Manual/Job Aid: CoViD-19: A FAQ for Clinicians
Owner: James C.S. Liu, M.D., MIT Medical
Current as of: September 28, 2020, 9:00 p.m.
Next Review Date: Ongoing
COVID-19: A FAQ for Clinicians
Of necessity a work in progress, this document aims to provide MIT Medical clinicians with answers to some commonly asked questions. Remember that this infection was first observed (in retrospect) in early November, first captured in a bronchoscopy on December 31, and first sequenced in mid January. New information keeps rolling in, some of it contradictory.
For literature reviews and guideline recommendations: http://doi.org/10.1001/jama.2020.12839 (excellent general review and summary), https://sccm.org/SurvivingSepsisCampaign/Guidelines/COVID-19 and https://www.idsociety.org/public-health/COVID-19-Resource-Center/
Medical Grand Rounds at Beth Israel Deaconess Medical Center/Harvard Medical School, with Dr. Anthony Fauci summing up the state of the art: https://vimeo.com/456649458
Links to an MIT Department of Biology survey course on CoViD-19: https://biology.mit.edu/undergraduate/current-students/subject-offerings/covid-19-sars-cov-2-and-the-pandemic/
NOMENCLATURE AND BIOLOGY
Infection: Coronavirus Disease 2019, a.k.a. CoViD-19
Virus: SARS-CoV-2 or 2019 Novel Coronavirus, a 30 kbp ssRNA enveloped coronavirus
Origin: Sequence analysis suggests similarity to coronaviruses found in bats and Malayan pangolins, leading to the suspicion that it jumped over to humans in a food market, rather than being deliberately genetically engineered by a nefarious Bond villain and released on an unsuspecting world (source: https://www.nature.com/articles/s41591-020-0820-9 )
Durability: droplets and fomites during close unprotected contact
· Viable virus in aerosols up to 3 hrs after aerosolization, 24+ hours on paper, 2-6 days on plastic, 24 hrs on a disposable gown, and 5 days on glass or metal (source: https://doi.org/10.1016/j.jhin.2020.01.022 and https://doi.org/10.1056/NEJMc2004973 )
· Efficiently inactivated by surface disinfection procedures with 62–71% ethanol (not most conventional distilled spirits), 0.5% hydrogen peroxide or 0.1% sodium hypochlorite within 1 minute. Other biocidal agents such as 0.05–0.2% benzalkonium chloride or 0.02% chlorhexidine digluconate are less effective. CDC have updated their guidelines suggesting lower risk from touching contaminated surfaces, though it is still prudent to regularly clean horizontal surfaces in particular.
· SARS-CoV1 and MERS viruses are not heat stable, but with protein can last longer; studies documenting elimination did pasteurization (140 F x 30 minutes; source: https://doi.org/10.1007/s00430-004-0219-0 ). A study of MERS documented inactivation with heating to 149 F (65 C) for 1 minute, but it is not clear if that will suffice when reheating food (source: https://doi.org/10.1111/irv.12261 ). No studies have been done yet with SARS-CoV2.
· 20 seconds scrubbing and 20 seconds rinsing with soap and water is more effective than hand sanitizer.
· J. Kenji López-Alt, a chef and food scientist (and MIT alumnus!) has reviewed the data on food safety and coronavirus at https://www.seriouseats.com/2020/03/food-safety-and-coronavirus-a-comprehensive-guide.html
· Dr. Atul Gawande has reviewed the data and spoken with epidemiologists in Singapore and HongKong at https://www.newyorker.com/news/news-desk/keeping-the-coronavirus-from-infecting-health-care-workers
EPIDEMIOLOGY AND TRANSMISSION
· For an excellent review of viral, host, and environmental factors in transmission: https://doi.org/10.7326/M20-5008
· Incubation: mean 4 days; 95% of patients develop symptoms within 14 days (source: https://doi.org/10.1056/NEJMoa2002032 , https://doi.org/10.1016/S1473-3099(20)30287-5 , and https://www.medrxiv.org/content/10.1101/2020.03.21.20040329v1.full.pdf )
· A rigorous contact tracing study in TaiWan showed the highest risk time for transmission is from presymptomatic patients and the first week after symptom onset. Presymptomatic spread makes social distancing crucial to controlling outbreaks (source: https://doi.org/10.1001/jamainternmed.2020.2020 ). A prospective cohort study in GuangZhou of close contacts over three months showed a 4% secondary infection rate, 6% of secondary infections being asymptomatic, and rates of transmission correlating to rates of severity in the index patient (source: https://doi.org/10.7326/M20-2671 )
· An outbreak at a nursing home showed a significant number of asymptomatic patients who were contagious before they became sick, though many eventually develop symptoms (source: https://doi.org/10.1056/NEJMoa2008457 ). 57% of patients with positive swabs had no symptoms, but within 1 week, only 13% were asymptomatic. Symptoms could include nonspecific URI symptoms (source: http://doi.org/10.15585/mmwr.mm6913e1 ) A careful study in a Korean community suggested that viral shedding rates were similar between asymptomatic, presymptomatic, and symptomatic patients, which further raises concerns about asymptomatic spread (source: http://doi.org/10.1001/jamainternmed.2020.3862 )
· Outbreaks at homeless shelters have been associated with rapid spread among clients and staff alike (source: http://doi.org/10.15585/mmwr.mm6917e1 ) and similar outbreaks have been documented in meat and poultry processing facilities (source: http://doi.org/10.15585/mmwr.mm6927e2 ), correctional facilities (source: http://doi.org/10.15585/mmwr.mm6919e1 with worrisome mortality data at http://doi.org/10.1001/jama.2020.12528 ), cruise ships (source: http://doi.org/10.15585/mmwr.mm6911e2 ), the military (source: http://doi.org/10.15585/mmwr.mm6923e4 ), church services (source: http://doi.org/10.15585/mmwr.mm6920e2 ), large family gatherings (source: http://doi.org/10.15585/mmwr.mm6915e1 ), choir rehearsals (source: http://doi.org/10.15585/mmwr.mm6919e6 ), spring break vacations (source: http://doi.org/10.15585/mmwr.mm6926e1 ), skilled nursing facilities (source: http://doi.org/10.15585/mmwr.mm6927e1 and http://doi.org/10.1001/jamainternmed.2020.3738 ), overnight camp (source: http://dx.doi.org/10.15585/mmwr.mm6931e1 ), and other places where people are in close quarters.
