Knowns and Unknowns

COVID-19: Knowns

Epidemiology

• Symptomatic infection fatality rate (IFR-S) in the U.S. is 0.8–1.5% and the case fatality rate (CFR) is ~6%.
• CFR for patients requiring invasive mechanical ventilation is ~45%; ~58% for those requiring ECMO.
• Seroprevalence of SARS-CoV-2–specific antibodies among adults remains very low at ~14%.
• Greater than 75% of Americans are at risk of severe COVID-19 based on the prevalence of known comorbidities.
• Outbreak clusters have been traced to flights, parties, nightclubs, bars, karaoke bars, and gyms.
• Universal face mask use, including the use of cloth masks, significantly reduces viral transmission, hospitalizations, and death.
• Effects of introducing and relaxing non-pharmaceutical interventions on SARS-CoV-2 transmission are delayed by 1–3 weeks.
• Testing of wastewater is useful in monitoring and predicting infection rates.
• Household transmission is likely a leading cause of infection, occurs quickly, and can originate from both children and adults.
• Symptom screening and temperature checks fail to identify most children with COVID-19.

Vaccines and Prevention

• The Pfizer vaccine appears to be 52% effective following the first dose and 95% effective at least 7 days following the second.
• For the Pfizer vaccine, it will take 4 weeks from the first vaccine dose to develop robust protective immunity.
• Allergic reactions to the Pfizer vaccine are rare and occur in 11.1 cases per million doses.
• The Moderna vaccine appears to be 94% effective following the second dose and to reduce asymptomatic infections by ~67%.
• For the Moderna vaccine, it will take 6–8 weeks from the first vaccine dose to develop robust protective immunity.

Viral Transmission

• Presymptomatic, and to a lesser extent asymptomatic, transmission play a substantial role in community spread.
• Asymptomatic cases account for ~20% of all infections.
• 10–20% of individuals may be responsible for 80% of transmission.
• Short range aerosol and droplet are the primary routes of spread.
• Longer-range aerosol transmission can occur in closed, poorly-ventilated spaces.
• Infected persons shed SARS-CoV-2 during respiration, toileting, and fomite contact.
• Fecal–oral transmission is plausible and could continue after patients test negative from respiratory samples.
• SARS-CoV-2 can remain viable and infectious in aerosols for hours and viable on surfaces for days.
• Mild and moderate patients are typically no longer infectious 10 days following diagnosis, severe patients after 20 days.
• Climate and temperature do not affect transmission.
• Infected domestic cats shed infectious virus for up to 5 days, while dogs do not appear to shed virus.
• Biting insects do not pose a transmission risk to humans or animals.

Immunology

• Mean SAR-CoV-2 incubation period is 5.7 days
• Peak viral load occurs 4-6 days after symptom onset.
• Viral load appears to be correlated with disease severity.
• Antibody responses are short-lived, particularly in mild or asymptomatic infections.
• Magnitude of the neutralizing antibody response appears to depend on disease severity.
• Memory B cell responses do not decay after 6 months, but instead continue to evolve.
• Presence of neutralizing antibodies is associated with a substantially reduced risk of reinfection in the ensuing 6 months.
• Late onset antibody response may be a risk factor for disease severity.
• IgM and IgG appear at approximately the same time.
• Type I interferon responses play a critical role during early infection.
• Prior infection with human coronaviruses appears to induce lasting cross-reactive T cell immunity that neutralizes SARS-CoV-2.
• Reinfection is possible but appears to be exceedingly rare at this time.

Virology

• Dominant strain of SARS-CoV-2 is the G614 strain that began spreading in Europe and the U.S. East Coast in Feb-Mar 2020.
• D614G marks the evolution of the initial D614 (Wuhan) strain to the globally dominant and more virulent G614 strain.
• A globally circulating mutation that lacks a full-length form of orf3b is found in ~24% of sequences.
• In late 2020 and early 2021, three new prevalent circulating variants of concern with 614G backgrounds were identified.
• These new variants are 501Y.1 (B.1.1.7/UK), 501Y.V2 (B.1.351/South Africa), and 501Y.V3 (P.1/Brazil).
• These three variants all possess the N501Y mutation, which appears to increase transmissibility by ~56% or greater.
• 501Y.V1 is forecasted to become the dominant variant in the U.S. in March 2021.
• 501Y.V2 and 501Y.V3 variants possess the E484K mutation which appears to reduce the efficacy of neutralizing antibodies.
• Another variant, L452R (CAL.20C), has been identified in an increasing proportion of infections in California.
• Another potentially immunovasive mutation, N439K, is now found in ~6% of European cases.
• A now extinct and less severe Δ382 strain began spreading in East Asia in Jan-Feb 2020.
• There is insufficient evidence to assert that SARS-CoV-2 was widely circulating in the U.S. prior to January 2020.
• SARS-CoV-2 is not a purposefully manipulated virus and it’s lineage has been circulating in bats for decades.

