• Coronavirus Disease 2019 (COVID-19) Daily Research Briefs

    September 24, 2020, Research Update

    Stopping the COVID-19 Pandemic with a Vaccine Would Require an Effective Vaccine and a High Vaccination Rate. We do not know how effective a vaccine will be in stopping the COVID-19 pandemic. These researchers used a computational modeling technique to determine how effective a vaccine must be and what proportion of residents of the United States would need to take the vaccine to reduce transmission sufficiently to prevent a pandemic or to stop an existing pandemic. To prevent a pandemic, if 100% of U.S. residents received the vaccine, vaccine efficacy would need to be 60%; if 75% of U.S. residents received the vaccine, it would need to be 70% effective in preventing individual infection; and if 60% of U.S. residents received the vaccine, it would need to be 80% effective to prevent a pandemic. To stop the current COVID-19 pandemic, the vaccine efficacy would need to be at least 60% if received by 100% of people and at least 80% if received by 75% of people to reduce the peak incidence by 85% to 86%, 61% to 62%, and 32% when vaccination occurs after 5%, 15%, and 30% of the population, respectively, have already been exposed to the COVID-19 coronavirus. The bottom line, according to the investigators, is that to extinguish the ongoing COVID-19 pandemic, the vaccine must have an efficacy of at least 80%, and 75% of people must receive it. Because this high vaccination coverage seems unlikely to happen soon, other measures such as social distancing and wearing masks will probably be important preventive measures for the foreseeable future.

    Written by John Hickner on September 22, 2020. (Source: Bartsch SM, O’Shea KJ, Ferguson MC, et al. Vaccine efficacy needed for a COVID-19 coronavirus vaccine to prevent or stop an epidemic as the sole intervention. Am J Prev Med. 2020;59(4):493−503.)

    September 23, 2020, Research Update

    Antibodies Persist for Four Months after Infection; Infection Fatality Ratio 0.3%, Much Higher in Older Patients. This Icelandic study measured a variety of IgG and IgM antibodies to SARS-CoV-2 in six groups of Icelanders who had either never been tested or had tested negative and in two groups of Icelanders who had tested positive and had recovered. They weighted the sample by age and sex to estimate the number of Icelanders who had been infected and used that to estimate the infection fatality ratio (deaths/[symptomatic + asymptomatic positives]) and case fatality ratio (deaths/symptomatic positives). Among patients who had experienced a symptomatic infection, IgG antibody levels remained stable over a four-month period, which is encouraging in terms of at least medium-term immunity. Those who smoked and those taking anti-inflammatory medications had lower antibody levels, although it is not clear whether this difference is clinically significant. This was not the case for IgM and IgA antibodies, which is what you would expect. They also estimate that the infection fatality ratio was 0.3% (95% CI, 0.2% to 0.6%), and the case fatality ratio was 0.6% (95% CI, 0.3% to 1.0%). The infection fatality ratio was 0.1% (95% CI, 0.0% to 0.3%) in people 70 years or younger and 4.4% in those older than 70 years (95% CI, 1.9% to 8.4%).

    Written by Mark H. Ebell MD, MS, on September 20, 2020. (Source: Gudbjartsson DF, Norddahl GL, Melsted P, et al. Humoral immune response to SARS-CoV-2 in Iceland [published online September 1, 2020]. N Engl J Med. 2020. DOI: 10.1056/NEJMoa2026116).

    September 22, 2020, Research Update

    Clinical Data and Labs Can Predict Mortality in Patients Hospitalized with COVID-19. This consortium of researchers used data from 35,463 patients hospitalized with COVID-19 to develop a clinical score, the Coronavirus Clinical Characterisation Consortium Mortality Score (4C Mortality Score) to predict mortality and then validated it on another sample of 22,361 patients. All the patients were adults admitted to one of 260 hospitals in England, Scotland, and Wales. They used robust approaches to guide this development and validation process. From 41 candidate variables, the final model (0 to 21 points, see Table 1 in the cited source) included age, sex, number of comorbidities, respiratory rate, oxygen saturation, level of consciousness, urea level, and C reactive protein. The overall mortality rate in the development cohort was 32% and 30% in the validation cohort. In the validation cohort, the model was 77% accurate, which they report is better than other scores. The model was generally best at ruling out mortality than ruling it in, as summarized in Table 2 in the source cited here. Finally, the score has limited applicability and would not be useful in the community setting with patients at lower risk of death because well over half of the patients were in the high-risk group.

    Written by Henry C. Barry, MD, MS, on September 15, 2020. (Source: Knight SR, Ho A, Pius R, et al. Risk stratification of patients admitted to hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: development and validation of the 4C Mortality Score. BMJ. 2020;370:m3339.)

    September 21, 2020, Research Update

    People Dining at a Restaurant or Going to a Bar/Coffee Shop More Likely to Have COVID-19. In this case-control study, 615 potential case-patients and 1,212 control-participants were randomly selected from those tested for SARS-CoV-2 at 11 sites from July 1 to 29 and were contacted by phone 14 to 23 days after the date they received SARS-CoV-2 testing to complete a survey. Among 802 adults contacted, 314 individuals were included in the final analyses; 154 who tested positive, and 160 who tested negative. All participants were symptomatic at the time of their SARS-CoV-2 test. Participants were asked about close contact (within six feet for ≥ 15 minutes) with a person with known COVID-19, workplace exposures, mask-wearing behavior, and community activities ≤ 14 days before symptom onset. Close contact with a person with known COVID-19 was more commonly reported among cases (42%) than among controls (14%). No significant differences were observed in the bivariate analysis between case-patients and control-participants in shopping, gatherings with ≤ 10 persons in a home, going to an office setting, going to a salon, gatherings with > 10 persons in a home, going to a gym, using public transportation, going to a bar/coffee shop, or attending a church/religious gathering. Case-patients were more likely to have reported dining at a restaurant (adjusted odds ratio [aOR] = 2.4, 95% CI = 1.5 to 3.8) in the two weeks before illness onset than controls. When the analysis was restricted to the 225 participants who did not report recent close contact with a person with known COVID-19, cases were more likely than were controls to have dined at a restaurant (aOR = 2.8, 95% CI = 1.9 to 4.3) or going to a bar/coffee shop (aOR = 3.9, 95% CI = 1.5 to 10.1). One limitation the authors report is the inability to evaluate bar and coffee shop exposure separately, which may represent different risks. 

    Written by John Hickner, MD, MS, on September 14, 2020. (Source: Fisher KA, Tenforde MW, Feldstein LR, et al. Community and close contact exposures associated with COVID-19 among symptomatic adults ≥18 years in 11 outpatient health care facilities—United States, July 2020. MMWR Morb Mortal Wkly Rep. 2020;69(36):1258–1264.)

    September 18, 2020, Research Update

    MRI Evidence of Myocarditis in Ohio State University Athletes with COVID-19. Due to reports of cardiac involvement in people infected with COVID-19, all collegiate athletes at Ohio State University with COVID were referred for cardiac magnetic resonance imaging (MRI) after quarantine (11 to 53 days). On the day of the MRI, the athletes also had electrocardiograms, echocardiograms, and serum troponin I performed. Twenty-six athletes (15 males, 11 females) agreed to participate. They do not report how many declined to participate nor what proportion of all athletes this represented. None of the athletes required hospitalization, 12 (46%) had mild symptoms and the remainder were asymptomatic. None of the athletes had electrocardiographic evidence of myocarditis or elevated troponin I levels. The authors also report that none of the athletes had echocardiographic or MRI evidence of abnormal ventricular enlargement or dysfunction. Four athletes (15%), all male, however, had MRI evidence of myocarditis. Additionally, 12 athletes (46%) had late gadolinium enhancement, indicative of past myocardial injury or perhaps part of the athlete's heart syndrome. Finally, it is unclear as to the clinical meaning and the prognosis of finding subclinical myocarditis. As with many things we have learned from COVID, we ought to proceed “with an abundance of caution.” 

    Written by Henry C. Barry, MD, MS, on September 12, 2020. (Source: Rajpal S, Tong MS, Borchers J, et al. Cardiovascular magnetic resonance findings in competitive athletes recovering from COVID-19 infection [published online September 11, 2020]. JAMA Cardiol. 2020. https://jamanetwork.com/journals/jamacardiology/fullarticle/2770645)

    September 17, 2020, Research Update

    Systematic Review Summarizes Myriad of Cardiovascular Manifestations among People with COVID-19. In a clumsily written article on a preprint server (not peer-reviewed) where the paper is long on narrative and mechanistic hypotheses and short on synthesis, the authors systematically searched PubMed and EMBASE as well as the reference lists of retrieved publications and review articles to identify papers of any variety that reported on cardiovascular outcomes among people with COVID-19. They do not describe assessing the quality of the included studies. Ultimately, they reviewed 86 papers and reported multiple cardiovascular manifestations with little summary data. They report that about 20% (range 19% to 28%) of patients with COVID-19 sustained cardiac injury or manifestations of myocarditis and 50% of those persons died. They also report that about 20% of patients experience thromboembolic manifestations and 30% of those persons died. Additionally, they report that arrhythmias are more common among patients admitted to intensive care units (44%) compared with 6% of those not requiring intensive care. There were 3% of patients experienced a stroke, and they estimate about that 40% of those persons died. Finally, they report data among patients who present with myocardial infarction but found no data on the rate of myocardial infarction or acute coronary syndrome among patients with COVID.

    Written by Henry C. Barry, MD, MS, on September 10, 2020. (Source: Thakkar S, Arora S, Kumar A, et al. A systematic review of the cardiovascular manifestations and outcomes in the setting of coronavirus-19 disease [pre-print, not peer reviewed, published online August 12, 2020]. https://www.medrxiv.org/content/10.1101/2020.08.09.20171330v2)

    September 16, 2020, Research Update

    Low Vitamin D Level Associated with Higher Risk of COVID-19. This retrospective cohort study determined the incidence of COVID-19 in those with and without vitamin D deficiency, as measured within the prior year. Of 489 people, vitamin D status was categorized as likely deficient for 124 participants (25%), likely sufficient for 287 (59%), and uncertain for 78 (16%). Overall, 71 participants (15%) tested positive for COVID-19. In the multivariate analysis, testing positive for COVID-19 was associated with likely deficient vitamin D status (relative risk, 1.77; 95% CI, 1.12 to 2.81; P = .02) compared with likely sufficient vitamin D status. Whether supplementation will reduce the risk of contracting COVID-19 or the severity of infection is not yet known. Low vitamin D levels are associated with many adverse outcomes, but nearly all randomized trials have NOT shown any benefit of vitamin D supplementation. More than 40 randomized trials of vitamin D supplementation to treat or prevent COVID-19 are listed on clinicaltrials.gov, so an answer about vitamin D and COVID-19 should be available within the next year.

    Written by John Hickner, MD, MS, on September 6, 2020. (Source: Meltzer DO, Best TJ, Zhang H, et al. Association of vitamin D status and other clinical characteristics with COVID-19 test results. JAMA Netw Open. 2020;3(9):e2019722.)

    September 11, 2020, Research Update

    Meta-Analysis Shows Pregnant Women Less Likely to Manifest COVID-19 Symptoms but More Likely to Go to Intensive Care Than Nonpregnant Women. These authors used modern meta-analytic methods, including searching multiple databases, to find studies that reported data on pregnant women with suspected or confirmed COVID-19. This is a “living systematic review” with frequent updates, including monthly reporting through a dedicated website (COVID-19: a living systematic map of the evidence). For this publication, they included 77 studies with 13,118 pregnant and recently pregnant women with COVID-19 and 83,486 nonpregnant women of reproductive age with COVID-19. Roughly one-third of the studies came from the United States and one-third from China. All of the studies used PCR to confirm the presence of COVID-19. Overall, for study trustworthiness (internal validity), 75 (96%) of the studies were at low risk of bias. However, only 10 of the studies were thought to be low risk of bias when it comes to representativeness (external validity). Overall, the rate of COVID-19 in pregnant and recently pregnant women was 10% (95% CI 7% to 14%), although the rate varied by the testing strategy. For example, in the studies that used universal testing, 7% of the pregnant women (range 4% to 10%) had COVID compared with 18% (range 10% to 28%) in the studies that tested based on symptoms. In the 26 studies that reported mortality data, 73/11,580 (0.1% but with high heterogeneity) of pregnant women with COVID-19 died. They fail to report the same rates for nonpregnant women or for uninfected pregnant women. Overall, pregnant women were less likely to have fever (OR 0.43, 95% CI 0.22 to 0.85, but high heterogeneity) and myalgias (OR 0.48, 95% CI 0.45 to 0.51; no heterogeneity). Compared with nonpregnant women of reproductive age with COVID-19, pregnant women with COVID-19 were more likely to require intensive care (OR 1.62, 95% CI 1.33 to 1.96; no heterogeneity) or mechanical ventilation (OR 1.88, 95% CI 1.36 to 2.60; no heterogeneity). Among the women who died, higher mortality was associated with increased maternal age, high body mass index, chronic hypertension, and preexisting diabetes. The presence of comorbidity was also associated with a higher risk of intensive care admission and mechanical ventilation. Overall, 17% (95% CI 13 to 21) of pregnant women with COVID-19 had preterm births and 6% (95% CI 3 to 9) had a spontaneous preterm delivery. Additionally, 18 of 2,837 (0.6%) pregnancies among women with COVID resulted in a stillbirth, and six of 1,728 neonates (0.3%) died. Overall, these data suggest that pregnant women who have COVID-19 are less likely to have typical symptoms and are more likely to require intensive care or mechanical ventilation. Although this paper is data intense, the limited reporting of comparison data prevents making too many conclusions.

    Written by Henry C. Barry, MD, MS, on September 4, 2020. (Source: Allotey J, Stallings E, Bonet M, et al. Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis. BMJ. 2020;370:m3320.)

    September 10, 2020, Research Update

    Meta-analysis of Seven RCTs Confirms That Systemic Corticosteroids Reduce 28-Day COVID-19 Mortality. The World Health Organization has created a Rapid Evidence Appraisal for COVID-19 Therapies (REACT) working group to perform an ongoing series of meta-analyses. This meta-analysis did a careful search of clinical trial registries to identify all ongoing or completed studies comparing a systemic corticosteroid with placebo or usual care in patients who were critically ill with COVID-19. Trials that included patients with mild or moderate disease or that had not recruited patients were excluded. They identified nine clinical trials, and seven agreed to share data with the REACT team for meta-analysis. Trials were done in six European countries, the United States, Canada, Brazil, New Zealand, Australia, and China. The median age of participants was 60 years, 29% were women, and all but one study required ICU admission. Data from the large UK RECOVERY trial was limited to the subgroup of patients who were mechanically ventilated. Risk of bias was assessed as low using the Cochrane Risk of Bias Tool for six of seven trials. In total, 678 patients were randomized to a corticosteroid and 1,025 to usual care or placebo. There was good consistency across trials in their results, with the I2 of 16% (that means that only 16% of the identified variance was between studies and that 84% was within studies). Corticosteroids significantly reduced mortality (odds ratio 0.66, 95% CI 0.53 to 0.82; risk ratio 0.80, 95% CI 0.70 to 0.91). I think risk ratios are more appropriate because odds ratios are only an approximation of relative risk and are most reliable when outcomes are rare (not the case here). Given a 41.4% mortality rate in the usual care/placebo group, applying the risk ratio of 0.80 yields a 20% mortality reduction to 33.2%, which corresponds to a number needed to treat to prevent one death of 12. They found no difference in outcomes by age, dose of steroid, or duration of illness prior to enrollment. Benefit was smaller for patients not receiving mechanical ventilation at randomization and possibly for those receiving vasoactive agents at randomization. This provides support for use of low-dose corticosteroids in critically ill patients but should not be applied to outpatients or patients not requiring supplemental oxygen.

