = angiotensin-receptor blocker; at 1 = type 1 angiotensin receptor; ras = renin-angiotensin system; sars-cov-2 = severe acute respiratory syndrome coronavirus 2. risks and impact of aceis or arbs in adults with sars-cov-2 infection selection criteria were as follows: observational studies of adults in any setting examining associations between use of aceis or arbs and risks for acquiring sars-cov-2 and covid-19, sars, or mers; observational studies of adults with covid-19, sars, or mers, in any setting, examining associations between acei or arb use and risks for a broad range of clinical outcomes, including death, severity of illness (mechanical ventilation, intensive care unit [icu] admission, length of stay, need for noninvasive ventilation, hospitalization, organ dysfunction), cardiovascular events, and radiologic findings; and trials in adults with covid-19, in any setting, comparing laboratory or clinical outcomes between patients treated with either aceis or arbs and those receiving "usual care," placebo, or other treatments. we did not limit selection criteria by language. we excluded case reports and case series with fewer than 10 patients. one author (v.j.k. or d.k.) examined titles and abstracts for potential relevance, and 2 authors (d.k. and k.m.) independently reviewed full-text articles for inclusion. one author (m.k. or e.l.) abstracted details of study setting, population, exposures, and outcomes of interest, and a second author (k.m. or d.k.) checked entries for accuracy. two authors (v.j.k, k.m., or d.k.) independently assessed the quality of observational studies by using the newcastle-ottawa quality assessment scale (26) . we synthesized evidence qualitatively. we collectively rated the certainty of the body of evidence by using criteria that assessed study limitations, directness of the population studied and the outcomes measured, consistency of results across studies, and precision of effect estimates (27) . we plan weekly literature surveillance of medline and the cochrane database of systematic reviews for studies about sars-cov-2 and covid-19 through march 2021 by using the search strategy presented in the supplement. we will use the selection, data abstraction, and quality assessment methods described earlier. if we identify clinical trials, we will use the cochrane risk of bias tool for quality assessment (28) . new evidence that does not substantively change our review conclusions will be summarized briefly on a monthly basis; a major update will be performed when new evidence changes the nature or strength of the conclusions. authors did not receive funding for this study outside of salary support. the prisma (preferred reporting items for systematic reviews and meta-analyses) (23) flowchart ( figure 2 ) summarizes the results of the search and study selection processes. as of 4 may 2020, we included 14 observational studies (29 -42) . three studies (33, 36, 37) , which included a total of 8766 patients with covid-19 and presented analyses adjusted for important confounding factors, had consistent results and provide moderate-certainty evidence that aceis or arbs are not associated with a higher likelihood of positive sars-cov-2 test results among symptomatic patients ( table 1) . two u.s. studies examined patients tested for sars-cov-2. a veterans health administration study found that prior acei or arb use was not associated with an increased likelihood of a positive sars-cov-2 test result (adjusted odds ratio [aor], 0.98 [95% ci, 0.78 to 1.23]) (36) . a study from the new york university langone health system found that the proportion of patients with positive sars-cov-2 test results was similar between patients treated and those not treated with aceis or arbs (adjusted median difference, ϫ0.5 [ci, ϫ2.6 to 3.6]) (37) . a community-based case-control study from the lombardy region of italy included all patients older than 40 years with diagnosed covid-19 (33 these results may not apply to patients with mild or no symptoms, because most of the patients included in these studies were probably symptomatic and had undergone testing before widespread testing of asymptomatic or mildly symptomatic patients was available. we found 13 retrospective cohort studies (29 -32, 34, 36 -42) and 1 case-control study (33) that examined whether a history of acei or arb use was associated with severity of illness in patients with covid-19. overall, these studies included a total of 23 565 patients with covid-19, had consistent results, and provided high-certainty evidence that a history of acei or arb use is not associated with increased severity of covid-19 illness. eight studies were conducted in china (32-37, 39 -41), 2 in italy (33, 38) , 1 in the united kingdom (29), 2 in the united states (36, 37) , and 1 in several countries (34) ( table 2) . nine studies included only hospitalized patients; the outcome of interest for most of these studies was death or severe or critical illness, defined as hypoxemic respiratory distress with or without the need for intensive care. one multicenter study from northern italy included patients with symptomatic covid-19 and examined hospitalization as an outcome (38) . one u.s. study (36) , conducted in the veterans health administration, examined hospitalization and icu admission as outcomes in all birth cohort veterans (ages 54 to 75 years) tested for covid-19. the risks and impact of aceis or arbs in adults with sars-cov-2 infection risks and impact of aceis or arbs in adults with sars-cov-2 infection review annals.org annals of internal medicine other u.s. study included patients with covid-19 in the new york university health system and examined icu admission, assisted ventilation, and death as outcomes (37) . seven studies, each including more than 200 patients with covid-19, found that a history of acei or arb use was not associated with more severe illness in analyses adjusted for important confounders, such as age and comorbid cardiovascular conditions (29, 33, 34, 36 -38, 42) . in an italian study, the unadjusted odds of severe illness were higher among patients with a history of acei or arb use, but the differences were no longer evident in adjusted analyses restricted to those with cardiovascular disease (adjusted hazard ratio, 1.12 [ci, 0.82 to 1.54]) (38) . likewise, in the veterans health administration study, the unadjusted odds of hospitalization or icu admission were higher among patients with acei or arb exposure (36) . when analyses were adjusted for age, race, comorbid conditions, and a composite of physiologic injury, this difference was no longer statistically significant for hospitalization risk (aor, 1.24 [ci, 0.79 to 1.95]), and the observed in-crease in icu admission risk was reduced after adjustment for confounders, although it remained statistically significant (aor, 1.69 [ci, 1.01 to 2.84]). three studies found that a history of acei or arb use was actually associated with lower odds of severe illness or death (29, 34, 42) . the 7 other studies either included small samples of patients with covid-19 or had few patients with a history of acei or arb use, or they did not adjust for important confounding factors (30, 32, 35, 39 -41) . unadjusted analyses of the data presented in these studies consistently showed that the odds of severe illness were not higher among patients with a history of acei or arb use. these smaller studies commonly did not include detailed information on how baseline use of aceis and arbs was verified. most studies did not specify the exact duration of follow-up for outcomes, although this probably would not have altered the results substantially because the outcomes of interest were typically short-term, hospital-based outcomes. of note, a trial in ireland is enrolling patients with covid-19 who are receiving aceis or arbs for hypertension and is randomly assigning them to continue this treatment or switch to an alternate antihypertensive therapy (43) . the primary outcomes of this study are the number of patients with covid-19 who die, require intubation in the icu, or require hospitalization for noninvasive ventilation, and the time from randomization to the first occurrence of any of these outcomes (43) . the study criteria exclude patients who have an indication for acei or arb therapy other than essential hypertension, such as heart failure or diabetes. although we found no completed studies addressing this key question, we discovered 4 potentially pertinent trials that are registered in the clinicaltrials.gov database of the u.s. national institutes of health: efficacy we conducted a systematic review examining the relationship between acei or arb use and covid-19 illness. we found moderate-certainty evidence from 3 studies (33, 36, 37) that acei or arb use was not associated with an increased likelihood of a positive sars-cov-2 test result among symptomatic patients, but we found no studies that examined whether acei or arb use is associated with a higher likelihood of acquiring mild or asymptomatic sars-cov-2 infection. we found no studies examining the efficacy of aceis or arbs in reducing the risk for complications in covid-19 illness, although trials examining this question are under way (43) (44) (45) (46) (47) . fourteen studies across several countries provided high-certainty evidence consistently showing that aceis and arbs do not increase the risk for more severe illness in patients with covid-19. as expected and appropriate, the body of evidence examining the question of potential harm related to acei or arb use in patients with covid-19 consists only of observational studies. our confidence in these findings is strengthened by several factors. the lack of association between acei or arb use and illness severity is consistent across all studies, across several continents. these studies included more than 23 000 patients with covid-19, and all studies included consecutive series of patients, which makes it unlikely that large cohorts of patients with covid-19 exist that are substantially different from those represented in these 14 studies. although initial studies addressing this question were smaller and had methodologic limitations, the rapidly expanding evidence base now includes large, methodologically sound observational studies. these larger studies have accounted for confounding factors, which is important because the factors that might compel acei or arb use, such as comorbid cardiovascular conditions or diabetes, might also contribute to more severe covid-19 illness. we would expect this type of "confounding by indication" to contribute to spuriously elevated odds of severe illness. unmeasured, or residual, confounding is a concern in interpreting any body of observational evidence. in this case, residual confounding factors would tend to inflate the association between acei or arb treatment and covid-19 outcomes-that studies still did not show an association of aceis or arbs with severe covid-19 illness strengthens our confidence in the findings. likewise, the factors contributing to our confidence in the lack of association between acei or arb use and the likelihood of positive sars-cov-2 test results include the consistency of findings, as well as the size and quality of these 3 studies (33, 36, 37) . however, our confidence in these findings is not as strong as for the question about severity of illness, because far fewer studies exist and we cannot draw conclusions about the association between acei or arb use and the risk for mild covid-19 illness or asymptomatic sars-cov-2 infection. in 5 studies (29, 30, 32, 34, 42) , acei or arb use was associated with a lower risk for severe illness. although these results are intriguing, they do not provide enough evidence to draw conclusions about the potential efficacy of these medications in treating covid-19. however, several trials are under way that are designed to examine this question. the concern about acei or arb use in patients with covid-19 stemmed largely from arguments of biologic plausibility, particularly the observation that aceis and arbs have the potential to upregulate ace2 receptors (which seem to be the cellular entry point for sars-cov-2) (5). however, even this observation has not been consistent across animal and human models, and biologic plausibility arguments suggest that arbs may be helpful in treating covid-19 (14, 20) . on the basis of the findings from this rapidly expanding literature, no indication exists to prophylactically stop acei or arb treatment because of concerns about covid-19. indeed, withdrawal of long-term aceis or arbs may be harmful, especially in patients with heart failure because observational studies and trials have suggested that discontinuation of acei or arb therapy is associated with worse outcomes (48 -50). the potential harms of not initiating acei or arb therapy in patients with a compelling indication also may be important to consider. limitations of our review methods include searching the clinicaltrials.gov and medrxiv.org databases risks and impact of aceis or arbs in adults with sars-cov-2 infection review annals.org annals of internal medicine by using keywords and the possibility that we missed relevant studies. however, we anticipate that many studies currently available in preprint form will eventually be published and that we will identify them through ongoing electronic literature surveillance. in conclusion, high-certainty evidence exists that patients receiving long-term acei or arb therapy are not at increased risk for poor outcomes from covid-19 illness. moderate-certainty evidence also exists that acei or arb use is not associated with a greater likelihood of positive sars-cov-2 test results among symptomatic patients. whether these medications are beneficial in covid-19 treatment remains uncertain. preventing a covid-19 pandemic are patients with hypertension and diabetes mellitus at increased risk for covid-19 infection? jnc 8: relaxing the standards cardiovascular disease and risk management: standards of medical care in diabetes-2020. diabetes care receptor recognition by the novel coronavirus from wuhan: an analysis based on decade-long structural studies of sars coronavirus novel ace2-fc chimeric fusion provides 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angiotensin converting enzyme inhibitors in treatment of covid 19 losartan for patients with covid-19 not requiring hospitalization clinical consequences of angiotensin-converting enzyme inhibitor withdrawal in chronic heart failure: a double-blind, placebo-controlled study of quinapril. the quinapril heart failure trial investigators initiation, continuation, or withdrawal of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and outcomes in patients hospitalized with heart failure with reduced ejection fraction withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (tred-hf): an open-label, pilot, randomised trial sonnen: va portland health care system veterans hospital road, mail code: r&d 71 the center for evidence-based policy critical revision for important intellectual content key: cord-294628-ecg13s7a authors: chia, ming li; him chau, dickson hong; lim, kheng sit; yang liu, christopher wei; tan, hiang khoon; tan, yan ru title: managing covid-19 in a novel, rapidly deployable community isolation quarantine facility date: 2020-09-17 journal: ann intern med doi: 10.7326/m20-4746 sha: doc_id: 294628 cord_uid: ecg13s7a singapore is one of the most densely populated small island–states in the world. during the coronavirus disease 2019 (covid-19) pandemic, singapore implemented large-scale institutional isolation units called community care facilities (ccfs) to combat the outbreak in the community by housing low-risk covid-19 patients from april to august 2020. the ccfs were created rapidly by converting existing public spaces and used a protocolized system, augmented by telemedicine to enable a low health care worker–patient ratio (98 health care workers for 3200 beds), to operate these unique facilities. in the first month, a total of 3758 patients were admitted to 4 halls, 4929 in-house medical consults occurred, 136 patients were transferred to a hospital, 1 patient died 2 weeks after discharge, and no health care workers became infected. this article shares the authors' experience in operating these massive-scale isolation facilities while prioritizing safety for all and ensuring holistic patient care in the face of a public health crisis and lean health care resources. singapore is one of the most densely populated small islandstates in the world. during the coronavirus disease 2019 (covid-19) pandemic, singapore implemented large-scale institutional isolation units called community care facilities (ccfs) to combat the outbreak in the community by housing low-risk covid-19 patients from april to august 2020. the ccfs were created rapidly by converting existing public spaces and used a protocolized system, augmented by telemedicine to enable a low health care worker-patient ratio (98 health care workers for 3200 beds), to operate these unique facilities. in the first month, a total of 3758 patients were admitted to 4 halls, 4929 in-house medical consults occurred, 136 patients were transferred to a hospital, 1 patient died 2 weeks after discharge, and no health care workers became infected. this article shares the authors' experience in operating these massive-scale isolation facilities while prioritizing safety for all and ensuring holistic patient care in the face of a public health crisis and lean health care resources. annals.org ann intern med. doi:10.7326/m20-4746 for author, article, and disclosure information, see end of text. this article was published at annals.org on 17 september 2020. * all authors contributed equally to the work reported in this article. i n singapore, the construction industry employs approximately 293 300 foreign workers. in april, an outbreak of coronavirus disease 2019 (covid-19) occurred among these workers, who lived in crowded dormitories (1) . as of 3 august 2020, 53 051 covid-19 cases were reported in singapore, 94.3% of which involved foreign workers living in dormitories (2) . as such, isolation centers called community care facilities (ccfs) were set up throughout the country to house patients with covid-19 who were at low risk for dying of the disease. the admission of patients to ccfs was mandated by the infectious diseases act, which authorizes the director of medical services to order any person who is-or suspected to be-infected with or carrying an infectious disease or who is a contact of such a person to be detained and isolated in a hospital or other place. the ccfs act as a step-down care facility after diagnosis and admit low-risk foreign workers from dormitories or patients who have recovered well in the hospital and have been discharged. patients may stay in the ccf for up to 2 weeks and are then transferred to another step-down isolation facility to serve the rest of the minimum 21-day isolation period after diagnosis. singapore's public health care system is divided into 3 clusters (3), each of which was tasked with operating the several ccfs rapidly created to manage the covid-19 outbreak. this article focuses on the initial experience (in may 2020) of the singhealth cluster, which ran halls 7 to 10 (3200 beds) of the ccf@expo facility. singapore expo has 100 000 square meters of column-free, indoor space spread over 10 halls. with a maximum capacity of 8000 beds, ccf@expo is one of the largest isolation facilities of its kind. the first 2 halls were retrofitted to purpose over 3 days and the remaining 8 halls within 20 days. each hall was repurposed to accommodate 800 patients, with due consideration given to fire emergencies and contingency plans. the 2.4-× 3.6-m twin-sharing patient cubicles were constructed with partition boards (figure) . patients were allowed to move freely within their designated hall. each hall was equipped with medical consultation rooms, pharmacies, self-monitoring stations, wi-fi access, recreational amenities, water dispensers, showers and toilets, and self-service laundry facilities. radiologic service was provided by vehicles retrofitted with imaging machines. because monitoring of vital signs is resource intensive, a patient self-monitoring strategy was used. fifteen self-monitoring stations were set up in each hall, with digital sphygmomanometers, pulse oximeters, thermometers, and computer tablets. instructions written in several languages guided patients in using the monitors, recording their vital signs on a computer tablet, and disinfecting the station after each use without supervision. the data were evaluated twice daily by a member of the health care team situated outside the halls. each hall had 2 primary care medical consultation rooms with pharmacy cabinets. it also had 2 sickbays for short-term patient monitoring-for example, if a patient was awaiting transfer to a hospital or a response to treatment. pharmacists from singapore general hospital were responsible for stocking key essential medications, such as antihistamines, antitussives, antibiotics, analgesics, antihypertensives, and diabetic medications, and packaging them to facilitate dispensing at ccf@expo. physicians prescribed and directly dispensed these drugs from the pharmacy cabinets. the electronic health record system in place monitored the pharmacy repository and ensured an adequate stockpile. unidirectional laminar airflow was created in the hall to prevent contamination of the surroundings. side entrances and wall spaces were sealed, and a negative pressure of 2.5 pa (2.4 atm) was generated, with the outflow air filtered through a hepa (high-efficiency particulate air) system before being released into the outside environment. two-doored anterooms were created at the hall's entry and exit points to ensure unidirectional airflow. security cameras were placed to monitor for any unauthorized exits. ccf@expo was operated by a team of administrators, pharmacists, 26 doctors, and 72 allied health staff (affectionately called "angels" and from various disciplines, including nursing and physiotherapy) mobilized layout plan of ccf@expo halls 7 to 10. the facility had 3 distinct areas: green, red, and orange. the green area was for rest and meals for the staff. the red area is where patients were housed. staff entered the red area through a designated double-door entrance located at even-numbered halls and exited via odd-numbered halls. patients were allowed to roam freely. the orange area is where patients departed busses or were picked up by ambulances. (image courtesy of singex.) managing covid-19 in a community isolation quarantine facility from the singhealth cluster. the 72 angels performed the same tasks of screening and monitoring the patients. round-the-clock medical care was provided, with both doctors and angels assigned to 12-hour shifts. during the day shift (8 a.m. to 8 p.m.), each hall was staffed by 3 or 4 doctors and 8 to 14 angels. during the night shift (8 p.m. to 8 a.m.), staffing was reduced to 1 doctor and 2 angels per hall. staff safety was paramount. all personnel had to be trained in the fitting and use of n95 masks and other personal protective equipment (ppe) before deployment. illustrated instructions were placed at gowning and degowning stations to remind staff of the proper steps for putting on and taking off their ppe. trainers also were placed at these stations to ensure that staff adhered to the gowning and degowning procedures. each health care worker was allowed in the hall for a period not exceeding 2 hours over a continuous stretch. clean areas were made available to all staff for rest periods. to ensure the facility's safety and prevent unauthorized exit, 6 security officers were stationed in each hall during each shift. a separate security team was available if needed. the ministry of health (moh) controlled the disposition of each patient with a positive covid-19 test result (defined as a positive result on polymerase chain reaction swab testing). the moh devised a risk-based classification system including symptoms, vital signs, age, existing comorbid conditions, national early warning system (news) score (appendix figure, available at annals.org) (4), body mass index, level of activities of daily living, radiologic findings, and date of disease onset. although several groups of patients were considered low risk, those chosen for admission to ccf@expo generally were young and had no severe symptoms (such as dyspnea), no serious medical comorbid conditions, normal vital signs, and a news score of 4 or less. the news score is a composite value based on commonly used parameters (respiratory rate, oxygen saturation, supplemental oxygen requirement, temperature, blood pressure, heart rate, and level of consciousness). a score lower than 4 in a patient with acute illness indicates that he or she is at low risk for deterioration (4) . chest radiography was performed in all patients older than 35 years. if pulmonary consolidation was detected on a radiograph, the patient was transferred to a general hospital. a team of angels was tasked with screening all patients referred to the facility by the moh for admission. patients were evaluated for serious medical comorbid conditions (such as ischemic heart disease or renal failure) and abnormal vital signs. if any abnormality was detected, the patient was referred to a physician who decided whether they were suitable for admission to ccf@expo. patients determined to be unsuitable were transferred to a general hospital for further care. on admission to the facility, patients received an orientation booklet that was written in their native language and included infographics. the booklet con-tained information on the patient's responsibility for monitoring their own medical condition as well as the medical facilities available to them-namely, the process for obtaining a medical consultation both during and after office hours, code blue buttons, and selfmonitoring stations. two medical consultation rooms were staffed by physicians from 9 a.m. to noon and 2 p.m. to 5 p.m. daily. during these times, patients could present to the consultation rooms as they would to a primary care provider in the community. for urgent after-hours consultations, patients were instructed to see a physician via teleconsultation; for emergencies, patients were instructed to press one of the code blue buttons located in highly visible areas. in addition, a hotline was created to answer any urgent queries from patients. we also actively surveyed for a secondary disease outbreak, such as chickenpox, measles, or gastroenteritis. although some of the physicians staffing the facility were specialists, the degree of care was kept at the primary care level. patients who needed further investigations or were acutely ill were transferred to a general hospital via an ambulance dedicated to patients with covid-19. during the night (8 p.m. to 8 a.m.), only security officers manned the halls; medical staff were stationed in the green area outside the hall. for medical consults after hours, a videoconference-enabled computer terminal was placed in one of the medical consultation rooms and was kept on live stream throughout this period. a physician monitored the videoconference via a computer terminal located in the clean area. keeping the videoconference on live stream throughout the whole period was necessary, because instructing the patients on how to set up the computer for a teleconference would be difficult. patients used a vital sign self-monitoring system that allowed detection of those whose condition may have been deteriorating. each patient was instructed to measure their vital signs at a self-monitoring station at several points during the day. if a substantially abnormal sign (defined as systolic blood pressure >180 or <90 mm hg, diastolic blood pressure >110 mm hg, heart rate >110 beats/min, or spo 2 [oxygen saturation as measured by pulse oximetry] <94%) was noted, the patient was asked to present to the medical consult room for review. telephone reminders were used to ensure adherence to vital sign monitoring. in the rare event a patient did not have a working mobile phone, a patient experience team was tasked with helping to secure one. apart from looking after patients' health, a patient experience team was created to ensure general wellbeing and to maintain morale among those housed at ccf@expo. the team made sure that information was easily understood by the patients. it also provided psyannals of internal medicine chological support while a medical humanities team provided language translation and translators. the group organized hairdressing and financial services, counseling, and culturally appropriate movie screenings, and ensured that dietary requirements were met. the team was also critical in preventing mass unrest within the halls. the facility had a free wireless connection so families could be kept up to date on their loved one's progress. these services were provided at no cost to patients. under moh authority, patients were discharged from all isolation facilities after day 21 of illness. the start of illness was determined by the date of onset of the first symptoms or, for asymptomatic patients, the date of the first positive swab test result. it has been demonstrated that severe acute respiratory syndrome coronavirus 2 (sars-cov-2) is probably not viable after the second week of illness, despite the persistence of rna detected on polymerase chain reaction assay (5) . therefore, it was deemed unlikely that persons would be contagious after day 14 of illness, and day 21 was chosen to err on the side of caution (5, 6) . most of our patients stayed at ccf@expo for around 2 weeks, after which they were discharged to other step-down facilities to complete the remaining isolation period. an audit of the first month's cases (10 may to 9 june 2020) showed that a total of 3758 patients were admitted to the facility during this period. each day, there were 121.2 admissions (sd, 67.9), 124.4 discharges (sd, 106.8), 2593.5 bed occupancies (sd, 227.0), and 159.0 medical consults (sd, 31.6). patient characteristics and early outcomes are provided in the table. a total of 4929 medical consultations occurred during the audit period; diagnoses made during the consultations are aggregated in the appendix table ( available at annals.org). patients presented for various reasons, both related and unrelated to covid-19; the most common were minor respiratory conditions, gastrointestinal conditions, and musculoskeletal disorder. the reasons for patient transfer to a general hospital are listed in the table. of the patients admitted to ccf@expo, 3.6% (n = 136) were transferred to a general hospital (table) . of this group, 1 patient required intensive care for post-covid-19 pneumonia complicated by staphylococcus aureus pyogenic myopericarditis and polymicrobial bacteremia. this patient was subsequently discharged well from the general hospital. one patient died of a massive pulmonary embolism 2 weeks after his discharge from the facility. adherence to vital sign monitoring was 99.3% after telephone reminders were issued. between 31 may and 9 june 2020, a mean of 4.1 patients (sd, 2.71) presented each day with persistently abnormal vital signs requiring a consult. isolation strategies may be divided broadly into institution-based and home-based isolation. the predominant problem with home-based isolation is the reliance on personal adherence. consequently, a modeling study showed that institution-based isolation is 3 times more efficient than home-based isolation in reducing the number of covid-19 cases (7) . like many countries, singapore decided to pursue an institution-based isolation strategy. before the pandemic, acute hospitals in singapore had a total of 11 321 beds (8), including 1100 intensive care beds (9). if we contained the disease by hospitalizing patients with covid-19, as was the strategy adopted in singapore during the 2003 sars outbreak (5), the nation's health care infrastructure would have been rapidly overwhelmed. foreign workers made up most of the covid-19 cases in singapore. to control the spread of the virus, the country underwent a lockdown from 7 april to 1 june 2020, and foreign workers were confined to their dormitories. to encourage foreign workers to report symptoms, the ministry of manpower issued an advisory in april managing covid-19 in a community isolation quarantine facility 2020 mandating that they be paid their salaries, through government assistance, during the lockdown period. workers who were diagnosed with covid-19 and subject to treatment order under the infectious diseases act were reassured that treatment would be provided at no cost them. ccf@expo was partly modeled after the fangcang shelter hospitals, the first large-scale covid-19 isolation facilities, which were built quickly by modifying exhibition centers and stadiums in wuhan, china (6 -9) . however, ccf@expo's design included a few unique considerations. first, it served as an isolation facility rather than a hospital. as such, patients who were identified to be at risk for deterioration were sent to a general hospital for further evaluation and monitoring. second, the staffing level at the facility was low to avoid overwhelming the health care system. third, the facility served a unique population-foreign workers living in crowded dormitories who were predominantly non-english speaking and had low literacy rates. we addressed the first and second issues by admitting only patients presumed to have a low risk for death and who could participate in self-monitoring. patients could have no serious medical comorbid conditions and had to be mostly asymptomatic. to address the high patient-health care staff ratio, we designed the facility as an isolation unit with primary care support, rather than using the admission and consultation process typically seen in a hospital setting (detailed clerking, daily rounding). instead, we relied on the patients to be responsible for their self-monitoring. the rapid conversion of an existing facility, together with a low patient-staff ratio, also allowed our facility to be functional within a short period. regarding the third issue, the patients were a unique group. many had difficulties communicating in english, and some were illiterate. to mitigate this challenge, we created admission kits (containing screening questions for suitability for admission to the facility) that were translated into various languages and also included infographics. in the medical consultation rooms, posters containing translated phrases and infographics were plastered on the walls. if these were insufficient, telephone translators were used. apart from language issues, we recognized that a high level of anxiety was present among persons housed at ccf@expo. therefore, the patient experience team canvassed the halls to collect feedback from the patients. this information led us to provide culturally appropriate food, modify lighting in the halls to mimic natural day-night lighting, and offer hairdressing services. a substantial challenge that we faced was the switch in mindset from tertiary to primary care. most of our team members were used to providing care in a high-volume center, and mental barriers existed early on among the team in delivering medical care at the primary level. overall, 1 patient died, 2 weeks after he was discharged from ccf@expo, of massive pulmonary thromboembolism after covid-19. even considering the young age of our patients, this death rate is substantially lower than the rates reported in most countries (10) . we postulate that the reason for this low mortality is the high covid-19 detection rate among asymptomatic persons because of compulsory mass testing of the foreign worker dormitories in singapore. although mandated institution-based isolation is highly effective from a public health perspective, we acknowledge that it substantially restricts individual freedom. it also may be a disincentive for patients to come forward if they have symptoms or have been in contact with others who have tested positive for covid-19. on a practical note, implementing these isolation measures met with little resistance, which may be a result of the collectivistic culture of asian societies (11) . however, applying such a strategy in countries with an individualistic culture (where individual freedom is more highly valued) or in less economically developed nations may be more difficult. nevertheless, the experience gleaned at ccf@expo shows that institution-based isolation can probably be performed safely outside the hospital setting. this approach prevents health care infrastructure from becoming overwhelmed by curtailing the spread of the virus, thereby reducing bed use in acute hospitals, without the need for a large staff. a substantial proportion of stable patients with covid-19 can be isolated safely outside a hospital setting with a small health care team. isolation facilities can be created rapidly to care for patients without serious adverse outcomes. lastly, the use of technology, telemedicine, and patient self-monitoring is effective in managing a large cohort of stable patients with covid-19. the relationship between infectious diseases and housing maintenance in indigenous australian households singapore ministry of health. covid-19 situation report reorganisation of healthcare system into three integrated clusters to better meet future healthcare needs. accessed at www.moh.gov.sg/news-highlights/details /reorganisation-of-healthcare-system-into-three-integrated-clusters -to-better-meet-future-healthcare-needs on 29 standardising the assessment of acute illness severity in the nhs. report of a working party epidemiology and control of sars in singapore fangcang shelter hospitals: a novel concept for responding to public health emergencies large-scale public venues as medical emergency sites in disasters: lessons from covid-19 and the use of fangcang shelter hospitals in wuhan, china fangcang shelter hospitals in covid-19 pandemic: the practice and its significance incidence and mortality of pulmonary embolism in covid-19: a systematic review and metaanalysis country comparison: individualism. accessed at www.hofstede-insights.com/country-comparison/singapore/#:~:text =in%20individualist%20societies%20people%20are,and%20their %20direct%20family%20only.