There have now been >8.2 million cases of COVID-19 in the world, with >440,000 deaths. The pandemic has recently begun to surge in Latin America, and Brazil now has the second most COVID-19-related deaths with >47,000. The United States continues to lead all countries, with >2.2 million cases and >120,000 deaths. All states have begun various degrees of “re-opening,” and the rate of new cases is now increasing in ~20 states. Although there is still fervent discussion of whether and/or when this winter the second wave of infections might begin, it is still not clear when this first wave of infections might actually end. However, there are signs that new effective treatment options are emerging and that infection may confer some degree of protection against re-infection.

Epidemiology

  • The true rate of asymptomatic infection remains unknown, although epidemiologic investigations of cruise ship passengers have been somewhat informative and suggest that only a small proportion (~10–20%) may develop symptoms. Although symptom screening, which has become widespread as communities begin the process of normalizing activities, may help identify this minority of patients, the asymptomatic patients will remain unidentified, a fact that makes mask wearing and social distancing that much more important.

    • Ing and colleagues (2020) report about a cruise to Antarctica in mid-March. None of the passengers or crew had been to any COVID-19 hotspot preceding the trip, were symptomatic, or had fevers. Given a passenger who became febrile on day 8, isolation protocols were commenced. All passengers and crew members were tested for SARS-CoV-2 on day 20, and 128 (59%) of the 217 persons on board were positive. Of these, only 19% had any symptoms.

    • In a letter to the editor of the New England Journal of Medicine, Sakurai and colleagues (2020) studied the natural history of asymptomatic infection in passengers on the cruise ship Diamond Princess. At the time of testing, 96 persons found to be positive for SARS-CoV-2 were asymptomatic. Of these individuals, 11 became symptomatic at a median of 4 days after the first positive test. The rest of the group remained asymptomatic and had negative testing a median of 9 days after the first positive.

    • Ellinghaus and colleagues (2020) performed a genome-wide association study that identified an association between blood type A and respiratory failure due to COVID-19 (odds ratio [OR], 1.45; 95% confidence interval [CI], 1.20–1.75); blood type O was associated with a protective effect (OR, 0.65; 95% CI, 0.53–0.79). Additionally, locus 3p21.31, a region that contains the genes SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6, and XCR1, was associated with severe COVID-19 disease (OR, 1.77; 95% CI, 1.48–2.11). Although a causative gene cannot be identified from this data, SLC6A20 encodes a protein known to interact with angiotensin-converting enzyme 2, the receptor for SARS-CoV-2, and CCR9 and CXCR6 help regulate trafficking of immune cells.

Treatment

  • A randomized, double-blind, placebo-controlled study found that hydroxychloroquine was not effective as a prophylaxis against developing an illness consistent with COVID-19. Boulware and colleagues (2020) randomized 821 participants who had high-risk or medium-risk exposure to someone with confirmed COVID-19 to placebo or hydroxychloroquine (800 mg once, followed by 600 mg in 6–8 hours, then 600 mg daily for 4 additional days), with the intervention starting within 4 days of exposure. There was no difference in the incidence of a COVID-19-compatible illness defined by symptoms (11.8% in the hydroxychloroquine group and 14.3% in the placebo group). Only 3% of all participants were confirmed to be SARS-CoV-2 positive by PCR testing. Given that >50% of patients were enrolled 3–4 days after exposure, these results suggest that hydroxychloroquine may not alter development of symptomatic disease, but the study design is unable to truly address whether hydroxychloroquine impacts rates of SARS-CoV-2 infection.

  • Investigators in the United Kingdom are beginning to publicize findings from the RECOVERY Trial, a large multisite trial that has randomized >11,000 hospitalized patients from 175 hospitals to various treatment arms. Although the results have not been published yet, their findings are likely to have immediate impact on clinical care of patients with COVID-19.

    • In one arm of the trial, there was no significant difference in 28-day mortality between hospitalized patients randomized to hydroxychloroquine (n = 1542) or standard of care (n = 3132; hazard ratio, 1.11; 95% CI, 0.98–1.26). Soon after the release of these findings, the U.S. Food and Drug Administration revoked its emergency use authorization to use hydroxychloroquine and chloroquine to treat COVID-19 outside of clinical trials.

    • In another arm of the trial, hospitalized patients who received dexamethasone (n = 2104) had lower mortality than patients randomized to standard of care (n = 4321). Specifically, this difference was present in ventilated patients (rate ratio, 0.65; 95% CI, 0.48–0.88), with no benefit among patients who did not require ventilatory support (rate ratio, 1.22; 95% CI, 0.86–1.75). This is the first drug to have a clear impact on COVID-19-related mortality and only the second drug to improve outcomes (remdesivir, which is in short supply, being the first). Based on these data, treatment of either ~8 ventilated patients or ~25 patients requiring oxygen alone would prevent 1 death.

Prevention

  • Although the race to develop the first SARS-CoV-2 vaccine is ongoing, there is renewed interest in whether existing live vaccines may offer nonspecific prevention against COVID-19. Chumakov and colleagues (2020) suggest in a perspective piece that oral polio virus and/or other live vaccines such as Bacille Calmette-Guérin (BCG) may be useful against SARS-CoV-2. Indeed, both vaccines have previously been demonstrated to protect against heterologous infections. Although this would require synchronous vaccination of the entire population in a given region to produce the necessary herd effects, if successful, it would potentially offer a way forward for whatever the next pandemic might be.

    • Hamiel and colleagues (2020) assessed the impact of BCG vaccination on SARS-CoV-2 infection by taking advantage of the fact that Israel stopped universal BCG vaccination in 1982. They compared rates of infection in individuals born 1979–1981 (n = 3064; 1.02% of birth cohort of that period) to those born 1983–1985 (n = 2869; 0.96% of birth cohort of that period). There was no significant difference in the infection rates between these cohorts (11.7% in the BCG-vaccinated group compared with 10.4% in the BCG-unvaccinated group; P = 0.09)

    • It remains unknown whether natural infection confers protection against reinfection. Chandrashekar and colleagues (2020) addressed this question using rhesus macaques. After infection with SARS-CoV-2, adult monkeys (n = 9) cleared the infection by day 10–14 in bronchoalveolar lavage (BAL) fluid and by day 21–28 in nasal swabs. All 9 animals developed binding and neutralizing antibodies. On day 35 following the initial infection, animals were rechallenged with SARS-CoV-2. Low levels of virus were present in BAL fluid at day 1 following rechallenge for 3 animals, with no virus detected thereafter for these animals or at any time point for the other 6 animals. Although this study demonstrates that macaques are protected against rechallenge, additional data are needed to better understand the duration of this protection.

References

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Boulware  DR et al: A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19. N Engl J Med, 2020 [Epub ahead of print].
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Chandrashekar  A et al: SARS-CoV-2 infection protects against rechallenge in rhesus macaques. Science, 2020 [Epub ahead of print].
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Chumakov  K et al: Can existing live vaccines prevent COVID-19? Lancet, 368:1187, 2020.
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Ellinghaus  D et al: Genomewide association study of severe Covid-19 with respiratory failure. N Engl J Med, 2020 [Epub ahead of print].
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Hamiel  U et al: Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: A multinational registry analysis. JAMA, 323:2340, 2020.
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Ing  AJ et al: COVID-19: In the footsteps of Ernest Shackleton. Thorax, 2020 [Epub ahead of print].
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Sakurai  A et al: COVID-19: In the footsteps of Ernest Shackleton. N Engl J Med, 2020 [Epub ahead of print].