    Written by Mark H. Ebell MD, MS, on September 3, 2020. (Source: The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis [published online September 2, 2020]. JAMA. 2020. https://jamanetwork.com/journals/jama/fullarticle/2770279)

    September 9, 2020, Research Update

    Hydrocortisone Likely to Reduce Need for Organ Support Interventions in Critically Ill COVID-19 Patients. The REMAP-CAP randomized clinical trials are adaptive trials designed to test several COVID-19 interventions in 121 sites in eight countries. For the hydrocortisone study, 384 of 403 enrolled critically ill patients with COVID-19 completed the open-label randomized trial in these three groups: fixed-dose hydrocortisone (137), shock-dependent (146), and no cortisone (101). The primary outcome was organ support-free days, defined as days alive and free of ICU-based respiratory or cardiovascular support within 21 days. The mean for organ support-free days was 11.5 days for the fixed-dose hydrocortisone group, 9.5 days for the shock-dependent hydrocortisone group, and 6 days for the no-hydrocortisone group. In the Bayesian analysis, there was a 93% probability of superiority for the fixed-dose hydrocortisone group over the no-hydrocortisone group and an 80% probability of superiority of shock-dependent dosing of hydrocortisone over no hydrocortisone. The trial was stopped early because of publication of the positive results from the RECOVERY trial on June 16, 2020, because the investigators believed that there was no longer clinical equipoise and that hydrocortisone should not be withheld from critically ill COVID-19 patients. A meta-analysis published simultaneously with this study confirms the benefit of corticosteroids for severe COVID-19 infection.

    Written by John Hickner, MD, MS, on September 4, 2020. (Source: The Writing Committee for the REMAP-CAP Investigators. Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: The REMAP-CAP COVID-19 corticosteroid domain randomized clinical trial [published online September 2, 2020]. JAMA. 2020. https://jamanetwork.com/journals/jama/fullarticle/2770278)

    September 8, 2020, Research Update

    Clinical Course and Viral Shedding of Children with COVID-19 in Korea. This case series of children younger than 19 years with laboratory-confirmed COVID-19 infections includes 91 of the 119 cases, symptomatic and asymptomatic, diagnosed in Korea from February 18, 2020, to March 31, 2020. These children were identified by the extensive contact-tracing system in Korea, and they were monitored closely for symptoms and viral shedding. The median age was 11 (range, 27 days to 18 years). Twenty children (22%) remained asymptomatic. Sixty percent had respiratory symptoms, 55% had nonspecific systemic symptoms, and 18% had gastrointestinal symptoms. Only two required supplemental oxygen, and none died. Mean viral shedding was 14.1 days in asymptomatic patients, 18.7 days for those with upper respiratory symptoms, and 19.9 days for those with lower respiratory track symptoms. Despite close surveillance, 52% of children had symptoms a median of three days prior to diagnosis, indicating that their symptoms were initially mild and nonspecific. The authors conclude that asymptomatic children and children with minimal symptoms may be a significant source of exposure to SARS-CoV-2.  

    Written by John Hickner, MD, MS, on August 31, 2020. (Source: Han MS, Choi EH, Chang SH, et al. Clinical characteristics and viral RNA detection in children with coronavirus disease 2019 in the Republic of Korea [published online ahead of print August 28, 2020]. JAMA Pediatr. 2020. https://jamanetwork.com/journals/jamapediatrics/fullarticle/2770150)

    September 4, 2020, Research Update

    Incidence of SARS-CoV-2 among Asymptomatic Children at 28 U.S. Hospitals Ranges from 0% to 2.2%. These authors compiled data from the charts of pediatric otorhinolaryngologists at 28 hospitals around the United States. As part of a quality-improvement initiative, 33,041 asymptomatic children had PCR testing before elective surgery, clinic visits, or hospital admissions. Overall, 250 (0.8%) children had positive tests, but the rates varied among the hospitals from 0% to 2.2%. They also found that the weekly incidence among the children generally followed the incidence in the general population. It is unclear whether children seeking care from otorhinolaryngologists are a reflection of the general population. Although the overall incidence among asymptomatic children is low, the amount of variability will make it difficult to make general recommendations about return to school.

    Written by Henry C. Barry, MD, MS, on August 30, 2020. (Source: Sola AM, David AP, Rosbe KW, et al. Prevalence of SARS-CoV-2 infection in children without symptoms of coronavirus disease 2019 [published online August 25, 2020]. JAMA Pediatr. 2020. https://jamanetwork.com/journals/jamapediatrics/fullarticle/2769878)

    September 3, 2020, Research Update

    Racial and Ethnic Disparities in COVID-19 Infection and Hospitalization Rates in the United States. It is well known that because of health and social inequities, COVID-19 disproportionately affects Black and Hispanic people in the United States. The following two epidemiological studies provide quantitative estimates of this increased risk of COVID-19. In the first study, from the CDC, the investigators summarize data from 205 hotspot counties in 33 states where COVID-19 cases were rising rapidly between June 5 to 18. Seventy-nine of these counties in 22 states reported race and ethnicity for at least 50% of cases, and in 96.2% of these counties, the proportion of cases in minorities was significantly greater than the population proportion in the county (see table).

    Racial/Ethnic group

    Mean of estimated differences, % (range)

    Mean of estimated ratios of proportion of cases to proportion of population (range)

    Hispanic/Latino

    30.2 (8.0 to 68.2)

    4.4 (1.2 to 14.6)

    Black/African American

    14.5 (2.3 to 31.7)

    2.3 (1.2 to 7.0)

    American Indian/Alaska Native

    39.3 (16.4 to 57.9)

    4.2 (1.9 to 6.4)

    Asian

    4.7 (2.7 to 6.8)

    2.9 (2.0 to 4.7)

    Native Hawaiian/Other Pacific Islander

    4.5 (0.1 to 31.5)

    8.5 (2.7 to 18.4)

    The other study analyzed hospitalizations in 12 U.S. states during a two-month period. There were 48,788 hospitalizations among a population of 66,796,666 individuals. The proportion of White individuals hospitalized for COVID-19 was considerably less than the population proportion in all 12 states, and the proportion of Black patients was greater than their population proportion in all 12 states. The greatest differences for Black patients were in Ohio (31.8% hospitalized vs. 13.0% of the state population), Minnesota (24.9% vs. 6.8%), Indiana (28.1% vs. 9.8%), and Kansas (22.0% vs. 6.1%). Eleven states report Hispanic ethnicity, and in 10 of these the hospitalized proportion was greater than the population proportion (Virginia [36.2% vs. 9.6%], Utah [35.3% vs. 14.2%], and Rhode Island [33.0% vs 15.9%]). Similar findings were reported for American Indian and Alaskan Native populations in eight states (Arizona, 15.7% of hospitalizations vs. 4.0% of the population). Asian Americans were less likely to be hospitalized.  

    Written by John Hickner, MD, MS, on August 29, 2020. (Source: Moore JT, Ricaldi JN, Rose CE, et al. Disparities in incidence of COVID-19 among underrepresented racial/ethnic groups in counties identified as hotspots during June 5–18, 2020 — 22 States, February–June 2020. MMWR Morb Mortal Wkly Rep. 2020;69(33):1122–1126. And Karaca-Mandic P, Georgiou A, Sen S. Assessment of COVID-19 hospitalizations by race/ethnicity in 12 states [published online, August 17, 2020]. JAMA Intern Med. 2020. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2769369)

    September 2, 2020, Research Update

    Similar Outcomes of Five Days of Remdesivir Vs. 10 Days of Remdesivir Vs. Usual Care in Patients with Moderate COVID-19 Pneumonia. We have previously summarized several studies of remdesivir published in NEJM. A Research Brief posted on April 17, 2020, described a case series with 53 patients with severe COVID-19. The ACTT study reported in a Research Brief posted on April 30, 2020 (updated in a Research Brief on June 2, 2020), was a randomized trial of 1,063 patients with COVID-19 with lung involvement that found speedier recovery and a trend toward lower mortality. In contrast, a Chinese randomized trial with 237 patients with COVID-19 pneumonia and hypoxia found no improvement in mortality. We also summarized a flawed study (Research Brief from June 3, 2020) that found comparable outcomes of five days and 10 days of remdesivir in patients with severe COVID-19. Finally, a recent systematic review (Research Brief from August 28, 2020, based on a study in BMJ) found that remdesivir had no overall benefit on mortality, use of mechanical ventilation, duration of mechanical ventilation, viral clearance, or hospital length of stay but that it decreased symptom duration and was unlikely to cause adverse events. We now have another randomized trial from the same team that compared five days and 10 days in patients with severe COVID-19 that was not included in the aforementioned systematic review. The researchers randomized patients hospitalized with moderate COVID-19 pneumonia (not requiring mechanical ventilation, no ARDS) to receive, unblinded, 10 days of remdesivir (n = 197), five days of remdesivir (n = 199), or usual care (n = 200). This study used a 7-point scale (ranging from death to hospitalized with various measures to not hospitalized) and had significant differences in baseline characteristics of the patients. For example, the patients randomized to 10 days of remdesivir were slightly more likely to have diabetes (44% vs. 37% and 38%), and about 10% of patients randomized to either remdesivir arms also received hydroxychloroquine compared with nearly half of the patients receiving usual care. Regardless, they report that after 11 days, compared with those receiving usual care, the distribution of clinical status based on the 7-point scale was significantly better statistically for those receiving five days of remdesivir but no different for those receiving 10 days of remdesivir. This oddity might be explained by serious remdesivir toxicity that accrues after five days or by inadequate accounting for baseline differences. It may also be purely a random finding. There may be other explanations, but this finding suggests that better studies are needed. The authors reasonably question whether the difference is clinically important.

    Written by Henry C. Barry, MD, MS, on August 26, 2020. (Source: Spinner CD, Gottlieb RL, Criner GJ, et al. Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: a randomized clinical trial [published online August 21, 2020]. JAMA. 2020. https://jamanetwork.com/journals/jama/fullarticle/2769871)

    September 1, 2020, Research Update

    High Incidence of Thrombotic Events in Hospitalized COVID-19 Patients. This study reports a consecutive series of 3,334 patients with COVID-19 hospitalized between March 1 and April 17, 2020, at NYU Langone Health Center, of whom 829 were in the ICU and 2,505 were not in the ICU. During this period most patients received thromboprophylaxis. The authors used medical record review, including natural language processing, to identify episodes of thrombosis. Rates of pulmonary embolism were 6.2% in the ICU and 2.2% on the ward; for deep vein thrombosis, rates were 9.4% in the ICU and 2.0% on the ward. Rates of stroke were 3.7% in the ICU and 0.9% on the ward, and for myocardial infarction were 13.9% in the ICU and 7.3% on the ward. All-cause mortality was significantly higher in those with thrombosis (43.2% vs. 21.0%, NNT = 5). Factors associated with thrombosis included increasing age, self-identified Hispanic ethnicity, underlying coronary artery disease, and increasing d-dimer on admission. Although there is no comparison with non-COVID-19 patients, the authors argue that these rates are higher than with other respiratory infections such as influenza. These findings are consistent with other studies and reinforce the value of measuring d-dimer on admission (it is an independent risk factor for mortality) to strongly consider providing a low-dose anticoagulant to all patients without a contraindication and to be vigilant for thrombotic complications.

    Written by Mark H. Ebell MD, MS, on August 25, 2020. (Source: Bilaloglu S, Aphinyanaphongs Y, Jones S, et al. Thrombosis in hospitalized patients with COVID-19 in a New York City health system. JAMA. 2020;324(8):799-801.)

    August 31, 2020, Research Update

    China Contains Beijing Outbreak in One Month. This research letter describes the response to an outbreak of COVID-19 in Beijing, China, that began in early June 2020. After 56 days of no new cases in Beijing, three cases exposed to SARS-CoV-2 at a seafood market on June 3 and 4 were diagnosed as confirmed cases on June 11 and 12. The first case triggered an immediate response that included aggressive contact tracing, testing, movement restrictions, and quarantine of cases in a hospital. The market was shut down on June 12, and all workers and residents of the surrounding community were tested. A total of 335 confirmed cases were identified, plus 33 asymptomatic infections; 93 people were presymptomatic at the time of diagnosis. The peak of diagnosed cases was on June 13 to 14, and the last case was reported on July 5 after a period of relatively steady decline. The combination of a rapid response, extensive testing, quick results reporting, and comprehensive contact resulted in an impressive and rapid end to the outbreak. It is impossible to imagine this happening in the United States with our fragmented health system and underfunded public health infrastructure.

    Written by Mark H. Ebell MD, MS, on August 25, 2020. (Source: Wu Z, Wang Q, Zhao J, et al. Time course of a second outbreak of COVID-19 in Beijing, China, June-July 2020 [published online August 24, 2020]. JAMA. 2020. https://jamanetwork.com/journals/jama/fullarticle/2769930)

    August 28, 2020, Research Update

    BMJ “Live” Systematic Review of Drugs for Treating SARS-CoV-2. This team performed a high-quality systematic review of randomized trials of treatments for people with suspected, probable, or confirmed COVID-19. Their review process included searching for studies from more than 31 databases and preprint servers every day and assessing the risk of bias of the included studies. The team extracted several kinds of data, including study characteristics (e.g., publication status, study status, design features, etc.), patient demographics, smoking habits, comorbidities, setting and type of care, COVID severity, and outcomes. The outcomes included a spectrum of less patient-relevant events such as time to viral clearing to more clinically important ones such as mechanical ventilation and death. In addition to the systematic review, the authors pooled data and performed network meta-analyses for the various outcomes. Their process identified 13 published trials (2,568 persons), 10 preprints (7,167 persons), and nine more (6,156 persons) upcoming. All except two studies were at “probably high” or “high” risk of bias. In other words, the data that exist are of questionable reliability, and there are lots more data that have yet to be peer-reviewed. This is a true work in progress. The BMJ online version of the paper includes a really nice interactive feature that allows you to quickly see summary data and conclusions for each of the eight individual outcomes, a few of which are summarized. In 15 trials (8,654 persons), only glucocorticoids were likely to reduce mortality compared with standard care (37 fewer deaths per 1,000 persons). In eight trials (6,953 participants), only glucocorticoids were likely to reduce the need for mechanical ventilation (30 fewer per 1,000 persons). In the 11 trials (1,875 participants) that reported adverse events, the authors found that remdesivir decreased the duration of symptoms and did not cause any additional harm compared with standard care and that hydroxychloroquine increased the risk of adverse events. It appears that more data are out there, and fortunately, the authors plan to revisit the data frequently.

