There have now been >6 million cases of COVID-19 worldwide, with >370,000 deaths. The United States continues to have a disproportionate share of the diagnosed cases (>1.8 million) and deaths (>107,000), although this may partially reflect differences in testing rates across the globe. This sobering milestone of more than 100,000 deaths, which was reached in just >4 months since the first known case of COVID-19 in the United States, surpasses all deaths that the U.S. military has suffered since the Korean War in the 1950s. Although the rate of new cases is not yet falling in many U.S. states or countries around the world, the realities of a populace that has largely been housebound for 1–2 months have prompted easing of many of the government-imposed restrictions around the world, which will have an unclear influence on the future trajectory of the pandemic. New insights have developed in the past few weeks into the timing of the origins of COVID-19 along with the early results from treatment and vaccine trials.

Origins and Epidemiology of COVID-19

  • Although COVID-19 was first identified near the end of December 2019 due to an outbreak in Wuhan, China, the first case (a 55-year-old individual) has now been traced back to November 17. “Patient zero” lived in Hubei province, which includes Wuhan. This timeline is consistent with what is now recognized as cases being present in multiple countries earlier than previously thought. A retrospective analysis of samples taken from intensive-care patients in France identified a COVID-19-positive case as early as December 27, 2019, a month earlier than previously thought. The first fatality in the United States was assumed to have occurred in the Seattle area on February 28, but autopsy samples revealed a death as early as February 6 in Santa Clara county in California. These findings confirm an earlier start to the pandemic overall and that local epidemic transmission did not occur as a result of every person with a serious infection.

  • Although there have been attempts from various countries to politicize the origins of the pandemic, genomic studies have confirmed that SARS-CoV-2 evolved from natural origins. In a letter to the editor in Nature Medicine, Andersen and colleagues (2020) provided genomic comparisons of many different coronaviruses, including SARS-CoV-2, with a focus on the spike proteins, which binds to its human receptor angiotensin-converting enzyme (ACE2). Although computer modeling suggested that SARS-CoV-2 would not bind well to ACE2, the virus actually bound quite well given its ability to take advantage of a previously unidentified alternate binding site. Given that this binding site would not have been predicted previously, it is difficult to envision this as a manmade virus; rather, there are robust data demonstrating that it arose via natural selection.

  • One critical, ongoing question is the prevalence of COVID-19 within the community. In a recent study in JAMA, Sood and colleagues (2020) examined this question in Los Angeles County by testing for SARS-CoV-2-specific antibodies in 865 individuals (50.9% of the 1952 individuals invited to participate; 2 had inconclusive test results and were excluded from the analysis). Testing was performed April 10–11 and April 13–14. Thirty-five individuals tested positive, which—after weighting the demographics against census data and adjusting for test sensitivity and specificity—results in a prevalence of 4.34%. Given the population of Los Angeles county, these data imply that ~367,000 adults had SARS-CoV-2 antibodies; however, there were only 8430 confirmed infections in the county as of April 10. Although selection bias of test subjects may have influenced these results somewhat, these findings highlight the fact that there are likely far more individuals who have been infected with SARS-CoV-2 than is reflected by the official case counts.

Prevention Strategies

  • There continues to be ongoing debate regarding the utility of face masks in preventing transmission. Although many countries offered early guidance urging their citizens to wear face masks anytime they leave home, the World Health Organization has only now endorsed universal mask-wearing in addition to its earlier recommendations for hand hygiene and physical distancing (measures also strongly encouraged by countries that have long mandated universal masking). Of note, the U.S. Centers for Disease Control and Prevention also initially restrained from endorsing universal mask-wearing until they reversed their position on April 3.

    • In countries that have encouraged the wearing of masks, the type of mask that should be worn remains a point of contention. Given that SARS-CoV-2 can be transmitted in aerosols (droplets <5 microns), many have argued that N95 masks should be preferentially used, particularly for healthcare workers who are at substantially higher risk than those in the community. In a meta-analysis of 172 observational studies of Middle Eastern Respiratory Syndrome, Severe Acute Respiratory Syndrome, or COVID-19 published this week in The Lancet, Chu and colleagues (2020) found that face masks reduce the risk of infection (adjusted odds ratio [aOR], 0.15; 95% confidence interval [CI], 0.07–0.34). N95 or similar respirators had a stronger association with reducing risk of infection than surgical masks (aOR, 0.04 vs 0.33). Moreover, physical distancing ≥1 m and wearing eye protection (e.g., face shields, goggles, glasses) also were protective (aOR 0.18 and 0.22, respectively).