&text=singapore%2c%20with%20a %20score%20of,other%20in%20exchange%20for%20loyalty) on 24 medicine and public issues managing covid-19 in a community isolation quarantine facility current author addresses: dr. chia: moh holdings. 1 maritime square department of urology, singapore general hospital, 20 college road department of anaesthesiology, 20 college road critical revision for important intellectual content key: cord-294369-e3jyihvm authors: del amo, julia; polo, rosa; moreno, santiago; díaz, asunción; martínez, esteban; arribas, josé ramón; jarrín, inma; hernán, miguel a. title: incidence and severity of covid-19 in hiv-positive persons receiving antiretroviral therapy: a cohort study date: 2020-06-26 journal: ann intern med doi: 10.7326/m20-3689 sha: doc_id: 294369 cord_uid: e3jyihvm background: the incidence and severity of coronavirus disease 2019 (covid-19) among hiv-positive persons receiving antiretroviral therapy (art) have not been characterized in large populations. objective: to describe the incidence and severity of covid-19 by nucleos(t)ide reverse transcriptase inhibitor (nrti) use among hiv-positive persons receiving art. design: cohort study. setting: hiv clinics in 60 spanish hospitals between 1 february and 15 april 2020. participants: 77 590 hiv-positive persons receiving art. measurements: estimated risks (cumulative incidences) per 10 000 persons and 95% cis for polymerase chain reaction–confirmed covid-19 diagnosis, hospitalization, intensive care unit (icu) admission, and death. risk and 95% cis for covid-19 diagnosis and hospital admission by use of the nrtis tenofovir disoproxil fumarate (tdf)/emtricitabine (ftc), tenofovir alafenamide (taf)/ftc, abacavir (abc)/lamivudine (3tc), and others were estimated through poisson regression models. results: of 77 590 hiv-positive persons receiving art, 236 were diagnosed with covid-19, 151 were hospitalized, 15 were admitted to the icu, and 20 died. the risks for covid-19 diagnosis and hospitalization were greater in men and persons older than 70 years. the risk for covid-19 hospitalization was 20.3 (95% ci, 15.2 to 26.7) among patients receiving taf/ftc, 10.5 (ci, 5.6 to 17.9) among those receiving tdf/ftc, 23.4 (ci, 17.2 to 31.1) among those receiving abc/3tc, and 20.0 (ci, 14.2 to 27.3) for those receiving other regimens. the corresponding risks for covid-19 diagnosis were 39.1 (ci, 31.8 to 47.6), 16.9 (ci, 10.5 to 25.9), 28.3 (ci, 21.5 to 36.7), and 29.7 (ci, 22.6 to 38.4), respectively. no patient receiving tdf/ftc was admitted to the icu or died. limitation: residual confounding by comorbid conditions cannot be completely excluded. conclusion: hiv-positive patients receiving tdf/ftc have a lower risk for covid-19 and related hospitalization than those receiving other therapies. these findings warrant further investigation in hiv preexposure prophylaxis studies and randomized trials in persons without hiv. primary funding source: instituto de salud carlos iii and national institutes of health. t he recent severe acute respiratory syndrome coronavirus 2 (sars-cov-2) pandemic (1, 2) has collided with the preexisting hiv pandemic. by 22 may 2020, 234 824 coronavirus disease 2019 (covid-19) cases and 28 628 covid-related deaths had been reported in spain (3), the country with the highest hiv prevalence in europe (4) . the relation between hiv and sars-cov-2, however, is unclear (5) (6) (7) . despite the higher mortality due to covid-19 reported among some persons with immunosuppression (8) , hiv infection was not identified as an important comorbid condition in hospitalized patients with covid-19 in new york city (9) or madrid (10) . one possibility is that hiv-positive persons do not develop the intense immunologic response that often complicates the clinical course of covid-19 (10) . yet, 8 hiv-positive patients with covid-19 in wuhan, china, had preserved cd4 cell counts (7) . in fact, covid-19 might be expected to be more severe in hiv-positive persons, because risk factors for severity-older age, male sex, hypertension, diabetes mellitus, chronic obstructive pulmonary disease, and kidney disease (9 -12)-are common in this population. in spain, more than 75% of hiv-positive persons are men (13, 14) , and among those older than 50 years who are receiving antiretroviral therapy (art), 24% have relevant comorbid conditions (coris: aids research network cohort. personal communication, 18 march 2020). hiv-positive persons have a greater prevalence of geriatric syndromes, such as frailty, at younger ages (15, 16) . the lack of increased risk for serious covid-19 among hiv-positive persons might be the result of their use of art. antiretroviral therapy was proposed as a protective factor against sars in 2003, but the small number of cases did not permit conclusions to be drawn (17) . studies of molecular docking and extension reactions with rna-dependent rna polymerase (rnadrnap) suggest that nucleos(t)ide reverse transcriptase inhibitors (nrtis), such as tenofovir disoproxil fumarate (tdf), tenofovir alafenamide (taf), abacavir (abc), and lamivudine (3tc), may be effective against sars-cov-2 by inhibiting rnadrnap (18 -24) . more than 90% of known hiv-positive persons in spain are receiving art (25), most often 2 nrtis plus an integrase inhibitor, a protease inhibitor, or a non-among 77 590 hiv-positive patients receiving art in spain. between 1 february and 15 april 2020, the hiv clinics of 60 spanish hospitals identified all polymerase chain reaction (pcr)-confirmed covid-19 diagnoses among hiv-positive patients receiving art. for each confirmed case, the clinics ascertained age, sex, and art regimen at the time of the covid-19 diagnosis. regimens were classified according to both the nrti backbone (tdf/ftc, taf/ftc, abc/3tc, or other drugs) and the third drug (integrase inhibitor, protease inhibitor, or nnrti). in addition, hiv clinics provided the total number of hiv-positive patients receiving art who were being followed in their units. we obtained the age and sex distribution, as well as the distribution of art regimens, of all hiv-positive persons from the 2019 national hiv hospital survey (13). to examine the possibility of recent changes in art prescription not captured by the 2019 national hiv hospital survey, we compared this information with that provided by hospital pharmacies. the distribution was similar among the 36 hospital pharmacies that reported this information, and virtually identical for all hospitals in madrid. we accessed the national covid-19 health information system to obtain the age and sex distribution of confirmed covid-19 diagnoses in the general population. the age and sex distribution of the population of spain was obtained from the national statistics institute. the diagnosis of laboratory-confirmed covid-19 required positive results from a pcr test following the ministry of health protocols (26). clinical severity was graded as diagnosis, hospital admission, intensive care unit (icu) admission, and death. length of hospitalization was calculated in days from the date of hospital admission to the date of discharge. for each patient, follow-up started on 1 february and ended on 15 april 2020. we therefore calculated the 75-day risk (cumulative incidence) and 95% ci for covid-19 diagnosis, hospital admission, icu admission, and death, overall and by age group, sex, and nrti regimen. we used multivariable poisson regression models to estimate risks and 95% cis for covid-19 diagnoses and hospital admissions by nrti regimen. we restricted the analyses to persons living in madrid, the region with the highest number of covid-19 diagnoses and largest between-hospital variability in art regimens (and, therefore, where the choice of regimen is more likely to be determined by local hospital preferences). finally, we compared age-and sexstandardized risks in hiv-positive patients receiving art with those in the general population aged 20 to 79 years. analyses were conducted with stata, version 15.0 (statacorp). this study was approved by the institutional review board at university hospital ramó n y cajal, madrid, spain. the funding sources had no role in the design, conduct, or analysis of the study or in the decision to submit the manuscript for publication. between 1 february and 15 april, 236 pcrconfirmed diagnoses of covid-19 were made among 77 590 hiv-positive persons receiving art in spain. of these, 151 (64%) were hospitalized, with 15 (6%) admitted to the icu, and 20 (8%) died ( figure) . table 1 shows the distribution of age group, sex, and art in the patients with covid-19 compared with all 77 590 hiv-positive persons. the most common nrti backbone used among hiv-positive patients was taf/ftc (33%), followed by abc/3tc (26%) and tdf/ ftc (16%). in contrast, only 9% of the patients with covid-19 received tdf/ftc. the proportion of persons receiving other regimens (only 3tc in dual therapies or nnrti in patients treated with protease inhibitor monotherapy) was similar among those with and without covid-19. most patients received regimens based on integrase inhibitors (50%), followed by nnrtis (21%) and protease inhibitors (19%), as the third drug. table 2 shows the risks per 10 000 persons for covid-19 diagnosis (30.4), hospital admission (19.5), icu admission (1.9), and death (2.6). after standardization to the age and sex distribution of spain, the risk per 10 000 among the 77 590 hiv-positive persons was 30.0 for covid-19 diagnosis and 3.7 for death. for comparison, in the spanish general population aged 20 to 79 years during the same period, the risk for covid-19 diagnosis was 41.7 per 10 000 (33.0 per 10 000 after health care workers were excluded) and the risk for death was 2.1 per 10 000. table 2 also shows the risks among hiv-positive persons stratified by their baseline characteristics. the risks for covid-19 diagnosis and hospitalization were greater in men than women and increased notably in those older than 70 years. after stratification by nrti regimen, persons receiving tdf/ftc had the lowest risk for covid-19 diagnosis (16.9 per 10 000) and hospitalization (10.5 per 10 000). the median duration of hospitalization for 116 discharged patients was 7 days (interquartile range [iqr], 4 to 10 days) and increased by age: 4 days (iqr, 3 to 8 days) in the 20-to 39-year age group, 6.5 days (iqr, 4 to 9 days) in the 40-to 49-year group, 6 days (iqr, 5 to 10 days) in the 50-to 59-year group, 8 days (iqr, 6 to 11 years) in the 60-to 69-year group, and 9 days (iqr, 9 to 11 years) in the 70-to 79-year group. the risks for diagnosis and hospitalization were 57% lower and 48% lower, respectively, in persons receiving tdf/ftc and those receiving taf/ftc. these estimates did not materially change after the analysis was restricted to persons younger than 60 years and to those living in the madrid region. the risks for diagnosis and hospitalization were 37% versus 20% lower, respectively, in 3 hospitals that predominantly used tenofovir as tdf/ftc versus 27 that predominantly used taf/ftc. the risks for pcr-confirmed covid-19 diagnosis, hospitalization, icu admission, and death among hivpositive persons receiving art in spain were greater in men and those older than 70 years. the risk for hospitalization varied by nrti regimen and was lower in patients receiving tdf/ftc versus those receiving other regimens. the observed age and sex patterns are consistent with those reported for hiv-negative persons (9 -12) . risks for covid-19 diagnosis in persons receiving art were notably higher only in those aged 70 to 79 years. however, risk for hospitalization, icu admission, and death, as well as duration of hospitalization, increased with age, consistent with the higher burden of comorbid conditions in older persons (9 -12) . the lower risk for covid-19 diagnosis among persons receiving tdf/ftc might be the result of less intensive testing for sars-cov-2 infection in this group compared with those receiving other art regimens. however, no data-or even circumstantial evidence after consultation with treating physicians-exist to support such differential testing. also, differential testing cannot explain the lower risk for hospitalization associated with tdf/ftc use. it is theoretically possible that persons who received tdf/ftc in february 2020 in spain are a highly select group from which those most susceptible to sars-cov-2 infection have been removed. we cannot think of any mechanisms that might explain such an extreme form of depletion of susceptible persons. alternatively, another explanation for these findings is that tdf/ftc prevents serious covid-19 in hivpositive persons. molecular docking (18 -23) and other in vitro studies (24) suggest that nrtis, such as tdf, taf, abc, and 3tc, might be effective against sars-cov-2 infection by inhibiting rnadrnap. this also might explain the 32% lower risk for covid-19 diagnosis in persons receiving abc/3tc compared with those receiving taf/ftc. tenofovir diphosphate (tfv-dp) is the common active triphosphate form of taf or tdf and, because of its smaller size, has been proposed to fit better in the active site of sars-cov-2 rnadrnap (24) . compared with taf, tdf produces higher blood levels of tfv-dp, and lower intracellular concentrations (27) . in addition to its inhibition of the reverse transcriptase of hiv to ensure antiviral activity, tenofovir has been described as having various immunomodulatory effects in several animal and human cell lines (28 -30) . interleukin (il)-6, interferon-␥, il-10, and monocyte chemoattractant protein-1 are increased in patients with severe covid-19 (31) , and tenofovir has been shown to diminish the production of the inflammatory cytokines il-8, il-10, and monocyte chemoattractant protein-1 in monocytes and peripheral blood mononuclear cells. this alters the cytokine balance toward il-12 and thus promotes a t-helper type 1 response by inducing production of interferon-␥ by t and natural killer cells (32) . whether higher extracellular levels of tenofovir correlate with an increased immunomodulatory action is unknown. in contrast to tdf (33) , phosphorylated tenofovir concentrations in genital tract and rectal tissue achieved with taf were almost unquantifiable in healthy seronegative volunteers (34) . penetration of antiretroviral drugs into the lung and other tissues has been shown for tenofovir in animal models (35) and for tenofovir, ftc, 3tc, and efavirenz in humans (36) . furthermore, tdf/ftc recently was shown to incidence and severity of covid-19 in hiv-positive persons receiving art reduce sars-cov-2 titers in nasal washes from ferret infection models (37) . the patients receiving art included in this study represent 65% of all persons receiving art in spain (25), the vast majority of whom do not have overt immunosuppression and 95% of whom have achieved hiv viral suppression (13, 25). in line with the greater all-cause mortality of hiv-positive persons compared with the general spanish population (38), we found greater age-and sex-standardized mortality from covid-19 in hiv-positive persons (3.7 per 10 000 compared) than in the general population (2.1 per 10 000). this comparison, however, is not straightforward, because biological age in persons with long-standing hiv infection is estimated to be 5 to 10 years greater than chronologic age (39 -42) , as the result of chronic immune activation by persistent gut microbial translocation, sustained chronic antigen stimulation, and coinfection by other pathogens (39, 42) . comparisons with the general population also must be done with caution because of the inevitable reporting delays in the midst of a public health emergency (43) . although reporting delays are not expected for the hiv-positive persons in our study (clinicians were individually prompted to provide data from hospital records), the risk for covid-19 diagnosis was lower in the hiv-positive population (30.0 per 10 000) than in the general population (41.7 per 10 000), even after removal of health care workers who were heavily tested (33.0 per 10 000). this risk was noticeably lower among hiv-positive persons receiving tdf/ftc (16.9 per 10 000). that this lower incidence of covid-19 diagnosis can be explained by less social interaction or lower diagnostic intensity is unlikely. in the context of outbreaks in spain, only clinically symptomatic persons seeking health care receive a pcr-confirmed diagnosis and, if anything, hiv-positive patients are expected to be investigated more intensely than the general population. in summary, we took advantage of the overlap between 2 ongoing pandemics (hiv and sars-cov-2) in spain. our results suggest that the risk for covid-19 diagnosis is not higher in hiv-positive persons than in the general population, and that hiv-positive patients receiving tdf/ftc had a lower risk for covid-19 and related hospitalization than other hiv-positive persons. these findings warrant further investigation in studies of hiv preexposure prophylaxis and in randomized trials for the treatment and prevention of covid-19 (44) in persons without hiv. world health organization. coronavirus disease (covid-19) pandemic. accessed at www.who.int/emergencies/diseases/novel -coronavirus a new coronavirus associated with human respiratory disease in china european centre for disease prevention and control. hiv/aids surveillance in europe covid-19 in hiv investigators. covid-19 in patients with hiv: clinical case series covid-19 in people living with human immunodeficiency virus: a case series of 33 patients. medrxiv. preprint posted online 1 a survey for covid-19 among hiv/aids patients in two districts of wuhan, china. lancet. preprint posted online 13 high-dimensional immune profiling by mass cytometry revealed immunosuppression and dysfunction of immunity in covid-19 patients and the northwell covid-19 research consortium. presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with covid-19 in the new york city area a cohort of patients with covid-19 in a major teaching hospital in europe china medical treatment expert group for covid-19. clinical characteristics of coronavirus disease 2019 in china analysis of the evolution 2004-2019. national center for epidemiology-carlos iii health institute/ national aids plan-gd of public health, quality and innovation/ national center for epidemiology. madrid choice of the initial antiretroviral treatment for hiv-positive individuals in the era of integrase inhibitors frailty phenotype: a clinical marker of age acceleration in the older hiv-infected population frailty, markers of immune activation and oxidative stress in hiv infected elderly consideration of highly active antiretroviral therapy in the prevention and treatment of severe acute respiratory syndrome nucleotide analogues as inhibitors of sars-cov-2 polymerase. biorxiv. preprint posted online anti-hcv, nucleotide inhibitors, repurposing against covid-19 ribavirin, remdesivir, sofosbuvir, galidesivir, and tenofovir against sars-cov-2 rna dependent rna polymerase (rdrp): a molecular docking study nucleotide analogues as inhibitors of viral polymerases. biorxiv. preprint posted online 31 flexibility as a strategy in nucleoside antiviral drug design pharmacologic treatments for coronavirus disease 2019 (covid-19): a review government of spain, national center of epidemiology-institute of health carlos iii/national aids plan-subdirectorate general directorate of public health, quality and innovation, hiv surveillance and behavioral monitoring unit. estimates for hiv continuum of care in spain committee for medicinal products for human use activation by 9-(r)-[2-(phosphonomethoxy)propyl]adenine of chemokine (rantes, macrophage inflammatory protein 1alpha) and cytokine (tumor necrosis factor alpha immunobiological activity of n-[2-(phosphonomethoxy)alkyl] derivatives of n6-substituted adenines, and 2,6-diaminopurines differential effects of acyclic nucleoside phosphonates on nitric oxide and cytokines in rat hepatocytes and macrophages clinical features of patients infected with 2019 novel coronavirus in wuhan tenofovir selectively regulates production of inflammatory cytokines and shifts the il-12/il-10 balance in human primary cells penetration of tenofovir and emtricitabine in mucosal tissues: implications for prevention of hiv-1 transmission single-dose pharmacokinetics of tenofovir alafenamide and its active metabolite in the mucosal tissues antiretroviral tissue kinetics: in vivo imaging using positron emission tomography measurement of antiretroviral drugs in the lungs of hiv-infected patients antiviral efficacies of fda-approved drugs against sars-cov-2 infection in ferrets overall and cause-specific excess mortality in hiv-positive persons compared with the general population: role of hcv coinfection early immune senescence in hiv disease hiv-1 infection accelerates age according to the epigenetic clock methylome-wide analysis of chronic hiv infection reveals five-year increase in biological age and epigenetic targeting of hla hiv infection, inflammation, immunosenescence, and aging randomized clinical trial for the prevention of sars-cov-2 infection (covid-19) in healthcare personnel (epicos) covid19%29+in+healthcare+personnel&draw = 2&rank = 1 on 2 current author addresses: drs. del amo and polo: national plan against aids, ministry of health university hospital ramó n y cajal, m-607, km. 9 dr. arribas: university hospital la paz, idipaz, paseo de la castellana critical revision for important intellectual content appendix: members of the spanish hiv/covid-19 collaboration writing committee (members of the spanish hiv/covid-19 collaboration who authored this work collaboration who contributed to this work but did not author it) covid-19 grupo de estudio del sida-seimc (gesida)* hospital san pedro, logroñ o), j. casado (hospital ramó n y cajal, madrid) tuesta participating hospitals and investigators andalucía hospital clínico san cecilio de granada: d. vinuesa, j. hernandez-quero hospital universitario reina sofía/instituto maimó nides de investigació n biomé dica de có rdoba granada barcelona: a. imaz, d. podzamczer hospital universitario joan xxiii, institut d'investigació sanitá ria pere virgili key: cord-270970-9gtnsyts authors: wolf, michael s.; serper, marina; opsasnick, lauren; o'conor, rachel m.; curtis, laura m.; benavente, julia yoshino; wismer, guisselle; batio, stephanie; eifler, morgan; zheng, pauline; russell, andrea; arvanitis, marina; ladner, daniela; kwasny, mary; persell, stephen d.; rowe, theresa; linder, jeffrey a.; bailey, stacy c. title: awareness, attitudes, and actions related to covid-19 among adults with chronic conditions at the onset of the u.s. outbreak: a cross-sectional survey date: 2020-04-09 journal: ann intern med doi: 10.7326/m20-1239 sha: doc_id: 270970 cord_uid: 9gtnsyts background: the evolving outbreak of coronavirus disease 2019 (covid-19) is requiring social distancing and other measures to protect public health. however, messaging has been inconsistent and unclear. objective: to determine covid-19 awareness, knowledge, attitudes, and related behaviors among u.s. adults who are more vulnerable to complications of infection because of age and comorbid conditions. design: cross-sectional survey linked to 3 active clinical trials and 1 cohort study. setting: 5 academic internal medicine practices and 2 federally qualified health centers. patients: 630 adults aged 23 to 88 years living with 1 or more chronic conditions. measurements: self-reported knowledge, attitudes, and behaviors related to covid-19. results: a fourth (24.6%) of participants were “very worried” about getting the coronavirus. nearly a third could not correctly identify symptoms (28.3%) or ways to prevent infection (30.2%). one in 4 adults (24.6%) believed that they were “not at all likely” to get the virus, and 21.9% reported that covid-19 had little or no effect on their daily routine. one in 10 respondents was very confident that the federal government could prevent a nationwide outbreak. in multivariable analyses, participants who were black, were living below the poverty level, and had low health literacy were more likely to be less worried about covid-19, to not believe that they would become infected, and to feel less prepared for an outbreak. those with low health literacy had greater confidence in the federal government response. limitation: cross-sectional study of adults with underlying health conditions in 1 city during the initial week of the covid-19 u.s. outbreak. conclusion: many adults with comorbid conditions lacked critical knowledge about covid-19 and, despite concern, were not changing routines or plans. noted disparities suggest that greater public health efforts may be needed to mobilize the most vulnerable communities. primary funding source: national institutes of health. t he severe acute respiratory syndrome coronavirus 2 (sars-cov-2) and resultant coronavirus disease 2019 (covid-19) have evolved into a pandemic, requiring persons around the world to attend to rapidly changing messages about public health and take immediate actions to minimize their risk for infection and the spread of the virus (1). this unprecedented global crisis has also been marked by miscommunication regarding the imminent threat of covid-19, leading to public confusion and inaction (2) . older adults and those with underlying health conditions are at greatest risk for severe infection and death due to covid-19 (3) . the same factors that make individuals more vulnerable are also associated with reduced ability to access and understand health information, make well-informed decisions, and take optimal health-promoting actions-a skill set commonly called "health literacy" (4, 5) . this is especially true when the health information itself is not timely, trusted, consistent, or actionable. health literacy has emerged over the past 3 decades as one of the strongest psychosocial determinants of health, and it has also been shown to explain a range of health disparities by age, race/ ethnicity, and socioeconomic status (6) . thus, in uncertain times like this, when the interpretation of critical and ever-changing public health messages is paramount, many vulnerable populations may be further marginalized by inadequate health communication, posing substantial risks to themselves and their communities. we did a time-sensitive study among higher-risk, older adults living with 1 or more chronic conditions to determine their current awareness of covid-19, their perception of the seriousness of its threat, their level of worry and concern related to contracting the virus, whether it is affecting their daily routine or existing plans, how prepared they feel to handle an outbreak, and their confidence in the federal government response. this took place from 13 through 20 march 2020 during the initial outbreak of the virus in the united states. we focused on the role of health literacy and other psychosocial health determinants in understanding risks for covid-19 and the initiation of preventive behaviors. health services, are sponsored by the national institutes of health, and are taking place among 7 primary care sites (5 academic internal medicine clinics and 2 federally qualified health centers) across the greater chicago area ( table 1) . health literacy and cognitive function among older adults (r01ag030611) is a cohort study examining cognitive and psychosocial factors associated with self-management and outcomes of chronic disease over time among predominately older adults. three randomized controlled trials-ehr-based universal medication schedule to improve adherence to complex regimens (r01nr015444), a universal medication schedule to promote adherence to complex drug regimens (r01ag046352), and transplant regimen adherence for kidney recipients by engaging information technologies: the take it trial (r01dk110172)-evaluate health system strategies that leverage electronic health records and available consumer technologies to improve patient adherence and safe use of complex drug regimens. these studies were selected because they enroll mostly middle-aged or older adults (range, 23 to 88 years) with 1 or more chronic conditions who therefore would be at greater risk for covid-19. the studies use common assessments, allowing for uniform measurement of many patient characteristics. the northwestern university institutional review board approved study procedures, and all patients included in this telephone survey had provided prior consent to be contacted for future research opportunities. data were collected from 13 through 20 march 2020. inclusion criteria varied across studies by age, presence of specific chronic conditions, having been prescribed complex regimens (≥5 medications), and being an active patient at specified primary care sites; table 1 provides study-specific eligibility criteria. methods of these studies have also been described in prior publi-cations (7) (8) (9) . in brief, recruitment procedures included identifying potentially eligible participants via electronic health record queries; sending them a letter describing the study; then telephoning any patients who did not opt out of being contacted to introduce the study, screen for eligibility, and schedule an in-person baseline interview. common exclusion criteria for all studies include the presence of a severe and uncorrectable cognitive, visual, or hearing impairment that would preclude a participant's ability to complete interviews. for this survey, we targeted participants whose last interview was done between 2018 and the present. this time frame was selected to ensure that previously collected data from each parent study-which were merged with data from this survey-were most current; participants with the most recently collected prior data were prioritized for recruitment. trained research interviewers contacted participants outside their normally scheduled research interviews to invite them to answer a short set of questions pertaining to covid-19 by telephone. participant responses were recorded by interviewers using redcap web-based survey software. on average, surveys took less than 10 minutes, and participants who completed the survey were told that they would be mailed a $10 gift certificate for their time. in total, 2010 adults were enrolled in the parent studies and were eligible for the survey; 733 were contacted during the week under investigation. of these, 27 declined participation and 76 could not be reached or asked to be contacted at a later date. in all, 630 completed the study, for an overall cooperation rate of 85.9%. across all 4 studies, there was prior, uniform collection of patient demographics (age, sex, race, and ethnicity), socioeconomic status (household income, num awareness, attitudes, and actions related to covid-19 awareness, attitudes, and actions related to covid-19 annals.org annals of internal medicine ber in household, educational attainment, employment status, and health insurance), and self-reported chronic conditions. all included the newest vital sign to assess health literacy (10) . the consumer health activation index was used to determine patient activation across studies (11) . in addition, a single item was used to capture self-reported overall health (excellent, very good, good, fair, or poor). for r01ag046352, both englishand spanish-speaking patients participated; limited english proficiency (lep) was determined by patients self-reporting how well they spoke english. survey items were adapted from questionnaires used to study prior outbreaks (12) . awareness of covid-19 was assessed using 3 items that asked whether participants had heard of the novel coronavirus, if they had been