· An outbreak in the Louisiana prison system showed up to 25% of positive cases were asymptomatic (source: http://doi.org/10.15585/mmwr.mm6926e2 ). Contact tracing of outbreaks associated with child care facilities in Utah showed substantial rates of asymptomatic carriage amoung young children that transmitted to household adult contacts (source: http://dx.doi.org/10.15585/mmwr.mm6937e3 )
· Basic but universal non-pharmaceutical interventions can contain outbreaks in these settings (source: http://doi.org/10.15585/mmwr.mm6922e2 on an Air Force base, http://doi.org/10.15585/mmwr.mm6926a4 in a psychiatric hospital, and http://doi.org/10.1001/jamanetworkopen.2020.20498 showing very low nosocomial rates of CoViD-19 at Brigham and Womens’ Hospital)
· Reproductive number of about 3 can be brought down to 0.3 with strict control measures focused on social distancing (source: https://doi.org/10.1001/jama.2020.6130 for WuHan, https://doi.org/10.1016/S2468-2667(20)30090-6 for HongKong, and http://doi.org/10.1001/jamanetworkopen.2020.12934 for ShenZhen). Social distancing, masks, and reduced density can also affect other respiratory illnesses; influenza rates plummeted in the summer of 2020 flu season in Australia, Chile, and South Africa (source: http://dx.doi.org/10.15585/mmwr.mm6937a6 )
· SARS-CoV-2 is known to be detectable in stool, and while fecal-oral transmission has not been documented, SARS-CoV-2 activity in wastewater has tracked surprisingly well with PCR surveillance data. http://www.mwra.com/biobot/biobotdata.htm shows activity detected in the Greater Boston area. (Update: An investigation https://doi.org/10.7326/M20-0928 in a high rise building suggests possible transmission by fecal aerosols in the wastewater drainage system)
· Coinfection: data are scant, but a review of swabs at Stanford showed up to 21% of patients with confirmed SARS-CoV-2 were also infected with other viruses (source: https://doi.org/10.1001/jama.2020.6266 ) In Los Angeles in March 2020, 5% of all patients presenting to a medical center with an influenza like illness tested positive for SARS-CoV-2, even as positive rapid flu swabs declined (source: https://doi.org/10.1001/jama.2020.4958 )
· There is ongoing controversy whether the infection spreads more through larger-volume droplets vs. smaller volume aerosols. Most documented spread has involved close contact with droplets, but prolonged indoor exposure in choir rehearsals and restaurants may have involved extended aerosol contact. A study of an outbreak in ZheJiang province suggests that airborne spread from recirculated air on a bus may be a mechanism (source: http://doi.org/10.1001/jamainternmed.2020.5225 ) http://doi.org/10.1001/jama.2020.12458 reviews the differences and the data that we have about influenza, other coronaviruses, and CoViD-19 to date.
· There has also been concern about spread via surface contamination of flat surfaces, but a study of a radiation oncology clinic doing standard cleaning procedures detected no viable virus in any samples (source: http://doi.org/10.1001/jamaoncol.2020.3552 )
· There is no data that warm, humid weather; cold snowy weather; taking a hot bath; spraying alcohol or chlorine; sucking on a blow dryer; nasal rinses; eating garlic; taking any particular supplements including vitamins or zinc can prevent coronavirus infection. UV irradiation is not recommended because of radiation exposure. Drinking bleach will kill the virus but has the unfortunate side effect of killing the person drinking it in the process (with some concern over mortality and morbidity from poisoning: http://doi.org/10.15585/mmwr.mm6916e1 ). Case reports suggesting protective effects from BCG immunization have not been borne out in an observational study (source: https://doi.org/10.1001/jama.2020.8189 ) Immunization against influenza and pneumococcus (if appropriate) is recommended, not because they will prevent COVID-19, but because they will protect against other infections that are also circulating at the same time (graphics: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/advice-for-public/myth-busters ) A preprint study suggests there may be some correlation between disease severity and weather, but not at a rate to suggest that the coming of spring will make a raging pandemic melt away (source: https://www.medrxiv.org/content/10.1101/2020.03.27.20045658v1.full.pdf )
· Pets: At the moment there is limited data suggesting at best modest spread of CoViD-19 among pets, reviewed at http://dx.doi.org/10.15585/mmwr.mm6923e3
· Protecting health care providers: https://www.idsociety.org/practice-guideline/covid-19-guideline-infection-prevention/ is a critical review of strategies of personal protective equipment (PPE) to prevent exposure to CoViD-19. There is an interesting study documenting what looks like good protection from SARS-CoV-2 using standard Personal Protective Equipment (PPE; source: https://doi.org/10.1001/jama.2020.3227 ). However, the data about what should go into the kit, and how one should be trained on donning and doffing is much shakier (source: https://dx.doi.org/10.1002/14651858.CD011621 ) At least theoretically, improper doffing could put your fingers into contact with germs on the PPE, then in contact with your face and even increase the risk of transmission. Testing of motivated general public in Singapore suggested that only 1 in 8 donned an N95 mask with proper fit (source: https://doi.org/10.1001/jamanetworkopen.2020.9670 ) For a video demonstrating how to don and doff, visit https://doi.org/10.1056/NEJMvcm2014809
· Mask vs. N95? A meta-analysis documented protection from influenza, SARS, and SARS-CoV-2, with masks, including health care workers, non-health care workers, and in families (source: https://doi.org/10.1016/j.tmaid.2020.101751 ). A simple test has documented variable rates of filtration of expelled droplets during speech depending on material, with unvalved N95 and surgical masks working best and bandanas and neck fleece being comparable or worse to no barrier (source: https://advances.sciencemag.org/content/early/2020/08/07/sciadv.abd3083 ). Studies of social distancing and comparisons of mask use have been summarized at https://doi.org/10.1016/S0140-6736(20)31142-9 though the studies are heterogeneous enough that it is not clear that their meta-analysis is valid. For a living systematic review of cloth masks, surgical masks, and N95 respirators, see https://doi.org/10.7326/M20-3234 A separate living rapid review uncovered few studies to date of masks vs. N95 respirators specifically to prevent SARS-CoV-2 exposure, with serious limitations (source: https://doi.org/10.7326/M20-3213 ) Adding a face shield to PPE in community health workers in India eliminated transmission from patients to health care workers (source: http://doi.org/10.1001/jama.2020.15586 )