    Written by Henry C. Barry, MD, MS, on August 25, 2020. (Source: Siemieniuk RAC, Bartoszko JJ, Ge L, et al. Drug treatments for covid-19: living systematic review and network meta-analysis. BMJ. 2020;370:m2980.)

    August 27, 2020, Research Update

    Hospital Mortality Similar for Black and White Patients in the United States. A prior single health system study in New Orleans found no difference in mortality between White and Black hospitalized COVID-19 patients after adjusting for age, chronic illness, and sociodemographic factors. This is a larger, similar study that included 92 hospitals in 12 states in the Ascension hospital system. In the analysis of mortality, the investigators adjusted for age, sex, insurance status, comorbidity, neighborhood deprivation, and site of care. This study included 7,139 adult patients hospitalized with COVID-19 infection between February 19, 2020, and May 31, 2020. Race was determined by self-report: 2,812 patients were Black, 3,127 were White, and the remainder were another race or not identified. Compared with White patients, the Black patients were on average younger, more likely to be women, and a greater burden of chronic illness and higher neighborhood deprivation scores. Overall, all-cause, in-hospital mortality was 20.3%, with 34.7% among those with an ICU stay and 38.1% for those receiving mechanical ventilation. There were 23.1% of White patients and 19.2% of Black patients who died during hospitalization. After adjusting for the factors noted previously, race was not significantly associated with increased risk of death (HR for Black vs. White, 0.93: 95% CI, 0.83 to 1.09). A limitation of this study is that the investigators were not able to identify ethnicity, so they were not able to study mortality for Hispanic White patients compared with Black or non-Hispanic White patients.

    Written by John Hickner, MD, MS, on August 24, 2020. (Source: Yehia BR, Winegar A, Fogel R, et al. Association of race with mortality among patients hospitalized with coronavirus disease 2019 (COVID-19) at 92 US Hospitals. JAMA Netw Open. 2020;3(8):e2018039.)

    August 26, 2020, Research Update

    Face Shields Reduced COVID-19 Infections in Community Health Workers. In this observational before-and-after study in India, the investigators assessed the effectiveness of adding face shields to the personal protective equipment of community health workers who provided in-home counseling to family members of COVID-19 patients. At the home visits, the workers met with the family in the front room of the house to explain important preventive measures and isolation procedures, and they wore three-layered surgical masks, gloves, and shoe covers. Family members were asked, but not required, to wear face masks. During the study, the community health workers lived in separate rooms in hostels and did not visit their homes or any public places, so their only possible exposure was work related. In the two weeks before the workers started using face shields in addition to the other protection, four of 62 workers developed symptomatic COVID-19 infection, and eight developed asymptomatic infections, a 19% attack rate. During these two weeks, they had visited 5,880 homes with 31,164 persons (222 subsequently tested positive for COVID-19). After face shields were introduced, 50 workers visited 18,228 homes and counseled 118,428 persons (of whom 2,682 developed COVID-19 infections), and none of the 50 workers developed symptomatic or asymptomatic COVID-19 infection. Face shields provided added protection from COVID-19 to these community health workers, and they have also been shown to reduce infections in hospital health workers.

    Written by John Hickner, MD, MS, on August 23, 2020. (Source: Bhaskar ME, Arun S. SARS-CoV-2 infection among community health workers in India before and after use of face shields [published online ahead of print August 17, 2020]. JAMA. 2020. https://jamanetwork.com/journals/jama/fullarticle/2769693)

    August 25, 2020, Research Update

    Peak COVID-19 Mortality rate in NYC Higher Than Peak 1918 Flu Mortality Rate. These investigators compared the estimated excess deaths in New York City from the COVID-19 pandemic with the estimated excess deaths due to the 1918 flu pandemic. They calculated the all-cause mortality rate per person-months for 61 days during the peak months of the 1918 flu epidemic (October and November 1918) and for the same months in 1914 to 1917 before the pandemic. They made the same calculation for COVID-19, using the peak 61 days of March 11 through May 11, 2020, and for the three prior years, 2017 to 2019. They divided this number by two to give a person-month unit. Using this method, they were able to determine the excess number of deaths due to flu or COVID-19 compared with the prepandemic periods.  The mortality incident rate ratio for the 1918 flu epidemic compared to the prepandemic years was 2.80, and the mortality incident rate ratio for COVID-19 in 2020 compared to the prepandemic years was 4.15. The mortality incident rate ratio, comparing the 1918 flu pandemic with the 2020 COVID-19 pandemic was 0.70, indicating that the proportional mortality increase for COVID-19 in March through May in New York City was 30% greater than the 1918 flu. In conclusion, in New York City, COVID-19 was more deadly in March through May of 2020 than the 1918 flu epidemic was during its peak months.

    Written by John Hickner, MD, MS, on August 17, 2020. (Source: Faust JS, Lin Z, del Rio C. Comparison of estimated excess deaths in New York City during the COVID-19 and 1918 influenza pandemics. JAMA Network Open. 2020;3(8):e2017527.)

    August 24, 2020, Research Update

    COVID-19 Hospitalization Rates Higher for Hispanic and Black Children Than for White Children. The COVID-19–Associated Hospitalization Surveillance Network (COVID-NET) is a population-based surveillance system that collects and reports to the CDC data on laboratory-confirmed COVID-19–associated hospitalizations in 14 states. From March 1 to July 25, 2020, the hospitalization rate for children younger than 18 years of age was 8.0 per 100,000, with a total of 576 children hospitalized in these 14 states. The highest hospitalization rate by age group was for children younger than 2 years of age (24.8 per 100,000). The hospitalization rate was much higher for Hispanic and Black children (16.4 and 10.5 per 100,000, respectively) compared with non-Hispanic White children (2.1 per 100,000). One in three hospitalized children required intensive care. The higher hospitalization rate for Hispanic and Black children is not fully understood but is possibly due to higher exposure rates and underlying conditions such as obesity. An improved understanding of social determinants of health is critical in reducing these disparities.

    Written by John Hickner, MD, MS, on August 11, 2020. Source: Kim L, Whitaker M, O’Halloran A, et al. Hospitalization rates and characteristics of children aged <18 years hospitalized with laboratory-confirmed COVID-19 — COVID-NET, 14 States, March 1–July 25, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(32):1081-1088.)

    August 21, 2020, Research Update

    Symptomatic and Asymptomatic COVID-19–Infected Individuals in Korea Test Positive for SARS-CoV-2 for 19.5 and 17 Days, Respectively. The investigators evaluated the clinical course and viral loads of 303 individuals with symptomatic (193) and asymptomatic (110) COVID-19 infections who were isolated in a community treatment center in Korea. These were mostly healthy young adults with a median of 25 years of age. PCR testing for SARS-CoV-2 was performed on days 8, 9, 15, and 16 of isolation, and additional tests were completed at physician discretion. Twenty-one of the 110 individuals (19%) who were initially asymptomatic developed symptoms, and the median time to develop symptoms was 15 days. By day 21, 75% of asymptomatic patients and 70% of symptomatic patients had converted to a negative COVID-19 test. The median time it took to convert to negative was 17 days in asymptomatic patients and 19.5 days in symptomatic patients. The conclusion is that asymptomatic COVID-19–infected patients may be infectious for nearly as long as symptomatic patients. A prior community contact-tracing study in Taiwan, however, found that the risk of transmitting COVID-19 after day 5 of infection was very low for symptomatic individuals (Cheng H-Y, Jian S-W, Liu D-P, et al.; Taiwan COVID-19 Outbreak Investigation Team. Contact tracing assessment of COVID-19 transmission dynamics in Taiwan and risk at different exposure periods before and after symptom onset [published online May 1, 2020]. JAMA Intern Med. 2020. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2765641).

    Written by John Hickner, MD, MS, on August 11, 2020. (Source: Lee S, Kim T, Lee E, et al. Clinical course and molecular viral shedding among asymptomatic and symptomatic patients with SARS-CoV-2 infection in a community treatment center in the Republic of Korea [published online August 6, 2020]. JAMA Intern Med. 2020. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2769235)

    August 20, 2020, Research Update

    Not All Face Coverings Offer Similar Degrees of Protection. Face masks have become a foundation of public health measures to mitigate the spread of respiratory illnesses such as COVID-19, but they have also become lightning rods for various political agendas. Some have used face coverings (e.g., bandanas, gaiters, etc.) as a more comfortable or fashionable alternative to face masks. Analogous to other studies that we have reported on the spread of respiratory droplets (April 22, 2020, Research Brief from a study in NEJM and May 19, 2020, Research Brief from the National Academy of Sciences), these researchers used fancy laser technology to evaluate the effectiveness of 14 different face coverings. They included commercial and homemade masks, various materials, number of layers, bandanas, gaiters, and a simple swath of mask material. They also included an unmasked control. One operator wearing each type of facial garb spoke into the darkened laser chamber, and the flow of respiratory droplets were recorded and analyzed. An additional four operators wore a selection of the face coverings. The authors are proud to point out that the main equipment costs about $200; using a cellphone camera means you can inexpensively replicate their work! The clear winner was the commercially made, fitted N95 masks that, compared with the unmasked controls, transmitted less than 0.1% of the droplets. The clear loser was the gaiter-type neck fleece that actually transmitted more droplets than the unmasked controls (110%)! Bandanas were only slightly better than controls. Although the study does not assess real-world performance, we have other empiric data showing various degrees of protection from commercial and homemade masks. 

    Written by Henry C. Barry, MD, MS, on August 11, 2020. (Source: Fischer EP, Fischer MC, Grass D, et al. Low-cost measurement of facemask efficacy for filtering expelled droplets during speech. Science Advances. 2020:eabd3083. https://advances.sciencemag.org/content/early/2020/08/07/sciadv.abd3083)

    August 19, 2020, Research Update

    Hydroxychloroquine Not Effective in Large British Randomized Controlled Trial. This is another report from the UK RECOVERY trial, which previously concluded that low-dose dexamethasone significantly reduces mortality in more severely ill patients with COVID-19 (preprint server, not peer reviewed). In this arm of the study, 1,561 hospitalized patients with COVID-19 were randomized to hydroxychloroquine (HCQ) 800 mg at 0 and 6 hours, followed by 400 mg every 12 hours for up to nine days, whereas 3,155 were allocated to usual care. They excluded anyone known to have a prolonged QTc interval. This was an open label trial, and allocation was appropriately concealed. The mean age of participants was 65 years of age, 38% were female, 57% had at least one major comorbidity, and 76% were receiving supplemental oxygen or assisted ventilation. Very little crossover occurred, with 92% in the HCQ group getting at least one dose (mean duration six days) and only 0.4% in the usual care group receiving the drug. No difference occurred between groups with regard to 28-day mortality (26.8% HCQ vs. 25.0% usual care, rate ratio [RR] 1.09, 95% CI 0.96 to 1.23). Patients in the HCQ group had a longer time to hospital discharge (16 vs. 13 days) and were less likely to be discharged alive within 28 days (60.3% vs. 62.8%, RR 0.92, 95% CI 0.85 to 0.99, number needed to treat [NNT] = 40). Patients in the HCQ group were also more likely to experience the combined outcome of mechanical ventilation or death (29.8% vs. 26.5%, RR 1.12, 95% CI 1.01 to 1.25, NNT = 30). This represents the strongest evidence to date of the lack of benefit and potential harm of HCQ as a treatment for COVID-19.

    Written by Mark Ebell MD, MS, on August 9, 2020. (Source: Horby P, Mafham M, Linsell L, et al. Effect of hydroxychloroquine in hospitalized patients with COVID-19: preliminary results from a multi-centre, randomized, controlled trial [pre-print, not peer reviewed, published online July 15, 2020]. https://www.medrxiv.org/content/10.1101/2020.07.15.20151852v1)

    August 12, 2020, Research Update

    Hydroxychloroquine Alone or Combined with Azithromycin Does Not Improve 15-Day Outcomes in Patients Hospitalized with Mild to Moderate COVID in Brazil. In this open-label study, funded by research institutes and industry, adult patients hospitalized at one of 55 Brazilian hospitals with mild to moderate COVID-19 (not requiring supplemental oxygen) were randomized to receive standard care (n = 227), standard care plus hydroxychloroquine (HCQ; 400 mg twice daily; n = 221), or standard care plus hydroxychloroquine plus azithromycin (HCQ+AZ; 500 mg daily for seven days; n = 217). Standard care was pretty much wild west: corticosteroids, antibiotics, antivirals, immunomodulators, or whatever else the treating team could imagine. The researchers assessed each patient’s status after 15 days. For patients who were no longer hospitalized, a research assistant unaware of treatment allocation contacted the patient to assess vital status—this appears to be the only time blinding occurred. The researchers evaluated the main outcome, a seven-point scale, using modified intention-to-treat based on those who had confirmed COVID-19. Of the 665 randomized patients, 504 (76%) had a positive PCR for COVID-10. Regardless of all of the design elements that tend to make interventions look better, the researchers were unable to find any improvements in the main outcome nor in any single category of outcome. For example, about two-thirds of patients in each group were no longer hospitalized and had no limitations on activities at 15 days. Only two patients died, both of whom received HCQ+AZ. About 15% of patients receiving HCQ or HCQ+AZ experienced prolonged QT intervals compared with 2% of those who received neither HCQ nor AZ.

    Written by Henry C. Barry, MD, MS, on August 3, 2020. (Source: Cavalcanti AB, Zampieri FG, Rosa RG, et al. Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19 [published online July 23, 2020]. N Engl J Med. 2020. https://www.nejm.org/doi/full/10.1056/NEJMoa2019014)

    August 11, 2020, Research Update

    Accuracy of Antibody Tests for COVID-19 Highly Variable. This meta-analysis identified 40 studies of serologic tests for IgG or IgM antibodies to SARS-CoV-2. The researchers searched standard databases and preprint servers. Studies were evaluated in parallel by at least two researchers, and study quality was assessed using the QUADAS-2 tool. Most of the studies were from China, used a case-control design, and studied inpatients. To estimate specificity, half of the samples were collected before the pandemic (good), whereas half of the samples were collected from patients not suspected to have COVID-19 (bad, as many cases are asymptomatic). The risk of bias for patient selection was high for all but one study because of case-control design and were high or unclear for the index test because of lack of blinding and uncertainty about how the cutoff for an abnormal test was determined. A mix of commercial and home-grown tests were used. The results are shown in the table below. The chemiluminescent had the best sensitivity by far and had good specificity. For all of the tests, sensitivity was unacceptably low for IgG and IgM until at least three weeks after symptom onset. Given the high risk of bias and lack of evaluation in outpatients, these tests should be used with caution and are not useful for acute diagnosis. An interactive calculator can be found at https://www.bmj.com/content/369/bmj.m1808.full.