told they had it or believed they did, or if someone they knew had been told they had it or believed they did ( table 2 lists the items). perceived concern for covid-19 (more plainly called "coronavirus") was evaluated by first asking participants to rate, on a scale of 1 to 10 (1 being no threat at all and 10 being very serious), how serious a public health threat they believed the coronavirus is or might become. in addition, a single question asked participants to rate their level of worry about getting the coronavirus (very worried, somewhat worried, a little worried, or not worried at all). to provide context, this same question was asked with regard to influenza, and participants were also asked whether they had received an influenza vaccine in the past year. demonstrated knowledge of covid-19 was assessed through open-ended questions asking participants to name 3 symptoms of the coronavirus and 3 actions they could take to avoid becoming infected. five trained expert clinician raters (m.s., j.a.l., t.r., d.l., and m.a.) documented and independently coded verbatim responses, which were then thematically analyzed by members of the research team. in addition, participants were asked to estimate the percentage of persons who acquire the coronavirus who will die of it and the percentage who will have only mild symptoms. participants were asked whether they were currently making changes to their daily routines as a result of the coronavirus and whether they had changed any of their plans. verbatim responses were documented for participants stating that they had changed plans, and responses were also independently coded by 2 trained raters and then thematically analyzed. respondents were asked about the likelihood of themselves or someone they know getting the coronavirus (very likely, somewhat likely, not that likely, or not at all likely). they also answered questions about their sources for information about the coronavirus, confidence that the federal government could prevent a national outbreak (very confident, somewhat confident, not very confident, or not confident at all), and perceived preparedness if a widespread outbreak were to occur (very prepared, somewhat prepared, a little prepared, or not prepared at all). descriptive statistics (means with sds and percentage frequencies) were calculated for all patient characteristics and survey responses. associations between patient characteristics and responses to covid-19 awareness, perceived concern, knowledge, and related awareness, attitudes, and actions related to covid-19 behavior items were then examined in bivariate analyses using 2 tests, t tests, or analysis of variance, as appropriate. multivariable linear regression models were used to estimate least-squares means (with 95% cis) for the continuous outcome of perceived concern. for dichotomous outcomes, a multivariable poisson distribution was used rather than odds ratios for the relative risk estimates (13) . all models included health literacy as a primary covariate of interest, additional variables affecting knowledge and behavior (age, gen-der, race, and income), day the survey was done, and parent study. statistical analyses were performed using stata/se, version 15 (statacorp). the study was supported by national institutes of health projects. the funding sources had no role in the design, conduct, or analysis of the study or the decision to submit the manuscript for publication. table 3 summarizes respondent characteristics. participants were older overall, and 59.7% were female. the sample was racially and ethnically diverse, and many participants were socioeconomically disadvantaged: nearly a third (29.4%) were living below the poverty level. about half of adults had low or marginal health literacy, all had at least 1 chronic condition, and two thirds (66.5%) were living with 3 or more chronic conditions. all participants had heard of the coronavirus (covid-19) , and most considered the potential threat to be high ( table 2) . one in 4 (24.6%) said that they were "very worried" about getting the coronavirus, and 12.9% were not worried at all ( table 2 ); in contrast, 10 .8% said that they were "very worried" about getting influenza, and 35.9% were not worried at all. half (50.4%) rated their worry about covid-19 and influenza the same, whereas 42.6% were more worried about getting covid-19. very few participants (9.5%) believed that they would definitely or probably get the coronavirus. the threat of a covid-19 outbreak was rated to be more serious by adults aged 70 years or older and by women before adjustment; those with 3 or more chronic conditions rated the threat as less serious than those with fewer conditions ( table 4) . black participants were more likely than white participants to report that they were "not worried at all" about getting the coronavirus; this was also true for those reporting poorer health. women, black and hispanic persons, those with lep, those living below the poverty level, those with lower health literacy, and unmarried persons were significantly more likely to respond that it was "not at all likely" that they would get covid-19. in multivariable analyses, women remained more likely than men to rate the seriousness of the covid-19 threat as high, whereas adults living below the poverty level rated it as less serious than those with higher incomes ( table 5 ). respondents' ratings of the seriousness of covid-19 also significantly increased by day of awareness, attitudes, and actions related to covid-19 interview, with higher ratings at the end of the survey period than at the beginning. blacks were more likely than whites to be only "a little worried" or "not worried at all" about getting the coronavirus, and black race, living below the poverty level, and low health literacy all remained independently associated with participants' belief that it was "not at all likely" that they would get sick with covid-19. on average, respondents estimated that more than half (53.6%) of infected persons will have only mild symptoms and 14.2% will die of covid-19 ( table 2) . most participants correctly identified 3 symptoms (71.7%) and 3 ways to prevent infection (69.8%). women estimated fewer mild cases and more deaths than men (table 4). this was also true for blacks relative to whites, for those living below the poverty level, and for those with lower health literacy. participants who were older, black, unmarried, unemployed, or retired; had poorer health; or had lower health literacy showed poorer knowledge of covid-19 ( table 4 ). those who identified as being hispanic and having lep demonstrated greater covid-19 knowledge. after multivariable adjustment, patient characteristics were no longer associated with knowledge of covid-19 symptoms or means of prevention ( table 5) . more than half of patients (58.6%) reported that the coronavirus had caused them to change their daily routine "a lot," whereas 78.1% said that they had changed existing plans as a result ( table 2 ). men; black persons; those with lep, lower health literacy, or 3 or more chronic conditions; those living below the poverty level; and persons who were unmarried, unemployed, or retired were less likely to makes changes because of the coronavirus ( table 4) . after multivariable adjustment, these patient factors were no longer associated with changes to either daily routine or existing plans. in contrast, respondents who were interviewed later in the 1-week survey period were more likely to report that their daily routine had changed "a lot" ( table 5) . one in 5 respondents (20.8%) reported that they were "very prepared" for a widespread outbreak. nearly a third (29.1%) had no confidence that the federal government could prevent a nationwide outbreak; 10.2% were very confident ( table 2) . black and hispanic adults; those with lep, lower health literacy, lower health activation, or poorer health; those living below the poverty level; and those who were unmarried, unemployed, or retired were more likely to conawareness, attitudes, and actions related to covid-19 annals.org annals of internal medicine sider themselves either "a little prepared" or "not prepared at all" ( table 4 ). in multivariable analyses, black race and low health literacy were both independently associated with a greater likelihood of feeling only "a little prepared" or "not prepared at all" ( table 5) . hispanic persons, those with lep, those living below the poverty level, and those with lower health literacy were also more likely to be "somewhat" or "very" confident in the federal government. in multivariable analyses, only low health literacy remained associated with feeling "somewhat" or "very" confident in the federal government's ability to prevent a nationwide outbreak ( table 5 ). in a survey of more than 600 sociodemographically diverse adults with chronic health conditions living in chicago, we found that most respondents perceived the threat of a covid-19 outbreak to be serious, although the level of worry varied; half equated the threat with that of influenza, and only a few reported being more worried about getting influenza than covid-19. nearly one third could not identify symptoms or proper measures to prevent infection. most respondents reported that the virus was affecting their daily routine and leading to changes in already made plans, yet 1 in 5 adults believed that it had little or no effect on their lives or plans. nearly 1 in 3 participants believed that they were only a little or not at all prepared for a covid-19 outbreak, whereas just 1 in 5 believed that they were very prepared. only 1 in 10 respondents was very confident that the federal government could prevent a nationwide outbreak of this virus. at the time of writing, illinois ranks seventh in the united states with more than 6980 covid-19 cases, and 141 state residents have died. when our c3 survey started on 13 march 2020, there were only 46 cases and no deaths; by the end of the survey on 20 march, there were 585 cases and 5 deaths. across the united states and worldwide, the outbreak was increasing at a rate of 40% to 50% more new cases daily during the week of the interviews. at the same time, several measures were announced in succession: schools began closing across illinois, employers were sending staff home to work remotely, various public restrictions were implemented (bar and restaurant closures and limitations on gatherings), and ultimately a "shelter at home" order was announced. thus, our findings provide a rare snapshot of how a cohort of mostly middle-aged and older adults with underlying health conditions adapted to this unprecedented time and took action, or not. our study identified concerning demographic and socioeconomic differences in how individuals perceived the threat of covid-19 and, perhaps, their own ability to take actions to prevent illness. specifically, those who were black, were living below the poverty level, and had low health literacy were less likely to believe that they might become infected, and black respondents were less worried about the pandemic. black adults also felt less prepared for an outbreak than white adults, and individuals with low health literacy reported not only being less prepared but also having more confidence in the federal government response. although the reasons for these findings are not clear, similar results were reported during the h1n1 influenza pandemic in 2009 (14) . trust in public health officials, information-seeking behaviors, sources of information, frequency of media exposure, knowledge, and worry related to the outbreak were all highlighted determinants of documented disparities in uptake of recommended behaviors. in our study, disparities by race, socioeconomic status, and health literacy were not reflected in ratings of the seriousness of the covid-19 threat, demonstrated knowledge of its symptom presentation or general means to prevent it, or reported changes to daily routines and plans. prior research has documented racial differences pertaining to trust in the health care system (15) (16) (17) . for those who are living below the poverty level or have low health literacy, perceptions of personal risk and the ability to prevent infection may be limited. this may be due to feeling less able to change one's social circumstance, or lack of public health communications that are explicit and actionable and provide clear, efficacious messaging pertaining to recommended protective behaviors (18, 19) . a previous report found socioeconomic and literacy disparities in mortality associated with the 1918 influenza pandemic; likewise, our findings should raise caution (20) . although the current public health infrastructure is different, existing efforts may not be adequately reaching these vulnerable populations. our study, working to quickly capture the opportunity to understand how the most vulnerable are processing current events, clearly has limitations. first, this survey was done among a selected group of patients who were all active participants in cohort studies or clinical trials sponsored by the national institutes of health in 1 large u.s. city. thus, these findings may have limited generalizability, especially for younger adults and those without underlying health conditions. however, our study samples purposefully include men and women who are socioeconomically, racially, and ethnically diverse and are at greatest risk for covid-19 because of age and underlying conditions. second, to rapidly implement our investigation and quickly recruit as large a sample as possible during the first of multiple waves of interviews, we were limited in the depth of our survey and number of items to use. prior research on virus outbreaks guided our selection and creation of survey items (12), but we lacked the time or opportunity to validate all questions, particularly in the midst of a public health crisis. however, items followed best practices for the design of assessments for use among persons with lower literacy (21) . third, our outcomes capture only initial awareness of covid-19, degree of worry, fundamental knowledge, attitudes, and a limited set of behaviors. understanding of the virus has since evolved, and we could not expand on those developments. items included in planned follow-up waves of original research awareness, attitudes, and actions related to covid-19 the survey will adapt accordingly and expand data capture on behaviors, among other just-in-time topics. finally, as a time-sensitive study, what we have learned in this initial, critical week, when covid-19 most fully took hold in the united states, is that public health messaging has dramatically changed: new policies, state restrictions, and information are being shared not just daily but hourly. it is likely that all of what we report in this 1-week glimpse has considerably altered. regardless, our findings depict the initial lack of clarity in understanding, perceived susceptibility, and personal efficacy regarding the pandemic among those at greatest risk. that is why we intend to continue to follow this cohort as part of an ongoing c3 initiative. this first wave of the c3 study revealed profound gaps in awareness, knowledge, concern, and preemptive public health action. the potential for the covid-19 pandemic to exacerbate health disparitiespotentially through mechanisms related to inadequate or conflicting public health messaging among those who are socioeconomically disadvantaged, belong to racial minority groups, or have more limited health literacy-may be exceptionally high. actions are needed now to ensure that as the pandemic unfolds, all citizens are adequately made aware of the gravity of the threat; with great clarity and attention to health literacy best practices, we need to explain specific steps that must be taken to avoid harm. grant support: by grants r01ag030611, r01ag046352, r01dk110172, and r01nr015444 from the national institutes of health (nih). disclosures: dr. wolf reports grants from the nih during the conduct of the study; grants from merck, the gordon and betty moore foundation, the nih, and eli lilly outside the submitted work; and personal fees from sanofi, pfizer, and luto outside the submitted work. dr. serper reports personal fees from biovie outside the submitted work. ms. batio reports grants from the nih during the conduct of the study. dr. ladner reports grants from the national institute of diabetes and digestive and kidney diseases during the conduct of the study. dr. persell reports grants from omron healthcare and pfizer outside the submitted work. dr. bailey reports grants from the nih during the conduct of the study; grants from merck, the nih, and eli lilly outside the submitted work; grants and personal fees from the gordon and betty moore foundation outside the submitted work; and personal fees from sanofi, pfizer, and luto outside the submitted work. authors not named here have disclosed no conflicts of interest. disclosures can also be viewed at www.acponline.org/authors /icmje/conflictofinterestforms.do?msnum=m20-1239. study protocol and statistical code: available from dr. wolf (e-mail, mswolf@northwestern.edu). data set: available to those who meet prespecified criteria; access allowed to deidentified data only. available from dr. wolf (e-mail, mswolf@northwestern.edu). corresponding author: michael s. wolf, phd, mph, ma, feinberg school of medicine, northwestern university, 750 north lake shore drive, 10th floor, chicago, il 60611; e-mail, mswolf@northwestern.edu. current author addresses and author contributions are available at annals.org. covid-19 coronavirus outbreak. accessed at www .worldometers.info/coronavirus on 24 coronavirus disease 2019: the harms of exaggerated information and non-evidence-based measures prevalence of comorbidities in the novel wuhan coronavirus (covid-19) infection: a systematic review and meta-analysis health literacy and functional health status among older adults the prevalence of limited health literacy the relationship between health literacy and health disparities: a systematic review rationale and design of the regimen education and messaging in diabetes (remind) trial literacy, cognitive function, and health: results of the litcog study development and rationale for a multifactorial, randomized controlled trial to test strategies to promote adherence to complex drug regimens among older adults quick assessment of literacy in primary care: the newest vital sign development and validation of the consumer health activation index perceptions and plans for prevention of ebola: results from a national survey a modified poisson regression approach to prospective studies with binary data what have we learned about communication inequalities during the h1n1 pandemic: a systematic review of the literature the role of risk perception in flu vaccine behavior among african-american and white adults in the united states determinants of influenza vaccination among high-risk black and white adults. vaccine association of patient perceptions of cardiovascular risk and beliefs on statin drugs with racial differences in statin use: insights from the patient and provider assessment of lipid management registry how does education lead to healthier behaviours? testing the mediational roles of perceived control, health literacy and social support disparities in influenza mortality and transmission related to sociodemographic factors within chicago in the pandemic of 1918 development of the patient education materials assessment tool (pemat): a new measure of understandability and actionability for print and audiovisual patient information original research awareness, attitudes, and actions related to covid-19 current author addresses: drs. wolf, o'conor, arvanitis, persell feinberg school of medicine, northwestern university, 750 north lake shore drive, 10th floor dr. ladner: feinberg school of medicine, northwestern university, 676 north saint clair street critical revision of the article for important intellectual content key: cord-267124-8efdzlc0 authors: wichmann, dominic; sperhake, jan-peter; lütgehetmann, marc; steurer, stefan; edler, carolin; heinemann, axel; heinrich, fabian; mushumba, herbert; kniep, inga; schröder, ann sophie; burdelski, christoph; de heer, geraldine; nierhaus, axel; frings, daniel; pfefferle, susanne; becker, heinrich; bredereke-wiedling, hanns; de weerth, andreas; paschen, hans-richard; sheikhzadeh-eggers, sara; stang, axel; schmiedel, stefan; bokemeyer, carsten; addo, marylyn m.; aepfelbacher, martin; püschel, klaus; kluge, stefan title: autopsy findings and venous thromboembolism in patients with covid-19: a prospective cohort study date: 2020-05-06 journal: ann intern med doi: 10.7326/m20-2003 sha: doc_id: 267124 cord_uid: 8efdzlc0 background: the new coronavirus, severe acute respiratory syndrome coronavirus-2 (sars–cov-2), has caused more than 210 000 deaths worldwide. however, little is known about the causes of death and the virus's pathologic features. objective: to validate and compare clinical findings with data from medical autopsy, virtual autopsy, and virologic tests. design: prospective cohort study. setting: autopsies performed at a single academic medical center, as mandated by the german federal state of hamburg for patients dying with a polymerase chain reaction–confirmed diagnosis of covid-19. patients: the first 12 consecutive covid-19–positive deaths. measurements: complete autopsy, including postmortem computed tomography and histopathologic and virologic analysis, was performed. clinical data and medical course were evaluated. results: median patient age was 73 years (range, 52 to 87 years), 75% of patients were male, and death occurred in the hospital (n = 10) or outpatient sector (n = 2). coronary heart disease and asthma or chronic obstructive pulmonary disease were the most common comorbid conditions (50% and 25%, respectively). autopsy revealed deep venous thrombosis in 7 of 12 patients (58%) in whom venous thromboembolism was not suspected before death; pulmonary embolism was the direct cause of death in 4 patients. postmortem computed tomography revealed reticular infiltration of the lungs with severe bilateral, dense consolidation, whereas histomorphologically diffuse alveolar damage was seen in 8 patients. in all patients, sars–cov-2 rna was detected in the lung at high concentrations; viremia in 6 of 10 and 5 of 12 patients demonstrated high viral rna titers in the liver, kidney, or heart. limitation: limited sample size. conclusion: the high incidence of thromboembolic events suggests an important role of covid-19–induced coagulopathy. further studies are needed to investigate the molecular mechanism and overall clinical incidence of covid-19–related death, as well as possible therapeutic interventions to reduce it. primary funding source: university medical center hamburg-eppendorf. s ince it was first detected in december 2019, the novel severe acute respiratory syndrome coronavirus-2 (sars-cov-2) spread from the central chinese province of hubei to almost every country in the world (1, 2) . most persons with covid-19 have a mild disease course, but about 20% develop a more severe course with a high mortality rate (3) . as of 26 april 2020, more than 2.9 million persons have been diagnosed with covid-19 and 210 000 of them have died (4) . why the new coronavirus seems to have a much higher mortality rate than the seasonal flu is not completely understood. some authors have reported potential risk factors for a more severe disease course, including elevated d-dimer levels, a high sequential organ failure assessment score, and older age (5, 6) . because of the novelty of the pathogen, little is known about the causes of death in affected patients and its specific pathologic features. despite modern diagnostic tests, autopsy is still of great importance and may be a key to understanding the biological characteristics of sars-cov-2 and the pathogenesis of the disease. ideally, knowl-edge gained in this way can influence therapeutic strategies and ultimately reduce mortality. to our knowledge, only 3 case reports have been published about covid-19 patients who have undergone complete autopsy (7, 8) . therefore, in this study we investigated the value of autopsy for determining the cause of death and describe the pathologic characteristics in patients who died of covid-19. in response to the pandemic spread of sars-cov-2, the authorities of the german federal state of hamburg ordered mandatory autopsies in all patients dying with a diagnosis of covid-19 confirmed by polymerase chain reaction (pcr). the legal basis for this was section 25(4) of the german infection protection act. because of legal regulations, no covid-19 death was exempted from this order, even if its clinical cause seemed obvious. the case series demonstrated herein consists of 12 consecutive autopsies, starting with the first known sars-cov-2-positive death occurring in hamburg (the second largest city in germany, with 1.8 million inhabitants). all autopsies were performed at the department of legal medicine of university medical center hamburg-eppendorf. the ethics committee of the hamburg chamber of physicians was informed about the study (no. wf-051/20). the study was approved by the local clinical institutional review board and com computed tomographic examination was done at the department of legal medicine with a philips bril-liance 16-slice multidetector scanner in accordance with an established protocol (9) . in brief, full-body computed tomography was performed from top to thigh (slice thickness, 1 mm; pitch, 1.5; 120 kv; 230 to 250 mas), complemented by dedicated scans of the thorax with higher resolution (slice thickness, 0.8 mm; pitch, 1.0; 120 kv; 230 to 250 mas). we performed external examinations and full-body autopsies on all deceased persons with sars-cov-2 positivity (pcr confirmed) as soon as possible after taking proper safety precautions original research (using personal protection equipment with proper donning and doffing), following guidelines from the german association of pathologists, which are closely aligned with relevant international guidelines. the recently published recommendations for the performance of autopsies in cases of suspected covid-19 were taken into account (10) . the interval from death to postmortem imaging and autopsy (postmortem interval) ranged from 1 to 5 days. during autopsy, tissue samples for histology were taken from the following organs: heart, lungs, liver, kidneys, spleen, pancreas, brain, prostate and testes (in males), ovaries (in females), small bowel, saphenous vein, common carotid artery, pharynx, and muscle. for virologic testing, we took small samples of heart, lungs, liver, kidney, saphenous vein, and pharynx and sampled the venous blood. tissue samples for histopathologic examination were fixed in buffered 4% formaldehyde and processed via standard procedure to slides stained with hematoxylineosin. for the lung samples, we also used the keratin marker ae1/ae3 (dako) for immunohistochemistry. tissue samples were ground by using ceramic beads (precellys lysing kit) and extracted by using automated nucleic acid extraction (magna pure 96 [roche]) according to manufacturer recommendations. for virus quantification in tissues, a previously published assay was adopted with modifications (11). onestep real-time pcr was run on the lightcycler 480 system (roche) by using a 1-step rna control kit (roche) as master mix. the c t (cycle threshold) value for the target sars-cov-2 rna (fluorescein) and wholeprocess rna control (cy5) was determined by using the second derivative maximum method. for quantification, standard in vitro-transcribed rna of the e gene of sars-cov-2 was used (12) . these samples were also analyzed in a study focusing on renal tropism of sars-cov-2 (puelles v, et al. multi-organ and renal tropism of sars-cov-2. in preparation). data that were normally distributed are presented as means (sds); data outside the normal distribution are presented as medians (ranges). categorical variables were summarized as counts and percentages. all data were analyzed with statistica, version 13 (statsoft). the sponsor was not involved in the design or conduct of the study, nor in the analysis of the data or the decision to submit the manuscript. the median age of the 12 patients included in this study was 73 years (interquartile range, 18.5); 25% were women. for all patients, preexisting chronic medical conditions, such as obesity, coronary heart disease, asthma or chronic obstructive pulmonary disease, peripheral artery disease, diabetes mellitus type 2, and neurodegenerative diseases, could be identified ( table 1) . two patients died out of the hospital after unsuccessful cardiopulmonary resuscitation, 5 died after treatment in the intensive care unit, and the remaining 5 had an advanced directive for best supportive care and died in the non-intensive care ward. laboratory results for clinical chemistry, hematology, and coagulation were not available for the patients who died out of the hospital. in the remaining patients, the most striking features of the initial laboratory test were elevated lev. table 2 provides an overview of the initial laboratory results. in 2 cases (2 and 4), pmct was not possible for logistic reasons. in the remaining cases, pmct demonstrated mixed patterns of reticular infiltrations and severe, dense, consolidating infiltrates in both lungs in the absence of known preexisting pathology (such as emphysema or tumor). a juxtaposition of antemortem and postmortem findings is demonstrated in figure 1 . a complete summary of pmct findings is presented in table 1 . in 4 cases (1, 3, 4, and 12), massive pulmonary embolism was the cause of death, with the thrombi deriving from the deep veins of the lower extremities. in another 3 cases (5, 8, and 11), fresh deep venous thrombosis was present in the absence of pulmonary embolism. in all cases with deep venous thrombosis, both legs were involved ( figure 2 ). in 6 of the 9 men (two thirds) included in the study, fresh thrombosis was also present in the prostatic venous plexus (appendix figure 1 , available at annals.org). in all 12 cases, the cause of death was found within the lungs or the pulmonary vascular system. however, macroscopically differentiating viral pneumonia with subsequent diffuse alveolar damage (a histologic diagnosis) from bacterial pneumonia was not always possible. typically, the lungs were congested and heavy, with a maximum combined lung weight of 3420 g in case 11. the mean combined lung weight was 1988 g (median, 2088 g). standard lung weights for men and women are 840 g and 639 g, respectively (13, 14) . only cases 6 and 9 presented with a relatively low lung weight: 550 g and 890 g, respectively (appendix table 1 , available at annals.org). the lung surface often displayed mild pleurisy and a distinct patchy pattern, with pale areas alternating with slightly protruding and firm, deep reddish blue hypercapillarized areas. on the cutting surfaces, this pattern was also visible ( figure 2 ). the consistency of the lung tissue was firm yet friable. in 8 cases, all parts of the lungs were affected by these changes. cases 6, 7, and 9 -occurring in the 3 women of the case series-presented with changes compatible with focal purulent bronchopneumonia. macroscopically, no changes were observed outside the lungs and respiratory tract, except for splenomegaly in 3 cases, which suggested a viral infection. during autopsy, all cases except for case 6 presented with preexisting heart disease, including highgrade coronary artery sclerosis (7 of 12); myocardial scarring, indicating ischemic heart disease (6 of 12); and congestive cardiomyopathy. mean heart weight was 503 g (median, 513 g). in addition to this finding, the most common accompanying diseases were pulmonary emphysema (6 of 12) and ischemic enteritis (3 of 12). often these conditions were known to the treating physician before death (compare columns 4 and 10 of table 1 ). the macroscopic autopsy findings are presented organ by organ in appendix table 2 (available at annals.org) and the lung findings in table 1 . a clear trend toward obesity was observed among the cases (mean body mass index, 28.7 kg/m 2 ; median, 28.7 kg/m 2 ). however case 9, involving a patient with known neuroendocrine tumor of the lung, presented with severe cachexia (body mass index, 15.4 kg/m 2 ). the comorbid conditions found are summarized in table 1 . histopathology of the lungs showed diffuse alveolar damage, consistent with early acute respiratory distress syndrome in 8 cases. predominant findings were hyaline membranes (figure 3, a and b) , activated pneumocytes, microvascular thromboemboli, capillary congestion, and protein-enriched interstitial edema. as described by wang and colleagues (15), a moderate degree of inflammatory infiltrates concurred with clinically described leukopenia in patients with covid-19 and predominant infiltration of lymphocytes fit the pic(figure 3, c) . long-term changes, such as destruction of alveolar septae and lymphocytic infiltration of the bronchi, were often visible as preexisting conditions. four cases (6, 8, 9, and 10) showed no diffuse alveolar damage but extensive granulocytic infiltration of the alveoli and bronchi, resembling bacterial focal bronchopneumonia. histologically, thromboemboli were detectable in cases 1, 3, 4, and 5 (figure 3, d) . microthrombi were regularly found within small lung arteries, occasionally within the prostate, but not in other organs. in addition to the lung changes described in table 1 , there were isolated histologic findings that might indicate a viral infection. the pharyngeal mucosa was examined in 7 cases. in 6 of them, hyperemia and alternating dense, predominantly lymphocytic infiltrates were found as signs of chronic pharyngitis. in 1 case (case 3), lymphocytic myocarditis was seen in the right ventricle (appendix figure 2 , available at annals.org). the remaining histologic changes were compatible with shock changes in part of the deceased patient (liver, kidneys, intestine) or corresponded to the macroscopically determined virus-independent preexisting pathology (such as ischemic cardiomyopathy). apart from findings related to sars-cov-2 infection, patients showed other histopathologic findings related to their chronic preexisting conditions, including hypertrophy of myocardial fibers or scarring of the myocardium. the peripheral veins, including those occluded by thrombi, showed no abnormalities on hematoxylin-eosin staining. quantitative reverse transcription pcr detected sars-cov-2 rna in the lungs of all 12 patients (range, 1.2 × 10 4 to 9 × 10 9 copies/ml) and in the pharynx of 9 patients. six patients showed moderate viremia (<4 × 10 4 copies/ml). in 5 of these patients, viral rna was also detected in other tissues (heart, liver, or kidney) in concentrations exceeding viremia. patients without viremia showed no or a low virus load in the other tissues. only 4 patients had detectable viral rna in the