· One case report in a newly diagnosed SARS-CoV-2 patient suggested good protection with only a surgical mask, in procedures with significant aerosol exposure (source: https://annals.org/aim/fullarticle/2763329/covid-19-risk-health-care-workers-case-report ) A study in Nature documented coronavirus, influenza virus, and rhinovirus in respiratory droplets and aerosols collected from symptomatic individuals. Surgical masks caused a dramatic drop in droplet and aerosol particles, suggesting that masks have significant benefit when placed properly on symptomatic patients (source: https://www.nature.com/articles/s41591-020-0843-2 ) Two hair stylists who worked while sick with CoViD-19 apparently did not infect any of 139 clients with a universal face covering policy in place (source: http://doi.org/10.15585/mmwr.mm6928e2 )
· In a similar way, there is limited work on extending the lifespan of PPE that were designed to be disposable. Face shields and plastic gowns can be wiped down with a sterilizing wipe. The CDC has guidance on reusing N95 respirators, storing them in paper bags, minimizing donning and doffing in the same day, and other cautions to reduce cross-contamination (source: https://www.cdc.gov/niosh/topics/hcwcontrols/recommendedguidanceextuse.html ) One study shows promising retention of high filtration rates with used N95 masks sterilized with ethylene oxide and hydrogen peroxide. N95 masks that did not fit ideally still had up to 90% filtration rates (source: http://doi.org/10.1001/jamainternmed.2020.4221 )
· Epidemiologic studies are centering on droplet transmission with prolonged close contact as the principal vector for SARS-CoV-2 transmission. Aerosol generating procedures theoretically also convey increased risk. A review of SARS-CoV-1 suggested that tracheal intubation, non-invasive ventilation, tracheotomy, and manual ventilation before intubation were associated with significant risk of transmission; other intubation associated procedures, endotracheal aspiration, suction of body fluids, bronchoscopy, nebulizer treatment, administration of oxygen, high-flow O2, manipulation of O2 mask or BiPAP mask, defibrillation, chest compressions, insertion of nasogastric tube, and collection of sputum did not significantly increase risk (source: https://doi.org/10.1371/journal.pone.0035797 ) There is some concern from a study of U.S. patients where less than half recalled a close contact for transmission (source: http://dx.doi.org/10.15585/mmwr.mm6926e3 )
· MMWR have reviewed cases of transmission of CoViD-19 from patients to health care providers in the United States; most cases appear to be linked to lapses in use of PPE with prolonged contact (source: http://doi.org/10.15585/mmwr.mm6915e5 and http://doi.org/10.15585/mmwr.mm6915e6 ) Universal masking of health care workers and patients at Massachusetts General Hospital turned an exponential rate of increasing infection to a linear rate of decrease (source: http://doi.org/10.1001/jama.2020.12897 )
· There is reasonable evidence to suggest that use of even homemade cloth masks by the general public can help to slow the rate of spread of SARS-CoV-2, with protection rates ranging from 40%-97% depending on the material (reviewed at https://www.preprints.org/manuscript/202004.0203/v1 and https://doi.org/10.7326/M20-2567 ); a review on strategies to reopen areas from quarantine is at https://www.newyorker.com/science/medical-dispatch/amid-the-coronavirus-crisis-a-regimen-for-reentry and a review of most of the above is at http://doi.org/10.1126/science.abc6197
· A multinational review suggested that implementing social distancing measures such as closure of schools, workplaces, restrictions on mass gatherings and public events, and restrictions on movement had a significant impact on the incidence of CoViD-19, with a greater impact, the sooner the measures were implemented. Closure of public transport systems were not associated with reduction of risk independent of the other measures (source: https://doi.org/10.1136/bmj.m2743 )
· Symptoms: fever (87.9%), dry cough (67.7%), fatigue (38.1%), sputum production (33.4%), shortness of breath (18.6%), sore throat (13.9%), headache (13.6%), myalgia or arthralgia (14.8%), chills (11.4%), nausea or vomiting (5.0%), nasal congestion (4.8%), diarrhea (3.7%), hemoptysis (0.9%), though percentages varied widely (source: https://www.who.int/docs/default-source/coronaviruse/who-china-joint-mission-on-covid-19-final-report.pdf ) There is limited data on rates of asymptomatic carriage, but studies reviewed at https://doi.org/10.7326/M20-3012 suggest that perhaps as many as 40-45% of infected patients may remain asymptomatic. A multi-city serologic survey showed positive antibody rates of 1-7%, suggesting total CoViD-19 infectious could be 6-24 times as high as the cases reported so far (reviewed at http://doi.org/10.1001/jama.2020.14017 )
· Loss of smell and/or taste has been cited as the most common neurologic symptom (reviewed at https://doi.org/10.1001/jama.2020.8391 ), though some have presented with nonspecific neurologic symptoms up to thromboembolic stroke with coagulopathy (source: https://www.nejm.org/doi/full/10.1056/NEJMc2009787 ). There have been case reports of acetylcholine receptor antibody-positive myasthenia gravis after CoViD-19 infection (source: https://doi.org/10.7326/L20-0845 ) Most patients developed fever and cough in a few days (source: https://doi.org/10.1001/jamaneurol.2020.1127 ) For a review of neurologic manifestations and considerations in CoViD-19, see https://doi.org/10.1001/jamaneurol.2020.2065 )
· A UK-based surveillance study showed a small rate of unusual neuropsychiatric manifestations including altered mental status and primary psychiatric syndromes such as new-onset psychosis (source: https://doi.org/10.1016/S2215-0366(20)30287-X ) A survey of U.S. adults showed marked increases in anxiety or depression symptoms, stressors, substance use, and suicidal ideation, particularly among young adults, ethnic minoriites, essential workers, and unpaid adult caregivers (source: http://dx.doi.org/10.15585/mmwr.mm6932a1 )
