June 4, 2020, Research Update
Adjusted In-Hospital Mortality from COVID-19 in Louisiana No Different for Black and White Patients. In this retrospective study from a single Louisiana health care system, the association between race and hospital mortality was determined for 1,382 hospitalized patients from a cohort of 3,481 black/non-Hispanic and white/non-Hispanic COVID-19 positive patients. Of these patients, 70.4% were black/non-Hispanic and 29.6% were white/non-Hispanic. The mortality results were adjusted for age, burden of chronic disease using the Charlson Comorbidity Index, public insurance status, residence in a low-income area, and obesity, factors all associated with increased odds of hospital admission. During the study period, 326 patients died. Among the patients who died, 70.6% were black/non-Hispanic, and 29.4% were white/non-Hispanic. The unadjusted case-fatality rate was 30.1% for white patients and 21.6% for black patients. Race was not associated with higher mortality (HR 0.89 for black/non-Hispanic vs. white/non-Hispanic, 95% CI, 0.68 to 1.17) when adjusted for the variables noted above and for severity of clinical illness at presentation to the hospital.
Written by John Hickner, MD, MS, on May 29, 2020. (Source: Price-Haywood EG, Burton J, Fort D, et al. Hospitalization and mortality among black patients and white patients with Covid-19 [published online May 27, 2020]. N Engl J Med. 2020. https://www.nejm.org/doi/full/10.1056/NEJMsa2011686(www.nejm.org))
June 3, 2020, Research Update
Outcomes Similar for 5 vs. 10 Days Remdesivir but Trial Had Flaws. The results of the ACTT-1 trial suggest that remdesivir for 10 days reduces the time to recovery and possibly mortality in patients with COVID-19. In this study sponsored by Gilead, 397 hospitalized patients were randomized to 5 vs. 10 days of remdesivir (200 mg loading dose on day 1 followed by 100 mg daily). The study had two major flaws that limit our ability to interpret its conclusion that results were similar for the two groups. First, this was an open-label trial, so patients and physicians knew who was getting the medication and for how long. Second, clinically important differences occurred between groups at baseline, with more patients requiring high flow oxygen, mechanical ventilation, or ECMO in the 10-day group at baseline (69 vs. 53). In the ACTT-1 trial, those patients appeared to benefit less from remdesivir. There is also no description of how randomization was performed or whether allocation to groups was concealed, so it seems likely that sicker patients were nonrandomly allocated to the 10-day group. The primary outcome was improvement of at least two grades on a 7-point scale ranging from death (grade 1) to not hospitalized (grade 7); all patients started at grades 2 to 5. Improvement occurred more often in those in the five-day group (65% vs. 54%), but this difference was no longer statistically significant after adjustment for baseline differences. The final assessment of the authors is that no difference occurred in outcomes between 5 and 10 days, so 5 days should be considered, especially if supplies are limited.
Written by Mark Ebell MD, MS, on May 28, 2020. (Source: Goldman JD, Lye DCB, Hui DS, et al. Remdesivir for 5 or 10 Days in patients with severe Covid-19 [published online May 27, 2020]. N Engl J Med. 2020; https://www.nejm.org/doi/full/10.1056/NEJMoa2015301(www.nejm.org))
June 2, 2020, Research Update
Remdesivir Shortens Recovery Time in Hospitalized Patients with COVID-19 and Lower Respiratory Tract Infections (ACTT-1). This preliminary report of a multicenter, multinational randomized trial caught a lot of news attention (see COVID-19 Research Brief from April 30, 2020), and it has now been published! The study, the Adaptive Covid-19 Treatment Trial (ACTT-1), took place in 60 different sites in the United States, Germany, Denmark, the United Kingdom, Greece, Korea, Mexico, Spain, and Japan. The researchers randomized 1,063 patients hospitalized with COVID-19 and evidence of lower respiratory tract involvement to receive remdesivir (n = 538; 200 mg IV on day 1 and then 100 mg IV daily for up to 10 days or hospital discharge) or matching placebo infusion (n = 521). There was a little controversy about this study because in mid-April, the primary endpoint was switched from mortality to time to recover. Time to recovery was significantly faster in the remdesivir-treated group than in those receiving placebo (11 vs. 15 days, p < 0.001). There was also a trend toward lower 14-day mortality in the remdesivir group (7.1% vs. 11.9%), but this was not statistically significant. If the mortality difference were significant, this would translate to a number needed to treat of 21. Projecting statistically, it is likely the study would have needed to continue for one to two weeks to accrue enough patients and events for the mortality data to become statistically significant. The rate of serious adverse events in the remdesivir-treated patients was slightly lower (21.1%) than in those receiving placebo (27.0%).
Written by Henry C. Barry, MD, MS, on May 27, 2020. (Source: Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of Covid-19—preliminary report [published online May 22, 2020]. N Engl J Med. 2020. https://www.nejm.org/doi/full/10.1056/NEJMoa2007764(www.nejm.org)(www.nejm.org))
June 1, 2020, Research Update
Large Multinational Cohort Study Finds the Use of Macrolide Antibiotics, Hydroxychloroquine, or Chloroquine Is Not Associated with Better Outcomes but Is Associated with Increased Harms. These authors reviewed registry data from 96,032 patients hospitalized with COVID-19 in one of 671 hospitals on six continents. Because these were not part of a formal protocol, the treatment choices by the treating clinicians were quite varied: 1,868 patients received chloroquine; 3,783 received chloroquine plus a macrolide; 3,016 received hydroxychloroquine; 6,221 received hydroxychloroquine with a macrolide; and 81,144 (84.4%) received none of these agents. Of these patients, 11% died while in the hospital. There was no significant difference in the proportion of patients with baseline qSOFA (sepsis-related organ failure assessment) scores less than 1 (80% to 83% of patients in each treatment group), but patients receiving one of these agents were minimally more likely to have oxygen saturation less than 94% (9.5% for control patients compared with 10.5% to 11.2% of the rest). The researchers were unable to find that the use of any of these agents was associated with any improved outcomes. On the contrary, they identified their use to be associated with significant harms. In-hospital mortality in the control patients was 9.3%, 16.4% for those taking chloroquine, 22.2% for those taking chloroquine plus a macrolide, 18.0% for those taking hydroxychloroquine, and 23.8% for those taking hydroxychloroquine plus a macrolide. Very few (0.3%) of control patients developed a new ventricular arrhythmia compared with 4.3% taking chloroquine, 6.5% of those taking chloroquine plus a macrolide, 6.1% of those taking hydroxychloroquine, and 8.1% of those taking hydroxychloroquine plus a macrolide. Finally, after adjusting for several factors associated with outcomes, the probability of being harmed was significantly greater for any intervention.
IMPORTANT NOTE: In light of the significant safety concerns, the overwhelming number of studies that fail to demonstrate any benefit and the recent suspension of randomized trials, the Daily Research Brief authors have decided not to cover other studies of hydroxychloroquine or chloroquine until such time there is evidence of benefit.
Written by Henry C. Barry, MD, MS, on May 22, 2020; updated June 1, 2020. (Source: Mehra MR, Desai SS, Ruschitzka F, et al. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis [published online May 29, 2020]. https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(20)31180-6.pdf(www.thelancet.com))
May 31, 2020, Research Update
Patients Receiving Convalescent Plasma at Mayo Clinic Had Few Transfusion-Related Serious Adverse Events. Many new treatments are being proposed for COVID-19, but safety assessment is often lacking. This report from the Mayo Clinic on a preprint server describes the safety outcomes for 5,000 consecutive patients from around the United States with COVID-19 treated with convalescent plasma as part of an FDA-approved Expanded Access Program that began in early April. The median was 62 years of age, and 81% had current severe or life-threatening disease while the remainder were at risk for severe disease. There were 36 serious adverse events (SAEs) within four hours of transfusion, of which only two were felt to be definitely related to the transfusion by the treating physician. The SAEs included 15 deaths (0.3), of which 4 (0.08%) were thought to be related to the transfusion. Other SAEs included transfusion-associated circulatory overload in seven patients, transfusion-related acute lung injury in 11 patients, and severe allergic transfusion reaction in three. Mortality at seven days was 14.9%, but without a randomized trial of convalescent plasma compared to usual care we do not know its effectiveness. At least it does appear to be safe. Primum non nocere.
Written by Mark Ebell MD, MS, on May 22, 2020. (Source: Joyner M, Wright RS, Fairweather D, et al. Early safety indicators of COVID-19 convalescent plasma in 5,000 patients [published online May 14, 2020]. MedRxIV. https://www.medrxiv.org/content/10.1101/2020.05.12.20099879v1(www.medrxiv.org))
May 30, 2020, Research Update
Patients Taking Biologic Agents Did Not Appear To Be at Increased Risk with COVID-19 in New York City. An unanswered concern is whether patients taking immune-modulating drugs for the treatment of inflammatory arthritis or inflammatory bowel disease are at greater risk of poor outcomes than the general population. This is a case series from a New York City health system of 86 such patients with COVID-19, of whom 14 were hospitalized, one died, and the remaining were managed as an outpatient. Most (87%) were taking an immune-modulating drug for their condition, with 72% taking any biologic or Janus kinase inhibitor, 44% a tumor necrosis factor inhibitor, and 20% methotrexate. The rate of hospitalization was slightly lower than that for New York City as a whole (16% vs. 26%); patients who were hospitalized tended to be older and have other comorbidities such as chronic lung disease. Use of nonbiologic agents such as methotrexate (43% vs. 15%), glucocorticoids (29% vs. 6%), and hydroxychloroquine (21% vs. 7%) was more common in the hospitalized patients. Overall this supports that chronic use of biologic agents does not significantly increase risk of adverse outcomes with COVID-19.