brain and saphenous vein. in this autopsy study of 12 consecutive patients who died of covid-19, we found a high incidence of deep venous thrombosis (58%). one third of the patients had a pulmonary embolism as the direct cause of death. furthermore, diffuse alveolar damage was demonstrated by histology in 8 patients (67%). to our knowledge, this is the first case series summarizing and comparing clinical data of consecutive covid-19 cases with findings obtained by a full autopsy, supplemented by pmct, histology, and virology. the high rate of death-causing pulmonary embolism at autopsy correlates well with the unsuccessful resuscitation of 3 of 4 patients, 2 of whom died out of the hospital. apart from that, no preclinical evidence had been reported of pulmonary embolism or deep venous thrombosis. in studies that examined deceased patients with covid-19 without relying on autopsy, no increased rates of pulmonary embolism were observed clinically. however, it is known that many cases of pulmonary embolism remain clinically overlooked and are often associated with sudden, unexpected death. this may have been aggravated by the method for diagnosing covid-19 in germany, which is based on pcr tests rather than computed tomographic imaging because of concerns about infection of medical staff and other top. contrast medium-enhanced computed tomography scan demonstrates the antemortem findings: bilateral ground glass opacities in the lower lobes of both lungs (yellow asterisks) and a chest tube (yellow arrow), which has been introduced to treat a pneumothorax (yellow arrowheads). bottom. computed tomography scan without contrast medium enhancement demonstrates the corresponding postmortem findings. for technical reasons, the postmortem image has a lower resolution. to protect the staff from potential infection, bodies were scanned in a double-layer body bag with the arms positioned alongside the body. although the findings correspond to the antemortem images, ground glass opacities in both lower lobes (yellow asterisks) and a chest tube (yellow arrow) are seen. in addition, a central venous line (red arrowhead) and gastric tube (red arrow) are visible. autopsy findings and venous thromboembolism in patients with covid-19 patients. a recent report described clinical features of 85 fatal cases of covid-19 from wuhan (16) . besides respiratory failure, the cause of death was multiorgan failure in 16% and cardiac arrest in 9%. no autopsies were performed. the gold standard for identifying cause of death is still the autopsy (17) . however, inhospital autopsy rates have declined worldwide over the past decades. also, because of pathologists' potential risk for sars-cov-2 infection, very few autopsies have been performed worldwide (18) . to our knowledge, only 3 case reports have been published on patients with covid-19 who have undergone complete autopsy and a few more in which only lung tissue was examined (7, 8) . other researchers have described coagulopathy as a common complication in patients with severe covid-19 (5, 6, 19) . in a recent study of 191 patients with covid-19, 50% of those who died had coagulopathy, compared with 7% of survivors. d-dimer levels greater than 1000 μg/l were associated with a fatal outcome (6) . covid-19 may predispose to venous thromboembolism in several ways. the coagulation system may be activated by many different viruses, including hiv, dengue virus, and ebola virus (20, 21) . in particular, coronavirus infections may be a trigger for venous thromboembolism, and several pathogenetic mechanisms are involved, including endothelial dysfunction, characterized by increased levels of von willebrand factor; systemic inflammation, by toll-like receptor activation; and a procoagulatory state, by tissue factor pathway activa-tion (22) . in a subgroup of patients with severe covid-19, high plasma levels of proinflammatory cytokines were observed (23) . the direct activation of the coagulation cascade by a cytokine storm is conceivable. with covid-19, severe hypoxemia develops in some patients (24) . thrombus formation under hypoxic conditions is facilitated both in animal models of thrombosis and in humans. the vascular response to hypoxia is controlled primarily by the hypoxia-inducible transcription factors, whose target genes include several factors that regulate thrombus formation (25) . lastly, indirect causes, such as immune-mediated damage by antiphospholipid antibodies, may partially contribute, as speculated by zhang and colleagues (26) . the macroscopic findings in our autopsy serieswith rather heavy, consolidated, friable, basically airfree lungs in most of the cases-were impressive and explain the difficulties in sufficiently ventilating some of these patients. the histopathologic changes in most of our cases with diffuse alveolar damage as the main finding resemble those described by xu and colleagues (7) and barton and colleagues (8) , who reported single cases; zhang and colleagues (26) , who reported on lung biopsy in a patient with sars-cov-2 positivity; and tian and colleagues (27) , who described macroscopic and histologic pulmonary findings in 2 patients with lung cancer who received positive results on sars-cov-2 testing. however, the full-blown picture of diffuse alveolar damage seems to be more prevalent in younger patients with fewer preexisting diseases and longer survival, whereas older patients with more coin line with clinical, macroscopic, and histopathologic findings, pcr detected the highest concentration of sars-cov-2 rna in lung and pharyngeal tissue. of interest, in most patients with disease, high titers of rna were also detected in postmortem samples. the clinical relevance of this is not yet clear. clearance of viral rna from blood 7 days after transfusion of covid-19 convalescent plasma was associated with substantial clinical improvement, but studies have not shown a correlation between viremia and acute respiratory distress syndrome in patients with severe covid-19 (28, 29) . as in patients with sars-cov-1, in whom viral replication could be detected in other organs, including the liver, kidney, spleen, and cerebrum (30), we detected viral rna at high titers in other organs (liver, kidney, and heart) in 5 patients. these data suggest that sars-cov-2 may spread via the bloodstream and infect other organs. to prove this, replication intermediates must be detected. the current study had some limitations: first, the sample size was small, possibly leading to overestimation of the rate of pulmonary embolism. however, both the clinical and postmortem observations agree well with the current knowledge about sars-cov-2 pathology. this includes the sex and age distribution as well as the preexisting conditions among the patients, but also the histologic findings. second, although viral titers in swabs (pharynx) taken longitudinally up to 7 days after death remained similar, we lack data on how postmortem processes affect viral titers and dynamics in different tissues and body fluids. moreover, the quantitative pcr assay used cannot discriminate between genomic and subgenomic rna. as stated earlier, to prove viral replication, detection of replication intermediates or antigenomic rna would be necessary. in conclusion, we found a high incidence of thromboembolic events in patients with covid-19. when hemodynamic deterioration occurs in a patient with covid-19, pulmonary embolism should always be suspected. that patients with covid-19 who have increased d-dimer levels, a sign of coagulopathy, may benefit from anticoagulant treatment seems plausible (31) . as demonstrated in our cohort, this might be important for hospitalized patients and outpatients. in this context, some professional societies have already made recommendations for antithrombotic therapy for patients with covid-19 (32) . robust evidence, however, remains scant, and further prospective studies are urgently needed to confirm and validate these results. autopsy findings and venous thromboembolism in patients with covid-19 and asklepios hospital saint georg, hamburg, germany world health organization. novel coronavirus-china a novel coronavirus from patients with pneumonia in china 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 abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study covid-19 autopsies, oklahoma, usa virtual autopsy as an alternative to traditional medical autopsy in the intensive care unit: a prospective cohort study collection and submission of postmortem specimens from deceased persons with known or suspected covid-19 detection of 2019 novel coronavirus (2019-ncov) by real-time rt-pcr the european virus archive goes global: a growing resource for research normal organ weights in men: part ii-the brain, lungs, liver, spleen, and kidneys normal organ weights in women: part ii-the brain, lungs, liver, spleen, and kidneys clinical course and outcomes of 344 intensive care patients with covid-19 clinical features of 85 fatal cases of covid-19 from wuhan: a retrospective observational study virtual autopsy with multiphase postmortem computed tomographic angiography versus traditional medical autopsy to investigate unexpected deaths of hospitalized patients: a cohort study autopsy in suspected covid-19 cases clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study multiple roles of the coagulation protease cascade during virus infection diagnosis, prevention, and treatment of thromboembolic complications in covid-19: report of the national institute for public health of the netherlands coagulation disorders in coronavirus infected patients: covid-19, sars-cov-1, mers-cov and lessons from the past sars-cov-2 and viral sepsis: observations and hypotheses german recommendations for critically ill patients with covid-19 the stimulation of thrombosis by hypoxia histopathologic changes and sars-cov-2 immunostaining in the lung of a patient with covid-19 pulmonary pathology of early-phase 2019 novel coronavirus (covid-19) pneumonia in two patients with lung cancer effectiveness of convalescent plasma therapy in severe covid-19 patients the characteristics of 50 hospitalized covid-19 patients with and without ards organ distribution of severe acute respiratory syndrome (sars) associated coronavirus (sars-cov) in sars patients: implications for pathogenesis and virus transmission pathways anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy covid-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up current author addresses dr. becker: department of pulmonology and internal intensive care, asklepios hospital barmbek dr. de weerth: department of internal medicine, agaplesion diakonie hospital author contributions: conception and design: d provision of study materials or patients standard weights for men and women (adopted from molina and dimaio [13, 14]), respectively, are as follows (the dependence of standard organ weights on body weight was not considered here): brain, 1401 g and 1233 g; heart, 331 g and 245 g; lung (right), 445 g and 340 g; lung (left), 395 g and 299 g; liver, 1561 g and 1288 g; kidney (right), 129 g and 108 g figure 1 . thrombosis of the prostatic vein (case 1) (arrows). * no abnormal findings were present in the testes or ovaries of any patient. appendix figure 2 . mononuclear infiltrations consisting of lymphocytes (arrows) in the myocardium of the right ventricle (case 3) (hematoxylin-eosin stain; original magnification, × 100). key: cord-289763-jek2pd31 authors: fisher, kimberly a.; bloomstone, sarah j.; walder, jeremy; crawford, sybil; fouayzi, hassan; mazor, kathleen m. title: attitudes toward a potential sars-cov-2 vaccine: a survey of u.s. adults date: 2020-09-04 journal: ann intern med doi: 10.7326/m20-3569 sha: doc_id: 289763 cord_uid: jek2pd31 background: coronavirus disease 2019 (covid-19) has rapidly instigated a global pandemic. vaccine development is proceeding at an unprecedented pace. once available, it will be important to maximize vaccine uptake and coverage. objective: to assess intent to be vaccinated against covid-19 among a representative sample of adults in the united states and identify predictors of and reasons for vaccine hesitancy. design: cross-sectional survey, fielded from 16 through 20 april 2020. setting: representative sample of adults residing in the united states. participants: approximately 1000 adults drawn from the amerispeak probability-based research panel, covering approximately 97% of the u.s. household population. measurements: intent to be vaccinated against covid-19 was measured with the question, “when a vaccine for the coronavirus becomes available, will you get vaccinated?” response options were “yes,” “no,” and “not sure.” participants who responded “no” or “not sure” were asked to provide a reason. results: a total of 991 amerispeak panel members responded. overall, 57.6% of participants (n = 571) intended to be vaccinated, 31.6% (n = 313) were not sure, and 10.8% (n = 107) did not intend to be vaccinated. factors independently associated with vaccine hesitancy (a response of “no” or “not sure”) included younger age, black race, lower educational attainment, and not having received the influenza vaccine in the prior year. reasons for vaccine hesitancy included vaccine-specific concerns, a need for more information, antivaccine attitudes or beliefs, and a lack of trust. limitations: participants' intent to be vaccinated was explored before a vaccine was available and when the pandemic was affecting a narrower swath of the united states. questions about specific information or factors that might increase vaccination acceptance were not included. the survey response rate was 16.1%. conclusion: this national survey, conducted during the coronavirus pandemic, revealed that approximately 3 in 10 adults were not sure they would accept vaccination and 1 in 10 did not intend to be vaccinated against covid-19. targeted and multipronged efforts will be needed to increase acceptance of a covid-19 vaccine when one becomes available. primary funding source: agency for healthcare research and quality. c oronavirus disease 2019 is caused by the ␤-coronavirus severe acute respiratory syndrome coronavirus 2 (sars-cov-2). this virus has rapidly become a major global threat, instigating a pandemic affecting more than 185 countries and 3 500 000 people and leading to nearly 250 000 deaths worldwide (1) . the pandemic has overwhelmed hospital systems, undermined economic activity worldwide, and instilled fear into the general populace (2, 3) . an international poll conducted in april 2020 found that 61% of those surveyed identified covid-19 as the most concerning national issue, overtaking unemployment, health care, and poverty (4) . in a separate survey conducted at the same time in the united states, more than 80% of participants were very or somewhat concerned about being infected with coronavirus (5) . in response to the massive global effects of covid-19, multiple laboratories worldwide are working to create an effective vaccine. the possibility that one will be available in 12 to 18 months is seen by many as the most promising means of controlling the covid-19 pandemic. over the past century, vaccinations have become a routine and effective preventive measure in reducing the rate of and eradicating or nearly eradicating certain viral illnesses (6) . besides providing direct immunity and preventing disease among vaccinated individuals, vaccines have been shown to reduce infections even among individuals who are not vaccinated, through herd immunity, if a sufficient proportion of the population is immune (7) . many pharmaceutical companies and research labs are currently working with messenger rna, dna, subunit, virus-like particles, and viral vectors to discover an effective vaccine for the covid-19 pandemic (8, 9) . on an unprecedented timeline, multiple vaccines have been developed and are currently being tested in large-scale phase 3 trials (10) , suggesting that a vaccine may be available in the foreseeable future. the great potential of a vaccine against covid-19 is tempered by rising vaccine skepticism in the united states and worldwide, which may present challenges to widespread vaccine uptake when a vaccine becomes available (11) (12) (13) (14) . it is unknown whether the unprecedented and severe effects of covid-19 in the united states will overcome vaccine skepticism and foster widespread acceptance of and demand for vaccination. we assessed intent to be vaccinated for the novel coronavirus with the question, "when a vaccine for the coronavirus becomes available, will you get vaccinated?" followed by the response options "yes," "no," and "not sure." participants who responded "no" or "not sure" were asked one of the following open-ended questions, respectively: "what makes you unwilling to get the vaccine?" or "what makes you unsure whether you will get the vaccine?." to assess perceived risks of infection, we asked, "what is your best guess as to whether you will get the coronavirus within the next 6 months?"; response options were "i don't think i will get the coronavirus," "i think i will get a mild case of the coronavirus," "i think i will get seriously ill from the coronavirus," or "i have already had the coronavirus." survey items are shown in appendix table 1 (available at annals.org). we conducted 2 rounds of pilot testing of the main question assessing intent to be vaccinated among a convenience sample of over 100 individuals and did not detect any problems. data on participant characteristics were provided by norc and included age, sex, race/ethnicity, educational attainment, household income, household size, marital status, employment status, geographic location, urban or rural location (addresses within a metropolitan statistical area were categorized as urban), receipt of influenza vaccination in the prior year, and self-rated overall health status. norc collects data on healthrelated variables (such as receipt of influenza vaccination and self-rated overall health status) upon enrollment or soon after for most panel members; if a panel member has not responded to a specific item, that item may be included on subsequent surveys. all data provided to the investigators were fully deidentified. participant characteristics were summarized by using frequencies and percentages. we used crosstabulations and 2 tests to estimate unadjusted associations of participant characteristics and perceived personal risk for coronavirus with the 3-category outcome intent to get vaccinated. to better distinguish characteristics associated with responses of "not sure" versus "yes" and characteristics associated with responses of "no" versus "yes," we also calculated separate 2 tests and associated p values for these 2 sets of comparisons. to estimate corresponding adjusted (multivariate) associations, we used multinomial logistic regression, an extension of binomial logistic regression that compares each of 2 or more nonordered outcome categories to the reference category. in particular, we modeled both natural log [pr (not sure)/pr (yes)] and natural log [pr (no)/pr (yes)] as a function of participant characteristics. this approach allows different associations with covariates for the 2 comparisons while providing overall p values for covariates. whereas coefficients from a binomial logistic regression model are typically exponentiated to obtain odds ratios, exponentiated coefficients from a multinomial logistic regression model are interpreted as relative risk ratios (rrrs). an illustrative calculation is provided in the footnote to table 3 . characteristics that were not statistically significant (p < 0.05) in the multivariate multinomial modeling were omitted in the final model; these characteristics were found to be correlated with predictors retained in the final model (for example, household income was related to education). we considered the possibility that inclusion of prior receipt of influenza vaccine in the model may obscure other predictors of covid-19 vaccine hesitancy owing to overlap in the reasons for reluctance to get an influenza or covid-19 vaccine. we therefore repeated the primary analysis after removing receipt of influenza vaccine from the model. adjusted percentages were calculated for each predictor category by fixing all other predictors at their observed disattitudes toward a potential sars cov-2 vaccine among u.s. adults tributions. to assess model performance, we calculated c-statistics and hosmer-lemeshow statistics separately for binomial logistic regressions for "not sure" versus "yes" and "no" versus "yes." all analyses incorporated survey sampling weights based on gender, age, education, race/ethnicity, and region. analyses were conducted by using sas, version 9.4. we used thematic analysis to inductively generate codes and identify themes in the responses to the open-ended query soliciting reasons for vaccine hesitancy (15) . the coding team included investigators with backgrounds in health communication, health literacy, patient-provider communication, clinical medicine, and clinical social work; all coding team members had prior experience in qualitative analysis. a coding framework was created on the basis of initial review of all responses. codes and associated definitions were revised and refined through iterative application and discussion. two analysts (k.f., s.b.) then independently coded all responses. more than 1 code could be assigned to a response if applicable. coding discrepancies were discussed until agreement was reached; the third member of the coding team was available to adjudicate but was not needed. codes were assigned in excel; final codes were merged into spss, version 25, to facilitate data manipulation and summarization. our study was determined to be exempt by the university of massachusetts medical school institutional review board. dr. fisher is supported by agency for healthcare research and quality grant k08hs024596. the funder had no role in the design, conduct, or analysis of this study. the amerispeak omnibus survey was released to 6247 panel members, and a total of 1003 (16.1%) responded. most participants (91.2%) completed the survey via the web; the remainder (8.8%) completed it via telephone interview. twelve participants did not respond to the question on intent to be vaccinated; all results presented here are based on the 991 participants who responded to this question. a majority of participants (63.3%) were white, approximately one third (30.0%) were 60 years of age or older, and 51.5% were female. participants had varied levels of educational attainment, with more than one third (37.8%) having a high-school diploma or less. most participants perceived their risk for coronavirus to be low, predicting that they will either not get the coronavirus (64.1%) or that they will get a mild case of the coronavirus (27.1%) in the next 6 months. only 58 participants (6.0%) predicted they will get seriously ill from the coronavirus. approximately one half (52.8%) of participants reported having received the influenza vaccine previously. additional participant characteristics are shown in table 1 . overall, 57.6% of participants (n = 571) intended to be vaccinated, 31.6% (n = 313) were not sure whether they would be vaccinated, and 10.8% (n = 107) did not intend to be vaccinated. participant characteristics associated with a higher chance of responding "no" or "not sure" versus "yes" were being younger (<60 years), female, or black or hispanic; having lower educational attainment, lower household income, or larger household size, and being less likely to report having received an influenza vaccine. in addition to these differences, participants who responded "not sure" were more likely to live in the south or west and to believe they were at less personal risk for coronavirus despite providing lower ratings of their overall health. participants who responded "no" were more likely to live in a rural setting ( table 2) . after adjustment for differences in participant characteristics ( table 3) , factors that were independently associated with vaccine hesitancy (response of "no" or "not sure") include younger age (<60 years), black race, educational attainment of less than a college degree, and not receiving an influenza vaccine in the prior year. participants who did not have a high school diploma had a nearly 8-fold higher relative likelihood of responding "no" versus "yes" compared with those who had a college degree or higher (rrr, 7.8 [95% ci, 3.1 to 19.6]). black race was associated with a more than 6-fold higher chance (rrr, 6.4 [ci, 3.2 to 13.0]) of not intending to be vaccinated versus intending to be vaccinated compared with white race. participants who had previously received an influenza vaccine had a 94% lower relative likelihood of responding "no" versus "yes" (rrr, 0.06 [ci, 0.03 to 0.11]) compared with those who had not received an influenza vaccine. other characteristics, such as female sex, some age strata, hispanic ethnicity, and perceived personal risk for coronavirus, were associated with vaccination intent but did not consistently achieve statistical significance for both response categories ("not sure" and "no"). living in a rural area was strongly associated with responding "no" when asked about intent to be vaccinated, but not with responding "not sure." household income, household size, region, and self-reported health were not significantly associated with vaccination intent after adjustment for the characteristics in table 3 . results including these as model predictors were similar (data not shown). removal of prior receipt of influenza vaccine from the multinomial model resulted in an increase in the relative risk ratios comparing "no" versus "yes" for 2 age groups (18 to 29 years and 45 to 59 years), such that the ci no longer included 1 while other results remained similar (appendix table 2 , available at annals .org). because one of the main goals of our study was to predict who may be hesitant to be vaccinated against covid-19 and prior receipt of influenza vaccine offers a pragmatic way to identify these individuals, we report the findings from the model that included prior receipt of influenza vaccine. hosmer-lemeshow statistics for "not sure" versus "yes" and for "no" versus "yes" were not statistically significant (p = 0.37 and 0.50, respectively), and corresponding c-statistics were 0.74 and 0.89, indicating excellent model fit and performance. of the 420 participants who were unsure or did not intend to be vaccinated, 303 (72.1%) provided a reason for their response and constitute the sample for the qualitative analysis. the 118 remaining participants who answered "not sure" or "no" (28.1%) did not provide a reason for their hesitancy (for example, they did not respond, responded simply "don't know," or provided an uninterpretable response). participants' reasons for being unsure or not intending to be vaccinated are broadly categorized as having specific concerns about the vaccine; needing additional information; holding antivaccine attitudes, beliefs, or emotions; and not trusting entities involved in vaccine development, testing, or dissemination ( table 4 ). the most common reasons cited by participants who were not sure whether they will be vaccinated included specific concerns about the vaccine (such as safety or effectiveness) or a need for more information. in contrast, the most common reasons provided by participants who did not intend to be vaccinated included antivaccine attitudes, beliefs, or emotions, and lack of trust. illustrative quotes are provided in appendix table 3 (available at annals .org). in this large, nationally representative sample, nearly one half (42.4%) of participants indicated hesitancy to be vaccinated against covid-19 when a vaccine becomes available. this finding is especially striking considering that the survey was conducted during mid-april 2020, when the number of deaths per day due to covid-19 were at or near peak levels of the initial surge in the united states (16). the percentage of individuals who intend to be vaccinated (57%) is only slightly higher than the percentage of adults who received the influenza vaccination (45%) during the 2018 -2019 influenza season (17); this is surprising, attitudes toward a potential sars cov-2 vaccine among u.s. adults given the increased severity, death rate, societal disruption, and resultant media coverage associated with the covid-19 pandemic. increasing vaccination rates are expected to confer substantial benefits, including reductions in covid-19related hospitalizations, strain on hospital capacity, and deaths. for example, it has been estimated that increasing influenza vaccination coverage by 5 percentage points could have prevented 4000 to 11 000 hospitalizations in the 2017-2018 influenza season (18) . the increased severity of covid-19 compared with influenza suggests that the magnitude of benefit of increased coronavirus vaccination coverage could be even greater. the percentage of individuals who will need to be vaccinated to achieve herd protection is not yet defined for covid-19 because it depends on vaccine effectiveness, patterns of population mixing, vaccination patterns, and the basic reproduction number (r 0 ) (7) of the novel coronavirus. using a pooled estimate of the r 0 of 3.32 (19) and assuming a best-case scenario in which a vaccine has perfect effectiveness yields a projection that at least 70% of the population will need to be vaccinated to achieve herd protection. in fact, a newly developed coronavirus vaccine is unlikely to be perfectly effective, so the coverage required to achieve herd immunity will almost certainly be higher than 70%. considering that intent as assessed in our study does not account for incomplete followthrough and barriers to vaccine access, it is likely that a substantial gap will exist in the number needed to be vac attitudes toward a potential sars cov-2 vaccine among u.s. adults cinated to achieve herd protection and the number who receive vaccination. concerted efforts will be needed to persuade the large percentage of individuals who are unsure about or opposed to being vaccinated against covid-19 if we are to realize the substantial benefits afforded by high immunization coverage rates. we found several independent predictors of being hesitant to be vaccinated against covid-19; the strongest were lower educational attainment, black race, not having had a recent influenza vaccination, and perceived personal risk for coronavirus, consistent with the findings of a national survey conducted by rti (20) . evidence that these characteristics are predictive of vaccine hesitancy could be useful in targeting vaccine messaging and outreach to populations at risk for not being vaccinated. our findings highlight the importance of social determinants of health, such as educational status (a close proxy for health literacy [21] ) and race/ethnicity, and their influence on preventive health behaviors (22) . racial disparities in vaccination rates have been described for other vaccinations. for example, rates of influenza vaccination among african american persons (39.4%) and hispanic persons (37.1%) were substantially lower than among white persons (48.7) during 2018 -2019 (17). these differences are particularly concerning given the disproportionately high toll of covid-19 among african american communities (23-26). the confluence of increased covid-19 disease burden and potential for decreased receipt of vaccination has the potential to substantially magnify health-related disparities experienced by african american persons. our findings highlight the need for vaccine implementation strategies that anticipate racial gaps in covid-19 vaccination. these strategies could draw on the approaches used to successfully close racial disparities in measles vaccination while being mindful of persistently lower rates of influenza vaccination rates among minority adults stemming from lack of trust in health care (27) . prior research has demonstrated the importance of social norms and perceived disease risk in influencing vaccination decisions among african american persons and could be explored as a means of fostering coronavirus vaccine acceptance among this population (28, 29) . the association between intent to be vaccinated and perceived risk for coronavirus suggests this may be a particularly important lever for promoting vaccination. in addition to being targeted for populations least likely to be vaccinated, such as members of racial and attitudes toward a potential sars cov-2 vaccine among u.s. adults annals.org annals of internal medicine ethnic minority groups and individuals of low health literacy, successful vaccination campaigns will need to leverage an understanding of why individuals may be hesitant to be vaccinated in order to tailor messaging to mitigate these concerns. concern about vaccine safety was one of the most commonly cited reasons for being unsure about accepting vaccination in the present study, consistent with studies of other vaccines (30). a reuters poll found that approximately 75% of americans would agree to be vaccinated against covid-19 if they received assurances about the safety of the vaccine (31). collectively, these findings suggest that transparent reporting of vaccine safety in a way that people of all educational levels can understand is likely to be an effective strategy to increase public uptake of vaccination. however, many participants in our study and the reuters poll indicated hesitancy to be among the first to be vaccinated, which will probably delay achievement of high vaccination coverage rates for covid-19. over one half (56.6%) of respondents who provided a reason for not intending to be vaccinated referred to antivaccine attitudes, beliefs, or emotions. of these, many indicated only that they did not like, want, or believe in vaccines, whereas others made explicit reference to scientifically inaccurate information, such as the association between vaccines and autism and that it is not possible to vaccinate against a virus. these beliefs and essentially emotional responses to vaccination are likely to be among the hardest to overcome, because information alone is unlikely to have an effect. it may be that messages designed to engage and influence emotions, such as narratives or stories, will be more effective than expository or informational health messages (32). lack of trust was the second most common reason for responding "no" to intent to be vaccinated. trust has been shown to be a determinant of vaccine uptake (33), suggesting this finding is likely to be of consequence and indicating a need for strategies aimed at increasing trust among individuals with greater degrees of vaccine skepticism. we found that circulating conspiracy theories about the coronavirus vaccination have taken hold among a small percentage of participants, in addition to more common misconceptions about vaccines. further research is needed to develop effective strategies to combat conspiracy theories and misinformation (34). some participants in our study also cited prior experience with the influenza vaccine "not working" as a reason to believe a vaccine against the coronavirus will not be effective, demonstrating the negative effects of perceived ineffective vaccines on overall vaccine acceptance. given the real possibility for variable rates of effectiveness among the covid-19 vaccines currently in development and the possible need for revaccination, public health officials might consider proactively acknowledging this possibility to avoid further loss of trust if or when this happens. surprisingly, very few vaccine-hesitant participants indicated a need or desire for a recommendation from a physician. however, there is evidence that patients whose physicians recommend a vaccine are more likely to be vaccinated than patients who do not (35). it has been argued that physicians are well-positioned to address misinformation, discuss risk, and convey the seriousness of covid-19 in a way that is tailored to the unique needs of the individual patient during an encounter (36). such conversations may be the ideal but may be difficult to implement in time-limited primary care encounters, where there are typically many competing priorities. in addition, the effectiveness of such conversations will almost certainly depend on the patient having trust in the physician and the physician having the requisite time, skills, and comfort to address the emotion-laden topic of vaccine hesitancy. given the time constraints of primary care and the potential need for physicians to receive additional training to enable them to successfully address vaccine-related concerns, health systems might consider an alternative strategy in which trained vaccine counselors use motivational interviewing to engage vaccine-hesitant individuals. this approach has been effective at increasing rates of infant vaccine coverage and adolescent human papillomavirus vaccination (37, 38). we have identified characteristics, such as not previously receiving an influenza vaccine, that are readily available in the electronic health record and could easily be used to identify covid-19 vaccine-hesitant individuals who might especially benefit from the motivational interviewing approach. our findings suggest that a multipronged approach may be needed in which trusted physicians promote vaccine uptake against a backdrop of innovative approaches and channels to combat vaccine misinformation, consistent with the body of literature of strategies to address vaccine hesitancy (39). a strength of our study is that the large, nationally representative sample allows generalization of our findings. in addition, the timing of the survey administration coincided with a peak time of the pandemic in many parts of the united states, making the findings particularly timely and salient. our study also has limitations. first, we queried individuals about their intent to be vaccinated at a time when a vaccination is not yet available. it is possible that as more details regarding a potential vaccine are known, some participants who indicated their response depended on additional information may change their response. in addition, our study was not designed to determine what additional information is needed, or how best to deliver it. future research is needed to better delineate the types of assurances needed and the messengers most likely to be trusted (for example, community leaders and religious leaders). in conclusion, we found that a substantial proportion (42.2%) of participants in a national survey conducted during the coronavirus pandemic would be hesitant to accept vaccination against covid-19. black race was one of the strongest independent predictors of not accepting vaccination; this is especially alarming, given the outsized impact of covid-19 among african-americans. our findings suggest that many of the individuals who responded "not sure" may accept vaccination if given credible information that the vaccine is safe original research attitudes toward a potential sars cov-2 vaccine among u.s. adults and effective. as vaccine development proceeds at an unprecedented pace, parallel efforts to proactively develop messages to foster vaccine acceptance are needed to achieve control of the covid-19 pandemic. 