· Dermatologic manifestations have been described: one Italian review reported 20.4% had skin manifestations including petechial rash mistaken for dengue fever (source: https://doi.org/10.1001/jamadermatol.2020.1741 ), digitate papulosquamous rash with findings suggestive of a cytokine storm (source: https://doi.org/10.1001/jamadermatol.2020.1704 ), erythematous rash, widespread urticarial, and chickenpox-like vesicles https://dx.doi.org/10.1111/jdv.16387 ) A French organization has also reported a “pseudo-frostbite” of the extremities, sudden onset of persistent, sometimes painful redness, and transient urticaria (source: https://www.syndicatdermatos.org/wp-content/uploads/2020/04/cp-covid-peau-6-avril.pdf ) though retrospective reviews of “CoViD toes” failed to show a consistent association with SARS-CoV-2 infection (source: http://doi.org/10.1001/jamadermatol.2020.2062 )
· Ophthalmologic manifestations can include a conjunctivitis like picture; some 2% of them had SARS-CoV-2 detected in conjunctival swabs (source: https://doi.org/10.1001/jamaophthalmol.2020.1291 ) 22.7% of children in WuHan hospitalized with CoViD-19 had conjunctivitis, 4.2% had conjunctivitis symptoms first (source: http://doi.org/10.1001/jamaophthalmol.2020.3690 )
· Gastroenterologic manifestations include non-specific gastroenteritis symptoms, though these aren’t typical (source: https://doi.org/10.14309/ajg.0000000000000620 )
· Adult cardiologic findings have sometimes included myocarditis-like inflammation, cardiomyopathy, and possibly congestive heart failure. It remains unclear how much of the general population will go on to have heart side effects, or how long symptoms will persist (source: http://doi.org/10.1001/jamacardio.2020.3575 )
· Lab findings: WBC <10K/µL in 70-99% of cases with median 4.7-6.0K/µL; about 55% have lymphopenia; LDH elevated in 41-76% of cases with median 205-286 U/L; mild thrombocytopenia of 160K/µL; procalcitonin is often low in early disease (summarized at https://i0.wp.com/emcrit.org/wp-content/uploads/2020/03/labsjpg.jpg?resize=1536%2C1115&ssl=1 )
· A range of coagulopathy has been described, most commonly elevated D-dimer and fibrinogen levels, paralleling a rise in inflammatory markers, but without the thrombocytopenia or elevated PT or PTT associated with disseminated intravascular coagulopathy. Elevated D-dimer is associated with mortality risk (reviewed at https://www.hematology.org/covid-19/covid-19-and-coagulopathy ) Some cases of hypoxemic pulseless electrical activity suggesting massive pulmonary embolism have been attributed to CoViD-19 (source: https://doi.org/10.1056/NEJMc2010459 ) and a small prospective autopsy series in Germany documented deep venous thrombosis and fatal pulmonary embolism that was not always clinically apparent (source: https://www.acpjournals.org/doi/10.7326/M20-2003 ) There is intriguing data that CoViD-19 coagulopathy has a grave prognosis that is improved with anticoagulant therapy; https://doi.org/10.1182/blood.2020006000 reviews CoViD-19 and its implications on thrombosis and anticoagulation.
· An international review of echocardiography in patients admitted with CoViD-19 illness (60% admitted to intensive care) showed new left ventricular abnormalities in roughly half of them, including nonspecific LV dysfunction, new myocardial infarction, myocarditis, and takotsubo cardiomyopathy (source: https://doi.org/10.1093/ehjci/jeaa178 )
· Pediatrics: An analysis of the outbreak in China indicated some 2000 cases (6% of the total reported nationwide), a lower (but nonzero) rate of critical illness (5.9% vs. 18.5% for adults) and one death. However, infants had a higher rate of critical illness (10.6%, dropped by age group to 3.0% for >15 y.o.; source: https://doi.org/10.1542/peds.2020-0702 ). Surveillance of pediatric oncology patients in New York showed that 29.3% of symptomatic patients were positive, while 2.5% of asymptomatic patients were positive. 14.7% of caregivers were asymptomatic but positive (source: https://doi.org/10.1001/jamaoncol.2020.2028 ). Screening in childrens’ hospitals in the U.S. of patients asymptomatic and presenting for surgical or medical care showed a prevalence of 0-2.2% of asymptomatic carriage, with rates paralleling community positive rates (source: http://doi.org/10.1001/jamapediatrics.2020.4095 ). A study in Korea showed high rates of asymptomatic carriage and more prolonged viral shedding than in adults, though it is not clear if that also implies prolonged contagiousness (source: http://doi.org/10.1001/jamapediatrics.2020.3988 ). In the United States, mortality has heavily disproportionately affected the Black and Latinx populations (source: http://dx.doi.org/10.15585/mmwr.mm6937e4 ) and disease incidence in school aged children has been unusually high in the Latinx population, with low overall rates of hospitalization and death, and a higher rate of complications in children with pre-existing risk factors (source: http://dx.doi.org/10.15585/mmwr.mm6939e2 )
· Clinical presentations vary from adults (https://doi.org/10.1001/jamapediatrics.2020.2438 ) There are reports of a Kawasaki-like multisystem inflammatory syndrome in children which has predominantly affected patients between 1-14 years old, and in the U.S., has disproportionately affected children of color. It appears to respond to rapid institution of immunomodulatory therapy. Not all patients were critically ill (reviewed at https://www.cdc.gov/coronavirus/2019-ncov/hcp/pediatric-hcp.html, http://doi.org/10.1001/jama.2020.10370, http://doi.org/10.1056/NEJMoa2021680, and http://dx.doi.org/10.15585/mmwr.mm6932e2 )
· A cross-sectional study of French patients over 70 showed a small number of similar presenting symptoms, mixed with more unusual features such as asthenia, diarrhea, lymphopenia, and accelerated frailty (source: https://doi.org/10.1093/cid/ciaa792 )
· Spectrum of Disease: Mild (81%); Severe (14%); Critical (5%); Death (1-3%) (source: https://jamanetwork.com/journals/jama/fullarticle/2762130 ) Data in the United States have shown a similar breakdown of spectrum and risk factors for deterioration (source: http://dx.doi.org/10.15585/mmwr.mm6924e2 )
· A large scale population study in Iceland showed that 91% of patients who recovered were seropositive, and antibody was durable or four months. Overall risk of death from infection was 0.3%, but 44% of patients who seroconverted were not tested with nasal PCR (and may have been asymptomatic; source: https://doi.org/10.1056/NEJMoa2026116 )