Written by Mark Ebell MD, MS, on May 22, 2020. (Source: Haberman R, Axelrad J, Chen A, et al. Covid-19 in immune-mediated inflammatory diseases—case series from New York [published online April 29, 2020]. N Engl J Med. 2020. https://www.nejm.org/doi/full/10.1056/NEJMc2009567(www.nejm.org))
May 29, 2020, Research Update
How Did Social Distancing Policies Affect Local Spread of COVID-19 in Georgia? Clarke County, Georgia, implemented mandatory social distancing policies on March 20, 2020, 14 days prior to statewide implementation on April 3. Counties surrounding Clarke followed the statewide guidelines. Using statewide case reports by county, the investigators estimated doubling time, an accepted measure of spread of infection, for Clarke compared with surrounding counties. By April 26, the five-day rolling average doubling time was twice as long in Clarke compared with surrounding counties (roughly 40 days vs. 20 days). A social distancing policy that prohibited events and gatherings of more than 10 people and that required individuals to remain at home 24 hours a day with very limited exceptions for essential travel was effective in slowing the spread of COVID-19.
Written by John Hickner, MD, MS, on May 20, 2020. (Source: Ebell MH, Bagwell-Adams G. Mandatory social distancing associated with increased doubling time: an example using hyperlocal data [published online May 7, 2020]. Am J Prevent Med. 2020. https://www.ajpmonline.org/article/S0749-3797(20)30185-9/fulltext(www.ajpmonline.org))
May 28, 2020, Research Update
Stay-at-Home Orders Reduced Incidence of COVID-19 in Illinois Compared with Iowa Border Counties. Do stay-at-home orders reduce COVID-19 spread? This study compared daily changes in COVID-19 cases in eight Iowa counties bordering Illinois (where no stay-at-home order was in place) with seven Illinois counties bordering Iowa (where stay-at-home orders were in place). Sensitivity analysis was used to account for differences in other factors such as closing of schools and nonessential business, county population density, and poverty rates. Trends in cumulative COVID-19 incidence were compared before and after March 21, the day the stay-at-home order went into effect in Illinois. At 10, 20, and 30 days after that date, cases increased more quickly in Iowa than Illinois counties, with a difference of 4.7 additional cases per 10,000 residents (95% CI, -8.64 to -0.78; p = 0.02) at 30 days. The estimated excess cases in Iowa was as high as 217 cases during that 30 days, which represents 30.4% of the 716 cases diagnosed in those Iowa counties by that date. The sensitivity analysis supported these findings.
Written by John Hickner, MD, MS, on May 20, 2020. (Source: Lyu W, Wehby GL. Comparison of estimated rates of coronavirus disease 2019 (COVID-19) in border counties in Iowa without a stay-at-home order and border counties in Illinois with a stay-at-home order. JAMA Netw Open. 2020;3(5):e2011102.)
May 27, 2020, Research Update
Seroprevalence of COVID-19 Infection in Los Angeles County. Counting only confirmed cases significantly underestimates the true incidence of COVID-19 infection because mild and asymptomatic cases are generally not diagnosed. Seroprevalence studies of antibodies to COVID-19 provide better estimates of population infection. A random sample of 1,952 Los Angeles (LA) county residents were invited to participate in a seroprevalence study, and 863 adults were tested. Thirty-five (4%) individuals tested positive; after adjusting for the sensitivity and specificity of the test and population weighting, the estimate was adjusted slightly upward to 4.6%. Assuming a similar infection prevalence across LA county, the estimated number of infected individuals as of April 11, 2020, is about 400,000 rather than 8,430, which was the cumulative number of confirmed COVID-19 cases reported by April 11. This is roughly a 50-fold difference, suggesting that about 98% of COVID-19 cases in LA county were not diagnosed. These results are similar to a prior COVID-19 seroprevalence study in Santa Clara, California, that we reported in a Daily Research Brief on April 27. (Source: Bendavid E, Mulaney B, Sood N, et al. COVID-19 antibody seroprevalence in Santa Clara County, CA [published online April 17, 2020]. https://www.medrxiv.org/content/10.1101/2020.04.14.20062463v1(www.medrxiv.org)(www.medrxiv.org))
Written by John Hickner, MD, MS, on May 20, 2020. (Source: Sood N, Simon P, Ebner P, et al. Seroprevalence of SARS-CoV-2-specific antibodies among adults in Los Angeles county, California, on April 10-11, 2020 [published online May 18, 2020]. JAMA. 2020. https://jamanetwork.com/journals/jama/fullarticle/2766367(jamanetwork.com))
May 26, 2020, Research Update
Neither Hydroxychloroquine nor Azithromycin Are Associated with Decreased In-Hospital Mortality in New York. These authors reviewed the records of 1,438 patients hospitalized with COVID-19. These patients represented nearly 90% of all patients with COVID-19 hospitalized in the New York metropolitan region. The overall in-hospital mortality was 20.3%. The mortality rate for patients taking hydroxychloroquine (HCQ) alone was 19.9%, whereas the rate for those taking HCQ plus azithromycin was 25.7%. The mortality rate for patients taking only azithromycin was 10%, whereas it was 12.7% for those taking neither. After taking into account other factors associated with in-hospital mortality, they found no association with either drug alone or in combination and decreased hospital mortality. They also found, however, that patients taking the combination of HCQ plus azithromycin were twice as likely to suffer a cardiac arrest (adjusted OR, 2.13; 95% CI, 1.12 to 4.05), whereas no increase in risk occurred for patients taking either drug alone.
Written by Henry C. Barry, MD, MS, on May 20, 2020. (Source: Rosenberg ES, Dufort EM, Udo T, et al. Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York state [published online May 11, 2020]. https://jamanetwork.com/journals/jama/fullarticle/2766117(jamanetwork.com))
May 25, 2020, Research Update
Hydroxychloroquine Ineffective in Oxygen-Requiring Patients in France. These authors analyzed care data from 181 oxygen-requiring patients with COVID-19 hospitalized at one of four tertiary care centers in France but who were not requiring intensive care. They compared outcomes of patients who received standard care with those who also received hydroxychloroquine (600 mg per day). They also tried to account for potential confounding factors. The survival rate without transfer to the intensive care unit at day 21 was 76% in the treatment group and 75% in the control group. Additionally, there was no difference in the overall survival at day 21 (89% and 91%, respectively). They also found no differences in the rates of developing acute respiratory distress syndrome or in the rate of successful weaning from supplemental oxygen. Eight patients (10%) taking hydroxychloroquine developed electrocardiographic abnormalities requiring discontinuation of treatment.
Written by Henry C. Barry, MD, MS, on May 20, 2020. (Source: Mahévas M, Tran V-T, Roumier M, et al. Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data. BMJ. 2020;369:m1844.)
May 24, 2020, Research Update
BCG Vaccine Not Associated with COVID-19 Infection in Israel. Some ecologic studies have pointed to lower rates of COVID-19 and less morbidity and mortality in countries where higher rates of BCG immunization occurred. These investigators took advantage of a natural experiment in their country. In Israel, BCG was no longer routinely administered after 1982. A study compared COVID-19 infection rates in 3,064 patients born three years before this cutoff (39 to 41 years of age) and 2,869 patients born three years after this cutoff (35 to 37 years of age). They found no difference in infection rates (11.7% vaccinated vs. 10.4% unvaccinated). No difference in rates of COVID-19 positive per 100,000 population occurred, either.
Written by Mark Ebell, MD, MS, on May 20, 2020. (Source: Hamiel U, Kozer E, Youngster I. SARS-CoV-2 rates in BCG-vaccinated and unvaccinated young adults [published online May 13, 2020]. https://jamanetwork.com/journals/jama/fullarticle/2766182(jamanetwork.com)(jamanetwork.com))
May 23, 2020, Research Update
Hydroxychloroquine Ineffective in Patients with Mild or Moderate COVID-19 in China. Researchers conducted an open-label randomized trial in one of 16 designated COVID-19 treatment centers in China. They randomized 75 patients to standard care and 75 patients to standard care plus hydroxychloroquine (HCQ; 1,200 mg daily for three days followed by 800 mg daily for two weeks in those with mild or moderate disease or three weeks for those with severe disease). All but two of the patients had mild or moderate COVID. Overall, the rate of resolution of viral shedding was similar (81% in controls and 85% in those receiving HCQ). Only 9% of the control patients experienced adverse events compared with 30% of the HCQ-treated patients. This was a research design with biases that generally favor the intervention group, strengthening the findings of no differences in outcomes.
Written by Henry C. Barry, MD, MS, on May 20, 2020. (Source: Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ. 2020;369:m1849.)