2) "there is no way i trust big pharma companies." vaccine development or testing processes 11 (5.0) 2 (2.4) "i'm thinking a vaccine now might be approved too quickly because of political pressure." "rushing to get a vaccine out will be a danger." continued on following page world health organization. coronavirus disease (covid-19): situation report 106. world health organization; 2020. accessed at www.who.int/docs/default-source/coronaviruse/situation-reports /20200505covid-19-sitrep-106.pdf?sfvrsn=47090f63_2 on 9 the socio-economic implications of the coronavirus pandemic (covid-19): a review asian critical care clinical trials group. intensive care management of coronavirus disease 2019 (covid-19): challenges and recommendations what worries the world topline & methodology. 2020. accessed at www.ipsos.com /sites/default/files/ipsos-coronavirus-us-aggregate-topline-050120 vaccines through centuries: major cornerstones of global health. front public health herd immunity": a rough guide current status of potential therapeutic candidates for the covid-19 crisis microneedle array delivered recombinant coronavirus vaccines: immunogenicity and rapid translational development accessed at www.nytimes.com/interactive/2020 /science/coronavirus-vaccine-tracker national update on measles cases and outbreaks-united states who releases list of 10 threats to global health institute for health metrics and evaluation projected population benefit of increased effectiveness and coverage of influenza vaccination on influenza burden in the united states estimate of the basic reproduction number for covid-19: a systematic review and meta-analysis predicting willingness to vaccinate for covid-19 in the us the prevalence of limited health literacy health literacy and preventive health care use among medicare enrollees in a managed care organization hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease 2019 -covid-net, 14 states racial and ethnic disparities in sars-cov-2 pandemic: analysis of a covid-19 observational registry for a diverse u.s. metropolitan population. medrxiv. preprint posted online 12 the influence of social norms on flu vaccination among african american and white adults open ended if not sure: what makes you unsure whether you will get the vaccine?open ended what is your best guess as to whether you will get the coronavirus within the next 6 months? i don't think i will get the coronavirus i think i will get a mild case of the coronavirus i think i will get seriously ill from the coronavirus i have already had the coronavirus appendix reference to specific conspiracy theories 6 (2.7) 6 (7.2) "[. . .] i personally do not believe that the virus was fully caused by infected animals in wuhan.[. . .] i believe that the vaccine is a governmental covert method to kill off more people, and then some." "as long as bill gates is involved with any of this, there's no way in hell i or anyone in my family would do this." "because i heard the government was to put a chip in you when you get the vaccination and i do not want a chip inside of me." distrust unspecified 2 (1.0) 13 (15.7) "i don't trust them." key: cord-275946-ofd2ipvs authors: cheng, matthew p.; yansouni, cedric p.; basta, nicole e.; desjardins, michaël; kanjilal, sanjat; paquette, katryn; caya, chelsea; semret, makeda; quach, caroline; libman, michael; mazzola, laura; sacks, jilian a.; dittrich, sabine; papenburg, jesse title: serodiagnostics for severe acute respiratory syndrome–related coronavirus-2: a narrative review date: 2020-06-04 journal: ann intern med doi: 10.7326/m20-2854 sha: doc_id: 275946 cord_uid: ofd2ipvs accurate serologic tests to detect host antibodies to severe acute respiratory syndrome–related coronavirus-2 (sars-cov-2) will be critical for the public health response to the coronavirus disease 2019 pandemic. many use cases are envisaged, including complementing molecular methods for diagnosis of active disease and estimating immunity for individuals. at the population level, carefully designed seroepidemiologic studies will aid in the characterization of transmission dynamics and refinement of disease burden estimates and will provide insight into the kinetics of humoral immunity. yet, despite an explosion in the number and availability of serologic assays to test for antibodies against sars-cov-2, most have undergone minimal external validation to date. this hinders assay selection and implementation, as well as interpretation of study results. in addition, critical knowledge gaps remain regarding serologic correlates of protection from infection or disease, and the degree to which these assays cross-react with antibodies against related coronaviruses. this article discusses key use cases for sars-cov-2 antibody detection tests and their application to serologic studies, reviews currently available assays, highlights key areas of ongoing research, and proposes potential strategies for test implementation. s ince the initial identification of severe acute respiratory syndrome-related coronavirus-2 (sars-cov-2) as the etiologic agent of coronavirus disease 2019 (covid19) , there have been over 5.3 million confirmed cases and around 340 000 deaths reported worldwide, according to the world health organization (who) (1) . however, given the prevalence of asymptomatic or minimally symptomatic individuals (2, 3) , the imperfect sensitivity of molecular assays performed at a single time point (4) , and limited molecular testing capacity in several parts of the world, the true number of infections probably exceeds the who's estimate by several fold. in addition to scaling up molecular testing for diagnosis of active disease, several countries have incorporated serologic surveillance studies to their covid-19 pandemic response. these studies can help elucidate disease transmission dynamics and improve disease burden estimates by identifying persons who were previously infected, even if pauci-or asymptomatic (5); assess transmission within and between subgroups in the population; and provide insight into the kinetics of humoral immunity after infection (6, 7) . serologic testing may also serve as an adjunct to molecular methods for covid-19 diagnosis in certain clinical scenarios (8) . despite a rapid increase in the number and availability of serologic assays to test for antibodies against sars-cov-2 (9), most have undergone minimal or no external validation or have poorly described validation panels, which hinders assay selection and interpretation of results. in addition, interpretation of serologic assays is limited at present because of critical knowledge gaps. for example, no definite serologic correlates of protection from infection or disease have been identified in humans, and the degree to which these assays cross-react with antibodies against related coronaviruses is poorly described. we discuss key use cases for sars-cov-2 antibody detection tests and their application to serologic studies. we review currently available assays, highlight key areas of ongoing research, and propose potential strategies for test implementation. we searched the medline ovid database for articles on sars-cov-2 serologic assays (the appendix, available at annals.org, shows the search strategy). additional studies were identified by hand-searching references of selected articles, consulting international experts, and searching covid-19 and sars-cov-2 preprints on medrxiv and biorxiv. this search was last updated on 20 may 2020. innate responses. of note, infection prevalence in the population being tested must always be considered. in patients with clinical features of covid-19, a highly specific test, such as sars-cov-2 polymerase chain reaction (pcr), has a high positive predictive value for true infection. conversely, if testing asymptomatic individuals when the true seroprevalence of a population is only 5%, an assay with a specificity of 95% would produce a false-positive rate of 50%. low specificity is particularly problematic in cases where incorrectly identifying an individual as immune could place them at significant risk-for instance, if they were to enter settings with high risk for exposure without appropriate personal protective equipment. the sensitivity of a serologic assay can be established by testing sera from patients who have been identified as infected on the basis of a reference standard. however, a single estimate of sensitivity to de-scribe test performance can be difficult to interpret when samples are collected at different time points since infection. sensitivity estimates will vary according to time since infection in the validation cohort. early (<7 days since symptom onset) and mid-stage (8 to 14 days) pcr-confirmed cases of covid-19 will have lower rates of seroconversion than in the later stage (>14 days); thus, antibody tests will have lower sensitivity to detect infection in earlier phases. likewise, antibody responses may be more easily detectable in severe cases (hospitalized patients) than in mild or asymptomatic infections (11) . establishing the analytic specificity of sars-cov-2 seroassays presents a challenge because of potential for cross-reactivity with antibodies to related coronaviruses (11, 12) . to address this, test reactivity thresholds used to define a positive result can be adjusted to optimize the tradeoff between sensitivity and specificity (13). with higher thresholds, sensitivity decreases as cases with low serum antibody levels are categorized as negative, but specificity improves as low amounts of nonspecific antibody are no longer considered positive. physicochemical assay variables can also be modified so that less specific antibodies, with less "avidity" for the antigen, are excluded. this also improves specificity at some expense to sensitivity. tests that target igm, which by its nature can be nonspecific, will probably have increased risk for false-positive results. validation of the clinical specificity of a serologic assay requires sera from different types of sources. in the case of covid-19, sera collected before the end of 2019 are presumed to be seronegative for sars-cov-2 (14). the samples chosen should be representative of the population of interest. in addition, individuals known to have been infected with various common pathogens, including other human coronaviruses, but who could not have been infected with sars-cov-2, should be evaluated to demonstrate the absence of cross-reactivity. finally, patients with illnesses known to stimulate high levels of polyclonal antibodies, such as epstein-barr virus infection, malaria, or conditions associated with production of rheumatoid factor, can be evaluated for cross-reactivity (15) (16) (17) . without these validations, assay specificity will be difficult to establish. once a particular assay is shown to have high sensitivity and high specificity, this assay can serve as a surrogate "gold standard" for the validation of other assays, as well as a standard for quantitative assays. to date, most published sars-cov-2 serologic assay validations have classified patient sera according to sars-cov-2 pcr results (18) . polymerase chain reaction assay is an imperfect comparator for sars-cov-2 diagnosis because of variable analytic performance across assays (19) , and because pcr sensitivity depends on sample type, quality of sampling, and timing relative to illness onset (4, 20) . this can lead to unpredictable directions of bias for seroassay accuracy estimolecular testing on respiratory specimens, the current gold standard for diagnosis of sars-cov-2 infection, is hampered by imperfect sensitivity and limited testing capacity. antibody testing has potential to aid in particular diagnostic scenarios, such as in rt-pcr negative patients who present later during disease course. antibody testing should not be used as the sole basis for diagnosis of acute covid-19. appropriately designed seroepidemiologic studies will play an essential part in the public health response to the covid-19 pandemic by characterizing transmission dynamics, refining disease burden estimates, and providing insight into the kinetics of humoral immunity to sars-cov-2. validation of novel antibody detection tests for sars-cov-2 must pay careful attention to the choice of source populations and reference standards, and to possible cross-reactivity with antibodies to other human coronavirus infections. plaque reduction neutralization assays are currently the reference standard for determination of host antibodies capable of inhibiting viral replication, but must be performed in a biosafety level 3 laboratory. urgent research is needed to determine the serologic correlates of immunity against sars-cov-2. mates. there is an urgent need for validation studies to provide more detail on pcr comparators and on study populations, especially regarding disease severity and timing in the illness course. furthermore, to enable a better understanding of the diagnostic accuracy of various sars-cov-2 serologic tests, the development of reference panels, including seroconversion panels, by using well-characterized sera is necessary. coronavirus spike (s) and nucleocapsid (n) envelope proteins are highly immunogenic and constitute important antigenic targets for the development of serologic assays (11, 21) . as with sars-cov-1, the s protein of sars-cov-2 binds to the cell surface angiotensin-converting enzyme 2 (ace2) receptor (21) (22) (23) . host neutralizing antibodies (nabs) appear to be predominantly directed at the s protein (24) . the n protein plays crucial roles in viral replication and assembly, is highly conserved, and induces antibodies sooner than s during infection (6, 25, 26) . commercial sars-cov-2 serologic assay development has focused on enzyme immunoassays, such as laboratory-based enzyme-linked immunosorbent assays (elisas) and rapid lateral flow assays (lfas). more complex serum neutralization assays are important as a reference standard and to assess immunity. only a subset of antibodies raised against a specific antigen have the property of neutralizing viral replication. neutralization assays, such as plaque reduction and microneutralization methods, provide essential data for the validation of candidate diagnostic tests and to define correlates of protective immunity. the primary drawback of functional assays of sars-cov-2 neutralization is that they can only be performed by experienced staff in a biosafety level (bsl) 3 laboratory owing to the need to culture live virus, which increases complexity and cost. thus, efforts to circumvent these obstacles have converged on finding surrogates of traditional neutralization titers. live pseudotyped viruses have been developed that incorporate the s protein of sars-cov-2, can be cultivated in bsl-2 conditions, and express a reporter enzyme when infecting cells through binding to the ace2 receptor, thereby allowing for automated quantification (27) . such reporter virus sys the figure shows a decision tree for interpreting antibody test results by symptomatology (symptomatic, postsymptomatic, asymptomatic or subclinical) and whether the patient is a suspected case. it is presumed herein that antibody tests with the highest possible sensitivity and specificity are used, and that the symptomatology is occurring early in the pandemic, when seroprevalence is low and before the availability of a vaccine. for sars-cov-2, the accuracy of antibody test results and the appropriate test interpretation both depend on clinical context. in some situations, the clinical context does not enable a single interpretation of the antibody test result. for example, a positive antibody test in a low-risk population could be the result of prior infection, or it could be a false-positive result. similarly, a negative antibody test in a high-risk population cannot a priori differentiate among preseroconversion, undetectable seroconversion, a false-negative result, or the absence of infection. sars-cov-2 = severe acute respiratory syndrome-related coronavirus-2. * the relationship between positive antibody results and protective immunity will vary among assays and must be validated individually. † includes high exposure, high risk, hot spots, and contact tracing. serodiagnostics for sars-cov-2: a narrative review tems would offer substantial advantages in terms of speed, cost, and scalability while providing a quasifunctional assessment of the host neutralizing antibody response (18) . other groups are striving to create surrogates of neutralization that bypass the need for viral culture through the use of blocking elisa formats (28) . for high-throughput and inexpensive (after initial capital outlay) screening in clinical laboratories, relevant antigenic targets can be purified or synthesized, and 1 or more can be incorporated into an elisa test platform. specific antibody-antigen reactivity is detected by using enzyme conjugates that produce color changes or other detector labels that can be objectively measured (29) . the elisas detect antibodies directed at the chosen antigen without regard for their ability to elicit viral neutralization. thus, interpretation of immune status from elisa results requires rigorous characterization of the assay with respect to a reference standard. for the moment, this work has not been done for sars-cov-2. furthermore, universal standards for reporting are lacking (some assays produce semiquantitative results, others are qualitative), and assays have variable test detection limits and reproducibility and use different analytes (igg, igm, iga) or combinations thereof, with unclear effect on performance (30) . it is thus not surprising that estimates of elisa test sensitivity and specificity vary widely across assays and even within assays evaluated by different investigators ( table 2 ) (31-47). the lfas leverage the same capture agents as an elisa in a lateral flow strip format (48) . the lateral flow format enables a simple and fast time to result (10 to 30 minutes), but with tradeoffs in detection that is severalfold less sensitive than their elisa counterpart, a higher cost per test, and lower throughput (49) . for lfas, follow-up confirmatory testing is typically recommended. most provide qualitative, visual results subjectively interpreted by the operator. the use of a small instrument reader can increase test sensitivity and may permit quantitative and more reproducible results (50, 51). to enable community-based and home testing, lfas should be paired with minimally invasive samples, such as finger-prick or oral fluid or swabs, and minimal sample processing. these tests are ideal for near-patient testing and low infrastructure settings, such as the lower levels of the public health system in low-and middle-income countries (52), where they have been used to effectively screen and triage cases of epidemic and nonepidemic diseases. particularly where resources are constrained, inexpensive lfas may be useful to expand diagnostic test capacity. many sars-cov-2 lfa antibody tests are available; however, the performance of these tests is still under evaluation, and their value needs to be carefully weighed depending on the use case. a recent large study found heterogeneous and inconsistent results among 10 lfas and identified signal interpretation as a major obstacle (41). population-based seroepidemiologic studies are an important source of evidence about sars-cov-2 transmission dynamics and will be critical for informing interventions to mitigate the effects of the covid-19 pandemic (53) . whereas reports of clinical cases identify persons with acute disease, seroepidemiologic studies identify those who were infected previously, including those who experienced mild disease or subclinical infections and thus may not be subject to biases due to health care-seeking behavior and limitations on eligibility for testing during acute disease. these assessments of seroprevalence overall and in specific groups can be used to estimate important characteristics of the pandemic (54 -56) . serologic surveillance studies can also assess the accumulation of persons with antibody responses over time to estimate incidence of sars-cov-2 infection (57, 58) and can track age-and jurisdiction-specific disease susceptibility and identify at-risk populations (59) . utilizing standard protocols for the design and implementation of serologic studies (60) and making protocols publicly available can improve scientific rigor and ensure comparability across studies undertaken in different populations. of note, the who unity studies aim to combine worldwide seroepidemiologic study data (61) . cross-sectional serologic surveillance studies are a key first step toward determining the proportion of a population that has been infected with sars-cov-2. when estimating age-specific seroprevalence is the primary aim, the gold-standard study design is the conduct of appropriately powered, cross-sectional, age-stratified, population-representative, randomly sampled, serologic studies in each population of interest. this study design, when implemented appropriately, ensures that the estimates obtained are representative of the population of interest and minimizes the potential that the results may have common sources of bias (62) . in addition, many variations of this design are also valuable for estimating agespecific seroprevalence, especially when statistical methods are used that can account for alternative design elements and sources of uncertainty (63) . layering seroprevalence surveys onto other existing observational or interventional studies or utilizing residual sera from blood donors or from routine lab tests can increase feasibility and timeliness of estimating seroprevalence at some risk to generalizability. to determine sars-cov-2 seroincidence, or the proportion of the population seroconverting over a certain time frame, longitudinal studies can be conducted among cohorts of individuals who are at high risk for exposure (such as health care workers) or among those for whom little is known about the risk for infection (such as children). furthermore, longitudinal serologic surveillance can be implemented to provide insight in situations where prevention and control measures are for instance, household-or workplace-based serologic studies can aid in the determination of secondary attack rates, especially when the proportion of asymptomatic infections may be high. in addition, well-designed seroepidemiologic studies are critical for informing mathematical models and forecasting tools to guide prevention and control strategies. a critical aspect in the interpretation of serologic tests is an understanding of the dynamic nature of the humoral response to sars-cov-2 infection. a few studies have defined the kinetics of antibody formation in patients with disease ranging from mildly symptomatic to critically ill. these studies have consistently shown that most patients seroconvert by 2 weeks after the onset of symptoms, and almost all patients have detectable antibodies by day 28 (6, 7, 20, 64, 65) . antibodies can be detected as early as 1 day after illness onset, with peak igm and iga titers occurring in the ensuing 7 to 14 days and waning thereafter. the igg response appears to peak simultaneously in some cases, or slightly later in others (66) , and plateaus between 15 and 21 days (6). in some cases, igg titer declines significantly within weeks (67) . some patients appear to have weak or undetectable seroconversion (44, 66) . illness severity probably affects antibody responses. critically ill patients had a delayed but more robust formation of igm and igg in one study (7) . anti-sars-cov-2 responses in subclinical infections have yet to be characterized. finally, the suitability of alternative specimen types to serum, such as saliva or dried blood spots (68, 69), must be established for sars-cov-2 serodiagnostics. correlates of protection are empirically derived, specific immune markers associated with protection against infection or disease (53) . seropositivity is often a useful correlate for clinical immunity, though cell-mediated immunity is known to be essential and antibody production is not the sole mechanistic contribution to protection (70) . the relationship between seropositivity and immune protection has not yet been established for coronaviruses. a recent report on 175 patients who recovered from covid-19 showed that nab titers were moderately correlated with antibodies binding to s protein domains (24) . surprisingly, 30% of patients developed only low titers of nabs after recovery, with younger patients (15 to 39 years of age) having significantly lower anti-sars-cov-2 and nab titers. this suggest that innate and adaptive cellular immunity are also likely to play a significant role in viral clearance and immunity to coronaviruses (71) . little is known regarding seropositivity and risk for reinfection to coronaviruses. in a challenge study with hcov-229e, healthy volunteers who had lower specific igg titers at baseline were more likely to develop clinically overt infection (72) . after the challenge, specific igg and nab peaked at 3 weeks and fell considerably at 12 weeks. one year later, 6 out of 9 previously infected participants became infected after a rechallenge, though they were asymptomatic and the duration of viral shedding was shorter than during the first challenge-suggesting at least partial protection induced by the first infection. of note, the immune response dynamics after sars-cov-1 and middle east respiratory syndrome-coronavirus (mers-cov) infection differ substantially from what was seen with hcov-229e challenge. values for igg and nab peaked 4 months after sars-cov-1 and decreased after 16 months. after mers-cov infection, 86% of patients had detectable igg and nabs for at least 34 months (11). evaluations of sars-cov-2 serologic assays must account for potential cross-reactivity with other coronaviruses, including the 4 endemic human coronaviruses: hku1, oc43, nl63, and 229e. a systematic review of antibody-mediated immunity to coronaviruses found that studies of serologic responses to human coronavirus n proteins suggest cross-reactivity within human alphacoronaviruses (229e and nl63) and human betacoronaviruses (oc43 and hku1), but not between human alpha-and betacoronaviruses (11) . the available evidence suggests that natural infections with endemic coronaviruses produce little cross-reactivity to emerging coronaviruses sars-cov-1 and mers-cov. regarding sars-cov-2 elisa using s1 protein epitopes, several pilot studies report positive results with sera from patients with sars-cov-1, and a lack of significant cross-reactivity when using sera from small numbers of patients seropositive for the endemic human coronaviruses (18, 44) . data regarding sars-cov-2 elisa based on the n protein are more limited. the specificity of 2 elisa and 10 lateral flow assays has also been assessed against 108 pre-covid-19 sera from u.s. patients collected in july 2018, and ranged from 84.3 to 100% (41). finally, in keeping with these results, a surrogate assay of sars-cov-2 viral neutralization tests was found to be highly specific among sera positive for endemic human coronaviruses antibodies but showed some degree of cross reactivity with sars-cov-1 positive sera (28) . thus, cross reactivity of sars-cov-2 serologic assays may be a concern in areas where sars-cov-1 and mers-cov circulated widely. overall, serologic tests based on s protein appear to distinguish between emerging and endemic coronaviruses. assays based on the n protein can serve as a marker of recent infection but might be expected to cross react more with endemic coronaviruses. convalescent plasma therapy, as a means of providing "passive" immunity to susceptible individuals and as early therapy after infection, has been used for many viral infections (73) . this approach was used in a small number of patients with sars-cov-1 and mers-cov and has shown promise in a few case series of sars-cov-2 infection (74 -77) . use of covid-19 convalescent plasma has been approved in several jurisdictions under the category of an emergency investigational new drug (78) . as a general principle, the efficacy of plasma therapy is a function of several factors, including timing of plasma donation (plasma obtained a few weeks after recovery during convalescence is considered more immunogenic, with higher titers of polyclonal neutralizing antibodies), dosage, and timing of administration in relation to onset of disease in the recipient. for covid-19, identifying "optimal" donors will prove to be an additional challenge, given the heterogeneity in antibody titers during convalescence and the lack of an established correlation between specific antibody titers and clinical efficacy (79) . as an example, in the treatment of influenza, plasma with high nab titers collected from a nonconvalescent general population did not show efficacy (80, 81) , suggesting that donor selection should not be based solely on serologic titers. eventually, antibody derived from vaccinated donors may deserve further study. serologic tests are essential to better understand the determinants of sars-cov-2 immunity and to guide vaccine development. for sars-cov-1 and mers-cov, the s protein was shown to be the most important antigen leading to production of nabs and inhibition of viral entry into the host cells (82) . since then, s protein has been the major target for vaccine candidates. previous experience using sars-cov-1 subunit vaccine based on the full-length s protein showed potent nab responses and protective immunity in animal models. however, some of these vaccines were also associated with a harmful immune enhance-review serodiagnostics for sars-cov-2: a narrative review ment, as seen in vaccine candidates for dengue or respiratory syncytial virus, leading to a potentially more severe disease in vaccinated individuals (83) . antibodydependent enhancement has also been seen among sars-cov-1-infected macaques injected with antispike igg (84) . for sars-cov-1 and mers-cov, the receptor-binding domain (rbd) of the s protein was shown to be the major immunodominant region. subunit vaccines targeting rbd specifically elicited high nab titers but were not associated with immune enhancement (82, 85) . in sars-cov-2-infected patients, among the binding antibodies to the different regions of the s protein (s1, s2, rbd), rbd-specific igg correlated best with nabs, suggesting that rbd is be a promising target for sars-cov-2 vaccine candidates (24) . however, because rbd is the most variable region of the genome (86) , there is still a theoretical risk for immunologic "escape," as well as immune enhancement development (87) . the n protein, a more conserved region of the genome, has been of interest for sars-cov-1 and mers-cov