· ICU admission in an ARDS type syndrome appears to occur after 9-10 days into the illness with abrupt deterioration and hypoxemia. This may be associated with a “cytokine storm” (reviewed in depth at https://doi.org/10.1016/j.jinf.2020.03.037 ) suggesting an immune reaction to the virus rather than direct viral pathogenesis. Some have observed that relatively low IL-6 levels and mediocre results from trials of immunomodulators raise questions about whether there is a CoViD-19 cytokine storm (source: http://doi.org/10.1001/jamainternmed.2020.3313 )
· Risk factors: Age (steep rise in mortality with increasing age); comorbidity such as COPD, diabetes and cardiac disease; small numbers of pregnant women have had a mild course though there have been some newborns who have contracted it (source: https://doi.org/10.1001/jama.2020.3633 with CDC review of U.S. data at http://doi.org/10.15585/mmwr.mm6915e3 ). One retrospective review identified old age, high serum lactate dehydrogenase (LDH), C-reactive protein (CRP), high red blood cell distribution width (RDW), blood urea nitrogen (BUN), direct bilirubin, and low albumin as risk factors for mild cases to deteriorate into severe CoViD-19 (source: https://doi.org/10.1093/cid/ciaa443 ) Studies in the U.S. have associated morbid obesity with adverse outcomes (reviewed at https://doi.org/10.7326/M20-5677 )
· It remains unclear why some patients get critically ill while others don’t. One study found genetic variations that are associated with increased risk, with a curious crossover with ABO blood types; type A was associated with increased risk and type O with decreased risk (source: https://doi.org/10.1056/NEJMoa2020283 ) though data have not been consistent (reviewed at http://doi.org/10.1001/jama.2020.16516 )
· In the United States, a disproportionate number of cases and deaths have fallen among minority populations, but a cohort review in Louisiana suggested that race alone did not account for increases in mortality after adjustment for differences in sociodemographics and comorbidities, suggesting that social determinants of health are a principal contributor (source: https://doi.org/10.1056/NEJMsa2011686 ) A review of pregnant women in New York correlated risk of infection with assessed home values, median incomes, unemployment rates, and household crowding (source: http://doi.org/10.1001/jama.2020.11370 ). A large survey of mortality showed strikingly higher rates of death in minorities under 65 years old compared with whites (source: http://dx.doi.org/10.15585/mmwr.mm6928e1 ). And in Utah, more than half of workplace outbreaks occurred in manufacturing, wholesale trade, and construction, and Hispanic and non-white workers accounted for 73% of the cases, even though they were 24% of the workers In the affected sectors (source: http://dx.doi.org/10.15585/mmwr.mm6933e3 )
· A retrospective review identified age, coronary artery disease, cerebrovascular disease, dyspnea, high procalcitonin, and elevated aspartate aminotransferase (AST) as predictors of mortality (source: https://doi.org/10.1016/j.chest.2020.04.010 )
· Preliminary data in the U.S. shows that as many as 38% of the patients hospitalized have been between the ages of 20-54. Some of my ICU physician friends have apocryphally confirmed a slightly younger skew, but if you look at Table 1 in the paper, the age distribution looks similar to me to other countries (source: http://dx.doi.org/10.15585/mmwr.mm6912e2 )
· Autopsy series have shown recurring themes of disseminated diffuse alveolar damage with perivascular lymphocyte-plasmacyte infiltration and persistent detection of SARS-CoV-2 in the respiratory tract (source: https://doi.org/10.1001/jama.2020.8907 ) Another autopsy series also noted an increased rate of alveolar capillary microthrombi and intussusceptive angiogenesis in Northern Europe (source: https://doi.org/10.1056/NEJMoa2015432 ) and in Italy (source: https://doi.org/10.1016/S1473-3099(20)30434-5 )
· Reports have come from several countries of patients who appear to be recovered from CoViD-19 illness, only to test recurrently PCR positive up to two weeks after having negative swabs. A case series in China showed no clear predictors of risk for recurrent positivity (source: https://doi.org/10.1001/jamanetworkopen.2020.10475 ) HongKong researchers documented a man who contracted a genetically distinct strain of SARS-CoV-2 after recovering from a first infection, though the second infection did not manifest symptoms (source: https://doi.org/10.1093/cid/ciaa1275 )
· In addition, a report in Italy showed that over 87% of patients had persistent symptoms up to two months after recovery (source: http://doi.org/10.1001/jama.2020.12603 ) A U.S. study showed that 19% of healthy young adults with no health history had persistent symptoms at 2-3 weeks (source: http://dx.doi.org/10.15585/mmwr.mm6930e1 )
· Secondary effects of CoViD-19: A review of the effects on various medical specialties was reviewed in the Journal of the American Medical Association in September 2020; summary editorial with links at http://doi.org/10.1001/jama.2020.18298 ) Examples include:
o surprising decreases in presentations of acute coronary syndromes (source: https://doi.org/10.1056/NEJMc2009166 ) and strokes (source: https://doi.org /10.1056/NEJMc2014816 ). Total ER visits have dropped by 42%, raising questions about whether there are major health problems going unaddressed (source: http://dx.doi.org/10.15585/mmwr.mm6923e1 and http://dx.doi.org/10.15585/mmwr.mm6925e2 )
o worrisome decreases in the rates of routine immunizations (source: http://doi.org/10.15585/mmwr.mm6919e2 ).
o increases in rate and severity of domestic violence as people are quarantined in close quarters (source: https://doi.org/10.1016/S2468-2667(20)30112-2 )
o a chilling estimate that some 20% of the excess mortality in New York City (over 5000 deaths) remain unexplained (source: http://doi.org/10.15585/mmwr.mm6919e5 ). From March to May, there were an estimated 122,300 excess all-cause deaths. CoViD-19 accounted for 78% of the excess deaths, while the other 22% remain unexplained (source: http://doi.org/10.1001/jamainternmed.2020.3391 ) http://doi.org/10.1001/jama.2020.11761 reviews the challenges around accurate estimates of mortality, including CoViD-19-associated mortality.