May 22, 2020, Research Update
Outdoor Transmission of COVID-19 Rare in China. In a case series, investigators studied the likely site of transmission for 7,324 of the 10,980 confirmed COVID-19 cases that occurred outside of Hubei province in China by February 11, 2020. They collected descriptions of each confirmed case from the local Municipal Health Commission website of 320 cities in mainland China, excluding Hubei province. They identified clusters of three or more cases linked temporally to the same infection venue. Among the identified clusters, 54% involved three cases, 26% involved four cases, and only 2% involved 10 or more cases. Exposure at home was the most common (254 of 318 clusters; 80%), followed by transportation (108; 34%). Many clusters had more than one exposure venue. Only one outbreak occurred involving two cases for which only outdoor exposure was identified. They conclude that COVID-19 transmission during outdoor exposure is rare in China. It is not known whether this is true in other countries where use of masks outdoors is less common.
Written by John Hickner, MD, MS, on May 15, 2020. (Source: Qian H, Miao T, Liu L, et al. Indoor transmission of SARS-CoV-2 [published online April 7, 2020]. https://www.medrxiv.org/content/10.1101/2020.04.04.20053058v1(www.medrxiv.org))
May 21, 2020, Research Update
Anticoagulation May Benefit COVID-19 Patients Who Have Significant Coagulopathy. Severe COVID-19 infection has a high mortality rate that may be improved with anticoagulation. In an observational study, 449 consecutive patients with severe COVID-19 out of 1,786 total COVID patients admitted to Tongji Hospital in Wuhan, China, were enrolled in the study, and 99 of them received heparin for seven days or longer. Overall no improvement in mortality occurred with heparin, except in patients with a sepsis-induced coagulopathy (SIC) score ≥ 4 (40.0% vs. 64.2%, P = .029) or D-dimer greater than sixfold upper limit of normal (32.8% vs. 52.4%, P = .017). These results suggest that anticoagulation of severely ill COVID-19 patients who have coagulopathy may benefit from heparin anticoagulation. Given that there were multiple post hoc comparisons, we should continue to be watching for better studies.
Written by John Hickner, MD, MS, on May 15, 2020. (Source: Tang N, Bai H, Chen X, et al. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020;18(5):1094-1099.)
May 20, 2020, Research Update
Outcomes with Anticoagulation in Hospitalized COVID-19 Patients in New York City. This observational study assessed the relationship between anticoagulation and the outcomes of mortality and length of stay among 2,773 hospitalized patients with COVID in the Mount Sinai Health System in New York City after adjusting for important confounders. A total of 786 patients received systemic anticoagulation (SAC), including intravenous, oral, and subcutaneous forms. There was no overall survival benefit of SAC (22.5% vs. 22.8%), although length of survival was greater with SAC (median of 21 days vs. 14 days without SAC). Longer duration of SAC treatment was associated with lower mortality (adjusted HR of 0.86 per day, 95% CI, 0.82 to 0.89, p < 0.001). Patients treated with SAC who required mechanical ventilation (N = 395) had a much lower mortality rate (29.1% vs. 62.7%). Significant bleeding was slightly more common with anticoagulation (3% vs. 1.9%). These results suggest that ventilator-requiring patients with COVID-19 may benefit substantially from anticoagulation.
Written by John Hickner, MD, MS, on May 15, 2020. (Source: Paranjpe I, Fuster V, Lala A, et. al. Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with COVID-19 [published online May 5, 2020]. J Am Coll Cardiol. 2020. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202841/pdf/main.pdf(www.ncbi.nlm.nih.gov))
May 19, 2020, Research Update
Respiratory Droplets Can Linger for Several Minutes after Normal Speech in Closed Spaces. We reported in a Daily Research Brief on April 22, 2020 (https://www.nejm.org/doi/full/10.1056/NEJMc2007800(www.nejm.org)), that respiratory droplets can travel up to 7.5 cm during normal speech and that droplets travel farther with louder speech. This same research team, using the same laser-based technology, now reports that louder speech also generates thousands of oral fluid droplets per second and that in a closed, stagnant air environment the droplets linger in the air for 8 to 14 minutes. This in vitro experiment demonstrates the significant potential for COVID-19 transmission in closed spaces. Imagine how much spray is generated in a loud bar.
Written by Henry C. Barry, MD, MS, on May 14, 2020. (Source: Stadnytskyi V, Bax CE, Bax A, et al. The airborne lifetime of small speech droplets and their potential importance in SARS-CoV-2 transmission [published online May 13, 2020]. Proceedings of the National Academies of Sciences; 2020. https://www.pnas.org/content/early/2020/05/12/2006874117(www.pnas.org))
May 18, 2020, Research Update
Decreased Hospitalization Rates for ACS during COVID-19 Outbreak in Italy, These researchers compared the rate of hospitalization for acute coronary syndrome (ACS) during three time periods: the first six weeks after the first COVID-19 case was reported in northern Italy (February 20 to March 31, 2020); the six weeks preceding this (January 1 to February 19, 2020); and the same time period the previous year (February 20 to March 31, 2019). Each hospital was a hub for performing primary coronary interventions. During the index period, an average of 13.3 patients were admitted daily for ACS compared with 18.0 during the preceding six weeks and 18.9 for the same time period the previous year. Combining these findings with recent data suggesting increased deaths from ACS during the COVID-19 pandemic suggests that many patients are not seeking care for important health issues.
Written on May 14, 2020, by Henry C. Barry, MD, MS. (Source: De Filippo O, D'Ascenzo F, Angelini F, et al. Reduced rate of hospital admissions for ACS during Covid-19 outbreak in northern Italy [published online April 28, 2020]. https://www.nejm.org/doi/full/10.1056/NEJMc2009166(www.nejm.org))
May 17, 2020, Research Update
Reduced Symptoms and Viral Shedding in Low-Risk Patients with COVID-19 on Four-Drug Regimen in China. A previous study of 199 patients found no benefit to lopinavir 400 mg and ritonavir 100 mg for COVID-19 (N Engl J Med. 2020; 382(19):1787-1799). In this study set in Hong Kong, 127 patients hospitalized with COVID-19 were randomized in a 2-to-1 ratio to a combination of ribavirin 400 mg twice daily, interferon beta-1b 8 million IU every other day, lopinavir 400 mg and ritonavir 100 mg twice daily, or to lopinavir 400 mg and ritonavir 100 mg alone twice daily as a control group. They initially recruited patients within seven days of symptoms, and patients recruited later in that window received fewer doses of interferon. The average age was 51, and the mean national early warning score 2 (NEWS2 - https://www.mdcalc.com/national-early-warning-score-news-2(www.mdcalc.com)(www.mdcalc.com)) was 2 at baseline for both groups, indicating low clinical risk. The mean time to a score of 0 was four days for the combination therapy group and eight days for the control group (p < 0.001). The time to a negative nasopharyngeal swab was seven days for the combination therapy group and 12 days for the control group (p = 0.001). There were no deaths in either group.
Written by Mark H. Ebell MD, MS, on May 14, 2020. (Source: Hung IF, Lung KC, Tso EY, et al. Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial [published online May 8, 2020]. Lancet. 2020. https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(20)31042-4.pdf(www.thelancet.com)(www.thelancet.com))
May 16, 2020, Research Update
Hydroxychloroquine Lacks Benefit for COVID-19 in a Large New York City Hospital. To date, several small, relatively poor quality RCTs have failed to find benefits of hydroxychloroquine (HCQ) for the treatment of COVID-19. This study from Columbia University and New York Presbyterian Hospital studied 1,376 consecutive patients who were admitted with COVID-19 and not on mechanical ventilation after 24 hours. They compared those treated with HCQ (58.9%) with those who were not for the outcome of mechanical ventilation or death. There were significant differences between those groups, with patients receiving HCQ somewhat older and also sicker based on the PaO2/FIO2 ratio. They used multivariate Cox regression and propensity score matching to match patients who were similar on all measured parameters other than receipt of HCQ. They did this analysis several ways, and each time the result was the same: no benefit of HCQ, with nonsignificant hazard ratios ranging from 0.97 to 1.04 depending on the method used.
Written by Mark H. Ebell MD, MS, on May 12, 2020. (Source: Geleris J, Sun Y, Platt J, et al. Observational study of hydroxychloroquine in hospitalized patients with Covid-19 [published online May 7, 2020; updated May 14, 2020]. N Engl J Med. 2020. https://www.nejm.org/doi/full/10.1056/NEJMoa2012410(www.nejm.org))
May 15, 2020, Research Update
Descriptions of Children with COVID Infections in Italy and China. Several studies have described the characteristics of children infected with COVID-19. A research letter in the NEJM summarized an Italian case series of 100 childhood cases and compared their results to four other studies. Of the Italian cases, only 54% presented with fever, 44% with cough, and 11% with shortness of breath. Mortality ranged from 0% to 0.6% in the five studies summarized. The most recent case series comes from China. They identified 2,135 cases, of which 728 (34.1%) were laboratory confirmation cases and 1,407 (65.9%) were suspected cases. Cases were initially identified based on clinical signs and symptoms and exposure history. The median age was seven years of age. More cases were boys (56.6%) than girls (43.4%). Of the confirmed cases, 12.9% were asymptomatic, 43.1% mild, 41% moderate, 2.5% severe, and 0.4% critical. Severe and critical cases were more prevalent in those under one year of age. On average, children were less severely ill compared to adult cases. Better data is needed to fully understand COVID-19 infections in children.