    Written by Mark H. Ebell, MD, MS, on July 31, 2020. (Source: Bastos ML, Tavaziva G, Abidi SK, et al. Diagnostic accuracy of serological tests for covid-19: systematic review and meta-analysis.  BMJ. 2020;370:m2516.)

    August 10, 2020, Research Update

    Outbreak in Israeli High School with High Rates of Transmission to Staff. As schools struggle with the decision to reopen in the fall, this report of an outbreak in an Israeli high school is informative. Because of COVID-19, all schools in Israel were closed on March 13, 2020, and reopened on May 17, 2020, with mandatory daily health reports, facemasks, sanitizers, social distancing, and reduced interaction between classes. During a heatwave from May 19 to 21, the mask requirement was lifted. The school in question had 162 staff and 1,190 students between 12 to 18 years of age. On May 26 and 27, two students from different grades were diagnosed with COVID-19. Especially because the cases were not epidemiologically linked, the school was closed, and almost all staff and students were tested. The attack rate was 17.3% to 32.6% in grades 7 to 9 and was 1.6% to 4.5% in grades 10 to 12. Overall, 13.2% of students and 16.6% of staff tested positive for COVID-19. Cases were symptomatic in 43% of students and 75% of staff. There were also 87 secondary cases among family and close contacts of the school cases, including people in their 50s, 60s, and older. As of June 30, about one-third of students and staff had still not recovered. Nationally, the proportion of cases in school-aged children was 19.8% before reopening and 40.9% after reopening. A review of conditions at the school found that social distancing was not possible and that recirculating air conditioners (implicated in other indoor outbreaks) ran continuously during the heatwave.

    Written by Mark H. Ebell, MD, MS, on July 27, 2020. (Source: Stein-Zamir C, Abramson N, Shoob H, et al. A large COVID-19 outbreak in a high school 10 days after schools’ reopening, Israel, May 2020. Euro Surveill. 2020;25(29):2001352.)

    August 7, 2020, Research Update

    Prevalence of Antibodies to SARS-CoV-2 about 10 Times Higher Than Reported Case Rate in United States. We previously summarized a Centers for Disease Control and Prevalence study of COVID-19 sero-prevalence in six regions of the United States on July 2, 2020. This report expands the scope of the same study to include 10 areas in the United States: San Francisco Bay area, California; Connecticut; south Florida; Louisiana; Minneapolis-St Paul-St Cloud metro area, Minnesota; Missouri; New York City metro area, New York; Philadelphia metro area, Pennsylvania; Utah; and western Washington state. A convenience sample of serum specimens drawn by a commercial lab for other reasons was tested for antibodies to SARS-CoV-2 antibodies, and the proportion testing positive was standardized to the site populations for age and sex and was then adjusted for test sensitivity and specificity. The prevalence of antibodies to SARS-CoV-2 ranged from 1.0% in the San Francisco Bay area to 6.9% in New York City. These prevalences were six to 24 times greater than the prevalence of reported cases reported during the same time period. For seven of the 10 sites, the estimated infections were 10 times greater than the reported number of cases. Therefore, it is likely that the true COVID-19 infection rate is roughly 10 times that of diagnosed cases. 

    Written by John Hickner, MD, MS, July 25, 2020. (Source: Havers FP, Reed C, Lim T, et al. Seroprevalence of antibodies to SARS-CoV-2 in 10 sites in the United States, March 23–May 12, 2020 [published online July 21, 2020]. JAMA Intern Med. 2020. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2768834)

    August 6, 2020, Research Update

    Successful Chinese Phase 2 Trial of a COVID-19 Vaccine. These researchers identified 508 healthy volunteers and randomized them to low-dose vaccine (5 x 1010 viral particles), high-dose vaccine (1 x 1011 viral particles), or placebo vaccine in a 2:1:1 ratio (this was an adenovirus type-5 vectored vaccine). Allocation was concealed, and patients and outcome assessors were masked. The mean was 40 years of age, with a range of 18 to 83 years, but only 13% of recipients were 55 years or older. Seroconversion of the binding antibody was high at 96% to 97% in the two vaccine groups at 28 days. Seroconversion of the neutralizing antibodies to SARS-CoV-2 occurred in 59% receiving the high-dose vaccine and 49% receiving the low-dose vaccine at 28 days. Note that binding antibodies bind to the viral antigen but do not prevent infection of the host cell, whereas neutralizing antibodies prevent infection. Evidence of humoral (T-cell mediated) immunity was detected in 90% of patients receiving the high-dose vaccine and 88% with the low-dose vaccine at 28 days. Patients with high preexisting titers to adenovirus type 5 and older patients had less vigorous immune responses and would likely require a second immunization. Severe adverse events (most commonly fever but also induration, headache, fatigue, dyspnea, and myalgia/arthralgia) occurred in 9% given the high dose and only 1% given the low dose. No serious or life-threatening adverse effects occurred.

    Written by Mark H. Ebell, MD, MS, on July 21, 2020. (Source: Zhu F-C, Guan X-H, Li Y-H, et al. Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial [published online July 20, 2020]. Lancet. 2020. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31605-6/fulltext)

    August 5, 2020, Research Update

    Oxford’s COVID-19 Vaccine Also Appears Promising. We have previously reported promising data from two small vaccine trials (a Research Brief on June 25 from a Lancet study of 108 participants and a Research Brief on July 24 from a New England Journal preliminary report of 45 participants). By far the largest study to date, this team randomized more than 1,000 healthy adults in the United Kingdom to receive a single intramuscular dose of Oxford University’s chimpanzee adenovirus-vectored vaccine (at a dose of 5 x 1010  viral particles) that targets the spike protein (n = 543) or a meningococcal vaccine (n = 534). They used an active comparator vaccine because of known local and systemic reactions that are likely to be less apparent with a simple saline placebo vaccine. The participants had no lab evidence of COVID-19 infection, no COVID symptoms, and could not be at high risk of exposure. The staff administering the vaccines, the investigators, and the laboratory teams all were blinded as to which vaccine the participants received. To illustrate some of the complexities involved with vaccine trials, the researchers divided the participants into four distinct study groups. They evaluated Group 1 participants for safety and immunogenicity at 3, 7, 14, 28, and 56 days after vaccination. The researchers took greater volumes of blood from Group 2 participants to allow for assessing humoral and cellular immunogenicity. Group 3 included 10 participants who received a booster dose 28 days after the first dose. Group 4 participants were evaluated only for humoral immune response. About 10% of participants in each vaccine wing took prophylactic paracetamol (acetaminophen). The rate of fatigue was the same whether the participant received paracetamol or not (70% vs. 71%), but headaches were slightly less common in those taking paracetamol (68% vs. 61%). Other common reactions included myalgias, malaise, chills, and feverishness, most of which were also slightly less in those taking paracetamol. Two weeks later, those receiving the active vaccine already had T-cell responses and by four weeks also had an antibody response: 91% had neutralizing antibodies. All participants receiving the booster had developed neutralizing antibodies. The report does not say what proportion of patients had developed cellular immunity. This study moves us a little closer to having a safe, effective vaccine.

    Written by Henry C. Barry, MD, MS, on July 20, 2020. (Source: Folegatti PM, Ewer KJ, Aley PK, et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial [published online July 20, 2020]. Lancet. 2020. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31604-4/fulltext)

    August 4, 2020, Research Update

    Household Transmission of COVID-19 Highest in People 10 to 19 Years of Age in South Korea. South Korea instituted a comprehensive contact-tracing program to control COVID-19 transmission. These investigators from the South Korean Centers for Disease Control and Protection studied COVID-19 transmission to 59,073 contacts of 5,706 COVID-19 infected index patients identified from January 20–March 27, 2020. They monitored the contacts for an average of 9.9 days after COVID-19 infection was detected in the index case. The transmission rate was much higher for the 10,592 household contacts (11.8%) than for the 48,481 nonhousehold contacts (1.9%). They also analyzed transmission rates by age group of the index case. The household transmission rate was highest for the 10 to 19 age group (18.6% [95% CI, 14.0% to 24.0%]) and lowest for the 0 to 9 age group (5.3% [95% CI, 1.3% to 13.7%]). For adults, transmission rates ranged from 7% for the 20 to 29 age group to 18% for the 70 to 79 age group. The finding of a higher transmission rate for children/teens 10 to 19 years of age has significant implications for school re-openings.

    Written by John Hickner, MD, MS, on July 20, 2020. (Source: Park YJ, Choe YJ, Park O, et al. Contact tracing during Coronavirus disease outbreak, South Korea, 2020 [published online July 16, 2020]. Emerg Infect Dis. 2020;26(10). https://wwwnc.cdc.gov/eid/article/26/10/20-1315_article)

    August 3, 2020, Research Update

    Proton Pump Inhibitors and Associated Risk of Contracting COVID-19. In this prepublication release from the American Journal of Gastroenterology, the authors report data from an online survey. To obtain the participants, the researchers recruited a nationwide, representative sample based on the U.S. census data on age, sex, and region. The participants had to be at least 18 years of age. The survey was administered solely in English, and the participants had to have internet access and language fluency, limiting the generalizability of their findings. The survey included questions about gastrointestinal symptoms and the frequency and duration of use of acid suppressing medications. Of the 264,058 people invited, 128,847 (48.8%) accessed the survey, and 86,602 (32.7%) eligible respondents completed it. The authors report on only 53,130 (20.1%), the subset of those who reported having gastrointestinal symptoms. Of these, 3,386 (6.4%) reported a positive COVID-19 test. After adjusting for a slew of other factors that might be associated with contracting COVID-19, they report that proton pump inhibitor use was independently associated with increased odds for reporting a positive test. Once daily use of proton pump inhibitors was associated with a lower risk (OR 2.15; 95% CI, 1.90 to 2.44) compared with twice daily use (OR 3.67; 95% CI, 2.93 to 4.60). In contrast, once daily use of histamine receptor antagonists was associated with a lower risk (OR 0.85, 95% CI, 0.74 to 0.99), and twice daily use was not significantly associated with reporting a positive COVID test. Much of the important data in this study is based on self-report; therefore, these findings should be considered exploratory.

    Written by Henry C. Barry, MD, MS, on July 19, 2020. (Source: Almario CV, Chey WD, Spiegel BMR. Increased risk of COVID-19 among users of proton pump inhibitors [published online July 7, 2020]. Am J Gastroenterology. 2020. https://journals.lww.com/ajg/Documents/AJG-20-1811_R1(PUBLISH%20AS%20WEBPART)

    July 31, 2020, Research Update

    Physical Distancing Measures Are Effective in Reducing COVID-19 Transmission. Most information about the effectiveness of physical distancing (e.g., school closures, workplace closures, restrictions on mass gatherings, public transportation closure, lock-down orders) in reducing COVID-19 transmission comes from modeling studies. This study uses empirical data regarding the effects of physical distancing on COVID-19 transmission in an interrupted time series analysis and random effects meta-analysis of data from interventions in 149 countries, the most comprehensive data to date. Investigators calculated the incidence rate ratios (IRR) of COVID-19 cases before and after physical distancing interventions as measured 30 days after the intervention or on May 30, wherever came first. Implementation of any physical distancing intervention reduced COVID-19 cases an average of 13% (IRR 0.87; 95% CI, 0.85 to 0.89; n = 149 countries). The results were essentially the same whether four or five interventions were in place; most countries implemented four or five of these interventions. The findings did not change in a detailed sensitivity analysis.

    Written by John Hickner, MD, MS, on July 18, 2020. (Source: Nazrul Islam N, Sharp SJ, Gerardo Chowell G, et. al. Physical distancing interventions and incidence of coronavirus disease 2019: natural experiment in 149 countries. BMJ. 2020;370:m2743.)

    July 30, 2020, Research Update

    Spanish RCT of Hydroxychloroquine for Patients with Early, Nonsevere COVID-19 Finds No Benefit. This Spanish study sought to determine whether early treatment with hydroxychloroquine is beneficial for patients with COVID-19. The researchers identified adults in Catalonia with a positive test for SARS-CoV-2, were symptomatic but did not require hospitalization, and were within five days of symptom onset. The mean age of the 293 included patients was 42 years, 69% were women, 87% were health care workers, and the median time from symptom onset to enrollment was three days. This was an open label study, but allocation to groups was concealed from patients and investigators; lab workers were masked to treatment assignment. Patients were followed for up to a month. Patients were randomized to hydroxychloroquine 800 mg on day 1 and 400 mg once daily on days 2 through 7 or usual care alone. The primary outcome was viral load at three and seven days, but they also tracked symptom improvement. Absolutely no difference occurred between groups at days 3 or 7 in viral load. No difference occurred in hospitalization rates (7.1% vs. 5.9% in the intervention group), and no deaths occurred during the study period. Also, no difference occurred in the mean days to resolution of symptoms (12 in the control arm vs. 10 in the treatment arm, p = 0.21). Adverse events (mostly gastrointestinal and nervous system related) were much more common in the treatment group (72% vs. 9%). No serious adverse events attributed to hydroxychloroquine occurred. 

    Written by Mark H. Ebell, MD, MS, on July 17, 2020. (Source: Mitjà O, Corbacho-Monné M, Ubals M, et al.; BCN PEP-CoV-2 Research Group. Hydroxychloroquine for early treatment of adults with mild Covid-19: a randomized controlled trial [published online July 16, 2020]. Clin Infect Dis. 2020. https://academic.oup.com/cid/article/doi/10.1093/cid/ciaa1009/5872589)

    July 29, 2020, Research Update

    United States/Canadian RCT of Hydroxychloroquine for Patients with Early, Nonsevere COVID-19 Finds No Benefit. It has been hypothesized that whereas hydroxychloroquine does not appear to work in severely ill patients, perhaps it could be helpful earlier in the course of illness or in patients with less severe illness. This study enrolled 491 nonhospitalized patients with confirmed or probable COVID-19 who were enrolled online. More than half were enrolled within one day of symptom onset. A limitation of this study is that only 149 had a positive polymerase chain reaction (PCR) test, whereas 280 had a PCR positive contact to enter the study and 37 had neither but had typical symptoms. Patients were randomized to hydroxychloroquine 800 mg, followed by 600 mg six to eight hours later, and then 600 mg once daily for four additional days. They initially assumed a 10% hospitalization rate, but this did not happen, so they changed the primary outcome to the difference between groups in symptom severity over 14 days. The median age was 40 years, 56% were women, 32% had a comorbidity, and 3% were Black. They found no difference in overall symptom severity or the percentage with symptoms between groups. Adverse effects were twice as common in the treatment group (43% vs. 22%, p < 0.001), mostly gastrointestinal. The number of hospitalizations (12 total) and deaths (two) was small and did not differ between groups. The lack of diagnostic confirmation in most patients is concerning; however, a second study in Spain with 293 patients with confirmed infection published July 16, 2020, in Clinical Infectious Diseases has similar results.