o Inappropriate off-label prescriptions of hydroxychloroquine and chloroquine to treat CoViD-19 before trial data shows benefit have led to surges in prescriptions and strained supplies for people with legitimate needs (source: https://doi.org/10.1001/jama.2020.9184 )
· The CDC has published a framework for health care systems encouraging expansion of telehealth services and working to restore services as places recover from outbreaks (https://www.cdc.gov/coronavirus/2019-ncov/hcp/framework-non-COVID-care.html )
· PCR testing of respiratory secretions is the diagnostic test of choice, though the CDC has a range of sampling options (practical details on how to collect, store, and transport specimens is at https://www.cdc.gov/coronavirus/2019-nCoV/lab/guidelines-clinical-specimens.html ). Reviews of testing methods, timing, and sensitivity and specificity are at https://doi.org/10.1001/jama.2020.8259 and https://www.idsociety.org/practice-guideline/covid-19-guideline-diagnostics
· MIT Medical uses the assay developed at the Broad Institute (https://covid-19-test-info.broadinstitute.org/ ), which has reported a sensitivity of 97% and specifity of 100% (source: https://www.statnews.com/2020/05/05/crispr-covid-19-test-could-be-simple-cheap-at-home-diagnostic/ )
· A multinational consortium have provided provisional guidance arguing against routine imaging for diagnosis of CoViD-19, though possibly for assessment of worsening respiratory status or in a resource constrained environment (source: https://doi.org/10.1016/j.chest.2020.04.003 )
· Immunity: Tests have been done to check for IgM and IgG antibodies to SARS-CoV-2. Studies have identified antibodies to the receptor-binding domain of the SARS-CoV-2 spike protein correlating with neutralizing, protective antibodies (source: http://dx.doi.org/10.1126/sciimmunol.abc8413 ). There are concerns about diminishing immunity to SARS-CoV and MERS (https://doi.org/10.1099/jgv.0.001439 ) about people losing antibodies to SARS-CoV-2 (source: http://doi.org/10.1001/jama.2020.18796 ) and a suggestion that more severe disease is associated with more durable immunity (source: https://doi.org/10.1038/s41392-020-00301-9 ). The official FDA advisory is at https://www.fda.gov/medical-devices/letters-health-care-providers/important-information-use-serological-antibody-tests-covid-19-letter-health-care-providers , the Infectious Disease Society of America reviews serology testing at https://www.idsociety.org/covid-19-real-time-learning-network/diagnostics/antibody-testing/ ),there is a narrative review of serology testing at https://doi.org/10.7326/M20-2854, and a meta-analysis raising significant concerns about problematic specificity and verification of serology test results at https://doi.org/10.1136/bmj.m2516 and https://doi.org/10.1002/14651858.CD013652 )
· Treatment guidelines from the Infectious Disease Society of America, with extensive references: https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management Guidelines from the NIH arrive at similar conclusions: https://covid19treatmentguidelines.nih.gov/ Graphical representations and slide decks with the data on treatment options are at the University of Washington’s https://covid.idea.medicine.uw.edu/ site.
· Data are being updated quickly on treatment options.
o A trial of 237 patients in China did not show significant improvement with remdesivir (source: https://doi.org/10.1016/S0140-6736(20)31022-9 ) though a larger trial centered on North America and Europe suggests a 30% reduction in length of hospital stay and mortality (source: https://doi.org/10.1056/NEJMoa2007764. An uncontrolled trial showed no significant difference between 5 and 10 days of treatment (source: https://doi.org/10.1056/NEJMoa2015301 ), while a three-arm trial in moderate disease showed modest effect from a 5 day course, and no improvement with a 10 day course (reviewed at http://doi.org/10.1001/jama.2020.16337 )
o A small phase 2 trial in HongKong showed better outcomes from a combination of lopinavir, ritonavir, ribavirin, and interferon beta-1b than lopinavir and ritonavir alone (source: https://doi.org/10.1016/S0140-6736(20)31042-4 ).
o A meta-analysis suggests increased mortality and length of hospital stay from use of corticosteroids, though there is disagreement on optimal dosing and timing, if any (source: https://doi.org/10.1016/j.jinf.2020.03.062 ) A living WHO guideline suggests that mid-dose corticosteroids are helpful in moderate to severe CoViD-19 disease, and not recommended in non-severe disease (source: https://doi.org/10.1136/bmj.m3379 )
o Initial reports suggesting promise from use of hydroxychloroquine or chloroquine have not been borne out by more rigorous studies (reviewed at https://doi.org/10.7326/M20-5041 and https://doi.org/10.7326/L20-1007 )
o Trials are also underway of agents that may help to stem inflammatory cytokine overload; a cohort study of tocilizumab which blocks IL-6 showed decreased mortality, though the treated patients tended to be healthier at baseline (source: https://doi.org/10.1093/cid/ciaa954 )
o A preliminary study suggested that plasma from convalescent patients may help to reverse the courses of critically ill patients, implying the possibility of testable immunity (source: https://doi.org/10.1001/jama.2020.4783 ) A living review of studies have not shown a convincing benefit from convalescent plasma (source: https://doi.org/10.1002/14651858.CD013600.pub2 ) A review from the FDA suggested no benefit in intubated patients treated with high-titer vs. low titer plasma. There was a modest effect in non-intubated patients, leading to no formal recommendation for now (source: https://doi.org/10.7326/M20-6448 ) Monoclonal antibody development is reviewed at https://doi.org/10.1001/jama.2020.10245
o Trials are in progress and use of these medications should be restricted to inpatients and clinical trials at this time.
· It is widely acknowledged that a successful immunization and cultivation of timely herd immunity that does not swamp the health care system are the keys to getting the pandemic under control. A review of what a vaccine might look like is at https://doi.org/10.1016/j.immuni.2020.03.007 and a blog with regular progress reports is at https://blogs.sciencemag.org/pipeline/ An mRNA vaccine has shown promising results in a phase 1 trial (https://doi.orgl/10.1056/NEJMe2025111 sums up where we are and the road ahead)
· Interim guidelines on basic and advanced life support in the context of CoViD-19 from the American Heart Association: https://doi.org/10.1161/CIRCULATIONAHA.120.047463 A review of 60 in-hospital cardiac arrests showed that they tended to occur in patients receiving mechanical ventilation, kidney replacement, or vasopressor support. 96% presented with an unshockable rhythm, with pulseless electrical activity the dominant rhythm. 53.7% of patients achieved return of spontaneous circulation, but none survived to discharge (source: http://doi.org/10.1001/jamainternmed.2020.4796 )
· Profound hypoxemia can occur as some CoViD-19 patients descend into Acute Respiratory Distress Syndrome, though sometimes without appearing intubation sick. Awake prone positioning showed promise in keeping hypoxemic patients off of mechanical ventilation (source: https://doi.org/10.1186/s13613-020-00650-2 ). A living systematic review of ventilation techniques and risk for transmission of CoViD-19 is at https://doi.org/10.7326/M20-2306
· Establishment of Recovery: CDC guidelines at https://www.cdc.gov/coronavirus/2019-ncov/hcp/disposition-in-home-patients.html have remained that isolation precautions may be discontinued after one of the following:
o Two consecutive negative SARS-CoV-2 swabs at least 24 hrs apart
o At least 72 hours since recovery (defined as afebrile without using antipyretics AND improvement in respiratory symptoms AND at least 10 days since symptoms first appeared.