Written by John Hickner, MD, MS, on May 8, 2020. (Sources: Parri N, Lenge M, Buonsenso D. Children with Covid-19 in pediatric emergency departments in Italy [published online May 1, 2020]. N Engl J Med. 2020. https://www.nejm.org/doi/full/10.1056/NEJMc2007617(www.nejm.org). Dong Y, Mo X, Hu Y, et al. Epidemiology of COVID-19 among children in China. Pediatrics. 2020;145(5):e20200702.)
May 14, 2020, Research Update
SARS-CoV-2 Infection Confers Humoral Immunity in at Least 99% of Patients. Researchers at the Icahn School of Medicine (preprint, nonpeer-reviewed) in New York identified 624 patients with previous PCR-confirmed SARS-CoV-2 infection who were volunteering to provide convalescent sera. In week 1, when most patients had just recovered, they tested both PCR and serum for IgG. As time went on, they dropped the PCR and tested only IgG. The IgG test was 92% sensitive and more than 99% specific. Strongly positive patients (IgG titer > 1:320) were referred for donation of sera, whereas those who were weakly positive or who were initially negative for IgG returned at least a week later for retesting. At the initial testing, 82% were strongly positive, 7% weakly positive, and 11% were negative. Of the 113 who were initially weakly positive or negative, 64 returned a median of 13 days later, and at that time 57 were strongly positive, four were weakly positive, and three were negative at follow-up (the PCR for these three was self-reported, a possible source of error). The median duration from onset of symptoms to development of IgG antibodies is 24 days, with a range of 7 to 50 days. This suggests that the vast majority of patients develop a vigorous antibody response, similar to influenza, which should provide some degree of protection against re-infection. Testing for antibodies should be delayed until at least three to four weeks after the onset of symptoms and repeated in one to two weeks if initially negative.
Written by Mark H. Ebell MD, MS, on May 7, 2020. Wajnberg A, Mansour M, Leven E, et al. Humoral immune response and prolonged PCR positivity in a cohort of 1343 SARS-CoV 2 patients in the New York City region [published online May 5, 2020]. https://doi.org/10.1101/2020.04.30.20085613(doi.org)(doi.org))
May 13, 2020, Research Update
No Antihypertensive Classes Associated with Contracting COVID-19 or Its Severity in New York City. These researchers, using their electronic medical record system, identified 12,594 patients tested for COVID-19 from March 1 to April 15, 2020. Of these, 5,894 (46.8%) were positive for COVID, 1,002 of whom (17.0%) had severe illness (ICU admission, mechanical ventilation, or death). The high rate of positive testing is reflective of highly selective test ordering, which makes comparisons with other settings challenging. A total of 4,357 (34.6%) of the tested patients had a history of hypertension, and 2,573 (59.1%) tested positive for COVID. Not surprisingly, antihypertensive medication (angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, beta blockers, calcium-channel blockers, or thiazide diuretics) use was higher in the COVID-infected patients than in those who tested negative. However, using a propensity analysis to account for known confounders, the authors found no association between any antihypertensive class and contracting COVID-19 or in the risk of having severe disease among those who tested positive.
Written by Henry C. Barry, MD, MS, on May 7, 2020. (Source: Reynolds HR, Adhikari S, Pulgarin C, et al. Renin-angiotensin-aldosterone system inhibitors and risk of Covid-19 [published online May 1, 2020; updated online May 6, 2020]. N Engl J Med. 2020. https://www.nejm.org/doi/10.1056/NEJMoa2008975(www.nejm.org))
May 12, 2020, Research Update
Saliva May Be Better Source for SARS-CoV-2 Samples Than Nasopharyngeal Swab. We usually use nasopharyngeal (NP) swabs to sample for respiratory viruses, but recent studies have reported similar sensitivity for detection of SARS-CoV-2 in saliva (Clin Infect Dis. February 2020; doi:10.1093/cid/ciaa149). The current study from Yale University (preprint server, nonpeer-reviewed) took paired saliva samples with NP swabs from 29 inpatients every three days for a total of 121 samples. They found that viral titers were higher in saliva, with fewer false negatives. A total of eight patients were negative using NP swab but positive using saliva, compared with only three positive using NP but negative using saliva. In five patients, NP swabs went from negative to positive over time, but this did not occur in the saliva samples of any patients. They also tested 98 asymptomatic healthcare workers and detected SARS-CoV-2 in saliva of two who were repeatedly negative by NP swab. Saliva samples are attractive because they can be self-collected and do not require personal protective equipment for the person obtaining the sample.
Written by Mark H. Ebell MD, MS, on May 6, 2020. (Source: Wyllie AL, Fournier J, Casanovas-Massana A, et al. Saliva is more sensitive for SARS-CoV-2 detection in COVID-19 patients than nasopharyngeal swabs [published online April 22, 2020]. https://doi.org/10.1101/2020.04.16.20067835(doi.org))
May 11, 2020, Research Update
ACEI/ARB Not Associated with Increased Risk of Contracting COVID-19 at Cleveland Clinic. Researchers at the Cleveland Clinic reviewed the records of patients with suspected COVID-19 seen in their healthcare system in Ohio and Florida between March 8, 2020, and April 12, 2020. They tested based on clinical suspicion of COVID based on symptoms, travel, and exposure history and being in a high-risk group (based on age and chronic diseases). They also tested healthcare workers purely based on symptoms. Because patients prescribed ACEIs or ARBs are more likely to also have serious comorbid conditions, the researchers performed a propensity-weighted analysis to attempt to adjust for known confounders. Of 18,472 patients tested, 1,735 (9.4%) had a positive PCR for SARS-CoV-2. Whereas patients taking an ACEI had a slightly lower risk and patients taking an ARB had a slightly higher risk of having been diagnosed with COVID-19, the odds were tiny and not statistically significant. However, patients on ACEIs were more likely to be hospitalized (OR 1.8, 95% CI, 1.2 to 2.8) or go to the ICU (OR 1.8, 95% CI, 1.07 to 2.9). Whereas patients taking ARBs were also at higher risk of hospitalization (OR 1.6, 95% CI, 1.04 to 2.5), there was no association with going to the ICU. The use of ACEIs or ARBs was not associated with the use of mechanical ventilation.
Written by Henry C. Barry, MD, MS, on May 6, 2020. (Source: Mehta N, Kalra A, Nowacki AS, et al. Association of use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with testing positive for coronavirus disease 2019 (COVID-19) [published online May 5, 2020]. JAMA Cardiol. https://jamanetwork.com/journals/jamacardiology/fullarticle/2765695(jamanetwork.com))
May 10, 2020, Research Update
About 1% of Close Contacts Get Infected with COVID-19 in Taiwan. Close contacts of 100 confirmed COVID-19 patients in Taiwan were identified and followed to ascertain what proportion of them became infected with the coronavirus. Among 2,761 contacts, there were 22 secondary infections, an attack rate of 0.7% (95% CI, 0.4% to 1.0%) The attack rate was highest among the 1,818 individuals exposed within five days of symptom onset (1.0%) compared with those with later exposure (zero cases from 852 contacts). The rate was also highest among household contacts (4.6%) and nonhousehold family contacts (5.3%). Contacts with only presymptomatic exposure had a 0.7% incidence of infection. This study suggests that isolation of infected individuals is insufficient to halt transmission of COVID-19.
Written by John Hickner, MD, MS, on May 4, 2020. (Source: Cheng HY, Jian SW, Liu DP, Ng TC, Huang WT, Lin HH. Contact tracing assessment of COVID-19 transmission dynamics in Taiwan and risk at different exposure periods before and after symptom onset. JAMA Intern Med. 2020 [published online May 1, 2020]. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2765641(jamanetwork.com))
May 9, 2020, Research Update
High Incidence of Thrombotic Events in Dutch ICU COVID-19 Patients. Investigators studied the incidence of thrombotic complications of all 184 ICU patients with COVID-19 pneumonia hospitalized at three Dutch academic medical centers. 31% of the patients had thrombotic complications, including 27% with venous thromboembolism and 3.7% with arterial thrombotic events. Pulmonary embolism was the most frequent complication (25% of all patients). The investigators recommend that all patients with COVID-19 admitted to the ICU receive thrombosis prophylaxis. This is consistent with the observation that high levels of d-dimer are associated with a worse prognosis.
Written by John Hickner, MD, MS, May 1, 2020. (Source: Klok F, Kruip M, van der Meer NJM, et. al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020 [published online ahead of print April 10, 2020]. https://www.thrombosisresearch.com/article/S0049-3848(20)30120-1/pdf(www.thrombosisresearch.com))
May 8, 2020, Research Update
Viral Shedding in Feces in Patients Hospitalized in China with COVID-19. Researchers in Zhejiang province evaluated 96 consecutive patients hospitalized with COVID-19, 22 of whom had mild disease and 74 had severe disease. To determine the amount of SARS-CoV-2 RNA, the patients had daily polymerase chain reaction assays of sputum, saliva, blood, urine, and stool. The researchers evaluated 3,497 samples and found SARS-CoV-2 RNA in 59% of the patients but only in one of the urine samples. The median duration of fecal shedding of SARS-CoV-2 RNA was 22 days compared with 18 days in the respiratory samples and 16 days in the serum samples. Patients with severe disease shed virus for one week longer than those with mild disease (21 days vs. 14 days, respectively). At this time, it is unclear how much virus is needed to infect another individual, but it appears to be low.