    Written by Mark H. Ebell, MD, MS on July 17, 2020. (Source: Skipper CP, Pastick KA, Engen NW, et al. Hydroxychloroquine in nonhospitalized adults with early COVID-19: a randomized trial [published online July 16, 2020]. Ann Intern Med. 2020. https://www.acpjournals.org/doi/10.7326/M20-4207)

    July 28, 2020, Research Update

    Children Less Likely Than Adults To Be the Index Case in Household COVID-19 Transmission. From March 10 to April 10, 2020, the Geneva University Hospital’s surveillance network in Switzerland identified 4,310 patients with COVID-19 infection, including 40 patients (0.9%) 16 years of age or younger. In addition to describing the symptoms and clinical outcomes of these children (all recovered), the study describes household transmission for these 40 children. Among the 111 household contacts of these 40 children, there were 88 adults and 23 children.  Adult household contacts were suspected or confirmed to have COVID-19 infection before the study child in 79% (31/39) of cases. The study child developed symptoms before any other household contact in only 8% (3/39) of households. In a similar international study of COVID-19 transmission in 31 household clusters from China, Singapore, South Korea, Japan, and Iran, the investigators found that in only three of the 31 (9.7%) household clusters was a child the first (index) case. There are several plausible explanations for these findings: Children may be less likely than adults to be infective; asymptomatic children may have spread the virus more frequently and not been identified; or because of quarantine measures, children were less likely than adults to be exposed to COVID-19.

    Written by John Hickner, MD, MS, on July 15, 2020. (Sources: Posfay-Barbe KM, Wagner N, Gauthey M, et al. COVID-19 in children and the dynamics of infection in families. Pediatrics. 2020;146(1):e20201576. Zhu Y, Bloxham CJ, Hulme KD, et al. Children are unlikely to have been the primary source of household SARS- CoV-2 infections [published online March 30, 2020]. medRxiv preprint. https:// www.medrxiv.org/content/10.1101/2020. 03.26.20044826v1)

    July 24, 2020, Research Update

    Promising Early Data from the United States on Another New Vaccine. Around the world, more than 100 candidate vaccines against SARS-CoV-2 are in various stages of development and testing. In a Research Brief published on June 25, 2020, we reviewed early data from a Chinese study in Lancet that included 108 people. The current study was an open-label Phase I trial on 45 healthy adults. The participants received two doses four weeks apart of Moderna’s messenger RNA vaccine (mRNA-1273) at doses of 25 μg, 100 μg, or 250 μg. There was no comparison group, and, a significant limitation, the researchers did not screen the participants for SARS-CoV-2 infection by serology or polymerase chain reaction before enrollment. The study protocol calls for assessments at multiple points after each vaccination: 7, 14, 57, 119, 209, and 394 days. On days 1, 15, 29, 36, 43, and 57, the researchers tested each participant for binding antibodies and for neutralizing activity. Three of the 45 participants did not receive the second dose, one of whom developed urticaria and one who was in isolation for suspected COVID. On day 57, the researchers were able to detect binding and neutralizing antibodies with all three doses by 14 days after immunization with a peak at 28 days. The high-dose vaccine induced the greatest immunogenic responses but also the highest rate of adverse effects. Additionally, as we have observed with the new recombinant zoster vaccine, the second dose triggers more frequent adverse events: 54%, 100%, and 100% for each of the three doses, respectively. Fortunately, most of these were considered to be mild, and only three participants receiving the highest dose reported one or more serious adverse effects (21%). The adverse events included fever, arthralgias, injection site pain, headache, and chills. These are early and incomplete data from a small study with no control group, but the data provide hope that an effective vaccination is feasible.

    Written by Henry C. Barry, MD, MS, on July 15, 2020. (Source: Jackson LA, Anderson EJ, Rouphael NG, et al. An mRNA vaccine against SARS-CoV-2—preliminary report [published online July 14, 2020]. N Engl J Med. 2020. https://www.nejm.org/doi/full/10.1056/NEJMoa2022483)

    July 23, 2020, Research Update

    Higher Incidence of Stillbirth during COVID-19 Pandemic. To determine whether more adverse obstetric/neonatal outcomes occurred during the COVID-19 pandemic, investigators from St George’s University Hospital in London compared stillbirth, preterm birth, cesarean delivery, and neonatal unit admissions from October 1, 2019, to January 31, 2020 (prepandemic), to these outcomes from February 1, 2020, to June 14, 2020 (during the pandemic). There were 1,681 births during the first period and 1,718 births during the pandemic period. No differences were found in preterm birth, cesarean delivery, or neonatal unit admissions. Stillbirth incidence, however, was higher during the pandemic (n = 16 [9.31 per 1,000 births]) than prior to the pandemic (n = 4 [2.38 per 1,000 births]), a difference of 6.93 per 1,000 births (95% CI, 1.83 to 12.0; P = .01) The significant difference remained after excluding late terminations for fetal abnormalities (6.98 vs. 1.19 per 1,000 births, a difference of 5.79 [95% CI, 1.54 to 10.1]). None of the women who experienced stillbirth had symptoms of COVID-19, nor did the postmortem or placental examinations show evidence of COVID-19 infection. But these women were not tested for COVID-19, so they may have had asymptomatic infections. Nineteen pregnant women were hospitalized for COVID-19, and none of these women had stillbirths. Many possible explanations can account for these findings, including asymptomatic COVID-19 infection, inferior prenatal care during the pandemic, or more high-risk referrals to St George’s Hospital during the pandemic. The study is small, retrospective, and from one hospital. It will take a larger, multicenter study to see whether this association is real. 

    Written by John Hickner, MD, MS, on July 12, 2020. (Source: Khalil A, von Dadelszen P, Draycott T, et al. Change in the incidence of stillbirth and preterm delivery during the COVID-19 pandemic [published online July 10, 2020]. JAMA. 2020. https://jamanetwork.com/journals/jama/fullarticle/2768389)

    July 22, 2020, Research Update

    Results of Study That Tested an Entire Town in Italy during the Peak of the Epidemic. This is one of the only whole population studies of COVID-19 to have been performed, and it is likely more representative of the real world than similar studies on cruise ships, aircraft carriers, prisons, and maternity wards. The Italian town of Vo’ was one of the first affected, and it was entirely locked down earlier in the epidemic. Researchers tested everyone they could, which included 86% of the population between February 21 and 29, 2020, and 72% on March 7, 2020. This is a very rich dataset; highlights are as follows. In late February, 2.6% of all samples were positive. Importantly, they found that 42.5% of those infected were asymptomatic at the time of testing and never became symptomatic. The time to clear the infection for those positive on the first survey and negative on the second ranged from eight to 13 days, with a mean of 9.3 days. The viral load was similar for symptomatic and asymptomatic individuals, and through contact tracing they determined that asymptomatic individuals can transmit the infection. The lockdown reduced the effective reproductive number from 2.49 to 0.41. Finally, they estimated an infectious period between 3.6 to 6.5 days, with infectiousness peaking on the day of symptom onset.

    Written by Mark H. Ebell MD, MS, on July 12, 2020. (Source: Lavezzo E, Franchin E, Ciavarella C, et al. Suppression of a SARS-CoV-2 outbreak in the Italian municipality of Vo’ [published online June 30, 2020]. Nature. 2020. https://doi.org/10.1038/s41586-020-2488-1)

    July 21, 2020, Research Update

    Super-Spreading Study of COVID-19 in Georgia. These investigators used sophisticated modeling to determine the temporal-spatial spread of COVID-19 infection in five counties in Georgia, focusing on super-spreaders—defined as “individuals who disproportionately infect a large number of secondary cases relative to an ‘average’ infectious individual.” Data sources included the Georgia Department of Public Health surveillance and Facebook’s Data for Good program, which is designed to track movement of cell phone users over time and space. The authors state, “Our model mechanistically integrates detailed individual-level surveillance data, geo-spatial location data and highly-resolved population density (grid-) data, and aggregate mobility data.” There were 9,559 consecutive cases reported between March 1, 2020, and May 3, 2020, available for analysis. They found that the top 2% of infected individuals (those that generate the highest number of infections per individual) are responsible directly for about 20% of total infections. These super-spreaders were more likely to be children and adults younger than 60 years of age. These data have significant implications for controlling the COVID-19 pandemic, especially with the recent resurgence of infections in the United States.

    Written by John Hickner, MD, MS, on July 10, 2020. (Source: Lau MSY, Grenfell B, Nelson K, et al. Characterizing super-spreading events and age-specific infectivity of COVID-19 transmission in Georgia, USA [published preprint online June 22, 2020]. medRxiv preprint. https://www.medrxiv.org/content/10.1101/2020.06.20.20130476v2)

    July 20, 2020, Research Update

    Persistent Fatigue, Dyspnea, and Other Symptoms Common Following Hospitalization for COVID-19. In this study set in Rome, Italy, patients who had been hospitalized but now met criteria for discontinuing quarantine (afebrile for three days, symptoms improved, and two negative polymerase chain reaction [PCR] tests 24 hours apart) were invited to attend a COVID-19 follow-up clinic. Of 179 eligible patients, 165 agreed to participate, but 22 had a positive PCR test and were excluded. The mean age was 57 years, and 63% were men. Patients were a mean of 60 days post symptom onset, and 87% still reported symptoms, with 32% reporting one or two symptoms and 55% reporting three or more persistent symptoms. Fully 44% reported a clinically significant 10-point decline in a 100 points quality of life scale compared with their pre–COVID-19 state. The most common post–COVID-19 symptoms at follow-up were fatigue (53%), dyspnea (43%), joint pain (27%), chest pain (22%), cough (17%), and anosmia (16%). Strengths of this study include a standard protocol for data collection and a good response rate among invited patients. This is important prognostic information for patients who were sick enough to be hospitalized; longer term follow-up in these patients as well as in patients who were less symptomatic will be important. Comparison with patients who have survived other serious pulmonary infections such as community acquired pneumonia and acute respiratory distress syndrome are also needed to provide context.

    Written by Mark H. Ebell MD, MS, on July 10, 2020. (Source: Carfi A, Bernabei R, Landi F, et al. Persistent symptoms in patients after acute COVID-19 [published online July 9, 2020]. JAMA. 2020. https://jamanetwork.com/journals/jama/fullarticle/2768351)

    July 16, 2020, Research Update

    Healthcare Workers in Wuhan, China, Wearing Personal Protective Equipment and Who Are Exposed to SARS-CoV-2 Did Not Become Infected. These authors followed 420 healthcare workers who were “on loan” to Wuhan from two hospitals in Guangzhou. For six weeks, they worked four to six hours per day for an average of 5.4 days per week. On average, they worked about 16 hours per week in intensive care units. All had direct contact with patients and reported at least one aerosol-inducing encounter. All of them wore personal protection equipment—the full body armor of masks, goggles, face shields, gowns, gloves, etc. Upon returning home, they were quarantined for two weeks and tested. None developed symptoms of COVID-19, and none had a positive polymerase chain reaction nor IgG or IgM antibodies. 

    Written by Henry C. Barry, MD, MS, on July 9, 2020. (Source: Liu M, Cheng S-Z, Xu K-W, et al. Use of personal protective equipment against coronavirus disease 2019 by healthcare professionals in Wuhan, China: cross sectional study. BMJ. 2020;369:m2195.)

    July 15, 2020, Research Update

    Clinical Manifestations of Children with Multisystem Inflammatory Syndrome Associated with COVID-19 in Two New Studies from the United States. We previously reviewed three case series of children with multisystem inflammatory syndrome in a Research Brief published on June 16. Two more recent papers report data from medical record audits of children hospitalized in New York and in 26 states in the United States. As in the other studies, there were differences in reporting. Overall, 285 children were included in these studies, 77 (27%) were Black children, 195 (68%) had lab-confirmed COVID-19, and 110 (39%) also met criteria for Kawasaki Disease. Gastrointestinal symptoms were seen in 250 (88%) of the children, much higher than what was previously reported. One of the studies (99 children) reported that 60 children (61%) had abdominal pain and that 57 (58%) had nausea or vomiting. Rash occurred in 169 (59%) of the children, but neither study reported on desquamation. Conjunctivitis occurred in 158 (55%) of the children. One study reported that 27 (27%) children had redness or swelling of the lips or mucous membranes. Coronary artery dilation and shock, reported in one study, occurred in 9 (9%) and 10 (10%), respectively. Myocarditis occurred in 158 (55%) children. One of the studies reported chest radiograph data; 79 of the 186 (42%) were abnormal. 

    Written by Henry C. Barry, MD, MS, on July 9, 2020. (Sources: Feldstein LR, Rose EB, Horwitz SM, et al. Multisystem inflammatory syndrome in U.S. children and adolescents [published online June 29, 2020]. Updated July 2, 2020. N Engl J Med. 2020. https://www.nejm.org/doi/full/10.1056/NEJMoa2021680(www.nejm.org); Dufort EM, Koumans EH, Chow EJ, et al. Multisystem inflammatory syndrome in children in New York state [published June 20, 2020]. N Engl J Med. 2020. https://www.nejm.org/doi/full/10.1056/NEJMoa2021756)

    July 14, 2020, Research Update

    Guillain–Barré Syndrome Associated with SARS-CoV-2 in Italy. These authors report on five patients from three hospitals in northern Italy. Four of the patients developed lower limb weakness and paresthesias, and one developed facial diplegia followed by ataxia and then paresthesias. The patients were ultimately diagnosed with Guillain–Barré Syndrome. At the onset of neurologic symptoms, four of the patients had positive swabs for SARS-CoV-2, and the other eventually developed antibodies. None of the patients had a positive polymerase chain reaction in their cerebrospinal fluid. The development of Guillain–Barré Syndrome should not be a surprise because it has been frequently associated with viral infections and with active immunizations.

    Written by Henry C. Barry, MD, MS, on July 9, 2020. (Source: Toscano G, Palmerini F, Ravaglia S, et al. Guillain-Barre syndrome associated with SARS-CoV-2. N Engl J Med. 2020;382(26):2574-2576.)