  • Multiple vaccines are entering phase 2 and phase 2/3 trials. Moderna released a teaser of results from their phase 1 study, commenting that all 45 patients who received 2 doses of the vaccine at the lower and middle doses (25 and 100 µg) or 1 dose at a higher dose (250 µg) developed antibodies that bound to SARS-CoV-2. Importantly, 8 patients (evenly split between the low and middle doses) developed neutralizing antibodies that are able to inhibit viral replication in vitro. Given that this information is from a company-issued press release and not a published, peer-reviewed paper, it is not yet clear whether the other 37 patients did not develop neutralizing antibodies or have just not yet been tested. Moreover, it is not known whether the presence of neutralizing antibodies represents an immunologic correlate of protection from disease (i.e., will they actually prevent people from getting infected) or how durable this response might be. However, this press release—albeit limited in scope and information—raises the hope that it is possible to produce a vaccine that elicits neutralizing antibodies, which are often (but not always) correlated with protection.

Treatment

  • The initial large-scale studies of remdesivir have now been published in the New England Journal of Medicine (Beigel et al, 2020). As highlighted in an earlier update, remdesivir treatment was associated with a faster time to recovery with no statistically significant difference in mortality rates. A more granular view of the data reveals that this effect on time to recovery was greatest for those with severe disease (12 days in remdesivir-treated patients vs 18 days in placebo-treated patients), with no difference observed for those with mild or moderate disease (5 days in both the remdesivir and placebo groups). Moreover, patients who were mechanically ventilated and/or receiving extracorporeal membrane oxygenation did not appear to have improved outcomes. Taken together, these findings suggest that timing of antiviral therapy initiation as well as patient characteristics may help drive therapeutic outcomes. Additional analysis of the results from this trial as well as other ongoing trials will hopefully shed additional light on these factors.

  • A companion article from Goldman and colleagues (2020) compared outcomes of patients who received remdesivir for 5 or 10 days (n = 200 and 197, respectively). After adjustment for baseline clinical status, there was no significant difference between these treatment durations. Moreover, given that there was no placebo control, it is unclear whether either group in this study received any benefit from the therapy. However, combined with the modest results seen in the study described above, it seems reasonable to limit therapy to 5 days, particularly in light of the currently limited supply of remdesivir.

  • A controversial study using a multinational registry assessed the efficacy of hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19 and was recently published in The Lancet (Mehra et al, 2020). This study utilized a proprietary data registry that claims to include data from 671 hospitals located in 6 continents. Ultimately, the authors analyzed the data from >96,000 patients with COVID-19; ~15,000 were in one of the treatment groups (1868 received chloroquine, 3783 received chloroquine with a macrolide, 3016 received hydroxychloroquine, and 6221 received hydroxychloroquine with a macrolide), and >81,000 patients were in the control group. Each of the 4 treatment groups was independently associated with an increased risk of in-hospital mortality (16.4–23.8% compared with 9.3% in the control group) and an increased risk of de novo ventricular arrhythmia during hospitalization (4.3–8.1% compared with 0.3% in the control group). Based on these results, the World Health Organization immediately halted their ongoing studies related to the efficacy of hydroxychloroquine and chloroquine pending further analysis.

    • Many have questioned the authenticity of the data contained within this vast registry, the existence of which was unknown to many in the field. An open letter to the authors and the editor of The Lancet, with >180 signatories, raised multiple questions regarding the statistical analyses and data integrity, highlighting issues such as the registry listing more cases in Australia than the government reports, an implausibly high 25% of all COVID-19 cases in Africa occurring in registry-associated hospitals, and medication-specific data that seem incompatible with the countries from which they are derived. Outside of a minor correction, the authors initially stood by their work and The Lancet had published an expression of concern stating that they were awaiting an independent audit of the provenance and validity of the data. Given that the independent reviewers were not able to get complete access to the underlying data, this paper has now been retracted.

References

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Andersen  KG et al: The proximal origin of SARS-CoV-2. Nat Med, 26:450, 2020.
[PubMed: 32284615]
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Beigel  JH et al: Remdesivir for the treatment of Covid-19—preliminary report. N Engl J Med, 2020 [Epub ahead of print].
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Chu  DK 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. Lancet, 2020 [Epub ahead of print].
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Goldman  JD et al: Remdesivir for 5 or 10 days in patients with severe Covid-19. N Engl J Med, 2020 [Epub ahead of print].
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Mehra  MR et al: Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: A multinational registry analysis. Lancet, 2020 [Epub ahead of print].
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Sood  N et al: Seroprevalence of SARS-CoV-2–specific antibodies among adults in Los Angeles County, California, on April 10–11, 2020. JAMA, 2020 [Epub ahead of print].