Written by Henry C. Barry, MD, MS, on April 30, 2020. (Source: Zheng S, Fan J, Yu F, et al. Viral load dynamics and disease severity in patients infected with SARS-CoV-2 in Zhejiang province, China, January-March 2020: retrospective cohort study. BMJ. 2020;369:m1443.)
May 7, 2020, Research Update
Case Series of Large-Vessel Stroke in Young Persons with COVID-19 in New York City. A case series reported findings regarding five persons with SARS-CoV-2 infection who presented during a two-week period with a large vessel stroke (seven times the usual rate of stroke in persons under 50 years). Their ages ranged from 33 to 49 years; two were healthy, one had hypertension and hyperlipidemia, one had undiagnosed diabetes, and one had diabetes and a history of mild stroke. The vessels involved include the middle cerebral artery in three, posterior cerebral artery in one, and internal carotid artery in one. All were treated with antiplatelet therapy, one with tissue plasminogen activator, and four with clot retrieval. All but one experienced at least some improvement in their symptoms, and three had been discharged at the time the article was written. D-dimer levels were significantly elevated in three patients; two patients delayed seeking care because of fears about COVID-19.
Written by Mark H. Ebell MD, MS, on April 29, 2020. (Source: Oxley TJ, Mocco J, Majidi S, et al. Large-vessel stroke as a presenting feature of Covid-19 in the young. N Engl J Med. 2020 [published online April 28, 2020]. https://www.nejm.org/doi/full/10.1056/NEJMc2009787(www.nejm.org))
May 6, 2020, Research Update
IDSA Guidelines on Treatment of COVID-19. The Infectious Diseases Society of America (IDSA) used modern guideline development methods that included a multidisciplinary team of clinicians, public health workers, and methodologists to develop critical PICO-format questions and to perform systematic searches of the research. They made seven recommendations for managing patients hospitalized with confirmed COVID-19, all contingent upon using these specific agents in the context of a clinical trial: administer hydroxychloroquine or chloroquine; give hydroxychloroquine/chloroquine plus azithromycin only (emphasis added) in the context of a clinical trial; give lopinavir/ritonavir; do not give corticosteroids to patients with COVID-19 pneumonia (conditional recommendation based on low certainty evidence); give corticosteroids to patients with respiratory distress syndrome; give tocilizumab only (emphasis added) in the context of a clinical trial; administer convalescent serum. The most important recommendation of the IDSA was the need to recruit patients into randomized trials to overcome the limitations of the existing research.
Written by Henry C. Barry, MD, MS, on April 23, 2020. (Source: Bhimraj A, Morgan R, Shumaker AH, et al. Infectious Diseases Society of America guidelines on the treatment and management of patients with COVID-19 [published online April 11, 2020; updated April 13, 2020]. https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/(www.idsociety.org))
May 5, 2020, Research Update
Mortality 21% for Hospitalized Patients with COVID-19 in New York City. This is a case series of the characteristics of 5,700 consecutive individuals infected with COVID-19 who were hospitalized at one of 12 hospitals in the New York City area between March 1, 2020, and April 4, 2020. The median age was 63 years of age, and 60% were men. Of the individuals, 57% of patients had hypertension, 34% had diabetes, and 42% were obese. Only 31% of patients were febrile, and 28% were receiving supplemental oxygen at triage. Outcomes are presented for the 2,634 patients who had been discharged or died by the end of the study period. A total of 553 (21%) died, 373 (14%) were treated in the ICU, and 320 (12%) received mechanical ventilation. Of those who were on a ventilator, 3% had been discharged alive, 25% had died, and 72% were still hospitalized at the end of the study period. In this case series, COVID-19 infection had a high mortality rate in hospitalized patients, especially those requiring mechanical ventilation.
Written by John Hickner, MD, MS, on April 23, 2020. (Source: Richardson S, Hirsch JS, Narasimhan M, et. al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA. [published online April 22, 2020]. https://jamanetwork.com/journals/jama/fullarticle/2765184(jamanetwork.com))
May 4, 2020, Research Update
Asymptomatic Carriage of COVID-19 in Pregnancy is Common in New York Sample. Two obstetric services in New York City instituted universal COVID-19 PCR testing in March 2020. This report summarizes screening of the first 215 pregnant women presenting in labor. Four women had symptoms consistent with COVID-19, and all tested positive. Of the remaining 211 asymptomatic patients, 29 tested positive. Twenty-nine of the 33 patients (88%) testing positive, therefore, were asymptomatic at the time of testing on admission to the hospital. The high rate of asymptomatic carriage of COVID-19 may have been due to the high prevalence of COVID-19 infections in New York City at the time of testing, though other surveillance reports also have found a high proportion of asymptomatic COVID-19 infections. This and other studies suggest that COVID-19 spread will be difficult to contain with medical isolation, quarantine, and contact tracing only.
Written by John Hickner, MD, MS, on April 23, 2020. (Source: Sutton D, Fuchs K, D'Alton M, et al. Universal screening for SARS-CoV-2 in women admitted for delivery. N Engl J Med. 2020 [published online April 13, 2020]. https://www.nejm.org/doi/full/10.1056/NEJMc2009316(www.nejm.org)(www.nejm.org))
May 3, 2020, Research Update
Characteristics of Adult Inpatients with COVID-19 in Wuhan. Researchers from Wuhan conducted a retrospective cohort study of 191 adults hospitalized with confirmed COVID-19 who had been discharged or had died by January 31, 2020. Most of the patients (72%) were discharged, and 28% died in the hospital. About half had a comorbidity: 30% had hypertension, 19% had diabetes, and 8% had coronary heart disease. The likelihood of in-hospital death was associated with older age, higher Sequential Organ Failure Assessment (SOFA) score, and d-dimer greater than 1 μg per mL on admission. The duration of viral shedding was a median of 20 days in survivors, and SARS-CoV-2 was detectable until death in nonsurvivors. The longest observed duration of viral shedding in survivors was 37 days.
Written by Henry C. Barry, MD, MS, on April 23, 2020. (Source: Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study [published correction appears in Lancet. 2020;395(10229):1038]. Lancet. 2020;395(10229):1054-1062.)
May 2, 2020, Research Update
Anosmia Common in SARS-CoV-2 Infection. Alteration in taste and smell has been reported informally in patients with COVID-19. The virus attaches selectively to angiotensin-converting enzyme 2 receptors, which are numerous in the nasal epithelium. This Italian study identified 374 consecutive adults who tested positive for SARS-CoV-2 during a four-day period at the regional hospital in Treviso, of whom 283 had contact information and 202 completed a telephone survey. Fully two-thirds (64.4%) reported any alteration in taste or smell, which was described as moderate, severe, or as bad as it can be in 102 out of 130 (78%). In 101 of 130 patients, the onset was concomitant with or after the onset of other symptoms. Although there is no comparison with patients who have noncoronavirus respiratory infections, and anosmia is a feature of sinus infections, this seems much higher than would ordinarily be the case with other viral respiratory infections.
Written by Mark H. Ebell MD, MS, on April 23, 2020. (Source: Spinato G, Fabbris C, Polesel J, et al. Alterations in smell or taste in mildly symptomatic outpatients with SARS-CoV-2 infection. JAMA. 2020 [published online April 22, 2020]. https://jamanetwork.com/journals/jama/fullarticle/2765183(jamanetwork.com))
May 1, 2020, Research Update
Chinese Study Reports Lack of Efficacy of Remdesivir in Patients Hospitalized with COVID-19 Pneumonia. In 10 hospitals in Hubei, China, researchers randomly assigned 237 patients hospitalized with COVID-19 pneumonia and hypoxia who were within 12 days of symptom onset to receive intravenous remdesivir (200 mg on day 1 followed by 100 mg on days 2 to 10 in single daily infusions) or the same volume of placebo infusions for 10 days. There were 158 patients in the remdesivir group, and 79 were in the placebo group. The treating teams were allowed to administer other therapies. In this study, there was no statistically significant improvement in time to recovery. About two-thirds of patients in each group reported adverse events, and more remdesivir-treated patients stopped treatment early due to adverse events than did placebo-treated patients (12% vs. 5%). They found no difference in mortality (12% vs. 13%). This contrasts with the NIH-sponsored ACTT trial that was terminated early because of clear improvement in the remdesivir-treated patients.