    July 13, 2020, Research Update

    Hydroxychloroquine Associated with Lower Mortality in Patients Hospitalized with COVID-19: Observational Study in Detroit. In this observational study from the Henry Ford Health System in Detroit, investigators examined the in-hospital mortality of 2,541 consecutive hospitalized COVID-19 patients in four treatment categories: hydroxychloroquine (HCQ) plus azithromycin (AZM), either drug alone, or neither drug. They excluded patients who died in the first 24 hours after admission and another 10% of patients for whom final outcome data were unavailable (e.g., still hospitalized, left against medical advice, or transferred to another facility). The median time to follow-up was 28.5 days. Overall in-hospital mortality was 18.1% (95% CI, 16.6% to 19.7%). Mortality for patients taking HCQ+AZM was 20.1% (95% CI, 17.3% to 23.0%); for HCQ alone, 13.5% (95% CI, 11.6% to 15.5%); for AZM alone, 22.4% (95% CI, 16.0% to 30.1%); and neither drug, 26.4% (95% CI, 22.2% to 31.0%). In the Cox regression analysis that adjusted for age, gender, comorbid conditions, and disease severity, the hazard ratio for mortality was reduced 66% (p < 0.001) compared with the group receiving neither HCQ nor AZM. The authors report wide variations in the use of corticosteroids among the different treatment groups: 36% in those treated with neither medication, 39% of those receiving AZM alone, 74% of those treated with both, and 79% of those receiving HCQ alone. This is an observational study. These kinds of studies can find associations but are fairly weak in determining a causal link between an exposure and an outcome. In this study, the findings are inconsistent with other observational studies and with data we have from the few randomized trials that exist. Additionally, they found no effect of steroids in the outcome, which is at odds with other studies (e.g., see Research Brief from June 30 on the effects of dexamethasone from the RECOVERY Collaborative Group), at least in those with severe COVID. Observational studies are subject to all kinds of bias and are subject to alternative explanations for the findings. For example, about 25% of the patients had missing measures of disease severity and were excluded from the regression model. The co-treatment with steroids is likely to reflect differences in disease severity. Observational studies are also unable to account for the “hidden” factors involved in how physicians decide the treatments they choose based on other patient characteristics. Finally, the regression analysis took into account only factors the authors chose and could not address residual confounding. In a randomized trial, the known and unknown factors associated with the outcome of interest are evenly distributed between the intervention groups. 

    Written by John Hickner, MD, MS, and Henry Barry, MD, MS, on July 7, 2020. (Source: Arshad S, Kilgore P, Chaudhry ZS, et al.; Henry Ford COVID-19 Task Force. Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19 [published online July 1, 2020]. Int J Infect Dishttps://www.ijidonline.com/article/S1201-9712(20)30534-8/fulltext)

    July 10, 2020, Research Update

    Gastrointestinal Symptoms Associated with Delayed Diagnosis and Prolonged Viral Shedding in Patients in Wuhan, China. These authors reviewed the medical records of 850 consecutive patients hospitalized for COVID-19 over a two-week period in February 2020 in Wuhan, China. From this group, they identified 206 patients with mild disease who had demonstrated viral clearing and were subsequently discharged. They defined mild disease when patients had no dyspnea and had no evidence of respiratory distress and were able to maintain oxygen saturation above 93% while at rest. It may seem curious that these patients were admitted to the hospital, but this was in the early days of the outbreak, and hospitals were used to facilitate quarantine measures. They identified patients with gastrointestinal (GI) symptoms (“cases”) and matched them to the next admitted patient who had no GI symptoms (“controls”). They classified the case patients by whether they experienced GI symptoms alone (n = 48) or both GI and respiratory symptoms (n = 69). The authors matched them to 69 control patients. Roughly 25% of the patients had hypertension and 10% had diabetes; only 10% could confirm an exposure to a person known to be infected with SARS-CoV-2. Of the 117 patients with GI symptoms, 67 (57%) reported diarrhea that lasted an average of 5.4 days (range 1 to 14 days). Additionally, only 73 (62.4%) patients with GI symptoms also had fever compared with 65 (73%) of patients without GI symptoms. Patients with GI symptoms had a longer interval from onset of symptoms to hospitalization (16.0 ± 7.7 days) than patients with respiratory symptoms alone (11.6 ± 5.1 days) and also had longer durations of viral shedding: 40.9 days for patients with GI symptoms alone, 42.0 days for patients with GI and respiratory symptoms, and 33.5 days for patients with respiratory symptoms alone. Unfortunately, they tested the stool for viral RNA in only 22 of the patients and found it in 3/5 (60%) patients with only GI symptoms, in 8/10 (80%) of those with GI plus respiratory symptoms (net for all patients with GI symptoms 11/15 or 73%), and in only 1/7 (14.3%) of patients with respiratory symptoms alone.

    Written by Henry C. Barry, MD, MS, on July 7, 2020. (Source: Han C, Duan C, Zhang S, et al. Digestive symptoms in COVID-19 patients with mild disease severity: clinical presentation, stool viral RNA testing, and outcomes. Am J Gastroenterol. 2020;115(6):916-923.)

    July 8, 2020, Research Update

    Ischemic Stroke in COVID-19 Patients Hospitalized in New York. This was a retrospective cohort study of 1,916 patients with COVID-19 who were hospitalized or had an emergency department visit at two New York hospitals between March 4, 2020, and May 2, 2020. They were compared with 1,486 patients who presented to the same hospitals with influenza A or B between January 1, 2016, and May 31, 2018. A stroke registry was used to determine the incidence of acute ischemic stroke in the influenza patients, and chart review by two board certified neurologists was used for the patients with COVID-19. Estimates of the incidence of stroke were adjusted for age, sex, and race. Among patients with COVID-19, 31 of 1,916 (1.6%, 95% CI, 1.3% to 2.6%) were diagnosed with acute ischemic stroke, compared with only three of 1,486 of the influenza patients (0.2%, 95% CI, 0.0% to 0.6%). After adjusting for age, sex, and race, the likelihood of acute ischemic stroke was far more likely in the patients with COVID-19 (OR 7.6, 95% CI, 2.3 to 25.2). Sensitivity analyses adding adjustment for vascular risk factors, symptoms, inpatient status, and location of treatment found similar results (OR 4.6 to 9.3).

    Written by Mark H. Ebell MD, MS, on July 6, 2020. (Source: Merkler AE, Parikh NS, Mir S, et al. Risk of ischemic stroke in patients with coronavirus disease 2019 (COVID-19) vs patients with influenza [published online July 2, 2020]. JAMA Neurol. 2020. https://jamanetwork.com/journals/jamaneurology/fullarticle/2768098)

    July 7, 2020, Research Update

    Counting Deaths in the United States due to the COVID-19 Pandemic. There has been controversy about the number of deaths in the United States due to the COVID-19 pandemic. Causes of death can be difficult to determine, and a significant reporting lag also occurs, making real-time estimates inaccurate. A good way to measure the impact of COVID-19 is to compare all-cause mortality before and during the pandemic. Two recent studies that used National Center for Health Statistics data and sophisticated modeling techniques reached similar conclusions about the under-reporting of COVID-19–related deaths. Woolf’s group compared weekly all-cause mortality counts for 2014-2019 with all-cause mortality during the COVID-19 epidemic for eight weeks in March and April 2020 to determine the excess deaths in 2020 over the expected number based on 2014-2019 statistics. The excess number of deaths was estimated to be 87,001, averaging 10,875 deaths per week. Weinberger used a similar methodology, comparing total deaths in the United States from March 1 through May 30, 2020, with average total deaths during the same period from 2015 through 2019. Comparing expected deaths to observed deaths, there were 122,300 excess deaths (95% prediction interval, 116,800 to 127,000), or 9,408 excess deaths per week. There were 95,235 reported deaths directly attributed to COVID-19 during the same time period, a figure that underestimates deaths due to the pandemic by about 28%. The excess mortality is likely because of a combination of undercounting of COVID-19 deaths, people for which COVID-19 was a significant contributing factor but not the “official” cause of death, and an excess number of deaths due to other causes for which people did not seek care because of the pandemic.

    Written by John Hickner, MD, MS, on July 3, 2020. (Sources: Woolf SH, Chapman DA, Sabo RT, et al. Excess deaths from COVID-19 and other causes, March-April 2020 [published online July 1, 2020]. JAMA. 2020. https://jamanetwork.com/journals/jama/fullarticle/2768086(jamanetwork.com); and Weinberger DM, Chen J, Cohen T, et al. Estimation of excess deaths associated with the COVID-19 pandemic in the United States, March to May 2020 [published online July 1, 2020]. JAMA Intern Med. 2020. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2767980)

    July 6, 2020, Research Update

    Colchicine Yields Small Clinical Improvement in a Preliminary Randomized Trial. In this preliminary clinical trial in Greece, 105 hospitalized patients with COVID-19 were randomized to receive colchicine or standard medical therapy for up to three weeks. The outcomes were cardiac and inflammatory marker levels and clinical outcomes. The primary clinical outcome was time from baseline to clinical deterioration, defined as a two-grade deterioration on a seven-point ordinal scale that ranges from 1 = ambulatory, normal activities to 7 = death. There were no significant differences in the levels of high-sensitivity troponin and time to maximum c-reactive protein level. Mean event-free survival time was 18.6 days in the control group vs. 20.7 in the colchicine group (log rank P = .03). Seven patients (14%) in the control group and one patient (1.8%) in the colchicine group had a two-point deterioration in the primary clinical outcome (odds ratio, 0.11; 95% CI, 0.01 to 0.96; = .02). The sample size was too small to test for differences in mortality. A larger trial is needed to see whether colchicine leads to meaningful clinical benefit for patients with COVID-19.

    Written by John Hickner, MD, MS, on July 2, 2020. (Source: Deftereos SG, Giannopoulos G, Vrachatis DA, et al. Effect of colchicine vs standard care on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019: the GRECCO-19 randomized clinical trial. JAMA Netw Open. 2020;3(6):e2013136. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2767593)

    July 3, 2020, Research Update

    Classroom Spread of SARS-CoV-2. The Centers for Disease Control and Prevention reports a fascinating case report with contact tracing in a classroom setting. A schoolteacher had been in Europe in February and became ill with headache, sore throat, myalgia, and fever. The teacher taught 16 classes, each with no more than 30 students, while still symptomatic. Six of the classes were non-interactive, but the remainder were interactive where the teacher walked about the classroom. The teacher tested positive for SARS-CoV-2 by polymerase chain reaction. The exposed students were asked to self-quarantine. Of the 120 students contacted, 21 volunteered to be tested serologically, which took place about two weeks after the teacher’s return. The students were between five and 18 years of age. Of the 21, five students were in the interactive classes. One of these students had a positive antibody test, one had an indeterminate result, and three tested negative. Whereas the symptoms may be “suggestable,” the student who tested positive reported one day of myalgias and rhinorrhea and three days of cough. The indeterminate student and one other student reported no symptoms. Two students who tested negative reported one day of mild symptoms: fever, headache, and rhinorrhea. None of these symptomatic children had polymerase chain reaction testing. The authors provide no information about the remaining 16 students. It is difficult to draw conclusions about modes of teaching and risk of transmission given the selective testing and reporting.

    Written by Henry C. Barry, MD, MS, on July 1, 2020. (Source: Brown NE, Bryant-Genevier J, Bandy U, et al. Antibody responses after classroom exposure to teacher with coronavirus disease, March 2020 [published online June 29, 2020]. Emerg Infect Dis. 2020;26(9). https://wwwnc.cdc.gov/eid/article/26/9/20-1802_article)

    July 2, 2020, Research Update

    Centers for Disease Control and Prevention Seroprevalence Study Reports Rate of 1.9% to 6.9% in Six States and Approximately 11 Total Cases Per Confirmed Case. This is the initial report of a seroprevalence survey conducted by the Centers for Disease Control and Prevention (CDC) in six states (Connecticut, south Florida, Missouri, New York metro area, Utah, and Washington State Puget Sound region). They identified a convenience sample of 11,933 blood specimens submitted to commercial laboratories for reasons other than COVID-19. The specimens were evaluated for antibodies to SARS-CoV-2 using a test that was 96% sensitive and 99.3% specific, with the results adjusted for the estimated false negative and false positive rates. The age-standardized positive rates were 1.1% in Washington, 1.9% in south Florida, 2.2% in Utah, 2.7% in Missouri, 4.9% in Connecticut, and 6.9% in the metro New York City region. Rates were higher in men than women in five of six jurisdictions, and no clear pattern by age group occurred, which varied in different jurisdictions. Based on the number of confirmed cases, they estimate a range of six to 24 total cases per confirmed case, with four of six jurisdictions having 10.8 to 11.9 total cases per confirmed case. They plan to perform ongoing surveillance every three to four weeks.

    Written by Mark Ebell MD, MS, on June 27, 2020. Centers for Disease Control and Prevention. Commercial laboratory seroprevalence survey data. Updated June 26, 2020.  https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/commercial-lab-surveys.html)

    July 1, 2020, Research Update

    ACEIs and ARBs Not Associated with COVID-19 Infection and Mortality. This Danish study is one of several investigations to find no association between use of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) and the incidence and adverse outcomes of COVID-19 infection. Using Danish national registries and adjusting for age, sex, and medical history, in a cohort study of 4,480 patients with COVID-19 that included 895 ACEI/ARB users and 3,585 nonusers, there was no significant increased risk of death (adjusted hazard ratio [HR] 0.83 [95% CI, 0.67 to 1.03]) or death or severe disease (adjusted HR 1.04 [95% CI, 0.89 to 1.23]) within 30 days of diagnosis of COVID-19. In the companion case-control study of patients with hypertension, there was no significant difference in ACEI/ARB use between those who contracted COVID-19 and those who did not (adjusted HR 1.05 [95% CI, -0.80 to 1.36]). In a similar case-control Spanish study of 1,139 patients taking ACEIs/ARBs and 11,390 population controls, adjusted for age, sex, cardiovascular comorbidities, and risk factors, there was no difference in hospital admission between ACEI/ARB users and nonusers (adjusted odds ratio 0.94 [95% CI, 0.77 to 1.15]).  Along with prior studies, we have substantial data to conclude that use of ACEI/ARBs does not increase risk of or worse outcomes from COVID-19 infection.

    Written by John Hickner, MD, MS, on June 26, 2020. (Sources: Fosbøl EL, Butt JH, Østergaard L, et al. Association of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use with COVID-19 diagnosis and mortality [published online June 19, 2020]. JAMA.https://jamanetwork.com/journals/jama/fullarticle/2767669; and de Abajo FJ, Rodríguez-Martín S, Lerma V; MED-ACE2-COVID19 Study Group. Use of renin–angiotensin–aldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: a case-population study. Lancet.2020;395(10238):1705-1714.)

    June 30, 2020, Research Update

    Corticosteroids Reduce Mortality in Hospitalized Patients with COVID-19 Requiring Oxygen or Ventilatory Support. The RECOVERY trial (Randomised Evaluation of COVid-19 thERapY) randomized 11,303 hospitalized patients with suspected or confirmed COVID-19 to one of six arms: azithromycin, lopinavir-ritonavir, tocilizumab, convalescent plasma, low-dose dexamethasone (6 mg once daily for 10 days), or usual care. This was an open-label trial, and allocation to groups was appropriately concealed. This study reports the results from the comparison of low-dose dexamethasone in 2,104 patients with 4,321 patients randomized to usual care. The primary outcome was 28-day mortality. The mean age of participants was 66 years of age, 36% were women, and 56% had at least one major comorbidity; groups were balanced at baseline. At the time the manuscript was written, 89% of patients had a positive test for COVID-19, 0.4% had a test result pending, and 10% apparently had a negative result. Follow-up was complete, and few crossovers occurred (8% in the usual care group received dexamethasone, whereas 5% in the dexamethasone group did not receive the drug). Mortality was significantly reduced overall (22.9% vs. 25.7%; rate ratio [RR], 0.83; 95% CI, 0.75 to 0.93; number needed to treat [NNT] = 36). The degree of benefit was strongly associated with the severity of illness. For patients requiring mechanical ventilation, mortality reduction was greatest (29.3% vs. 41.4%; RR, 0.64; 95% CI, 0.51 to 0.81; NNT = 8), whereas patients requiring oxygen but who were not mechanically ventilated benefitted somewhat less (23.3% vs. 26.2%; RR, 0.82; 95% CI, 0.72 to 0.94; NNT = 35). Patients randomized to dexamethasone were also less likely to require mechanical ventilation (5.7% vs. 7.8%; RR, 0.77; 95% CI, 0.62 to 0.95). No benefit, and in fact a trend toward harm, was observed for hospitalized patients not requiring oxygen or mechanical ventilation (mortality 17.8% vs. 14.0%; RR, 1.19; 95% CI, 0.91 to 1.55). The latter finding has important implications for the care of outpatients not receiving oxygen—they should not be started on a glucocorticoid in the absence of another compelling indication. 