vaccine candidates and was thought to be at lower risk for immune enhancement; however, it was not shown to elicit nabs (82) . the role of the n protein in sars-cov-2 immune response is still unknown. in conclusion, the covid-19 pandemic has revealed several gaps in our diagnostic arsenal and is highlighting the essential role of serodiagnostics as part of our public health response. with the use of carefully validated assays, appropriately designed serologic studies will help characterize transmission dynamics and refine disease burden estimates. urgent scientific research is needed to link specific serologic variables with immunity against sars-cov-2. ); school of population and global health brigham and women's hospital and harvard medical school & harvard pilgrim healthcare institute ); and mcgill interdisciplinary initiative in infection 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enhancement anti-spike igg causes severe acute lung injury by skewing macrophage responses during acute sars-cov infection prospects for a mers-cov spike vaccine a pneumonia outbreak associated with a new coronavirus of probable bat origin current status of epidemiology, diagnosis, therapeutics, and vaccines for novel coronavirus disease 2019 (covid-19) analysis and interpretation of the data drafting of the article administrative, technical, or logistic support: c. caya. collection and assembly of data antibodies, viral antibody-dependent enhancement middle east respiratory syndrome coronavirus enzyme-linked immunosorbent assay fluoroimmunoassay hemagglutination inhibition tests key: cord-276428-oy8e2cpx authors: krishnan, lakshmi; ogunwole, s. michelle; cooper, lisa a. title: historical insights on coronavirus disease 2019 (covid-19), the 1918 influenza pandemic, and racial disparities: illuminating a path forward date: 2020-06-05 journal: ann intern med doi: 10.7326/m20-2223 sha: doc_id: 276428 cord_uid: oy8e2cpx the coronavirus disease 2019 (covid-19) pandemic is exacting a disproportionate toll on ethnic minority communities and magnifying existing disparities in health care access and treatment. to understand this crisis, physicians and public health researchers have searched history for insights, especially from a great outbreak approximately a century ago: the 1918 influenza pandemic. however, of the accounts examining the 1918 influenza pandemic and covid-19, only a notable few discuss race. yet, a rich, broader scholarship on race and epidemic disease as a “sampling device for social analysis” exists. this commentary examines the historical arc of the 1918 influenza pandemic, focusing on black americans and showing the complex and sometimes surprising ways it operated, triggering particular responses both within a minority community and in wider racial, sociopolitical, and public health structures. this analysis reveals that critical structural inequities and health care gaps have historically contributed to and continue to compound disparate health outcomes among communities of color. shifting from this context to the present, this article frames a discussion of racial health disparities through a resilience approach rather than a deficit approach and offers a blueprint for approaching the covid-19 crisis and its afterlives through the lens of health equity. the coronavirus disease 2019 (covid-19) pandemic is exacting a disproportionate toll on ethnic minority communities and magnifying existing disparities in health care access and treatment. to understand this crisis, physicians and public health researchers have searched history for insights, especially from a great outbreak approximately a century ago: the 1918 influenza pandemic. however, of the accounts examining the 1918 influenza pandemic and covid-19, only a notable few discuss race. yet, a rich, broader scholarship on race and epidemic disease as a "sampling device for social analysis" exists. this commentary examines the historical arc of the 1918 influenza pandemic, focusing on black americans and showing the complex and sometimes surprising ways it operated, triggering particular re-sponses both within a minority community and in wider racial, sociopolitical, and public health structures. this analysis reveals that critical structural inequities and health care gaps have historically contributed to and continue to compound disparate health outcomes among communities of color. shifting from this context to the present, this article frames a discussion of racial health disparities through a resilience approach rather than a deficit approach and offers a blueprint for approaching the covid-19 crisis and its afterlives through the lens of health equity. ann intern med. doi:10.7326/m20-2223 annals.org for author, article, and disclosure information, see end of text. this article was published at annals.org on 5 june 2020. * drs. krishnan and ogunwole contributed equally to this work. t he coronavirus disease 2019 (covid-19) pandemic has killed more than 100 000 persons in the united states (1) . nationwide data indicate that ethnic minority communities, particularly black, latinx, and native or indigenous communities, suffer disproportionately (2) (3) (4) (5) (6) (7) . this has significant historical antecedents; as evelynn hammonds recently argued, epidemic diseases "lay bare and make visible inequalities in a society" (8) . yet, at the onset of the crisis, few reported its effect on minorities (9) . even now, we may not know the full scope and details. many states have published limited statistics, and race-stratified data, once fully released, will need to be carefully interpreted to address the causes of inequity rather than to perpetuate stigma and discrimination (10) . unfortunately, this comes as no surprise to health equity researchers and historians of medicine and public health. the united states has a long history of racial and socioeconomic disparities, with the current pandemic further revealing the rifts created by historical injustice, structural racism, and interpersonal bias (11-13). although some have touted covid-19 as a "great equalizer" that strikes across age, sex, race/ethnicity, and geography, we contend that it has magnified the many "unequalizers" in our society (14, 15) . to understand the current crisis, physicians and public health researchers have mined history for insights (16) . most have focused on a century-old outbreak, the 1918 influenza pandemic (misleadingly called the "spanish flu"), because covid-19 most closely approximates it in scope and effect (17) (18) (19) . of the accounts comparing the 1918 influenza pandemic and covid-19, only a notable few discuss race (8, 20, 21 ). yet, a rich, broader scholarship on race and epidemic disease as a "sampling device for social analysis" exists (22) (23) (24) (25) (26) (27) . given the excessive mortality due to covid-19 in minority communities, reexamination of such historical antecedents is fruitful. although this scholarship hesitates to offer predictions, this kind of analysis can provide orienting frameworks, reveal nuance, and modulate our approach to the current crisiswhich has been called "unprecedented," reflecting a lack of historical context. we examine the historical arc of the 1918 influenza pandemic, focusing on black americans and showing the complex, sometimes surprising ways it triggered particular responses both within a minority community and in wider racial, sociopolitical, and public health structures. shifting to the present, we frame a discussion of racial health disparities through a resilience approach versus a deficit approach and offer a blueprint (table) for approaching the covid-19 crisis and its afterlives through the lens of health equity. elected leaders should exercise an abundance of precaution when facing potential public health threats. providing accurate information, overpreparing, and not underreacting are key. leaders (whether community based or elected) are role models. communities of color may look to these persons to guide their own behaviors. persons in positions of power or influence should be held to high standards and model the importance of strict adherence to strategies aimed at controlling and reducing infectious disease spread. transparency and communication are key to timely adoption of mitigation strategies by the general public; when these are absent, erosion of trust ensues. early transparency and communication are key to timely adoption of mitigation strategies by the general public. however, even with these strategies, historical precedence may make it difficult for communities of color to trust information from the government. in this scenario, it is especially important to engage trusted messengers, such as community leaders and faith-based organizations, to help deliver critical information. for communities of color, each conversation and transfer of information is an opportunity to either rebuild trust or further substantiate mistrust. elected leaders should thus be held accountable for misinformation, and the public should be aware of credible sources of information. counting and reporting are critical for measuring disparities in health and planning equitable interventions. technology should be leveraged to support data collection for public health surveillance and social service needs. data collected on disease incidence should be stratified by key demographic factors. blaming specific groups for infectious disease spread is counterproductive and can be dangerous for the groups indicted. disinformation based on racism and stigma is unacceptable; leaders in all sectors should rely on scientific facts to guide conversations on infectious disease spread. they should maintain neutral positions and should not place blame on specific groups. social determinants of health are key drivers of health disparities and also affect the ability to participate in infectious disease mitigation strategies. policy initiatives must address social determinants of health before pandemics arise. support for social services must be better integrated into the health care system. health systems should anticipate increased need for social support during pandemics and have strategies in place to deliver services to the most vulnerable populations. this includes enhanced access to technology to support telecommunication for vulnerable populations. chronic medical conditions are significant contributors to morbidity and mortality during the pandemic. health care policy changes are needed to enable access to primary care and preventative services throughout the life course. there will be long-term sequelae related to covid-19 (both directly because of virus-related morbidity and indirectly as a result of reduced access to care during social distancing periods). the health care system should plan for and anticipate a surge in the need for primary and specialty care services. institutional and structural forces keep communities of color from achieving their full potential. a restorative justice approach that includes the following strategies, among others, should be used: • investments in early education • financial assistance for higher education or trade schools; forgiveness for previously accumulated education debt • investment in public housing; fair and equitable access to home loans • fair and equitable access to business loans; incentives for minority-owned businesses • investment in neighborhood environments: resources for community-led neighborhood violence prevention strategies, increases in green space, walking trails, reduction in food deserts • universal access to health care, including mental health care • integration of faith-based organizations into the health care system • restructuring of the criminal justice system; employment opportunities after incarceration communities of color lead, persevere, and innovate. they play an essential role in building bridges toward trust in the health care system and improving health outcomes within their communities. their contributions help to advance science and medicine and deserve recognition. communities of color should be given opportunities to actively participate in agenda setting, research, and policy initiatives aimed at improving their communities so they can be recognized and acknowledged for their contributions. building and restoring trust is an ongoing process that is necessary to advance medicine, science, and health care. this can be aided through some of the following measures: • support for strategies aimed at improving and maintaining a diverse health care workforce • community-based participatory research throughout all phases of the research process (design, implementation, dissemination, and evaluation) • utilization of trusted community partners and community health workers to aid in community education; improvement in recruitment and participation in research, including clinical trials; gathering of quantitative and qualitative data in the field throughout all phases of pandemic response covid-19 = coronavirus disease 2019. * all phases should be responsive to the possibility of future waves of disease. historical insights on covid19, 1918 influenza, and racial disparities on black americans, who, for example, accounted for an overwhelming number of the 50 000 deaths in the 1862-1867 smallpox epidemic (26) . contagion also augmented biologically deterministic beliefs, including that blacks were innately immune to certain diseases. during the 1792-1793 yellow fever epidemic in philadelphia, white physicians, such as benjamin rush, asked black community leaders absalom jones and william gray to "furnish nurses to attend the afflicted" because of the erroneous assumption that blacks could not contract the disease (32, 33) . however, in the context of these preceding epidemics, the 1918 influenza pandemic forms a unique case study. although all-cause morbidity and mortality in the early 20th century was higher for black americans than white americans, the few studies examining racial differences in the 1918 pandemic found that the black population had lower influenza incidence and morbidity but higher case fatality (23, 34) . black physicians shared this view, as evidenced in the journal of the national medical association and local newspaper articles (35, 36). meanwhile, white public health figures, like chicago commissioner of public health john dill robertson, used these findings to justify biological determinism, concluding that "the colored race was more immune than the white to influenza" (37) . rebuttals to these innate immunity theories circulated in the black print media. respected and widely read periodicals, such as baltimore's afro-american, the chicago defender, and the philadelphia tribune, carefully documented influenza's effect, with personal columns, church registers, and town updates listing the many community members who had the "flu," shaming those not taking it seriously, or mourning others, such as a promising young teacher and morgan college graduate (38 -42). other articles warned black americans to take adequate precautions and discounted theoretical immunity: "while the death rate from the epidemic of influenza is not as high as the white death rate, colored people are far from being immune of the disease" (43) . in december 1918, african american columnist william pickens debunked the claim of a white west virginian who claimed the "influenza germ had shown that god was partial in favor of black people." pickens countered that for whites, "when negroes die faster, it is often escribed [sic] to their inferiority," but if spared, "well, that proves they are not human like the rest of us" (44) . these critiques highlight differences between pandemic coverage and explanatory models in the "mainstream" versus black press-the latter was community-centered, focused on trusted sources and internal solutions, and skeptical about the veracity and benevolence of white responses. how do we account for black americans' lower influenza infection rates and all-cause mortality but higher case-fatality rate during the 1918 influenza pandemic? alfred crosby hypothesizes that higher exposure to the less virulent early wave may have made black americans less susceptible to the fall/winter wave (45, 46) . this assumes many interlinked circumstances, including higher likelihood of blacks living in over-crowded environments and therefore greater exposure during the spring/summer wave; poorer access to sanitation, potable water, and hygiene than white counterparts; and early exposure conferring immunity against the deadlier autumn wave. segregation may also have functioned as an unintentional cordon sanitaire, quarantining blacks from whites. finally, recall that supporting data are limited by likely underreporting (23) . nonetheless, it is worth noting the higher case-fatality rate, which could be attributed to several factors still present today: higher risk for pulmonary disease, malnutrition, poor housing conditions, social and economic disparities, and inadequate access to care. in sum, if a black person caught influenza in 1918, they were more likely to die-an outcome which, despite lower infection and all-cause mortality rates, has significant repercussions. aggregate influenza data before and after the 1918 -1919 season reflect a more familiar pattern: significantly higher morbidity and mortality among nonwhites compared with whites (47) . that the outcomes of black americans did not improve in the interim suggests that the influenza pandemic did little to mobilize national responses for improving their health status, a precedent that we hope is not replicated in the current crisis. the broader context of the 1918 pandemic is critical for understanding the historical, as well as contemporaneous, landscape of health disparities. a confluence of factors, including social policies of racial exclusion and discrimination, unequal provision of health care, housing inequality, malnutrition, chronic respiratory disease, and increased epidemiologic burden of infectious diseases (such as tuberculosis, typhoid fever, whooping cough, and infant diarrheal illnesses), contributed to lower life expectancy for black americans (25) . new academic disciplines, such as anthropology, evolutionary biology, genetics, and eugenics, helped promote theories of biological determinism, which compounded older views attributing poor health outcomes to the inferior qualities of black americans (48) . the jim crow laws boosted white supremacy with these ideologies to enforce racial segregation, and between 1916 and 1919, in the thick of the influenza pandemic, approximately half a million blacks fled the punitive south for midwestern and northern cities in the now-famous great migration. however, those cities often greeted them with prejudice, stigma, segregationist policies, and violence, allegedly aimed at improving public health. a march 1917 chicago daily tribune headline proclaimed, "rush of negroes to city starts health inquiry"; during the pandemic, the headline "half a million darkies from dixie swarm to the north to better themselves" appeared. reporter henry m. hyde named southern black migrants as disease vectors: "compelled to live crowded in dark and insanitary rooms; they are surrounded by constant temptations" (20, 49) . these views provided justification for draconian public health ordinances and restrictive housing covenants that maintained housing color lines and prevented black chicagoans from leaving overcrowded conditions ("the black (50) . residential segregation also played a role in the outbreak in baltimore, the first large american city to pass drastic housing legislation in 1910. consequently, many black baltimoreans lived in "alley districts" or high-occupancy "tenant houses" with poor sanitation and ventilation and higher rates of epidemic disease (25, 51) . influenza overwhelmed medical resources straining under the burden of urban density, unequal living conditions, and a high concentration of military training camps (52, 53) . downplaying by authorities like health commissioner dr. john d. blake, who called it the "same old influenza" physicians have long treated, exacerbated the problem (54). blake eventually reversed course, imposing citywide restrictions and "social distancing," but not in time to stanch the tide. segregation and structural racism extended to medical education and health care delivery, but community mobilization, well under way before the pandemic, was a counterbalance. by the early 20th century, black activists and professionals led many health institutions and flagship organizations: howard university college of medicine (founded in 1868), tuskegee institute hospital and nurse training school (founded in 1892), meharry medical college (founded in 1876), the national medical association (founded in 1895), and the national association of colored graduate nurses (founded in 1908). at the same time, the flexner report (published in 1910) disadvantaged minority health education-only 2 of the initial 7 black medical schools survived its reforms, and they struggled financially during the influenza pandemic (55) . black nurses, excluded from world war i service by the u.s. army medical corps and the red cross and battling for inclusion in the u.s. armed forces nurses corps, nevertheless served on influenza frontlines. in october 1918, afro-american declared that these essential workers were "at a premium," noting that the self-same "red cross leaders are appreciative of the response colored women have made . . ." (56) . yet, black patients were often disbarred from care, leading to local and decentralized efforts to provide care within the community. black professionals took great pride in their role fighting influenza. as dr. john p. turner wrote (57): the negro physician played a most prominent part in treating and relieving victims of every race . . . [yet] will possibly never be cited in the history to be written of the 1918 epidemic. however we want to call to the attention of the medical profession of america the unselfish devotion to duty that impelled three thousand legal practitioners of medicine of african de-scent to work night and day to aid in checking the monster scourge. although most black health professionals did not receive due praise or recognition, disruptions in the wake of world war i and the 1918 pandemic did shift the u.s. medical landscape. it was partly because of the "scarcity of white medical men" as well as ardent community efforts and activism that places like the harlem hospital desegregated (1919 -1935) ; louis t. wright, later a prominent surgeon and civil rights activist, became the first black physician to join its staff in 1919 (58) . historians remark that, unlike other cataclysmic events, the 1918 pandemic left minimal traces in public memory and culture; its neglect has led to its being called the "forgotten pandemic" (46). however, this assertion overlooks its multivariate effect on the african american community. although the influenza pandemic does not reveal ready associations between deleterious social, cultural, and economic conditions and poor outcomes (aside from higher case-fatality rate) for black americans, the gaps in historical documentation may reflect inherent disparities and consequences of limited racial/ethnic data collection. this absent archive may indeed have been a setback for public health and health equity-a missed opportunity to intervene on the basis of the specific contexts and unique vulnerabilities of different groups. in this way, the 1918 influenza pandemic is an illuminating case study for understanding the role of pandemics in the history of health disparities and the broader health equity movement. for black americans, surviving and fighting the 1918 pandemic was a catalyzing step up the social ladder, a cause for communal effort and activism, and a justification for profound engagement with health, which was seen as bound to the greater social condition. it concretized the spirit of community resilience and helped contribute to desegregation and the nascent civil rights movement. however, because of minimal national mobilization to improve the health of communities of color, it also compounded mounting distrust in the u.s. government to intervene and help improve the health and lives of its nonwhite citizens, a wariness that we see replayed in the covid-19 pandemic. reflecting on the 1918 influenza pandemic in the setting of covid-19, we note important parallels while recognizing many differences in context. despite the past century's therapeutic evolution, we find ourselves in a situation similar to 1918, without a vaccine or proven treatments for a deadly disease. furthermore, structural inequities have historically contributed and continue to compound disparate health outcomes in communities of color. evaluating historical trends is critical for health equity work, and through attending to the complexities of the 1918 pandemic, we have the opportunity to ground our current and future strategies in this historical context, deliver a more equitable panhistorical insights on covid-19, 1918 influenza, and racial disparities demic strategy, and reduce disparities in marginalized communities. as physicians who also serve other roles (health equity researchers, historians of medicine, educators, and advocates), we propose several areas for intervention and mobilization throughout the various phases of pandemic response. delaying swift public health measures significantly affected the pandemic curve trajectory in the 1918 influenza pandemic. cities that enacted swift and sustained nonpharmaceutical interventions had lower excess mortality rates than their counterparts (58 -60) . similarly, initial failure to acknowledge severe acute respiratory syndrome coronavirus 2 as a credible threat hampered containment and mitigation efforts (61). several months later, as much of the nation strategizes reopening, we must maintain vigilant mitigation strategies while aligning recommendations with emerging epidemiologic data. failure to do so could result in new waves of disease, as was the case in 1918. within the african american community, specific communication barriers, augmented by a lack of covid-19 -related demographic data, contributed to underestimating the pandemic's effect. misinformation and recycled, erroneous narratives about black immunity circulated through social media (62) . historical distrust of biomedicine amplified these effects (63) . however, as available data emerged outlining covid-19's devastating disparities, black organizations, leaders, and media outlets aggressively campaigned to dispel myths, implored citizens to heed sanitation and containment advice, and advocated for community resources. this kind of community-led strategy has repeatedly been critical in counteracting national failures to protect minorities. furthermore, such interventions bridge divides forged by historical mistrust-they are central to dissemination of information and community activation (64) . however, misinformation, oversight, and delayed mitigation strategies alone do not fully explain differential covid-19 incidence. many have deeply analyzed the effect of social determinants on covid-19 disparities (15, 65, 66) . this historical inheritance, of which the 1918 influenza pandemic forms just 1 episode, shapes how social conditions obstruct minority participation in public health mitigation and containment measures. it also extends to risk factors for chronic disease development, making african americans more susceptible to covid-19 -related morbidity and mortality (67) . as a result of redlining, for instance, minority residential environments bear substantial barriers to health optimization, such as reduced green space access, disproportionate tobacco and alcohol marketing, low perceived neighborhood safety, and food deserts (68) . health equity researchers have proposed reforms, including interventions by local governments to provide food, housing, education, employment, and technological support, but this approach is necessarily reactive rather than reparative and preventive (69, 70) . an advantage of the current era compared with 1918 is our ability to collect robust data that can inform a more proactive strategy. structural, environmental, and economic data on essential goods and services can enhance epidemiologic data. when stratified at the level of key social determinants of health, this information can be used to identify which communities are most vulnerable and ensure prudent and equitable dissemination of resources. in addition to the relief response, we must examine the nature of blame and stigma during pandemics, paying particular attention to dangerous narratives of personal responsibility as a key driver of health outcomes (71) . these accounts place the burden of differential outcomes on minorities rather than acknowledging the lasting legacy of structural racism. they also detach minority health from that of the majority rather than viewing it as part of the nation's collective mission. the trajectory of the covid-19 pandemic remains uncertain; it may abate, or we may face resurgent waves during reopening, as seen during the 1918 influenza pandemic. if the latter, we must acknowledge the history of public health response, correcting prior mistakes and attempting to duplicate applicable practices. if the former, we must still consider our path toward equity in recovery. challenges for communities of color will include long-term covid-19 sequelae, exacerbation of underlying chronic conditions, and mistrust in the health care system, perhaps reinforced by the current crisis. creating antidotes to this mistrust will be critical; components should include collaboration with trusted community and media partners, a diverse health care workforce to offer racially concordant care teams, and community-based participatory research. this will in turn support the actions needed to reduce disparities, including recruiting a representative population into future covid-19 -related clinical trials and epidemiologic studies, ensuring adequate uptake during vaccination campaigns, enhancing engagement with primary care for improved chronic disease prevention and management, and seeking the narrative and lived experience of minorities to guide future public health communication and strategy (16, 72) . however, there is reason to be hopeful. perhaps the most important conclusion drawn from an analysis of the 1918 influenza pandemic is that minority communities are resilient, are resourceful, and find restoration in community. the most successful strategies to advance health equity would be to 1) examine the historical arc contextualizing current disparities in vulnerable communities; 2) recognize the inherent strengths in these communities, empowering them to participate in research and generate solutions alongside those who traditionally hold power; 3) acknowledge the contributions of frontline workers in communities of color; 4) prepare for future public health emergencies by enhancing minority civic participation; and 5) use a restorative justice framework to acknowledge and make amends for the structures contributing to disadvantages in these communities (73, 74) . taken together, these strategies provide the opportunity to use this challenging moment to transform clinical and public health practice by grounding it in social justice. although the covid-19 pandemic will eventually abate, its aftershocks will be perceptible for generations. there is no doubt that it will change public health practice and clinical delivery, which are intimately intertwined. yet, it will also shift the political and social landscapes. as arundhati roy recently wrote in "the pandemic is a portal": "we can choose to walk through it, dragging the carcasses of our prejudice and hatred, our avarice, our data banks and dead ideas . . . or we can walk through lightly, with little luggage, ready to imagine another world. and ready to fight for it" (75) . when the dust settles in the wake of covid-19, let us not allow ourselves to fall into a great amnesia, another forgotten pandemic. let us remember whom this disproportionately affected and why. taking this as impetus for mobilization, let us begin to rewrite the story of health disparities in america. in this new chapter, we will be better prepared to offer all citizens a fair and just opportunity to attain their highest level of health. current author addresses and author contributions are available at annals.org. covid-19 dashboard covid-19 fatalities covid-19 infection rates based on education and race. abc news chicago's coronavirus disparity: black chicagoans are dying at nearly six times the rate of white residents, data show hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease 2019 -covid-net, 14 states, march 1-30 arizona: 16 percent of covid-19 deaths are native americans. indian country today early data shows african americans have contracted and died of coronavirus at an alarming rate. propublica accessed at www.propublica.org/article/early-data -shows-african-americans-have-contracted-and-died-of-coronavirus -at-an-alarming-rate on 15 how racism is shaping the coronavirus pandemic minority groups at risk as states withhold, provide partial covid-19 racial data institute of medicine. unequal treatment: confronting racial and ethnic disparities in health care. national academies pr; 2003. 12. washington ha. medical apartheid: the dark history of medical experimentation on black americans from colonial times to the present you are a sweet, beautiful guy and my best friend. if anyone is #newyorktough it's you covid-19 and african americans this time must be different: disparities during the covid-19 pandemic historian draws parallels between the 1918 spanish flu and today's coronavirus pandemic the spanish flu killed more than 50 million people. these lessons could help avoid a repeat with coronavirus the 1918 influenza pandemic and covid-19. pbs race colors america's response to epidemics: a look at how jim crow affected the treatment of african americans fighting the spanish flu. the undefeated history in a crisis-lessons for covid-19 african americans, public health, and the 1918 influenza epidemic. public health rep childhood's deadly scourge: the campaign to control diphtheria infectious fear: politics, disease, and the health effects of segregation sick from freedom: african-american illness and suffering during the civil war and reconstruction immunities of empire: race, disease, and the new tropical medicine, 1900-1920 the health and physique of the negro american the geography and mortality of the 1918 influenza pandemic influenza: the mother of all pandemics the influenza epidemic and jim crow public health policies and practices in chicago an account of the bilious remitting yellow fever, as it appeared in the city of philadelphia, in the year 1793. thomas dobson the myth of innate racial differences between white and black people's bodies: lessons from the 1793 yellow fever epidemic in race and 1918 influenza pandemic in the united states: a review of the literature american pandemic: the lost worlds of the 1918 influenza epidemic report and handbook of the department of health of the city of chicago for years 1911 to 1918 inclusive. department of health of the city of chicago; 1919. 