Written by Henry C. Barry, MD, MS, on April 29, 2020. (Source: Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020 [published online April 29, 2020]. https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(20)31022-9.pdf(www.thelancet.com))
April 30, 2020, Research Update
Initial Report of Efficacy of Remdesivir for COVID-19 (ACTT). The National Institute of Allergy and Infectious Diseases (NIAID) released initial results (not peer reviewed, full data not yet available) for the Adaptive COVID-19 Treatment Trial. The study recruited 1063 hospitalized patients with SARS-CoV-2 infection and evidence of lung involvement. They were randomized to remdesivir (200 mg IV on day 1 and then 100 mg IV daily for up to 10 days or hospital discharge) or matching placebo injection. The primary outcome was time to recovery, which was significantly faster in the remdesivir group (11 vs. 15 days, p < 0.001). There was also a trend toward lower mortality in the remdesivir group (8.0% vs. 11.6%, p = 0.059, NNT = 28). Harms or other outcomes such as need for mechanical ventilation are not reported.
Written by Mark H. Ebell MD, MS, on April 29, 2020. (Source: https://www.niaid.nih.gov/news-events/nih-clinical-trial-shows-remdesivir-accelerates-recovery-advanced-covid-19(www.niaid.nih.gov) and https://www.niaid.nih.gov/news-events/nih-clinical-trial-remdesivir-treat-covid-19-begins(www.niaid.nih.gov))
April 29, 2020, Research Update
Transmission of COVID-19 in a Restaurant. The investigators report a cluster of 10 COVID-19 cases that were most likely spread from one infected person at a restaurant in Guangzhou, China. The index case and three family members traveled from Wuhan on January 23, 2020, and had lunch at a small restaurant. The index case reportedly did not feel ill at lunch but developed cough and fever later that day. Within two weeks, nine other people who were in the restaurant became ill; four family members of the index case, three members of a family sitting at a neighboring table, and two family members sitting at the table on the other side. The distance between tables was three feet. The exposure time to the other two families was about one hour in the restaurant. The investigators could find no other exposures to COVID-19 for the other two infected families. The investigators hypothesize that the infection may have been spread by the direction of airflow from the air-conditioning unit. If so, this report has significant implications as the United States opens restaurants and other business venues requiring close physical proximity and ventilation. Maintaining social distancing and possibly the use of well-constructed face masks seem essential for reducing spread of COVID in close public spaces.
Written by John Hickner, MD, MS, on April 23, 2020. (Source: Lu J, Gu J, Li K, et al. COVID-19 outbreak associated with air conditioning in restaurant, Guangzhou, China, 2020. Emerg Infect Dis. 2020;26 [published online April 2, 2020]. https://wwwnc.cdc.gov/eid/article/26/7/20-0764_article(wwwnc.cdc.gov))
April 28, 2020, Research Update
Hydroxychloroquine Not Effective for COVID-19 in U.S. Veterans. This is the first published evaluation of hydroxychloroquine (HCQ) with or without azithromycin (AZ) in U.S. patients. The authors identified patients hospitalized with COVID-19 in all U.S. Veteran’s Administration hospitals. They identified 97 patients who had been given HCQ, 113 who had been given HCQ plus AZ, and 158 who had not received HCQ. They used propensity score matching to identify patients who looked similar other than the fact that one had received HCQ (or HCQ + AZ) and one had not received HCQ. In the unadjusted analysis, the risk of death was 27.8% in the HCQ group, 22.1% in the HCQ + AZ group, and 11.4% in the no HCQ group. After propensity score matching, the adjusted hazard ratio for death was 2.61 (95% CI, 1.10 to 6.17) for HCQ compared with no HCQ. However, the risk of death was not significantly increased for patients given the combination HCQ and AZ compared with those receiving no HCQ (adjusted hazard ratio 1.14, 95% CI, 0.56 to 2.32). There was no significant difference between groups with regard to the need for mechanical ventilation in the adjusted analysis.
Written by Mark H. Ebell, MD, MS, on April 22, 2020. (Source: Magagnoli J, Narendran S, Pereira F, et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19 [updated online April 23, 2020]. https://www.medrxiv.org/content/10.1101/2020.04.16.20065920v2(www.medrxiv.org))
April 27, 2020, Research Update
The initial report on a preprint server of a community serosurvey is from Santa Clara County, California (population 1.9 million). At the time of the study, 956 cases had been confirmed, and the county had some of the earliest reported cases (January 31, 2020). On April 3 and 4, they obtained serum from 3,330 adults and children. After adjusting for age distribution in the population and trying to account for false positives and negatives, they estimate a prevalence of 2.5% to 4.2% of antibodies to SARS-CoV2. That provides a range of 48,000 to 81,000 infections, far higher than the number reported on April 1 of 956 cases.
Written by Mark H. Ebell MD, MS, on April 18, 2020. (Source: Bendavid E, Mulaney B, Sood N, et al. COVID-19 antibody seroprevalence in Santa Clara County, CA [published online April 17, 2020]. https://www.medrxiv.org/content/10.1101/2020.04.14.20062463v1(www.medrxiv.org))
April 26, 2020, Research Update
A Chinese study published on a preprint server (not peer reviewed) randomized 150 patients to hydroxychloroquine (HCQ) plus usual care vs. usual care alone. All of them but two patients had mild or moderate disease, and the mean time from symptom onset to randomization was 16 days. They found no difference in the rate of conversion to nondetectable SARS-CoV-2 between groups within 28 days (85% for HCQ plus usual care vs. 81% for usual care alone). There was also no difference in symptom alleviation at 28 days or the number of days until symptom alleviation. They did many comparisons, including post hoc analyses, that report a benefit during the second week of therapy, but this is speculative at best. Mortality is not reported, and adverse events were more common in the HCQ group.
Written by Mark H. Ebell MD, MS, on April 18, 2020. (Source: Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with COVID-19: an open-label, randomized, controlled trial. MedRxiv. 2020 [published online April 14, 2020]. https://doi.org/10.1101/2020.04.10.20060558(doi.org))
April 25, 2020, Research Update
COVID-19 is highly contagious. Spread during the presymptomatic and early symptom phase, such as with the influenza virus, could make it difficult to institute effective quarantine procedures. Researchers from China studied the temporal pattern of viral shedding in 94 COVID-19 positive patients and modeled viral shedding in another 77 infector-infectee transmission pairs. The 94 COVID-19 infected individuals had a total of 414 throat cultures for COVID-19 from symptom onset to 32 days after onset. The greatest viral load shedding was at the time of symptom onset, and they surmised that infectiousness peaks at or before symptom onset. In the separate study of 77 infector-infectee pairs, based on epidemiological modeling and a mean incubation period of 5.2 days, they inferred that infectiousness starts 2.3 days before symptom onset with a peak infectiousness at 0.7 days prior to symptom onset. They estimated that 44% of secondary cases they studied were infected during the presymptomatic phase of the person who infected them. They conclude that there is substantial presymptomatic transmission.
Written by John Hickner, MD, MS, on April 19, 2020. (Source: He X, Lau EHY, Wu P, et al. Temporal dynamics in viral shedding and transmissibility of COVID-19. Nat Med. 2020 [published online April 15, 2020]. https://www.nature.com/articles/s41591-020-0869-5(www.nature.com))
April 24, 2020, Research Update
The National Academies of Sciences reviewed the evidence for effectiveness of homemade fabric masks in prevention of the spread of influenza and SAR-CoV-2 (COVID-19). These viruses can be spread by visible and invisible droplets as small as 5 microns and even smaller bioaerosols. Which size is most dangerous is unknown. Effectiveness depends on how the mask is made and how well it is made. Leakage around the mask is a problem, so fit must be as tight as possible. One must consider filtration efficiency and how much the mask impedes breathing (wearability). They found seven studies that evaluated the ability of the mask to protect the wearer or to prevent spread of infection from a wearer. Performance ranged from very poor to reducing exposure to the wearer by about 60% depending on the material used. Jayaraman found a filtration of only 0.7% of 0.3 micron-sized particles with a four-layer woven handkerchief fabric, 35.3% for five-layered woven brushed fabric, and 50% for four layers of polyester-knitted cut-pile fabric. A recent study of COVID-19 infected patients found that surgical and cotton masks were not effective at blocking the virus from disseminating during coughing. On the other hand, two studies of cotton mask wearers suggest moderate protection against inhalation of infectious-sized particles. In the only randomized trial, however (performed in healthcare workers), cotton two-layer masks were much worse than medical masks (three layers of nonwoven material) in protecting from respiratory infection (RR = 13).
Written by John Hickner, MD, MS, on April 16, 2020. (Source: National Academies of Sciences, Engineering, and Medicine, 2020. Rapid expert consultation on the effectiveness of fabric masks for the COVID-19 pandemic; April 8, 2020. Washington, DC: The National Academies Press. https://doi.org/10.17226/25776(doi.org))
April 23, 2020, Research Update
On April 7, 2020, using existing research, the National Academies Press published a rapid report on whether heat or humidity have any impact on SARS-CoV-2 survival. Basically, they found conflicting data, poor quality studies, multiple confounders, and insufficient time since the start of the COVID-19 pandemic to make much judgment. Because we are seeing COVID-19 on both sides of the equator, in tropical and temperate climates, we really should not assume any seasonality to COVID-19.