    Updated by Mark H. Ebell, MD, MS, on July 27, 2020. (Source: The RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with COVID-19—preliminary report [published online July 17, 2020]. N Engl J Med. 2020. https://www.nejm.org/doi/10.1056/NEJMoa2021436)

    June 29, 2020, Research Update

    About 12 Undetected Cases Per Confirmed Case in Swiss Prevalence Study. In the Swiss canton around Geneva, the first confirmed case of COVID-19 was detected on February 26, with 5,160 confirmed cases by May 9, 2020. To determine the true prevalence of previous infection in this population, they planned a series of 12 weekly seroprevalence surveys; these are the results from the first five weeks. Each week, 1,300 participants in an ongoing health study were randomly selected and invited to participate, and if they agreed, they underwent antibody testing with a test that the research team determined was 93% sensitive and 100% specific. In their calculations, they adjusted for differences in the age and sex distribution of their sample and the overall population. At five weeks, 35% of invitees had become participants, 3% were ineligible, and the remainder were waiting to book an appointment or waiting to be recontacted. The seroprevalence ranged from 3.5% in week 1 to 6.0% in weeks 2 and 4, and 10.6% in weeks 3 and 5. Seropositivity was lower for children younger than 10 years than in those older (0.8% vs. 4.1% to 9.9%, depending on age stratum). Based on the seroprevalence and the number of confirmed cases, they estimate that there are 11.6 infections in the community for every confirmed case.

    Written by Mark Ebell, MD, MS, on June 25, 2020. (Source: Stringhini S, Wisniak A, Piumatti G, et al. Seroprevalence of anti-SARS-CoV-2 IgG antibodies in Geneva, Switzerland (SEROCoV-POP): a population-based study [published online June 11, 2020]. Lancet. 2020. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31304-0/fulltext)

    June 26, 2020, Research Update

    High Mortality Rate for Cancer Patients with COVID-19 Infection. This is a cohort study from the United States, Canada, and Spain of 928 cancer patients with COVID-19 infection. It is the largest outcome study of COVID-19 infection in cancer patients to date. The primary outcome was 30-day mortality from the time of diagnosis of COVID-19. The mean age was 66 years. Thirty-nine percent of patients were on active anticancer treatment. Forty-three percent had active cancer. At the time of analysis on May 7, 2020, 13% of patients had died. Risk factors for death were increased age, male sex, smoking, number of comorbidities, and active cancer. This mortality rate is similar to the 11% mortality reported in a cohort of 334 patients with cancer and COVID-19 infection from the Mount Sinai Health System. (Mehta V, Goel S, Kabarriti R, et al. Case fatality rate of cancer patients with COVID-19 in a New York hospital system [published online May 1, 2020]. Cancer Discov. 2020. https://cancerdiscovery.aacrjournals.org/content/early/2020/04/29/2159-8290.CD-20-0516). The investigators do not provide a comparison group of patients with cancer and no COVID-19 infection. Nonetheless, the mortality rate is high.

    Written by John Hickner, MD, MS, on June 25, 2020. (Source: Kuderer NM, Choueiri TK, Shah DP, et. al. Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study. Lancet. 2020;395(102410):1907-1918. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31187-9/fulltext)

    June 25, 2020, Research Update

    Promising Early Data from China on a Vaccine. Around the world, over 100 candidate vaccines against SARS-CoV-2 are in various stages of development and testing. These authors from China present data from a small open-label, nonrandomized study of CanSino’s nonreplicating adenovirus type-5 vectored COVID-19 vaccine. The study included 108 persons who had no evidence of SARS-CoV-2 infection, as indicated by negative serum specific IgG or IgM antibodies, negative SARS-CoV-2 nucleic acid on pharyngeal swabs or sputum and anal swabs, and a clear chest CT. The study participants were sequentially enrolled to receive an intramuscular infection of this recombinant vaccine in one of three doses: 5 x 1010, 1 x 10¹¹, and 1.5 x 10¹¹ viral particles). Note that there was no control group. The first group (n = 36) received the low-dose injection and were followed up for a minimum of three days before proceeding to recruit further participants (n = 36) who received the middle dose. After safety observation for three days, the last group of participants (n = 36) received the high dose. The researchers collected blood 14 and 28 days after the vaccinations to assess antibody response, including neutralizing antibodies. During the first 14 days after the vaccination, study investigators confirmed patient-reported adverse events; afterward, they used only patient-reported events. Most (81%) of the participants reported at least one adverse event within seven days of vaccination, and the overall rate was similar across all three doses. Just over half (54%) experienced injection site pain with little difference among the three doses. The most commonly reported systemic adverse reactions overall were fever (46%), fatigue (44%), headache (39%), and muscle pain (17%). More than half (56%) of the persons receiving the high dose developed fever. Most of the adverse effects were mild. The researchers were able to detect specific antibodies and neutralizing antibodies with all three doses by 14 days after immunization with a peak at 28 days. The high-dose vaccine induced the greatest immunogenic responses. This is early data from a small study with no control group but provides hope that an effective vaccination is feasible.

    Written by Henry C. Barry, MD, MS, on June 24, 2020. Source: Zhu F-C, Li Y-H, Guan X-H, et al. Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial. Lancet. 2020;395(10240):1845-1854.)

    June 24, 2020, Research Update

    Fecal Viral Shedding of SARS-CoV-2  and Reports of Gastrointestinal Symptoms. These authors searched two bibliographic databases and two preprint servers as well as the reference lists of all retrieved studies to identify studies reporting clinical symptoms of patients infected with SARS-CoV-2 and for studies that reported testing of stool samples in patients with COVID-19. They excluded studies that were only reported as abstracts. They ultimately included 23 peer-reviewed papers and 6 pre-print studies with 4,805 patients. Most of the studies were observational and most came from mainland China. Overall, the studies were of moderate quality, and 12% of patients presented with gastrointestinal symptoms. Most of the studies reported on diarrhea, roughly occurring in 7.8% of patients, but there was marked variability in the reports of frequency. Twelve studies measured the presence of vomiting or nausea and found these occurred in 3.9% of the patients (with significant variability). Eight studies reported on viral shedding, finding that 40.5% (significant heterogeneity) of patients with COVID-19 shed the virus in their stools.

    Written by Henry C. Barry, MD, MS, on June 17, 2020. (Source: Parasa S, Desai M, Thoguluva Chandrasekar V, et al. Prevalence of gastrointestinal symptoms and fecal viral shedding in patients with coronavirus disease 2019: a systematic review and meta-analysis [published online June 11, 2020]. JAMA Netw Open. 2020;3(6):e2011335. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2767009)

    June 23, 2020, Research Update

    Natural History of Asymptomatic COVID-19 Infection in Cruise Ship Passengers. These researchers identified 712 of 3,711 passengers and crew members of the Diamond Princess cruise ship who had tested positive polymerase chain reaction (PCR) for SARS-CoV-2, 410 of whom (57.6%) had no symptoms. It is not clear how they identified them, but 96 of these asymptomatic persons and 32 of their cabin mates who tested negative were transferred to a hospital in Japan for seven days of observation. During the subsequent week, 11 (11.5%) developed symptoms, typically three to five days after the first positive test. Eight of the 32 (25%) cabin mates had a positive PCR within three days of quarantine but were asymptomatic. That means that 85 infected passengers and their eight infected cabin mates in this subset of the asymptomatic cruise passengers remained asymptomatic, for a total of 93 persons (73%) with asymptomatic COVID-19. Resolution, defined as two consecutive negative PCR tests, occurred in 90 (97%) of these asymptomatic persons. A longer time to resolution occurred more frequently in older persons and in those with comorbid conditions such as hypertension or diabetes.

    Written by Henry C. Barry, MD, MS, on June 17, 2020. (Source: Sakurai A, Sasaki T, Kato S, et al. Natural history of asymptomatic SARS-CoV-2 infection [published online June 12, 2020]N Engl J Med. 2020. https://www.nejm.org/doi/full/10.1056/NEJMc2013020?query=featured_coronavirus)

    June 22, 2020, Research Update

    COVID-19 Patients with Chronic Diseases Are Much More Likely To Be Hospitalized and To Die. This Center for Disease Control and Prevention (CDC) report summarizes COVID-19 cases reported to the CDC from January 22 through May 30, 2020. There were 1,761,503 cases reported and 103,700 deaths. The seven-day average number of cases peaked in the United States on April 12 (31,994 cases), and daily deaths peaked on April 21 (2,856). The CDC had sufficient information on 287,320 individuals with COVID-19 infection to report outcomes of patients with and without chronic diseases. Cardiovascular disease was present in 32% of cases, diabetes in 30%, and chronic lung disease in 18%. Of all patients with COVID-19 reported to the CDC during this time period, 184,673 (14%) patients were hospitalized, 29,837 (2%) were admitted to an ICU, and 71,116 (5%) died. The hospitalization rate was six times higher among patients with a chronic disease (45.4% vs. 7.6%), and the death rate was twelve times higher (19.5% vs. 1.6%).

    Written by John Hickner, MD, MS, on June 17, 2020. Source: Stokes EK, Zambrano LD, Anderson KN, et al. Coronavirus disease 2019 case surveillance—United States, January 22–May 30, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(24):759-765.)

    June 19, 2020, Research Update

    Corticosteroids Reduce Mortality in Hospitalized Patients with COVID-19 Requiring Oxygen or Ventilatory Support. Editor’s Note: This research brief is based on a press release. We will update it when the article is published. We are covering it because a highly respected team of researchers from Oxford University is reporting the results in considerable detail, and it is funded by the UK government.

    The RECOVERY trial (Randomised Evaluation of COVid-19 thERapY) randomized more than 11,500 hospitalized patients with COVID-19 to one of six arms: azithromycin, lopinavir-ritonavir, tocilizumab, convalescent plasma, low-dose dexamethasone (6 mg once daily for 10 days), or usual care. This announcement reports the results from the comparison of low-dose dexamethasone in 2,104 patients, with 4,321 patients randomized to usual care. The primary outcome was 28-day mortality. The risk ratio for mortality in patients requiring mechanical ventilation was 0.65 (95% CI, 0.48 to 0.88); for those receiving only oxygen, it was 0.80 (95% CI, 0.67 to 0.96). No benefit was observed for patients not requiring oxygen or mechanical ventilation. I applied those risk ratios to the mortality rates in the usual care groups to calculate absolute risk reductions and numbers needed to treat (NNT). For patients on mechanical ventilation, the mortality rates are 26.6% vs. 41%, for an NNT of 7. For patients receiving only oxygen, the mortality rates are 20% vs. 25%, for an NNT of 20 (the authors report slightly different NNTs of eight for patients on a ventilator and 25 for those receiving oxygen). They provide no data on the patient demographics, any harms or complications, or the effect on time to recovery. We await the full report.

    Written by Mark H. Ebell MD, MS, on June 16, 2020. (Source: press release from Oxford University [released June 16, 2020]. https://www.recoverytrial.net/news/low-cost-dexamethasone-reduces-death-by-up-to-one-third-in-hospitalised-patients-with-severe-respiratory-complications-of-covid-19)

    June 18, 2020, Research Update

    Econometric Study: Large Number of Cases Prevented by Nonpharmaceutical Interventions. This report is from a team of economists and public health experts primarily at the University of California, Berkeley. They take econometric methods that are generally used to study the impact of nonpharmaceutical interventions on economic growth (e.g., does raising a minimum wage increase unemployment?) and apply them to the question of whether policy changes affect a different kind of growth (e.g., that of the COVID-19 pandemic). The researchers gathered data from 1,717 administrative units in six countries (United States, Iran, Italy, South Korea, China, and France). They estimated a daily growth rate of 43% overall in new cases in the absence of any measures, ranging from 34% in the United States to 68% in Iran. Their econometric modeling concludes that implementation of all policy measures (such as school closures, social isolation guidelines, and travel bans) resulted in reductions in the rate of growth of cases, with larger reductions in Iran, China, South Korea, and Italy and smaller reductions in the United States and France. They estimate that these measures reduced the number of confirmed cases in those six countries by more than 60 million, with a reduction of confirmed cases in the United States by 4.8 million and total cases by 60 million (assuming that many cases were asymptomatic or never confirmed). This study provides an estimate of the magnitude of benefit of these nonpharmaceutical interventions and is consistent with that of a study applying epidemiologic methods to the same question by Imperial College researchers. These estimates are broadly consistent with those of the University of California, Berkeley, researchers using completely different econometric modeling approaches.

    Written by Mark H. Ebell MD, MS, on June 10, 2020. Source: Hsiang S, Allen D, Annan-Phan S, et al. The effect of large-scale anti-contagion policies on the COVID-19 pandemic [published June 8, 2020]. Nature. 2020. https://www.nature.com/articles/s41586-020-2404-8; and Flaxman S, Mishra S, Gandy A, et al. Estimating the effects of non-pharmaceutical interventions on COVID-19 in Europe [published online June 8, 2020]. Nature. 2020. https://www.nature.com/articles/s41586-020-2405-7)

    June 17, 2020, Research Update

    A Large Proportion of Individuals with COVID-19 Infection Are Asymptomatic. This narrative review quantifies the proportion of people with COVID-19 infections who are asymptomatic at the time of testing. It includes 16 cohorts of COVID-19–positive individuals from Iceland, Italy, Greece, France, Japan, Argentina, and the United States, including four ship outbreaks, ranging in size from 76 to 13,080 individuals. The percentage of people who tested positive who had no symptoms at the time of testing ranged from a low of 6.3% in nursing home residents at a facility in King County, Washington, to highs of 87.8% of occupants in a Boston homeless shelter, 87.9% in an obstetric service in New York City, and 96% of 3,146 inmates in state prison systems in Arkansas, North Carolina, Ohio, and Virginia. The three cohorts that came from representative samples of the population suggest that the rate of asymptomatic infection is in the range of 40% to 45%. As we noted in a study of infector–infectee pairs in China, transmission from asymptomatic individuals may account for approximately 40% of cases. Therefore, quarantine alone is insufficient to prevent spread; social distancing and use of face masks are important preventive measures.