38. personal. afro-american (1893-1988) whole families in lewes have flu. afro-american proquest historical newspapers: the baltimore afro-american proquest historical newspapers: the baltimore afro-american closed on last sunday: one pastor boasted that services would be held at his church as usual. the board of health acts. philadelphia tribune baltimore afro-american baltimore afro-american. 20 december 1918 greenwood pr; 1976. 46. crosby aw. america's forgotten pandemic: the influenza of 1918 protection of racial/ethnic minority populations during an influenza pandemic germs and jim crow: the impact of microbiology on public health policies in progressive era american south half a million darkies from dixie swarm to the north to better themselves. chicago daily tribune black metropolis: a study of negro life in a northern city germs know no color: racial segregation in baltimore during the influenza pandemic of 1918-1919 apartheid baltimore style: the residential segregation ordinances of 1910-1913 /25/archives/baltimore-tries-drastic-plan-of-race-segregation-strange -situation the flexner report and black medical schools black nurses in the great war: fighting for and with the american military in the struggle for civil rights epidemic influenza and the negro physician desegregating harlem hospital: a centennial. the new york academy of medicine nonpharmaceutical interventions implemented by us cities during the 1918-1919 influenza pandemic public health interventions and epidemic intensity during the 1918 influenza pandemic baltimore city plans coronavirus ad campaign to combat myth that african american residents are immune. baltimore sun coronavirus fight shifts to baltimore's poor neighborhoods as city leaders battle mistrust. baltimore sun public communications and its role in reducing and eliminating health disparities. in: institute of medicine (us) committee on the review and assessment of the nih's strategic research plan and budget to reduce and ultimately eliminate health disparities examining the health disparities research plan of the national institutes of health: unfinished business failing another national stress test on health disparities covid-19 and health equity-a new kind of "herd immunity hospitalization and mortality among black patients and white patients with covid-19 social sources of racial disparities in health a game plan to help the most vulnerable data and policy solutions to address racial and ethnic disparities in the covid-19 pandemic what the surgeon general gets wrong about african americans and covid-19. cnn. 15 reducing racial inequities in health: using what we already know to take action restorative justice & other public health approaches for healing: transforming conflict into resiliency. lorenn walker blog accessed at www.ft.com/content/10d8f5e8-74eb-11ea-95fe-fcd274 e920ca on 17 history of medicine historical insights on covid-19, 1918 influenza, and racial disparities current author addresses: dr. krishnan: johns hopkins university school of medicine suite #2-300a critical revision of the article for important intellectual content historical insights on covid-19, 1918 influenza, and racial disparities key: cord-309513-dleo9rpl authors: zhang, huilan; zhou, peng; wei, yanqiu; yue, huihui; wang, yi; hu, ming; zhang, shu; cao, tanze; yang, chengqing; li, ming; guo, guangyun; chen, xianxiang; chen, ying; lei, mei; liu, huiguo; zhao, jianping; peng, peng; wang, cong-yi; du, ronghui title: histopathologic changes and sars–cov-2 immunostaining in the lung of a patient with covid-19 date: 2020-03-12 journal: ann intern med doi: 10.7326/m20-0533 sha: doc_id: 309513 cord_uid: dleo9rpl nan biopsy lung sections were analyzed with hematoxylineosin staining, and immunostaining for sars-cov-2 was conducted as reported elsewhere (1) . throat swabs were assessed for sars-cov-2 by using real-time reverse transcriptase polymerase chain reaction assays (2) . the ct scans revealed patchy bilateral ground glass-like opacifications ( figure 1a -c, arrows). despite antiviral therapies, respiratory and hemodynamic instability continued and the patient died 3 weeks after diagnosis. permission for postmortem transthoracic needle biopsy, but not autopsy, was obtained from the patient's family. histopathologic examination of lung biopsy tissues revealed diffuse alveolar damage, organizing phase. denuded alveolar lining cells ( figure 2 , a-1, arrow 1), with reactive type ii pneumocyte hyperplasia, were noted ( figure 2 , a-1, arrow 2). intra-alveolar fibrinous exudates were present ( figure 2 ( figure 2 , b, bottom panel, green arrows). in contrast, viral protein expression was minimally detectable on blood vessels ( figure 2 , b, dashed black line) or in the interstitial areas between alveoli (figure 2, b, bottom panel, blue arrows) . immu-nostaining of huh7 cells infected with sars-cov and of lung sections from an hiv-positive patient who died of fungal infection served as positive and negative staining controls, respectively (figure 2, c) . a. histopathologic examination revealing diffuse alveolar damage, organizing phase (a-1); denudation of alveolar lining cells (arrow 1), with presence of reactive type ii pneumocyte hyperplasia (arrow 2) (a-2); intra-alveolar fibrinous exudates (arrow 3) and interstitial loose fibrosis with chronic inflammatory infiltrates (arrow 4) (a-3); and intra-alveolar loose fibrous plugs (arrow 5) (a-4). in most foci, intra-alveolar organizing fibrin is seen (arrow 6). b. immunostaining of sars-cov-2 in lung sections. images were taken under light and fluorescent conditions, respectively (×100 magnification). merged images were also generated. blue arrows indicate interstitial areas between the alveoli, and green arrows indicate injured epithelial cells desquamated into the alveolar spaces. the dashed black lines indicate the blood vessel. immunostaining of sars-cov-2 was done by using a rabbit polyclonal antibody (made in house, 1:100) against the rp3 np protein, which is highly conserved between sars-cov and sars-cov-2, followed by probing with a cy3-conjugated goat antirabbit igg (1:50, abcam, ab6939). c. positive and negative controls for immunostaining. for the positive control, the huh7 cells were infected with sars-cov-2 at multiplicity of infection of 0.5 for 48 hours. after extensive washes, the cells were then fixed with 2.5% (wt/vol) glutaraldehyde. the infected cells were stained in red, and nuclei were stained with dapi (beyotime, wuhan, china) in blue. for the negative control, biopsy lung sections derived from a patient with hiv who died of fungal infection were stained in parallel with lung sections from the patient with covid-19 as above. note: authors indicated with an asterisk disclosures: authors have disclosed no conflicts of interest. forms can be viewed at www.acponline.org/authors/icmje/conflictofinterest forms.do? by the national natural science foundation of china (grants 81974456 and 91749207); the clinical research physician program of tongji medical college, huazhong university of science and technology (grant 5001540075); and the sars-cov-2 pneumonia emergency technology public relations project (grants 2020fca009 and a pneumonia outbreak associated with a new coronavirus of probable bat origin detection of 2019 novel coronavirus (2019-ncov) by real-time rt-pcr key: cord-313423-g50oh15t authors: lynch, holly fernandez; bateman-house, alison; joffe, steven title: emergency approvals for covid-19: evolving impact on obligations to patients in clinical care and research date: 2020-11-03 journal: ann intern med doi: 10.7326/m20-6703 sha: doc_id: 313423 cord_uid: g50oh15t there currently is debate regarding whether u.s. institutions and clinicians may or should restrict patient access to covid-19 drugs and vaccines that have been granted emergency use authorization by the u.s. food and drug administration. the authors provide their views on the legal, ethical, and clinical ramifications of such restriction. a central question for institutions and clinicians is whether their obligations to patients require them to offer eua products. these obligations depend not on a product's legal availability, but rather on the weight of the evidence supporting it. traditional fda approval typically supports clinical adoption of new standards of care because approval reflects a determination that a product's benefits outweigh its risks on the basis of a demonstration of safety and substantial evidence of effectiveness, a higher threshold than that required for an eua. in contrast, an eua should lead clinicians to shift the standard of care only if sufficient evidence exists to convince them that providing the intervention is in their patients' best interests. short of this, institutions can choose whether to offer the eua product to patients outside the standard of care, as can clinicians when permitted to do so by their institution's policy. although eua provisions allow the fda to lower its evidentiary standards temporarily, they do not compel others to do so. emergency use authorizations based on strong evidence can support a shift in the standard of care, even if important questions remain unanswered. for example, remdesivir's eua was based in part on topline data from the double-blind, randomized, placebo-controlled actt-1 (adaptive covid-19 treatment trial) demonstrating a shortened time to recovery for severely ill patients with covid-19 (5), a benefit confirmed upon final analysis (6) . results from the world health organization's solidarity trial subsequently called the drug's efficacy into question (7), demonstrating the evolving nature of these issues, although the fda ultimately granted remdesivir traditional marketing approval. despite concerns about whether that approval was warranted, given the data existing when the eua was granted and consensus guidelines recommending remdesivir's use, failing to offer the drug (when available) might have been viewed as improperly withholding an intervention from which severely ill patients could expect to benefit. in contrast, if an eua is based on weak evidence, such as observational data or uncontrolled trials-as in the case of convalescent plasma-institutions and clinicians can reasonably decline to offer the product without wronging eligible patients (8) . although malpractice litigation may follow, a successful claim requires that patients demonstrate a breached duty of care. the fda, nih, and idsa statements about convalescent plasma make that demonstration unlikely. litigation always carries some uncertainty, and even failed attempts are unpleasant and expensive, but treatment decisions should be guided by evidence, not fear of lawsuits. institutions and clinicians choosing not to offer authorized but unproven interventions may nevertheless wish to pursue trials of those interventions to develop critical evidence. limiting access to eua products exclusively to patients in trials may be justified on 2 grounds: first, uncertainty about whether the product's benefit-risk balance is truly favorable, and second, a desire to minimize recruitment problems stemming from nontrial access. although resolving uncertainty rapidly is critical for patients facing serious and lifethreatening conditions, such as covid-19, the trialsonly approach may prompt concerns about both voluntariness and fairness (9). this article was published at annals.org on 3 november 2020. restricting an eua product to trials clearly limits patients' choices and, when imposed by institutions, clinicians' discretion. this limitation is especially pronounced when transfer between institutions is difficult or impossible. if an eua is based on weak evidence, however, restricting access to trial participants is not coercive because patients are not threatened with the withholding of a standard-of-care intervention to which they are entitled. to the contrary, this approach is analogous to restricting off-label use of drugs being studied for new, as yet unproven indications, as well as to regulations restricting "expanded access" to patients who cannot enroll in a trial (9) . although patients may prefer nontrial access, restricting it in these circumstances is commonly viewed as a reasonable limitation while the necessary data are gathered. a more compelling concern about the trials-only approach is the potential for unjust disparities in access, especially given valid reasons for patients to distrust both research and medical institutions, including racism and other concerns. however, there is no guarantee that unproven interventions will be distributed more fairly outside of trials. moreover, especially in a public health emergency, it is reasonable to prioritize efforts to expeditiously resolve questions about the safety and efficacy of unproven products because this is what has the greatest potential to promote patient benefit (10) . institutions that restrict eua products to trials should inform surrounding communities and newly admitted patients of these constraints, although this is an imperfect solution. finally, to avoid injustice, institutions adopting such policies must not disproportionately be those serving disadvantaged communities and must not make exceptions for privileged patients. the authority to make drugs rapidly available may be useful in an emergency, but it entails important tradeoffs. emergency use authorizations expand treatment options, but only evidence should shift the standard of care. regardless of whether an eua has been granted, institutions and clinicians are not obligated to offer unproven interventions; rather, they must assess available evidence and treat patients accordingly. the decision to offer unproven eua products exclusively through clinical trials is therefore ethically permissibleand may be critical to enabling evidence-based treatment decisions. emergency use authorization letter for covid-19 convalescent plasma dozens of u.s. hospitals poised to defy fda's directive on covid plasma. kaiser health news national institutes of health. the covid-19 treatment guidelines panel's statement on the emergency use authorization of convalescent plasma for the treatment of covid-19. accessed at www .covid19treatmentguidelines.nih.gov/statement-on-convalescent -plasma-eua on 21 infectious diseases society of america guidelines on the treatment and management of patients with covid-19, part 1: treatment and management-recommendation 8: convalescent plasma vs. no convalescent plasma for hospitalized patients. last updated 25 emergency use authorization letter for veklury (remdesivir) actt-1 study group members. remdesivir for the treatment of covid-19 -final report repurposed antiviral drugs for covid-19-interim who solidarity trial results. medrxiv. preprint posted online 15 convalescent plasma for the treatment of covid-19: perspectives of the national institutes of health covid-19 treatment guidelines panel ethically allocating covid-19 drugs via pre-approval access and emergency use authorization treating covid-19-off-label drug use, compassionate use, and randomized clinical trials during pandemics disclosures: disclosures can be viewed at www.acponline.org /authors/icmje/conflictofinterestforms.do?msnum=m20-6703. key: cord-290070-534936lf authors: bornstein, sue s.; mire, ryan d.; barrett, eileen d.; moyer, darilyn v.; cooney, thomas g. title: the collision of covid-19 and the u.s. health system date: 2020-06-02 journal: ann intern med doi: 10.7326/m20-1851 sha: doc_id: 290070 cord_uid: 534936lf in this article, leaders from the american college of physicians (acp) discuss key recommendations from acp's vision for u.s. health care that can advise how we can act now during the covid-19 pandemic and in the future in service to patients, our peers, and the profession. t he coronavirus disease 2019 (covid-19) pandemic is wreaking havoc and causing fear, illness, suffering, and death across the world. this outbreak lays bare the fault lines in our society and highlights that the united states could have been better prepared for the pandemic had we a more equitable and just health care system. as leaders in the american college of physicians (acp), we have helped develop acp's wide-ranging policies on health care in the united states. the college has adopted a "health in all policies" approach, integrating health considerations into policymaking across sectors to improve the health and health care of all communities and people, which we believe, if enacted, would have enabled the united states to more effectively respond to the covid-19 pandemic. in january 2020, acp released a series of far-reaching position papers on acp's vision for the u.s. health care system (1) . as background to these papers, acp posed a question: what would a better health care system be like for all americans? in response, we proposed ways to achieve improved access to care, decrease per capita health care costs, and reduce complexity of our health care system. here, we focus on key recommendations from acp's position papers that can advise how to act now and in the future in service to patients, our peers, and the profession. before the covid-19 pandemic, at least 30 million americans were uninsured and many more underinsured (2) . although most u.s. workers have employerbased insurance, those covered decreased from 67.3% in 1999 to 55.9% by 2017, while increasing deductibles and copays were adding to the financial burden in accessing care. (3) more than 36 million americans have filed for unemployment since march 2020. for most, losing a job means losing employer-based health care. those who lose coverage can purchase insurance, but this is often prohibitively expensive. the $2 trillion cares act (coronavirus aid, relief, and economic security act) did not include insurance subsidies for the unemployed, mandates that companies receiving government assistance provide health care coverage for workers who get laid off, or requirements that affordable care act exchanges reopen enrollment (4) . equitable access to health care depends on having a robust primary care system. the pandemic highlights the need for increasing investment in primary care, which serves a particularly critical role during crises. primary care provides a sentinel surveillance system, firstline response, and mitigation of the burden currently placed on our nation's overrun emergency departments and hospitals. robust primary care with universal coverage can be a tool for health justice that can reduce morbidity and mortality, particularly in currently and historically marginalized patient groups. the covid-19 pandemic has underscored the adverse effects of our current system on primary care: in a recent survey of primary care practices, 76% reported severe or close-to-severe strain on their practice (5) . the american college of physicians envisions a health care system where everyone has coverage for and access to the care they need, at a cost they and the country can afford. to achieve this vision, the acp recommends the following policies: the the american college of physicians supports greater investment in primary care and preventive health services, including support for the unique role played by internal medicine specialists in providing high-value primary, preventive, and comprehensive care of adult patients. as described in the january 2020 acp position papers, universal coverage would reinforce our increasingly underfunded safety net and ensure all americans have accessible, affordable, and comprehensive health care. the continued trajectory of increasing per capita spending on u.s. health care threatens the stability of our current system when we can least afford it. in comparison to countries with nationally coordinated systems of health care that have successfully limited spread of the virus, such as australia, new zealand, and taiwan, the u.s. response to covid-19 was delayed, uncoordinated, and less effective (6, 7) . methods employed by new zealand and taiwan, including tracking travel and contact history for every patient, timely mass testing, and early restriction of activity, could have been replicated in the united states if it had a robust this article was published at annals.org on 2 june 2020. system for primary care and national coordination under a universal coverage model. prior pandemics disproportionately affected groups that have been marginalized and excluded on the basis of socioeconomics, race, and ethnicity. the covid-19 pandemic is no exception. across the united states, deaths from covid-19 are disproportionately high in african-american, latinx, and native american communities (8, 9) . these same groups have the highest rates of low health literacy (10) . racial and ethnic minorities make up a significant percentage of "essential workers" with a greater risk for exposure to the virus. similarly, immigrants who work in places like meatpacking factories and the incarcerated population face higher risk. social distancing is more difficult in areas with high population density, multigenerational households, or high reliance on public transit. public policies that relieve environmental, geographic, occupational, educational, and nutritional inequities must be implemented to reduce disparate health outcomes and engender trust in the health care system. the american college of physicians envisions a health system that ameliorates social factors that contribute to poor and inequitable health (social determinants); overcomes barriers to care for vulnerable and underserved populations; and ensures that no person is discriminated against based on characteristics of personal identity, including but not limited to race, ethnicity, religion, gender or gender identity, sex or sexual orientation, or national origin. we believe more than ever that better is possible. the covid-19 pandemic has further demonstrated that the status quo is unacceptable and strengthens our resolve to help shape a better health care system for all americans. this pandemic has ripped the seams of the u.s. health care system wide open, thrusting front and center our health care inequities and injustices. the bigger challenge moving forward is how we can take the lessons learned from this time of great suffering and fear to create an equitable and just system of care for all. health and public policy committee and medical practice and quality committee of the american college of physicians. envisioning a better u.s. health care system for all: a call to action by the american college of physicians who are the remaining uninsured and why do they lack coverage? findings from the commonwealth fund biennial health insurance survey coverage at work: the share of nonelderly americans with employer-based insurance rose modestly in recent years, but has declined markedly over the long term the daily 202: losing a job can also mean losing health coverage, adding to anxiety amid coronavirus pandemic commonwealth fund to the point [blog coronavirus: how australia's 'suppression' approach is rapidly flattening the curve. the independent president of taiwan: how my country prevented a major outbreak of covid-19 covid-19's devastating toll on black and latino americans in one chart coronavirus has been devastating for the navajo nation, and help for a complex fight has been slow awareness, attitudes, and actions related to covid-19 among adults with chronic conditions at the onset of the u.s. outbreak: a cross-sectional survey current author addresses: dr. bornstein: 3111 beverly drive mire: 4230 harding road american college of physicians, 190 n. independence mall west department of medicine op30, 3181 sw sam jackson park road administrative, technical, or logistic support: s.s. bornstein. collection and assembly of data the collision of covid-19 and the u.s. health system key: cord-318876-m1v0ij84 authors: spagnolo, primavera a.; manson, joann e.; joffe, hadine title: sex and gender differences in health: what the covid-19 pandemic can teach us date: 2020-05-08 journal: ann intern med doi: 10.7326/m20-1941 sha: doc_id: 318876 cord_uid: m1v0ij84 the authors of this commentary call for sexand gender-specific and differentiating factors to be urgently included in the research, prevention, and therapeutics implementation response to the coronavirus disease 2019 pandemic. s ex; biological and physiologic traits characterizing males and females; and gender, a continuum of socioculturally constructed roles and behaviors associated with men, women, and gender-spectrum diversity, are among the most important determinants of health and disease outcomes. however, these fundamental factors are often ignored in biomedical research and are rarely incorporated into clinical care. we call for sex-and gender-specific and differentiating factors to be urgently included in the research, prevention, and therapeutics implementation response to the coronavirus disease 2019 (covid-19) pandemic. although available sex-disaggregated data for covid-19 show equal numbers of cases between sexes, current evidence indicates that fatality rates are higher in men than in women. a recent report (23 april 2020) from the italian national institute of health shows that of 23 188 deaths from covid-19 infection in italy, approximately 70% were in men. in the united states, provisional death counts for covid-19 from february to april 2020 similarly indicate a sex bias in fatality rates: of 37 308 deaths reported by the national center for health statistics, 59% were in men. similar trends have been reported in china (1) and south korea (2) . taken together, these preliminary data suggest that sex-and gender-related factors may be implicated in covid-19 vulnerability. as scientists, we may consider this an interesting observation to be explored in post hoc analyses, using available sex and gender data. or we can investigate a priori the specific role of these factors and potentially leverage the mechanisms implicated in sex and gender differences in covid-19 risk, progression, and outcomes, to identify effective prevention and treatment interventions for the entire population. adopting a sex-and gender-informed perspective in research has already shown to improve patient care for cardiovascular diseases and other conditions that affect both women and men (3) . translating this perspective to the study of covid-19 infection requires the first and essential step of collecting large-scale sex-and gender-disaggregated data. this task may pose some methodological challenges for gender, given the lack of validated tools to assess gender. using sex when reporting biological factors and gender when reporting gender identity or sociocultural factors, and asking individuals about both their sex assigned at birth and their current gender identity, may facilitate data collection and improve comparability across studies. however, truly sex-and gender-informed research exceeds mere stratification by these variables. researchers should also systematically assess biological (such as hormonal state, immune function, comorbid conditions, and concurrent treatments) and genderrelated (such as lifestyle and socioeconomic status) factors in patients with covid-19. furthermore, as clinical trials investigating novel therapeutics to prevent and treat covid-19 infection are being launched worldwide, it is imperative to incorporate sex-and genderrelated data into these trials and to analyze and report treatment outcomes disaggregated by sex and gender. taking these actions will be crucial to address several fundamental questions related to covid-19. for example, we may elucidate to what extent sex biases in covid-19 outcomes are linked to differences in sex hormone profiles. sex hormones contribute to different immunologic responses in men and women: as a general rule, estrogens promote both innate and adaptive immune responses, which result in faster clearance of pathogens and greater vaccine efficacy. conversely, testosterone has largely suppressive effects on immune function, which may explain the greater susceptibility to infectious diseases observed in men (3) . notably, changes in sex hormone may further shape the immune response to pathogens, highlighting the importance of studying factors that affect such levels (for example, age, pregnancy, menstrual cycle, exogenous sex-hormone therapies, men, and transgender individuals). sex-related biological data may also be critical to investigate the contribution of sex hormones to sex differences in inflammatory response. in particular, reduction in testosterone levels in aging men has been associated with increased proinflammatory cytokine levels (4), which may contribute to worse covid-19 progression in older men. sex differences in disease progression may also be linked to estrogen-induced decreased expression of angiotensin-converting enzyme 2 (5), which acts as a functional receptor for sars-cov-2 (the virus causing covid-19) to enter host target cells. investigating sex hormone-influenced mechanisms and, more broadly, conducting sex-and genderinformed research may optimize the development of novel therapeutics and shed light on drug efficacy, safety profiles, and adherence to treatments currently tested for covid-19, given that sex differences in pharmacokinetics and pharmacodynamics influence therapeutic effects and risk profiles of numerous medications, and that gender-related factors affect adherence to treatment, access to health care, and health-seeking behaviors (3) . stress-related disorders and the long-term consequences of covid-19 on health outcomes highlight another important effect of sex and gender. beyond being a pandemic infectious disease, covid-19 also acts as a potent stressor, with millions of individuals experi-this article was published at annals.org on 8 may 2020. encing fear and social isolation over a prolonged period. exposure to persistent stress is associated with increased vulnerability to and severity of stress-related psychiatric disorders (such as posttraumatic stress disorder, panic disorder, and major depression), which occur more frequently in women than men (6) . indeed, preliminary evidence from china during the initial phase of the covid-19 outbreak shows an increased prevalence and severity of depressive, anxious, and posttraumatic symptoms in women than in men (7). this gender bias is supported by evidence of sex differences in stress response systems, which increase endocrine, affective, and arousal responses to stress in females (6, 8) , who also appear to be more susceptible to social isolation (9) . gender-related factors, such as the predominant roles of women as family caregivers and as frontline health care workers, further exacerbate stress exposure. we have the unprecedented opportunity to conduct large longitudinal studies to directly test whether the relationship between stress exposures and the prevalence and presentation of stress-related psychiatric disorders is mediated by sex-and genderrelated factors. on the basis of these observations, we call on scientists and biomedical institutions to recognize the importance of investigating sex-and gender-specific and differentiating effects of covid-19 to develop and implement prevention and treatment interventions able to address the acute and long-term effects of this pandemic on the health and well-being of the population. by doing so, we will reshape the way we think about diseases as we conceive and conduct research, thus optimizing health for the entire population. clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study disparities in age-specific morbidity and mortality from sars-cov-2 in china and the republic of korea. clin infect dis clinical advances in sexand gender-informed medicine to improve the health of all: a review the anti-inflammatory effects of testosterone sex-specific sars-cov-2 mortality: among hormone-modulated ace2 expression, risk of venous thromboembolism and hypovitaminosis d sex differences in vulnerability and resilience to stress across the life span prevalence and predictors of ptss during covid-19 outbreak in china hardest-hit areas: gender differences matter sex-specific mechanisms for responding to stress sexually dimorphic neuronal responses to social isolation gender, and the covid-19 pandemic key: cord-280672-6x968dwk authors: fisman, david n.; greer, amy l.; tuite, ashleigh r. title: age is just a number: a critically important number for covid-19 case fatality date: 2020-07-22 journal: ann intern med doi: 10.7326/m20-4048 sha: doc_id: 280672 cord_uid: 6x968dwk in their article, sudharsanan and colleagues show the importance of adjusting for the age distribution of cases of coronavirus disease 2019 before doing cross-country comparisons of case-fatality rates. the editorialists explore the effect of age distribution on these rates and other determinants of between-country variation in the severity of this disease. a pandemic, by definition, represents worldwide, simultaneous epidemics caused by a novel pathogen. the multinational nature of such an event inevitably leads to cross-national comparisons of epidemic growth, impact, and public health response. such comparisons lend themselves to ecological research: for example, the apparent slower epidemic growth rates in countries that use bacilli calmette-gué rin (bcg) vaccine has caused some researchers to assert that bcg vaccination may affect susceptibility to severe acute respiratory syndrome coronavirus 2 (1) . others have made similar observations about higher mean temperature and slower growth of the coronavirus 2019 (covid-19) epidemic (2) . these national-level comparisons are vulnerable to "ecological fallacy," or attribution of individual-level outcomes to aggregate exposures (3). however, they also represent "unfair comparisons" (3), because the countries in question differ fundamentally on a confounder known to be associated with covid-19 severity: age. the association among age, disease severity, and covid-19 case recognition has been clear since february 2020 (4) . older cases are more likely to be represented in surveillance data owing to greater severity and hence ascertainment. failure to recognize younger, milder cases diminishes the denominator in case-fatality ratio (cfr) calculations (that is, deaths/cases), so between-country differences in age structure explain some fraction of observed between-country variation in epidemic severity and case-fatality. an analysis by sudharsanan and colleagues (5) used data from 9 countries to demonstrate the importance of adjusting for the age distribution of cases before doing cross-country comparisons of cfr. to ensure that between-jurisdiction comparisons are fair comparisons, the authors used the epidemiologic tool of standardization (6) . direct standardization by