Written by Henry C. Barry, MD, MS, April 16, 2020. (Source: National Academies of Sciences, Engineering, and Medicine 2020. Rapid expert consultation on SARS-CoV-2 survival in relation to temperature and humidity and potential for seasonality for the COVID-19 pandemic; April 7, 2020. Washington, DC: The National Academies Press. https://www.nap.edu/catalog/25771/rapid-expert-consultation-on-sars-cov-2-survival-in-relation-to-temperature-and-humidity-and-potential-for-seasonality-for-the-covid-19-pandemic-april-7-2020(www.nap.edu))
April 22, 2020, Research Update
Aerosolized droplets generated during speech have been implicated as a possible source of transmitting COVID-19. In an in vitro experiment published online April 15, 2020, researchers used fancy laser gadgets to determine how far respiratory droplets travel during speech, the sizes of droplets, and the effect of speaking through a slightly damp washcloth (not sure why they did not try a homemade mask as a better test in the real world). They repeated the phrase "stay healthy" at different volumes. The droplets traveled between 5 to 7.5 cm, and they ranged in size from 20 to 500 micrometers; louder speech resulted in droplets that traveled farther. Using the damp washcloth resulted in dramatic reductions in number and size of droplets as well as distance traveled. The authors are clear to report that they did not assess viral transmission.
Written by Henry C. Barry, MD, MS, April 16, 2020. (Source: Anfinrud P, Stadnytskyi V, Bax CE, et al. Visualizing speech-generated oral fluid droplets with laser light scattering. N Engl J Med. 2020 [published online April 15, 2020]. https://www.nejm.org/doi/full/10.1056/NEJMc2007800(www.nejm.org))
April 21, 2020, Research Update
The widespread use of quarantine measures has created a need for telehealth in a setting where few are trained or have planned infrastructures. Although these are not research, the BMJ and the CDC have published two useful tools. On March 25, 2020, Greenhalgh, Koh, and Car published a nice overview of how telehealth sessions ought to occur as well as the necessary infrastructures that need to be in place. The article has a one-page summary (www.bmj.com/content/368/bmj.m1182(www.bmj.com)). The CDC has created an explicit script with branch points and specific care messages (www.cdc.gov/coronavirus/2019-ncov/hcp/phone-guide/index.html). For example, patients reporting symptoms of hypoxia or hypotension are directed to the emergency department, and the script also cautions the patient to inform the medical providers of possible COVID-19 exposure.
Written by Henry C. Barry, MD, MS, April 16, 2020.
April 20, 2020, Research Update
On April 8, 2020, the National Academies Press published a rapid report based on existing research on the duration of viral shedding and antibody response in patients infected with SARS-CoV-2. By consensus, they suggest that two sequential negative PCR tests be used to indicate that the virus is no longer being shed. They report that viral shedding occurs two to three days before the onset of symptoms and that the amount of shedding is greatest earlier in the illness. They found no correlation between COVID-19 severity and amount of shedding, but patients with more severe disease shed for longer durations. The virus can be detected for up to a week after resolution of symptoms, although they report a single case of persistent shedding for 49 days. As for antibody response, the report describes issues related to accuracy of various tests and which viral antigen is used. Their best guesses are that IgM can be detected a median of five days after onset of symptoms and IgG 10 to 18 days (median 14) after symptom onset. They found no correlation between antibody titers and disease severity, and they found no correlation between timing of seroconversion and clinical outcomes.
Written by Henry C. Barry, MD, MS, April 16, 2020. (Source: National Academies of Sciences, Engineering, and Medicine 2020. Rapid expert consultation on SARS-CoV-2 viral shedding and antibody response for the COVID-19 pandemic; April 8, 2020. Washington, DC: The National Academies Press. https://www.nap.edu/catalog/25774/rapid-expert-consultation-on-sars-cov-2-viral-shedding-and-antibody-response-for-the-covid-19-pandemic-april-8-2020(www.nap.edu))
April 17, 2020, Research Update
An uncontrolled case series published in the New England Journal of Medicine reported the outcomes for 53 patients treated with remdesivir, with 40 receiving the full course of therapy (200 mg on day 1, 100 mg once daily on days 2 through 10). The median age was 64 years of age, and median follow-up duration was 18 days. Of the 34 receiving invasive ventilation, six died, nine were still on a ventilator, three had improved to noninvasive ventilation, and 16 were on room air or had been discharged. Of the seven on noninvasive ventilation, one died, one was on invasive ventilation, and five had been discharged. Of the 12 on low flow oxygen or room air, all had been discharged. Although the outcomes compare favorably with other published series, randomized trials are ongoing to provide suitable evidence that this drug is effective.
Written by Mark H. Ebell, MD, MS, on April 11, 2020. (Source: Grein J, Ohmagari N, Shin D, et al. Compassionate use of remdesivir for patients with severe COVID-19. N Engl J Med. 2020 [published online April 10, 2020]. https://www.nejm.org/doi/full/10.1056/NEJMoa2007016(www.nejm.org))
April 16, 2020, Research Update
The Cochrane Collaboration recently published a Rapid Review (April 8, 2020) evaluating 29 studies (10 modeling studies of COVID-19; four observational studies; and 15 modeling studies of SARS or MERS) that demonstrates that quarantine measures are consistently found to be effective in damping the spread of an epidemic. Quarantine is most effective when implemented early and in conjunction with other public health measures such as closing schools, restricting travel, and social distancing. The Ohio Department of Health just released a clever public service announcement illustrating why social distancing can work: https://www.youtube.com/watch?v=YxVxc6ccqtQ(www.youtube.com).
Written by Henry C. Barry, MD, MS, on April 10, 2020. (Source: Nussbaumer-Streit B, Mayr V, Dobrescu AI, et al. Quarantine alone or in combination with other public health measures to control COVID-19: a rapid review. Cochrane Database Syst Rev. 2020;:CD013574.)
April 15, 2020, Research Update
In this open-label trial, researchers in Wuhan enrolled patients hospitalized with COVID-19 and oxygen saturation 94% or less on room air. They randomized the patients to receive standard care (n = 100) or standard care plus an HIV medication, lopinavir/ritonavir (Kaletra; 400 mg/100 mg; n = 99), twice a day for 14 days. They found no difference between groups in time to clinical improvement (median 16 days for both). Although the patients treated with lopinavir/ritonavir had fewer deaths at 28 days (19.2% vs. 25.0%), this was not statistically significant, but the study was underpowered to detect this difference. A study would need just more than 800 patients in each group, so hopefully this will be studied further.
Written by Henry C. Barry, MD, MS, on April 8, 2020. (Source: Cao B, Wang Y, Wen D, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl J Med. 2020 [published online March 18, 2020; updated online April 14, 2020]. https://www.nejm.org/doi/pdf/10.1056/NEJMoa2001282(www.nejm.org))
April 14, 2020, Research Update
The Chinese Center for Disease Control and Prevention reported the characteristics of 72,314 cases of COVID-19 infected patients in China. The first case occurred December 8, 2019, and the COVID-19 virus wasa identified January 7, 2020. Most cases (62%) had a laboratory confirmed diagnosis, 37% were diagnosed clinically, and 1% were asymptomatic with a positive test; 87% were between 30 to 70 years of age, 3% were older than 80 years, and only 2% were younger than 20 years. The overall case fatality rate of laboratory confirmed cases was 2.3% and was 14.8% for those older than 80 years. Most cases were mild (81%), and only 5% were considered critical. Mortality of critical cases was 49%. COVID-19 spread very rapidly, from one city to the entire country in 30 days.
Written by John Hickner, MD, MS, on April 9, 2020. (Source: Wu Z, McGoogan JM. 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. JAMA. 2020;323:1239-1242.)
April 13, 2020, Research Update
In a systematic review of studies reporting diagnostic and prognostic prediction models, Wynants and colleagues identified 27 studies that reported 31 prediction models. Only one study took place outside of China, and most were at high risk of bias. Nonetheless, the most frequently reported predictors of the presence of COVID-19 included age, body temperature, and signs and symptoms. The most reported predictors of severe prognosis (deterioration to severe or critical disease, prolonged hospitalization, or death) in patients with COVID-19 included age, sex, computed tomography findings, C-reactive protein, lactic dehydrogenase, and lymphopenia. Given the high risk of bias, estimates of model accuracy are unreliable.
Written by Henry C. Barry, MD, MS, on April 8, 2020. (Source: Wynants L, Van Calster B, Bonten MMJ, et al. Prediction models for diagnosis and prognosis of COVID-19 infection: systematic review and critical appraisal. BMJ. 2020;369:m1328 [published online April 7, 2020].)
April 10, 2020, Research Update
In a New England Journal of Medicine editorial, Harvey Fineberg, MD, PhD, former dean of the Harvard School of Public Health, provost of Harvard University, and president of the Institute of Medicine, strongly recommends six steps to "crush" the coronavirus outbreak in the United States. (1) Establish unified command. (2) Make millions of diagnostic tests available. (3) Supply health workers with personal protective equipment and equip hospitals to care for a surge in severely ill patients. (4) Differentiate the population into five groups: infected, presumed to be infected, exposed, not known to be exposed or infected, and adequately immune. (5) Inspire and mobilize the public. (6) Learn while doing through real-time, fundamental research.