    Written by John Hickner, MD, MS, on June 10, 2020. (Source: Oran DP, Topol EJ. Prevalence of asymptomatic SARS-CoV-2 infection: a narrative review [published online June 3, 2020]. Ann Intern Med. 2020. https://www.acpjournals.org/doi/10.7326/M20-3012)

    June 16, 2020, Research Update

    Clinical Manifestations of Children with Multisystem Inflammatory Syndrome Associated with COVID-19 in Three Studies from New York, France, and England. The pediatric multisystem inflammatory syndrome shares many features with Kawasaki disease and causes great concern because it carries a worse prognosis than what is otherwise expected in children infected with SARS-CoV-2. Three recent papers report data from medical record audits of children hospitalized in New York, France, and England. These case series are challenging to summarize because of differences in reporting, but we can still glean some common elements. Overall, 96 children were included in these studies, 38 (40%) were black, 81 (84%) had lab-confirmed COVID-19, and 33 (34%) also met criteria for Kawasaki disease. Two studies reported that 36 (38%) had gastrointestinal symptoms. The other study reported that 31 children (32%) had abdominal pain and that 26 (27%) had vomiting. Rash occurred in 58 (60%) of the children, and desquamation, only reported in two studies, occurred in 7 of 28 (25%). Fifty-four (5%) had conjunctivitis, and 42 (44%) had redness or swelling of the lips or mucous membranes. Coronary artery dilation occurred in 13 (14%) of the children, myocardial dysfunction in 24 (25%), and shock in 57 (59%). Only two of the studies reported chest radiograph data; 22 of the 38 (58%) were abnormal. 

    Written by Henry C. Barry, MD, MS, on June 10, 2020. (Sources: Toubiana J, Poirault C, Corsia A, et al. Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational study. BMJ. 2020;369:m2094. Cheung EW, Zachariah P, Gorelik M, et al. Multisystem inflammatory syndrome related to COVID-19 in previously healthy children and adolescents in New York City [published online June 8, 2020]. JAMA. 2020. https://jamanetwork.com/journals/jama/fullarticle/2767207. Whittaker E, Bamford A, Kenny J, et al. Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 [published online June 8, 2020]. JAMA. 2020. https://jamanetwork.com/journals/jama/fullarticle/2767209)

    June 15, 2020, Research Update

    A Third of Patients with COVID-19 Early in the China Outbreak Had Neurologic Symptoms. These authors reviewed the records of 214 consecutive patients hospitalized for COVID-19 between January 16 and February 19, 2020. The study took place in three hospitals in Wuhan, China. In addition to collecting demographic information, comorbidities, and common respiratory symptoms, the authors also looked for the presence of neurologic symptoms. Because they do not tell us whether the hospitals had an explicit approach to prospectively collect this information, we can assume only that the frequency of each element potentially is underestimated. Additionally, because they were trying to minimize direct contact with patients, much of the information was based on subjective symptoms and initial exam findings. They classified neurologic manifestations into three categories: central nervous system (CNS; dizziness, headache, impaired consciousness, stroke, ataxia, seizure), peripheral nervous system (PNS; altered taste or smell, vision impairment, nerve pain), and skeletal muscle injuries (pain and elevated serum creatine kinase). Overall, 78 patients (36%) had neurologic manifestations. Patients with severe COVID-19 infections were more likely to have neurologic symptoms (46%) than those with mild disease (30%). About 25% of all patients had CNS manifestations; 31% of those with severe COVID and 21% of those with mild infection. About 9% had PNS manifestations, with no difference based on COVID severity. Skeletal muscle injuries occurred once in patients with severe COVID and once in patients with mild COVID.

    Written by Henry C. Barry, MD, MS, on June 10, 2020. (Source: Mao L, Jin H, Wang M, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 2020;77(6):683-690.)

    June 12, 2020, Research Update

    Convalescent Plasma Marginally Improved COVID-19 Outcomes in Severely Ill Patients in China. In this open-label, multicenter, randomized clinical trial (RCT), 103 patients (median 70 years of age) with severe or life-threatening COVID-19 infection in Wuhan, China, were randomized to receive convalescent plasma or to not receive it. The primary outcome was time to clinical improvement within 28 days, defined as the patient was discharged alive or a reduction of 2 points on a 6-point disease severity scale (1 = discharged, 6 = death). Clinical improvement occurred in 52% (27/52) of the convalescent plasma group and 43% (22/51) in the control group, not statistically significant (hazard ratio [HR], 1.40 [95% CI, 0.79 to 2.49]; P = .26). Among those with severe disease, the primary outcome occurred in 91% (21/23) of the convalescent plasma group vs. 68% (15/22) of the control group (HR, 2.15 [95% CI, 1.07 to 4.32]; P = .03); among those with life-threatening disease (the most severely ill patients) the primary outcome occurred in 21% (6/29) of the convalescent plasma group vs. 24% (7/29) of the control group (HR, 0.88 [95% CI, 0.30 to 2.63]; P = .83). There was no significant difference in 28-day mortality (15.7% vs. 24.0%; OR, 0.65 [95% CI, 0.29 to 1.46]; P = .30) or time from randomization to discharge (51.0% vs. 36.0% discharged by day 28; HR, 1.61 [95% CI, 0.88 to 2.93]; P = .12). The trial was terminated early after 103 of the planned 200 patients were enrolled because of the rapid decline in COVID-19 cases in Wuhan. A larger study is needed to confirm or refute the results in this underpowered RCT.

    Written by John Hickner, MD, MS, on June 5, 2020. (Source: Li L, Zhang W, Hu Y, et al. Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial [published online June 3, 2020]. JAMA. 2020.  https://jamanetwork.com/journals/jama/article-abstract/2766943)

    June 11, 2020, Research Update

    Self-Collected Swabs Are Accurate in Detecting SARS-CoV-2 in Ambulatory Settings. These researchers in the United States identified 530 symptomatic patients seen in ambulatory clinics in the Puget Sound area of Washington. After brief training, the patients were also asked to collect tongue, nasal (inserted vertically into nasal passage), and midturbinate (inserted horizontally) samples, in that order. Afterward, trained staff collected swab samples from the nasopharynx. The authors estimated they would need to have 48 patients test positive for SARS-CoV-2 to have adequate power. Not surprisingly, most of the time patients tested positive at more than one site, regardless of who gathered the sample. Using the staff-collected sample as the first-choice standard, the authors determined that self-collected samples were 89.8% sensitive (one-sided 97.5% CI, 78.2 to 100.0) for tongue samples, 94.0% sensitive (97.5% CI, 83.8 to 100.0) for nasal samples, and 96.2% sensitive (97.5% CI, 87.0 to 100.0) for midturbinate samples. This study suggests that patient-collected samples are reasonably accurate and have the potential to decrease the frequency of exposing staff to potentially infectious material.

    Written by Henry C. Barry, MD, MS, on June 4, 2020. (Source: Tu Y-P, Jennings R, Hart B, et al. Swabs collected by patients or health care workers for SARS-CoV-2 testing [published online June 3, 2020]. N Engl J Med. 2020. https://www.nejm.org/doi/full/10.1056/NEJMc2016321)

    June 10, 2020, Research Update

    Effects of Physical Distance, Face Masks, and Eye Protection on Virus Transmission in Health Care and Community Settings. This meta-analysis, sponsored by the World Health Organization, identified 172 observational studies of the effects of physical distancing, face masks, and eye protection on virus transmission in health care and community settings. The investigators found no randomized trials, but they found 44 observational comparative studies that included 25,697 people. Transmission of viruses was lower with physical distancing of 1 meter (roughly 3 feet) or more compared with a distance of less than 1 meter, an absolute risk difference (RD) of -10.2%, a finding with moderate certainty. Protection improved as distance increased (relative risk [RR] of 2.0 per meter). Face mask use was associated with RD of -14.3%, but with low certainty of evidence. There was stronger evidence for risk reduction with N95 or similar respirators compared with disposable surgical masks or reusable cotton masks. Eye protection also was associated with lower infection risk (RD -10.6%). Randomized trials are needed, but this meta-analysis summarizes the best available evidence for effectiveness of these interventions to date.

    Written by John Hickner, MD, MS, on June 5, 2020. (Source: Chu DK, Akl EA, Duda S, et al. Physical distancing, face masks, and eye protection to prevent person-to-person transmission of SARS-CoV-2 and COVID-19: a systematic review and meta-analysis [published online June 1, 2020]. Lancet. 2020. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31142-9/fulltext)

    June 9, 2020, Research Update

    Postexposure Prophylaxis with Hydroxychloroquine Is Not Effective. This study is different from all other hydroxychloroquine (HCQ) studies in that it studied postexposure prophylaxis in healthy patients. Patients were identified who had a high-risk exposure to someone with confirmed COVID-19—defined as at least 10 minutes, less than six feet away, and without facial covering—or a moderate-risk exposure that allowed a face mask but no eye shield. They randomized 821 initially asymptomatic persons within four days of exposure to HCQ (800 mg once, then 600 mg in six to eight hours, and then 600 mg once daily for four days) or matching placebo. The primary outcome was laboratory-confirmed or clinically suspected COVID-19 (testing was not yet widely available) in the next 14 days after enrollment. Median age was 40 years, and healthcare workers accounted for two-thirds of the participants. No difference occurred between groups in the primary outcome, with 49/414 (11.8%) reporting infection in the HCQ group and 58/407 (14.3%) in the placebo group (risk difference -2.4%; 95% CI, -7.0 to 2.2). The findings were the same at 5, 10, and 14 days.

    Written by Mark H. Ebell, MD, MS, on June 3, 2020. Boulware DR, Pullen MF, Bangdiwala AS, et al. A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19 [published online June 3, 2020]. N Engl J Med. 2020. https://www.nejm.org/doi/full/10.1056/NEJMoa2016638

    June 8, 2020, Research Update

    Systematic Review: Fever, Cough, Elevated C-Reactive Protein, and Ground Glass Opacities Common in Patients Diagnosed with COVID-19 in China. These authors identified 43 studies with 3,600 patients in China who were diagnosed with COVID-19. They excluded studies that took place outside of mainland China. They extracted and summarized the frequency of symptoms and laboratory and radiographic findings. They found substantial variability in the data as well as significant publication bias. Only nine of the studies were at low risk of bias, and 30 were of moderate risk of bias. Among the symptoms they report, the most common include fever (83%) and cough (60%), fatigue (38%), myalgias (29%), and dyspnea (25%). In addition, 8% had diarrhea; other studies have shown significantly higher risk of transmission among patients with diarrhea. The following laboratory findings were also commonly elevated: C-reactive protein (68.6%), lactate dehydrogenase (51.6%), and d-dimer (29.3%). Finally, 80% of patients had radiographic findings of ground glass opacities, and 73.2% had bilateral pneumonia. 

    Written by Henry C. Barry, MD, MS, on June 2, 2020. (Source: Fu L, Wang B, Yuan T, et al. Clinical characteristics of coronavirus disease 2019 (COVID-19) in China: a systematic review and meta-analysis. J Infect. 2020;80(6):656-665.)

    June 7, 2020, Research Update

    Increased COVID-19 Mortality among Blacks, Asians, and Other Minority Groups in the UK. These researchers used data from the United Kingdom’s National Health System and identified patients who died while hospitalized for COVID-19 and applied estimated standardized mortality rates (SMR) using the entire English population as a reference. The SMRs, adjusted for age and geographic region, were lowest among white Irish (SMR 0.52; 95% CI, 0.45 to 0.60) and white British ethnic groups (0.88; 95% CI, 0.86 to 0.0.89) and were higher among black African (3.24; 95% CI, 2.90 to 3.62), black Caribbean (2.21; 95% CI, 2.02 to 2.41), Pakistani (3.29; 95% CI, 2.96 to 3.64), Bangladeshi (2.41; 95% CI, 1.98 to 2.91), and Indian (1.70; 95% CI, 1.56 to 1.85) minority ethnic groups. So, in a nation with universal healthcare coverage, socioeconomic factors are still important predictors of adverse health outcomes.

    Written by Henry C. Barry, MD, MS, on June 1, 2020. (Source: Aldridge RW, Lewer D, Katikireddi SV, et al. Black, Asian and minority ethnic groups in England are at increased risk of death from COVID-19: indirect standardisation of NHS mortality data. Wellcome Open Research. 2020;5(88). https://wellcomeopenresearch.org/articles/5-88)

    June 6, 2020, Research Update

    Face Masks and Disinfecting Reduced Household COVID-19 Transmission in China. Most transmission of COVID-19 occurs among household and close social contacts. The investigators studied transmission in Beijing, China, among household members in 124 families that had at least one COVID-19 infected individual. Secondary transmission occurred in 41/124 families (77 cases). The other 83 families had no secondary transmission cases. The secondary attack rate in families was 23% (77/335). Face masks, if worn by the index case prior to symptoms and by other family members, were 79% effective in reducing secondary infections. Daily use of chlorine or ethanol-based disinfectant was 77% effective in preventing spread. Household transmission was 18 times more likely with frequent daily close contact with the primary case and four times higher if the primary case had diarrhea.

    Written by John Hickner, MD, MS, on June 1, 2020. (Source: Wang Y, Tian H, Zhang L, et. al. Reduction of secondary transmission of SARS-CoV-2 in households by face mask use, disinfection and social distancing: a cohort study in Beijing, China [published May 28, 2020]. BMJ Global Health. 2020. https://gh.bmj.com/content/5/5/e002794)

    June 5, 2020, Research Update

    Patients Actively Being Treated for Cancer Not at Increased Risk for Death from COVID-19 Compared with Other Cancer Patients. This UK study prospectively identified 800 patients with a broad range of active cancers (defined as treated in the past 12 months) who were newly diagnosed with symptomatic COVID-19. Of 800 patients, 34% were not currently being treated, 35% were receiving cytotoxic chemotherapy, 10% radiotherapy, 10% surgery, 8% hormone therapy, 6% immunotherapy, and 4% surgery within four weeks of their diagnosis. The mean age was 69 years, and 28.3% died of COVID-19. Comparing the 66% of patients who were recently treated with the 34% not currently being treated, multivariate analysis found no association between current treatment and increased risk of death. The primary independent predictors of death were increasing age, male sex, and comorbidities such as hypertension and cardiovascular disease.

    Written by Mark Ebell MD, MS, on May 29, 2020. (Source: Lee LYW, Cazier JB, Starkey T, et al. COVID-19 mortality in patients with cancer on chemotherapy or other anticancer treatments: a prospective cohort study [published online May 28, 2020]. Lancet. 2020. https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(20)31173-9.pdf)

    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)

    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)

    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)

    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.

    Study retracted.

    (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)

    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)

    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)

    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)

    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)

    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)

    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

    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)

    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)

    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)

    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)

    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)

    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) 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)

    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)

    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. 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)

    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)

    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

    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 Cardiolhttps://jamanetwork.com/journals/jamacardiology/fullarticle/2765695)

    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)

    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)

    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)

    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/)

    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)  

    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)

    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)

    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)

    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[7] [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;[4]: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[13]: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 Univhttp://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