· Systemic corticosteroids associated with prolonged viral replication; still indicated for COPD or asthma flares, and asthma patients should not discontinue steroid inhalers (sources: https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html and https://community.aafa.org/blog/coronavirus-2019-ncov-flu-what-people-with-asthma-need-to-know and https://www.who.int/publications-detail/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected ) A review of steroid use in severe CoViD-19 shows inconsistent, low quality evidence of effect (source: https://doi.org/10.1503/cmaj.200645 )
· NSAIDs: Concern has been raised about use of ibuprofen or naproxen being associated with worse outcomes in COVID-19 patients with ARDS. However, there is little data documenting positive or negative effects with NSAID use, even some use of indomethacin for treatment of other coronavirus illnesses (source: https://doi.org/10.3332/ecancer.2020.1022 ). The FDA has advised against discontinuation; suggestion is to use acetaminophen, with caution when giving this advice about screening for alcohol use and other drug interactions (source: https://www.fda.gov/drugs/drug-safety-and-availability/fda-advises-patients-use-non-steroidal-anti-inflammatory-drugs-nsaids-covid-19 )
· ACE inhibitors and ARB’s: A Lancet article raised concern about SARS-CoV2 binding cells through angiotensin converting enzyme 2 receptors (source: https://doi.org/10.1016/S2213-2600(20)30116-8 ) However, a living review of observational and trial data also did not show elevated risk of adverse outcome or contraction of CoViD-19 associated with ACE-I or ARB use (source: https://doi.org/10.7326/M20-1515 ) and a meta-analysis of heterogeneous observational studies even suggested a possible protective effect (source: https://doi.org/10.1111/jcpt.13246 ) Until there is randomized trial data, patients on ACE-I’s and ARB’s should continue their medications as prescribed (reviews of the observation studies are at https://doi.org/10.1056/NEJMe2012924 and http://doi.org/10.1001/jama.2020.11401 )
· Diabetes mellitus has been identified as a possible risk factor for poor outcomes. https://doi.org/10.1016/S2213-8587(20)30152-2 reviews practical recommendations for management; quarantine-induced decreases in physical activity and increased stress and boredom eating could contribute to worsening diabetes control, and dehydration should be avoided particularly with metformin, sodium-glucose-cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors.
· Immunosuppressive agents: The American College of Rheumatology is advising usual care, holding biologic agents only if there is concern for an active infection, given risk for autoimmune flares (source: https://www.rheumatology.org/announcements ) A case series in New York suggested no increase in risk for hospitalization or adverse outcomes from baseline use of immunosuppressives or biologic agents (source: https://doi.org/10.1056/NEJMc2009567 ) and a meta-analysis showed no definitive evidence that specific cytotoxic drugs, low dose methotrexate for autoimmune disease, JAK kinase inhibitors, or anti-TNFα agents are contraindicated (source: https://doi.org/10.3332/ecancer.2020.1022 ).
· A review of kidney transplant patients showed less fever, lower T-cell counts, and more rapid clinical progression with high mortality, suggesting that transplant immunosuppressives need to be managed carefully with CoViD-19 (source: https://doi.org/10.1056/NEJMc2011117 ) A review of heart transplant patients in New York showed a 25% mortality rate, but that sounds comparable to that expected in a population with an average age of 64 years (source: https://doi.org/10.1001/jamacardio.2020.2159 )
· Gastroenterology: The American Gastroenterological Association has published advisories on CoViD-19 and inflammatory bowel disease (there is no data suggesting increased risk of poor outcomes but suggestions are made for strategies of managing immunosuppressive agents: https://doi.org/10.1053/j.gastro.2020.04.012 ) They have also made recommendations about endoscopic procedures (https://doi.org/10.1053/j.gastro.2020.03.072 ) A study suggested that critically ill patients were at higher risk for gastroenterologic complications such as mesenteric ischemia (source: http://doi.org/10.1001/jama.2020.19400 )
· Inherited anemias can be associated with variable increased risk for poor outcomes from CoViD-19. With sickle cell anemia, there are often other risk factors for poor outcomes (source: https://doi.org/10.3201/eid2610.202792 ), and pain can often be the presenting symptom of CoViD-19 infection (source: https://www.hematology.org/covid-19/covid-19-and-sickle-cell-disease ) Thalassemias can be associated with risk, though studies have not necessarily demonstrated increased risk (source: https://hematology.org/covid-19/covid-19-and-thalassemia )
· Transfusions: SARS-CoV-2 has been picked up in PCR testing of blood, but it remains unclear if transfusion is associated with exposure risk. A study suggests this remains unlikely, consistent with epidemiologic data (source: https://doi.org/10.1111/trf.15841 ) Social distancing and respiratory precautions would make sense for blood donations.
· Cancer patients: There is theoretical increased risk from CoViD-19 in patients with a history of cancer or chemotherapy. Study data are mixed: a multicenter study of 105 patients suggests hematologic cancer, lung cancer, and metastatic cancer were associated with a markedly higher frequency of severe events (source: https://doi.org/10.1158/2159-8290.CD-20-0422 ). A multicenter cohort study in China (source: https://doi.org/10.1016/S1470-2045(20)30309-0 ) and a multinational cohort study (source: https://doi.org/10.1016/S0140-6736(20)31187-9 ) showed increased mortality associated with cancer-specific risk factors in addition to known comorbidity risk factors. Another cohort study in Britain did not demonstrate a significant effect specific to cancer diagnosis, chemotherapy, immunotherapy, or hormonal therapy (source: https://doi.org/10.1016/S0140-6736(20)31173-9 ) https://doi.org/10.7326/M20-1133 provides advice on the challenges of managing new diagnoses and active cases in a time of emptying hospitals and social distancing.