Written by John Hickner, MD, MS, on April 5, 2020. (Source: Fineberg H. Ten Weeks to Crush the Curve. N Engl J Med. [published online April 1, 2020]. https://www.nejm.org/doi/full/10.1056/NEJMe2007263(www.nejm.org))
April 9, 2020, Research Update
In a prospective study, French investigators assessed virologic and clinical outcomes of 11 consecutive hospitalized patients (seven men and four women with mean age of 59 years) who received hydroxychloroquine ([HCQ] 660 mg/d for 10 days) and azithromycin (500 mg on day 1 and 250 mg on days 2 to 5); eight patients had significant comorbidities. At the time of treatment initiation, 10 out of 11 had fever and received nasal oxygen therapy. Within five days, one patient died and two were transferred to the ICU. In one patient, HCQ and azithromycin were discontinued after four days because of a prolongation of the QT interval. Repeated nasopharyngeal swabs in 10 patients (not completed in the patient who died) using a qualitative PCR assay were still positive for SARS-CoV2 RNA in eight of 10 patients at days 5 to 6 after treatment initiation. These virologic results stand in contrast with those reported by Gautret, et al., and cast doubts about the strong antiviral effectiveness of this combination.
Written by John Hickner, MD, MS, on April 5, 2020. (Source: Molina JM, Delaugerre C, Goff JL, et al. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection. Médecine et Maladies Infectieuses. [published online March 30, 2020]. https://www.sciencedirect.com/science/article/pii/S0399077X20300858?via%3Dihub(www.sciencedirect.com))
April 8, 2020, Research Update
A UK trial randomized 20,066 persons living in households with others to receive either access to a brief online handwashing intervention or no access. The primary outcome was the likelihood that a participant had a respiratory tract infection during a four-month period, which was decreased in the intervention group (51% vs. 59%, p < 0.001, number needed to treat [NNT] = 12). The intervention also decreased the number of gastrointestinal infections (21% vs. 25%, p < 0.001, NNT = 25) and the number of respiratory infections in a household member (44% vs. 49%, p < 0.001, NNT = 20). The site has been updated for COVID-19 and is freely available at germdefence.org.
Written by Mark H. Ebell, MD, MS, on April 4, 2020. (Source: Little P, Stuart B, Hobbs FDR, et al. An internet-delivered handwashing intervention to modify influenza-like illness and respiratory infection transmission (PRIMIT): a primary care randomised trial. Lancet. 386(10004):1641-1639.)
April 7, 2020, Research Update
C-reactive protein (CRP) is associated with more severe illness and higher mortality in COVID-19 cases. These authors retrospectively evaluated the impact of age and CRP to identify three risk groups for mortality in 577 patients in Wuhan, China. Low-risk group (0% 12-day mortality): age < 60 years and CRP < 34 mg/L. Moderate risk group (6% 12-day mortality): age 60+ years and CRP < 34 mg/L OR < 60 years and CRP ≥ 34 mg/L. High-risk group (33% 12-day mortality): ago 60+ years and CRP ≥ 34 mg/L.
Written by Mark H. Ebell, MD, MS, on March 27, 2020. (Source: Lu J, Hu S, Fan R, et al. ACP risk grade: a simple mortality index for patients with confirmed or suspected severe acute respiratory syndrome coronavirus 2 disease (COVID-19) during the early stage of outbreak in Wuhan, China. Preprint only, not peer reviewed. https://www.medrxiv.org/content/10.1101/2020.02.20.20025510v1(www.medrxiv.org))
April 6, 2020, Research Update
A trial randomized 62 patients with mild COVID-19 infection to hydroxychloroquine (HCQ) 200 mg twice daily for five days or usual care. Although the authors describe the study as double-blinded, there is no mention that patients in the control group received placebo. All had oxygen saturation greater than 93% or PaO2/FIO2 ratio > 300. Patients in the HCQ group experienced relief from fever (2.2 vs. 3.2 days, p < 0.001) and cough (2.0 vs. 3.1 days, p = 0.002) about one day sooner than controls. Of 31 patients in the control group, nine worsened, five were unchanged, and 17 improved at five days. This compares with two worsened, four unchanged, and 25 improved in the HCQ group. However, concerns about the study design and the fact that it is on a preprint server awaiting peer review means we should interpret these results cautiously.
Written by Mark H. Ebell, MD, MS, on March 27, 2020. (Source: Chen Z, Hu J, Zhang A, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. Preprint only, not peer reviewed. https://www.medrxiv.org/content/10.1101/2020.03.22.20040758v2.full.pdf(www.medrxiv.org))
April 3, 2020, Research Update
This report from Imperial College in London and others provides updated estimates of the infection fatality ratio (IFR, deaths/all infections, including mild and asymptomatic) and the case fatality ratio (CFR, death/symptomatic or confirmed infections). They estimate a mean duration from symptom onset to death of 18 days and for survivors the time from symptom onset to hospital discharge of 25 days. They do a good job of trying to adjust for biases in the data attributable to oversampling of severe cases early in a pandemic, failure to adjust for age, and the lag between case identification and death. The overall IFR is estimated to be 0.66%, and the overall CFR is 1.38%. The CFR increases from 0.06% for those in their 20s to 0.15% in their 30s, 0.30% in their 40s, 1.3% in their 50s, 4.0% in their 60s, 8.6% in their 70s, and 13.4% for those 80 and older. The proportion hospitalized increases from 1% in their 20s to 4% in their 40s to 12% in their 60s.
Written by Mark H. Ebell, MD, MS, on March 31, 2020. (Source: Verity R, Okell LC, Dorigatti I, et al. Estimates of the severity of coronavirus disease 2019: a model-based analysis. Lancet Infect Dis. [published online March 30, 2020]. https://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(20)30243-7.pdf(www.thelancet.com))
April 2, 2020, Research Update
In this initial report of a small randomized trial in Shanghai, China, 30 patients with COVID-19 infection were randomized to hydroxychloroquine (HCQ) 400 mg per day for five days plus usual care versus usual care alone. At seven days, there was no difference in the rates of negative viral swabs by PCR (87% in the HCQ group versus 93% in the control group). There was also no difference regarding incidence of severe disease (one patient in the HCQ group and none in the usual care group), time to discharge, and time to being afebrile. While larger trials are needed and are ongoing, these results are not encouraging.
Written by Mark H. Ebell, MD, MS, on March 27, 2020. (Source: Chen J, Liu D, Liu L, et al. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19) [published online March 2020]. J XheJiang Univ. http://www.zjujournals.com/med/EN/10.3785/j.issn.1008-9292.2020.03.03(www.zjujournals.com))
April 1, 2020, Research Update
A case series identified five patients with severe COVID-19 pneumonia and acute respiratory distress syndrome (ARDS) who were mechanically ventilated and had a PaO2/FIO2 < 300. They were all given convalescent sera from donors who had recovered from SARS-CoV-2 infection; fever resolved in four out of five patients within three days, and ARDS resolved in four out of five patients by 12 days after the transfusion of convalescent sera. At the time of writing, three had been discharged from the hospital, and two were in stable condition. While promising, clinical trials are needed given the small number of patients and uncontrolled design.
Written by Mark H. Ebell, MD, MS, on March 27, 2020. (Source: Shen C, Wang Z, Zhao F, et al. Treatment of 5 critically ill patients with COVID-19 with convalescent plasma [published online March 27, 2020]. JAMA. https://jamanetwork.com/journals/jama/fullarticle/2763983(jamanetwork.com))
March 31, 2020, Research Update
A report published March 19 reports on a case series of 21 critically ill COVID-19 patients at a single ICU in Washington state. Patients were admitted between February 20 and March 5, 2020. The mean age of patients was 70 years (range 42 to 90), and 11 of 21 were male. Patients had symptoms an average of 3.5 days prior to hospital admission. Similar to published series in China, lymphopenia was seen in 67% of patients. Comorbidities including chronic kidney disease (48%), heart failure (43%), diabetes (33%), COPD (33%) and obstructive sleep apnea (29%) were common, with 86% having at least one comorbidity. Fifteen patients required mechanical ventilation, all due to ARDS, with one-third developing cardiomyopathy. As of March 17, 14 had died, five remained in the ICU, and two had been discharged.
Written by Mark H. Ebell MD, MS, on March 25, 2020. (Source: Arentz M, Yim E, Klaff L, et al. Characteristics and outcomes of 21 critically ill patients with COVID-19 in Washington state [published online March 19, 2020]. JAMA. https://jamanetwork.com/journals/jama/fullarticle/2763485(jamanetwork.com))
March 25, 2020, Research Update
While the case fatality ratio (CFR) is higher in Italy than in China (7.2 % vs 2.3%), once stratified by age the CFRs are very similar within each age group up to age 70. For example, 0.4% for both countries for ages 40 to 49, 1.0% for Italy versus 1.3% for China for ages 50 to 59, and 3.5% vs 3.6% for patients aged 60 to 69. For patients in their 70s (12.8% vs 8.0%) and 80’s (20.2% vs 14.8%), CFRs were higher in Italy. This may be in part due to more very old in Italy, and differences between countries in determining cause of death in patients with multiple comorbidities.
Written by Mark Ebell MD, MS, on March 25, 2020. (Source: Onder G, Rezza G, Brusaferro S. Case-fatality rate and characteristics of patients dying in relatin to COVID-19 in Italy [published online March 23, 2020]. JAMA. https://jamanetwork.com/journals/jama/fullarticle/2763667(jamanetwork.com))
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