age requires estimation of age-specific risk from different populations, which are then applied to a standard population, such that resultant differences in overall risk cannot be due to differences in population age structure. in their analysis, the authors show that adjusting for differences in population age structure substantially reduces the observed differences between country-specific cfrs. to further explore the effect of age distribution on cfr, we can take the standardization approach used by sudharsanan and colleagues and turn it on its head. we can apply age-specific risk from a single epidemic to other countries, to observe how an identical epidemic, from an age-specific attack rate point of view, might be perceived differently in different places, simply due to different age structures. here, we use data from mainland china for the 66-day period from 7 december 2019 to 11 february 2020 (4). the analyses described below can be further explored in an associated app (https ://art-bd.shinyapps.io/time_to_outbreak_detection/). when the reported cfr for february 2020 in mainland china (2.3%) is age-standardized using population pyramids from other countries (7), standardization to a country with a younger population structure, such as indonesia, markedly reduces observed cfr (1.7%), whereas adjustment to a country with an older population, such as italy, increases the cfr (3.9%). we can also estimate epidemic size using this approach but need to adjust for population size as well (larger countries, for a given attack rate, will have larger epidemics). we define the ratio of population in the other, comparator country (p o ) to the chinese population (p c ) as r p = p o /p c . the ratio of the epidemic size in the other, comparator country (e o ) to observed chinese epidemic size (e c ) is defined as r e = e o /e c . the "ratio of ratios" is r e /r p , which can be interpreted as the relative apparent outbreak size when an outbreak with identical age-specific attack rates occurs in a population with an age-structure that differs from that of mainland china. just as cfr for an identical epidemic is expected to be higher in countries with older populations, the ratio of ratios, r e /r p , is greater than 1 for countries with older populations (1.15 for italy) and less than 1 for countries with younger populations (0.81 for indonesia). in other words, identical epidemics, adjusted for population size, appear smaller in countries with younger populations (shorter life expectancy) than in those with older populations (increased life expectancy), even with identical age-specific attack rates. age structure may also affect the time to recognize an epidemic. countries with younger populations are likely to have more silent spread and be slower to identify epidemics. this may have been the root cause of a controversy that emerged early in the covid-19 pandemic: indonesia was predicted by models to have early importation of covid-19 cases, but this was not consistent with indonesian observations (8) . critical illness and death associated with covid-19 may result in initial outbreak identification and are more likely to occur in older individuals; we can arbitrarily define "older" as age greater than 59 years. we can calculate the incidence rate for observed infection, and the rate of transition to death, among susceptible older individuals in the mainland chinese population in the early days of the epidemic by using an exponential failuretime model combined with published natural history data (4, 9) . when we simulate the mainland china epidemic in other countries, deaths accumulate more quickly in countries with high life expectancy (older populations) and more slowly in those with low life expectancy (younger populations). this is not to say that age distribution is the only determinant of between-country variation in epidemic severity. as sudharsanan and colleagues (5) show, once age-related effects are removed, variability in cfr estimates remains. differential outbreak responses are likely responsible for some of this variability (2): weak public health responses that result in overwhelmed intensive care units will cause case fatality to inflect upward. failure to adequately protect long-term care facilities from covid-19 will swell cfr estimates as well. availability of testing is another key determinant of observed case fatality: a recent analysis found that more testing increases the case numbers in the cfr denominator, resulting in lower cfr, with residual variability in cfr explained by age structure and country per capita gross domestic product (10) . finally, decisions about which deaths to classify as "covid-19attributable" vary across countries. serologic testing will ultimately help determine the true infection fatality ratio for covid-19 and better quantify underrecognition of cases by age, but until such data are widely available, standardization provides a straightforward first step to ensure that between-country comparisons are fair comparisons. correlation between universal bcg vaccination policy and reduced morbidity and mortality for covid-19: an epidemiological study. medrxiv. preprint posted online 28 impact of climate and public health interventions on the covid-19 pandemic: a prospective cohort study ecological fallacy and aggregated data: a case study of fried chicken restaurants, obesity and lyme disease vital surveillances: the epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (covid-19)-china, 2020. china centers for disease control weekly the contribution of the age distribution of cases to covid-19 case fatality across countries. a 9-country demographic study standardization: a classic epidemiological method for the comparison of rates r: a language and environment for statistical computing. r foundation for statistical computing. 2020. accessed at www.r-project using predicted imports of 2019-ncov cases to determine locations that may not be identifying all imported cases. medrxiv. preprint posted online 11 mathematical modelling of covid-19 transmission and mitigation strategies in the population of ontario estimating the global infection fatality rate of covid-19. medrxiv. preprint posted online 11 key: cord-323054-m8hkj1dm authors: schwartz, rachel; sinskey, jina l.; anand, uma; margolis, rebecca d. title: addressing postpandemic clinician mental health: a narrative review and conceptual framework date: 2020-08-21 journal: ann intern med doi: 10.7326/m20-4199 sha: doc_id: 323054 cord_uid: m8hkj1dm previous pandemics have seen high psychiatric morbidity among health care workers. protecting clinician mental health in the aftermath of coronavirus disease 2019 (covid-19) requires an evidence-based approach to developing and deploying comprehensive clinician mental health support. in a narrative review of 96 articles addressing clinician mental health in covid-19 and prior pandemics, 7 themes emerged: 1) the need for resilience and stress reduction training; 2) providing for clinicians' basic needs (food, drink, adequate rest, quarantine-appropriate housing, transportation, child care, personal protective equipment); 3) the importance of specialized training for pandemic-induced changes in job roles; 4) recognition and clear communication from leadership; 5) acknowledgment of and strategies for addressing moral injury; 6) the need for peer and social support interventions; and 7) normalization and provision of mental health support programs. in addition to the literature review, in collaboration with the collaborative for healing and renewal in medicine (charm) network, the authors gathered practice guidelines and resources from health care organizations and professional societies worldwide to synthesize a list of resources deemed high-yield by well-being leaders. studies of previous pandemics demonstrate heightened distress in health care workers years after the event. the covid-19 pandemic presents unique challenges that surpass those of previous pandemics, suggesting a significant mental health toll on clinicians. long-term, proactive individual, organizational, and societal infrastructures for clinician mental health support are needed to mitigate the psychological costs of providing care during the covid-19 pandemic. t he coronavirus disease 2019 (covid-19) pandemic has exacerbated preexisting burnout and moral injury in health care professionals. clinicians are dying not only of physical manifestations of covid-19, but also of the emotional and mental health repercussions of caring for persons who are suffering without loved ones by their side (1) (2) (3) . concerns about adequate personal protective equipment (ppe), reliable testing, absence of specific treatments, risk for infection to self and family, lack of access to up-to-date information among ever-changing guidelines, and uncertainty about containment of disease also threaten clinician well-being (4, 5) . many health organizations have already committed resources to clinician well-being, including chief wellness officer positions and well-being programs (6) . these institutions must adapt their existing well-being infrastructure to meet evolving needs. other organizations have yet to establish such programs and will benefit from a blueprint for a coordinated, systemic approach. evidence from previous epidemics and disasters underscore clinicians' high risk for long-term mental health issues and emphasize the need for continued support during and after the pandemic (7) (8) (9) (10) . the covid-19 pandemic has necessitated rapid development and deployment of innovative solutions in medicine, including well-being resources for clinicians. as we look to an uncertain future, a conceptual framework for how to develop and deploy these resources will facilitate well-being endeavors and provide a foundation for addressing long-term needs. we performed a literature review and compiled a comprehensive guide to clinician mental health and well-being resources compiled by well-being leaders. we provide a conceptual map for allocation of these resources at the individual, organizational, and societal levels, focusing on addressing clinician well-being needs in the postpandemic phase. this narrative review targeted the existing literature on clinician mental health and wellness needs in response to both covid-19 and previous pandemics. psycinfo, pubmed, scopus, and web of science were searched by using the keywords "covid* or corona*" "mental health", "trauma", "resilienc*", "coping", "anxiety", "burnout", "wellness or wellbeing", "occupational stress" "frontline or medical or hospital or health care workers or medical students or physician or nurse" "pandemic or outbreak or surge". articles were included if they provided evidence on 1) prevalence of mental health symptoms during or after the pandemic and 2) individual, organizational-level, or societal-level responses to or assessment of mental health in health care workers. the dates of the literature search were july 2004 (to capture the first severe acute respiratory syndrome [sars] outbreak) through may 2020. ongoing updates to the initial search were conducted through the end of may 2020 to capture additional in-press articles. each author was responsible for searching 1 database, and included articles were reviewed by all 4 authors to determine their relevance. this peer-review process yielded 96 articles included in the narrative review. in addition to the comprehensive literature search described, we peer-reviewed well-being resources gathered by the collaborative for healing and renewal in medicine (charm) network. the charm network is a group of medical educators, leaders in academic medicine, experts in burnout research and interventions, and trainees working together to promote well-being among trainees and practicing physicians (11) . this action-oriented group, through regular teleconferences and electronic communication, focused on creating deliverables for widespread dissemination during the covid-19 pandemic to support the well-being of health care workers and their organizations. we reviewed practice guidelines and resources from numerous health care organizations and professional societies worldwide across various specialties (table) . through the charm network, we gathered and then reviewed and annotated various media, including web site resources, podcasts, popular media articles, web-based applications, and any resource deemed high-yield by well-being leaders. clinician well-being efforts fall into 3 interrelated categories: individual (for example, emotional awareness and self-care), organizational (for example, mental health support programs, engaged leadership), and societal (for example, supportive culture in medicine, national policies that enhance well-being) (12) (figure) . this review yielded insight in 2 areas: the prevalence of clinician mental health needs during and after a pandemic, and postpandemic strategies for comprehensive clinician mental health support. the mental health toll of past pandemics on health care workers has been well documented. chong and colleagues (8) estimated 75% psychiatric morbidity among health care workers in a tertiary hospital in china during the recovery phase of the sars epidemic. goulia and colleagues (13) found that 56.7% of health care worker participants reported moderately high anxiety during the a/h1n1 pandemic in greece, noting that degree of worry was an independent correlate of anxiety. maunder and colleagues (14) reported significantly higher levels of distress, burnout, and posttraumatic stress in health care workers who treated patients the covid-19 pandemic presents unprecedented psychological threats to clinician well-being; evidence from previous epidemics and disasters underscore clinicians' high risk for long-term mental health issues and emphasize the need for comprehensive mental health support during the covid-19 recovery phase. addressing clinician wellness requires proactive support, because this population is known for not seeking support and for putting others' needs before their own. developing institutional and societal infrastructure that ensures clinicians' basic needs are met and arms them with psychological and social support tools is necessary to mitigate the known psychological costs of providing care during a pandemic. with sars compared with their colleagues who did not have direct contact with patients with sars. health fear, social isolation, and job stress were mediating factors. two months into the sars pandemic, chan and huak (15) found that about 20% of health care workers in a hospital in singapore reported symptoms indicative of posttraumatic stress. after the sars outbreak in taiwan, bai and colleagues (16) reported a range of stressrelated responses, such as acute stress disorder, feelings of stigmatization and rejection, and reluctance to go to work. there has been growing evidence of distress and mental health issues among health care workers treating patients with covid-19. dzau and colleagues (6) noted moral distress, anxiety, and suicide as negative effects of the covid-19 pandemic and caution about possible increases in burnout. depression, anxiety, insomnia, and distress have been reported among health care workers in china during this pandemic (17) . a systematic review of covid-19 -related studies reported stress, anxiety, depression, and insomnia among health care workers (18) . excessive work hours, inadequate ppe, infection rate among medical staff, feeling a lack of support, and extensive media coverage were noted as factors associated with adverse psychological outcomes. in trying to understand anxiety associated with covid-19, maben and bridges (19) outlined possible mental health-related issues in nurses in the united kingdom, such as moral distress and fatigue, discomfort, and difficulties in communication due to wearing masks and full ppe. stigma among the larger community and being perceived as a threat to safety of others were other issues that they outlined. kisely and colleagues (10) conducted a systematic analysis of studies documenting the mental health effects of pandemics, such as covid-19, sars, middle east respiratory syndrome, h1n1, h7n9, and ebola. they reported that staff in direct contact with patients had higher levels of posttraumatic stress and psychological distress. women, younger clinicians, and parents with dependent children were demographic fac-tors associated with greater psychological distress. shanafelt and colleagues (4) found that 8 themes emerged in discussions with health care workers: inadequate ppe, exposure to self and carrying of infection to family members, lack of rapid testing availability in the face of symptom development, exposing others at work, access to child care resources, support for other personal and family needs, uncertainty about organizational support, lack of up-to-date information and communication, and feelings of inadequacy if deployed to new areas. a qualitative study with general surgery residents in 2 boston centers found that the health of their family, risk for being infected by patients, risk for carrying infection to family members, anticipatory overwork due to patients with covid-19, and risk for infecting patients were common concerns (20) . in a survey of surgical residents, more than one half of respondents reported psychological strain as a result of the pandemic (21) . environments that combine high levels of anxiety with prolonged uncertainty and reduced agency place clinicians at high risk for developing persistent stress exposure syndromes and burnout (22) . the covid-19 pandemic presents unprecedented challenges due to prolonged uncertainty and heightened anxiety, immediate threat to personal and family safety, social isolation, witnessing physical suffering and death, and evolving professional demands. these individual stressors combine to induce hyperarousal, hypervigilance, sleep disturbance, intrusive thoughts, depression, and grief (23). schreiber and colleagues (24) reported that when first responders experienced 6 or more cumulative stress factors or 3 specific factors (performing duties outside their perceived skill set; witnessing a coworker become sick or injured, or die; and feeling that their own life is in danger), they were at higher risk for developing posttraumatic stress disorder 3 months later. seven themes, and associated interventions, emerged from the literature (figure) : 1) the need for resilience and stress reduction training; 2) providing for clinicians' basic needs (food, drink, adequate rest, quarantine-appropriate housing, transportation, child care, ppe); 3) the importance of specialized training for pandemic-induced changes in job roles; 4) recognition and clear communication from leadership; 5) acknowledgment of and strategies for addressing moral injury; 6) the need for peer and social support interventions and; 7) normalization and provision of mental health support programs. across studies, there was an emphasis on implementing training programs that target clinician selfcare, normalize anticipated psychological response to crisis, and promote adaptive response and self-efficacy (22, 24 -27) . schreiber and colleagues' (24) anticipate, plan, and deter (apd) model incorporates pre-event training ("anticipate"), explaining the nature of cumulative responder stressors and anticipated stress reactions; development of a personal resilience plan ("plan") to identify and document anticipated challenges and positive coping strategies; and trains participants on self-monitoring stress exposure to know when to implement personal resilience plans ("deter"). albott and colleagues (22) developed a psychological resilience intervention that focused on self-care, selfefficacy, and social connection while providing rapid ongoing access to mental health support. blake and colleagues (26) developed and disseminated a digital e-package with evidence-based guidance for psychological well-being. the content focused on self-care strategies at work and home, managing emotions, and encouraging help-seeking behavior. fessell and cherniss (25) identified actionable "micropractices" for physicians to implement during the workday, such as wellness selfchecks and naming emotions. practice implications. given the demonstrated value of stress reduction and resiliency training, integrating these practices as a key part of clinician training may reduce distress. strategies for addressing clinicians' basic needs during the covid-19 pandemic ranged from covering basic meals and transportation needs to establishing a "well-being area" within the hospital in which staff and volunteers could rest (28) and providing living quarters, complete with food and living supplies, so that clinicians to safely quarantine from family (4, 29 -31). one chinese hospital helped clinicians create videos of their work routines to share with family to assuage concerns (29) . institutions in urban settings, where most rely on public transit, chose to subsidize clinicians' transportation, exploring bicycle and car rental options (30) . child care coverage and ppe are other essential needs (4, 31, 32). some cities provided centers for children of health care workers, whereas other institutions developed volunteer programs connecting nonessential employees with frontline clinicians (30) . practice implications. ensuring that clinicians' basic needs (food, adequate rest, shelter, transportation, child care, and ppe) are met is essential for their psychological well-being. although not mentioned in the reviewed articles, the unfolding financial impact of the covid-19 pandemic is another stressor whose effect has yet to be measured. delivering care during a pandemic requires operating in a high-anxiety environment and, in many cases, being prepared to assume new professional roles to meet evolving needs. training clinicians on infection control was shown to alleviate stress (33), because it arms them with protective tools. formalized training on how to identify and respond to patients' psychological distress was requested as another strategy for clinician support (29) . finally, redeployment to a new clinical role in the case of a patient surge was a core source of anxiety that could be addressed through assessment of clinician skill sets before redeployment, targeted training, and improved information about redeployment plans (27, 34) . practice implications. hospitals should consider adopting specialized skills assessment and training programs and use clear communication practices around redeployment to prepare for future needs. many articles spoke to the importance of clinicians receiving recognition from leadership and the effect this had on well-being. receiving recognition from hospital and government leaders was a motivational factor that supported covid-19 clinicians' ability to continue delivering care (5) . transparent, bidirectional communication empowers clinical teams and improves morale (31, 32) . delivering current, reliable, and reassuring messaging improves transmission of critical information to clinical teams (30) . effective strategies include synthesizing information into a daily digest that links to a comprehensive resource page and providing weekly virtual town halls to disseminate critical information (30) . practice implications. leadership can leverage communication strategies to provide clinicians with up-to-date information and reassurance. the ethical, social, and professional obligations toward their profession are frequently reported as the core motivator for clinicians' decision to provide care while putting themselves at risk (5, 35) . this commitment to serving others, even at the cost of their own well-being, makes clinicians a uniquely vulnerable pop-review addressing postpandemic clinician mental health ulation. moral injury is defined as psychological distress caused by a betrayal of what is right by someone in authority in a high-stakes situation (36) , or witnessing, perpetrating, or failing to prevent acts that transgress core moral beliefs (37) . the covid-19 pandemic presents multiple potential sources of moral injury for clinicians, such as determining which patients will not receive life support owing to inadequate resources or bearing witness to (and having to enforce) policies that lead to patients dying alone (31) . williamson and colleagues (38) identified a set of strategies for addressing moral injury in frontline covid-19 clinicians. they recommend making clinicians aware of the possibility of moral injury and associated symptoms. encourage clinicians to seek informal support from colleagues, managers, or chaplains and provide rapid access to professional help; however, it is known that those suffering from moral injury often fail to discuss it owing to shame and guilt. as a result, leadership must proactively and routinely monitor the psychological well-being of their teams. practice implications. clinicians are unlikely to disclose moral injury. psychological well-being should proactively be assessed, and both informal and professional support should be readily available to clinicians. depriving humans of social connection comes at a high psychological cost (33) , and the covid-19 pandemic interferes with the ability to connect with colleagues and even one's own family owing to mandatory infection control precautions. social support is associated with decreased stress and anxiety and increased self-efficacy and sleep quality (39) . to sustain clinician well-being, heightened attention must be paid to fulfilling their social support needs. whereas peer support occurs on an individual level, institutional programs provide a structured approach to building peer support and connection. one innovative strategy by albott and colleagues (22) involved implementing a "battle buddy" model borrowed from the military that paired individuals on the basis of clinical area of practice, career stage, and life circumstance. each partner in the team engages in daily conversation and looks out for the other's well-being. if distress is observed, mental health support is proactively deployed. walton and colleagues (31) provide a comprehensive description of the physical, behavioral, emotional, and cognitive indicators of acute stress reactions; training clinicians to be aware of these reactions, in themselves and others, may allow for better peer support and intervention. other proposed solutions include routinely holding schwartz rounds, an interprofessional forum for health care professionals to discuss the emotional, social, and ethical challenges of work, during changing shift periods (40) . practice implications. providing routine opportunities for social connection can improve clinician well-being. the provision of clinician mental health support is not currently standard practice in the united states. self-report questionnaires and observations of frontline clinicians during the covid-19 pandemic demonstrated that they are unlikely to seek out psychological support resources (5, 29, 38) , despite the availability of these resources. leadership can normalize mental health support by modeling self-care and help-seeking behaviors (31) , ensuring that available mental health resources are well-publicized, and developing a culture of caring with frequent check-ins with colleagues to assess psychological well-being and a protocol for professional referrals as needed. establishing opportunities for clinicians to anonymously share concerns allows them to safely advocate for themselves and their patients (6) . on a societal level, it is necessary to establish new infrastructure that will sustain and supplement existing clinician support programs. dzau and colleagues (6) recommend allocation of federal funding to care for clinicians who have been impacted by their covid-19 service and establishing a national epidemiologic tracking program to track clinician well-being and the effect of wellness interventions. developing multidisciplinary mental health teams at the regional and national levels can allow clinicians greater access to needed resources (18, 41) . practice implications. routine provision of mental health education and support needs to be delivered proactively to protect long-term clinician well-being. federal funding for clinician well-being is needed to track clinician wellness and establish the resources necessary to care for those negatively affected by their covid-19 service. crisis and virtual mental health services must be easily accessible for health care workers. the table provides details on the resources discussed in this section. the physician support line (42) is a national, free, and confidential support line service made up of volunteer psychiatrists, joined together to provide peer support for their physician colleagues. for those in crisis, additional resources include the national suicide prevention hotline (43) and crisis text line (44) which operate 24/7. mindfulness resources for emotional regulation have been shown to decrease physician burnout (45) . headspace (46) , a popular mindfulness web-based application, is offering free membership to u.s.-based health care professionals to help cope with stress and anxiety with resources for sleep, meditation, and movement exercises. the accreditation council for graduate medical education (acgme) aware well-being resources (47) include video workshops, podcasts, and a web-based application designed to promote wellbeing in the graduate medical education community. the well-being in the time of covid-19 podcast by stuart slavin, md, (acgme's senior scholar for wellbeing) provides well-being strategies for residents, fellows, and other clinicians from resources that include psychology and psychiatry, peer support programming, the military and veterans affairs, and literature for support of first responders to mass casualty events. the national academy of medicine (48) web site is a clearinghouse of resources to support the health and well-being of clinicians that includes links to numerous global health, governmental, and medical society recommendations. the centers for disease control and prevention (49) collated a comprehensive list of factors to consider during covid-19 related to coping and stress, including considerations for first responders, and also serves as a resource for communities, families, and people at higher risk for serious illness. the center for the study of traumatic stress (50) is a high-yield, well-edited resource library with material targeted for health care workers, leaders, and families, including fact sheets, journal articles, textbook chapters, webinars, and infographics within the public domain. the united kingdom's intensive care society (51) offers a well-being resource library includes visual resources that can be displayed to educate staff on self-care, sustaining staff well-being during covid-19, and specific critical care workplace interventions to improve local environments. across studies, frontline workers are at highest risk for developing acute stress, depression, anxiety, and insomnia (17, 33, 52) . approximately 45% of 1153 italian covid-19 frontline clinicians experienced at least 1 physical symptom of burnout in the previous 4 weeks. increased irritability, change in food habits, difficulty falling asleep, and muscle tension were frequently experienced by the majority of respondents (53) . one covid-19 study showed twice the rates of anxiety and depression in frontline providers compared with nonclinical staff (54), whereas a sars study showed psychiatric morbidity in hospital workers to be 3 times higher than the general population (8) . nurses may be more likely than other clinicians to show symptoms of posttraumatic stress (33) . loss of professional control-for example, due to changes in work assignment or work security-is associated with high levels of distress (33) . a perception of inadequate institutional support, as reflected by feedback from frontline staff not reaching hospital administrators, inadequate health care insurance or compensation, or insufficient psychological support from employers, were all risk factors for poor mental health (33) . tools for routine assessment of mental health status, such as zung's self-rating depression scale and self-rating anxiety scale for self-monitoring (55-57); training health care workers to identify physical, behav-ioral, emotional, and cognitive indices of distress in themselves and colleagues; and regular visits from mental health clinicians to assess the well-being of frontline providers are needed (18, 31, 58) . studies of previous pandemics demonstrate heightened distress in health care workers more than 2 years after the event (7). however, covid-19 presents challenges not seen in previous pandemics, including a protracted timeline, severe financial implications, and a global scale. as a result, its effects on the mental health of health care workers can be expected to exceed those observed in previous pandemics. proactive mental health support for health care providers is essential for protecting their long-term mental health (59) . in conclusion, clinicians require proactive psychological protection specifically because they are a population known for putting others' needs before their own. to mitigate the known psychological costs of providing care during a pandemic and recovering from associated experiences, comprehensive institutional and societal infrastructure for clinician well-being is needed, especially as we enter this unprecedented, global postpandemic era. this support should target resilience and stress reduction training, ensure that clinicians' basic needs are met, provide routine opportunities for social connection, and proactively normalize and deliver mental health care to clinicians. top e.r. doctor who treated virus patients dies by suicide mondello kills himself after less than three months on the job clinician mental health and wellbeing during global healthcare crises: evidence learned from prior epidemics for covid-19 pandemic 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medical staff members during the covid-19 outbreak in guiyang impact on mental health and perceptions of psychological care among medical and nursing staff in wuhan during the 2019 novel coronavirus disease outbreak: a cross-sectional study current author addresses: dr. schwartz: 300 pasteur drive, mc 5603 mayo clinic college of medicine and science, office of student services margolis. administrative, technical, or logistic support: r. schwartz, r.d. margolis. collection and assembly of data the authors thank eugenie heitmiller, md, faap; tait shanafelt, md; stuart slavin, md, med; and larissa thomas, md, mph, for reviewing and providing useful feedback on the manuscript. they also thank their colleagues in the charm network for gathering and sharing the well-being resources featured in the article. authors have disclosed no conflicts of interest. forms can be viewed at www.acponline.org/authors/icmje /conflictofinterestforms.do?msnum=m20-4199. 