· HIV on highly active antiretroviral therapy (HAART): A large cohort study of patients in Spain on HAART showed a fairly low rate of SARS-CoV-2 positivity, and hospitalization and death rates comparable to the general population. There was modest variability in mortality depending on HAART regimen of unknown significance (source: https://doi.org/10.7326/M20-3689 )
· Pregnant and breastfeeding patients: https://www.acog.org/Clinical-Guidance-and-Publications/Practice-Advisories/Practice-Advisory-Novel-Coronavirus2019 has updated information and an algorithm for managing the pregnant patient of concern. https://www.cdc.gov/coronavirus/2019-ncov/hcp/inpatient-obstetric-healthcare-guidance.html has CDC guidance on inpatient management. JAMA has reported on possible vertical transmission but the data remain unclear (reviewed at https://doi.org/10.1001/jama.2020.4868 and the strongest case report for vertical transmission is at https://doi.org/10.1038/s41467-020-17436-6 ) A screening study of obstetric patients in New York City showed 1.9% were symptomatic and SARS-CoV-2 positive, and 13.5% were asymptomatic and SARS-CoV-2 positive. Only 10% of those 13.5% developed symptoms (source: https://doi.org/10.1056/NEJMc2009316 ). In New Haven CT, 4% of screened pregnant patients were positive, 73% of whom were asymptomatic (source: https://doi.org/10.1001/jama.2020.8904 ) A meta-analysis showed similar outcomes in pregnant and non-pregnant women, but an increased rate of fetal prematurity and Caesarean (source: https://doi.org/10.1093/cid/ciaa828 ) A study of breastfeeding women showed a positive RNA in one of 18 patients, with a negative viral culture (source: http://doi.org/10.1001/jama.2020.15580 ) A 14 state retrospective review showed over half of pregnant women with CoViD-19 were asymptomatic. Among the symptomatic pregnant women, 16% were admitted to an ICU, 8.5% required mechanical ventilation, and just under 1% died (source: http://dx.doi.org/10.15585/mmwr.mm6938e1 )
· Nebulizers and CPAP machines: One review of mostly observational trials suggests that non-invasive ventilation techniques such as CPAP and BiPAP may help improve outcomes in CoViD-19, but the aerosols generated by the machines could increase the risk of transmission to health care workers (source: https://doi.org/10.7326/M20-2306 ) It would seem advisable to use metered dose inhalers with spacers or other non-nebulizer methods to manage asthma and COPD. Humidification for CPAP machines is trickier, as we would not discourage doing this, so I am advising that people use CPAP in relative isolation if possible, and wipe down surfaces the following morning. (Advice: https://aasm.org/coronavirus-covid-19-faqs-cpap-sleep-apnea-patients/ and https://www.aaaai.org/ask-the-expert/nebulizers though there is no trial data to substantiate this suggestion)
RELIABLE AND REGULARLY UPDATED WEB SITES
Centers for Disease Control: https://www.cdc.gov/coronavirus/2019-ncov/index.html with health care specific advice including a summary FAQ at https://www.cdc.gov/coronavirus/2019-nCoV/hcp/index.html a history of how the virus was found at https://tools.cdc.gov/medialibrary/index.aspx#/media/id/406092 and a rich array of conference calls and webinars at https://emergency.cdc.gov/coca/
World Health Organization: https://www.who.int/emergencies/diseases/novel-coronavirus-2019 with health care specific resources at https://www.cdc.gov/coronavirus/2019-nCoV/hcp/index.html
Massachusetts Department of Public Health: https://www.mass.gov/resource/information-on-the-outbreak-of-coronavirus-disease-2019-covid-19
Massachusetts Medical Society: http://www.massmed.org/COVID-19/
Harvard Medical School resources, including webinars and grand rounds from Massachusetts General Hospital (CME eligible): https://postgraduateeducation.hms.harvard.edu/continuing-education/covid-19-resources-providers
McLean Hospital webinar series on CoViD-19 and mental health: https://home.mcleanhospital.org/covid-webinars
Infectious Disease Society of America guidelines on …
Cochrane Collaborative content on CoViD-19: https://www.cochranelibrary.com/covid-19
Massachusetts Emergency Management Agency breakdown of Massachusetts cases by county and hospital with mortality rates, case rates in New England, and Johns Hopkins worldwide data: https://memamaps.maps.arcgis.com/apps/MapSeries/index.html?appid=9ef7ef55e4644af29e9ca07bfe6a509f
A plot that shows rate of growth of cases, plottable by country and by state in the United States: https://91-divoc.com/pages/covid-visualization/
Brigham and Womens Hospital ICU protocols (work in progress, but has more gory detail): https://www.covidprotocols.org/
Internet Book of Critical Care, section on COVID-19 (even more details backed up by data on practical aspects of management of COVID-19, particularly in the ICU: https://emcrit.org/ibcc/covid19/ )
University of Washington guide to preparing emergency departments and ICU’s for COVID-19: https://em.uw.edu/faculty/uw-department-emergency-medicine-edicu-covid-19-preparedness
CDC’s CoViD-19 self assessment tool (includes a way to sign up for text message updates about availability of large scale screening: https://www.humandx.org/covid-19/assessment )
A practical guide to staying safe during the Coronavirus pandemic: https://firstname.lastname@example.org/a-practical-guide-to-staying-safe-during-the-coronavirus-pandemic-52a7f5abd38a
The CDC guide to coping with life during a pandemic: https://www.cdc.gov/coronavirus/2019-ncov/daily-life-coping/index.html
Dr. Anthony Fauci’s Q&A about CoViD-19 with Steph Curry of the Golden State Warriors: https://youtu.be/cRwkNQXbGKg
FDA supply chain updates: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-supply-chain-update
American Cancer Society: https://www.cancer.org/latest-news/common-questions-about-the-new-coronavirus-outbreak.html
American College of Obstetrics and Gynecology: https://www.acog.org/Clinical-Guidance-and-Publications/Practice-Advisories/Practice-Advisory-Novel-Coronavirus2019
American Heart Association: https://www.heart.org/en/about-us/coronavirus-covid-19-resources
American Society of Nephrology: https://www.asn-online.org/ntds/
JAMA network’s COVID collection: https://jamanetwork.com/journals/jama/pages/coronavirus-alert
NEJM CoViD collection: https://www.nejm.org/coronavirus
Annals of Internal Medicine CoViD collection: https://annals.org/aim/pages/coronavirus-content
The Lancet: https://www.thelancet.com/coronavirus
NIH curated portfolio of CoViD-19 related articles: https://icite.od.nih.gov/covid19/search/
A list of retracted papers on CoViD-19 and articles where significant concerns have been raised: https://retractionwatch.com/retracted-coronavirus-covid-19-papers/