Treatment and Management

• As with other viral upper respiratory infections, there is no outpatient treatment regimen other than supportive care.
• Corticosteroids appear to marginally reduce mortality in hospitalized patients requiring mechanical ventilation.
• Delaying intubation and using non-invasive ventilation can reduce complications and possibly avoid clinical deterioration.
• Therapeutic anticoagulation appears to reduce the need for mechanical ventilation in moderately ill hospitalized patients.
• Proning may improve oxygenation in select patients.
• Convalescent plasma does not appear to reduce mortality or progression to severe disease.
• Monoclonal antibodies appear ineffective as monotherapy but could be play a role in very early treatment.
• Remdesivir, hydroxychloroquine, tocilizumab, lopinavir–ritonavir, and interferon have little or no effect on hospitalized patients.
• Little data exists on the efficacy of vitamin D, favipiravir, famotidine, ivermectin, and almitrine for the treatment of COVID-19.
• Early superinfections are rare but late infections, including invasive pulmonary aspergillosis, are a risk in critically ill patients.
• Cardiopulmonary resuscitation is ineffective in hospitalized COVID-19 patients in cardiac arrest.
• Improved survival rates are due to better patient management, reduced hospital capacity, and expanded use of steroids.

Clinical

• Age, sex, and comorbidities, especially obesity, have a major impact on disease severity and mortality.
• Inflammatory vascular and thromboembolic complications are frequently encountered in severe infections.
• Venous thromboembolism occurs in approximately 8% of non-ICU patients and 23% of ICU patients.
• Pulmonary embolism occurs in approximately 4% of non-ICU patients and 14% of ICU patients.
• Biomarkers, including IL-6, NLR, and TNF-α, can predict disease progression and complications.
• Severe disease with respiratory failure is associated with a robust type 2 proinflammatory immune response (cytokine storm).
• Acute myocardial injury occurs in ~30% of hospitalized COVID-19 patients.
• Acute kidney injury occurs in 26% of hospitalized patients and is associated with a 3-fold increase in mortality.
• Anosmia, dysgeusia/aguesia, gastrointestinal symptoms, and cutaneous lesions are all associated with COVID-19.
• Conjunctivitis may also be a presenting symptom, especially in pediatric patients.
• Use of ACEI, ARB, or NSAIDs is not contraindicated in COVID-19.
• There is little evidence of direct neurological involvement aside from anosmia.
• Pregnant women appear to be at higher risk of severe infection and increased need for mechanical ventilation.
• Maternal IgG antibodies are in most cases transferred across the placenta after infection during pregnancy.
• Children have generally mild illness but rarely can develop an immune-mediated Multisystem Inflammatory Syndrome (MIS-C).
• Adults with previous infection can develop a similar Multisystem Inflammatory Syndrome in Adults (MIS-A).

Testing

• Nucleic acid amplification tests to detect viral RNA should be used for screening and diagnosis.
• Antigen, or rapid, tests are diagnostic tests, not screening tests, and for use in patients with signs or symptoms.
• Detection of viral RNA via PCR does not necessarily indicate infectiousness following symptom resolution.
• Sensitivity of diagnostic tests can depend on specimen and assay type and is time-dependent.

Personal Protective Equipment

• Health care workers are at risk but can be protected by appropriate PPE.
• Masks with exhalation valves or vents are completely ineffective.
• Face shields are not a substitute for masks and are used for eye protection.
• Masks do not affect gas exchange, including in older persons, and do not decrease oxygen or increase carbon dioxide levels.
• Wearing gloves does not protect against SARS-CoV-2 infection.

COVID-19: Unknowns

Epidemiology and Viral Transmission

• How can superspreader events be avoided?
• Is temperature screening at all effective as a control strategy given the prevalence of presymptomatic transmission?
• Why do infection rates and severity vary so widely among individuals and countries?
• Why are global COVID-19 mortality rates falling?

Vaccines and Prevention

• Can vaccines, especially mRNA vaccines, induce long term protective immunity?
• In those infected following vaccination, how do vaccines affect disease severity and transmission?
• Can upgrading ventilation systems in businesses and schools facilitate reopening?

Immunology

• What are the correlates and durability of protective immunity?
• Does low-level viral exposure lead to protective immunity?
• What role do T and B cells play in long term protective immunity?
• What type of T cell response elicited by vaccines will be the best predictor of protective immunity?
• Will memory T cells in the upper respiratory tract provide durable protection from lower pulmonary disease upon reinfection?
• What is the impact of prior exposure to endemic seasonal coronaviruses?
• What is the role of mucosal immunity in COVID-19?

Virology

• Are emerging variants of concern resistant to convalescent and vaccine-induced antibodies?
• Does viral diversity influence illness severity?

Clinical

• What are late complications and how can they be managed and/or prevented?
• What is long COVID-19 and how can it be managed?

Treatment

• What is the treatment for mild disease?
• How does the timing of intubation affect mortality?
• Are vitamin D, famotidine, favipiravir, ivermectin, almitrineor, or interferon effective in the treatment of COVID-19?
• Is there a role for monoclonal antibodies in the very early treatment of COVID-19?
• When should antifungal prophylaxis be considered?
• Is there a role for immunomodulatory agents in addition to corticosteroids?
• How should the timing of immunomodulatory interventions be optimized?
• Why does convalescent plasma seem to provide little or no benefit?

Testing

• What is the accuracy of antigen compared to viral RNA testing?

Inspired by Fang FC, et al. COVID-19—Lessons Learned and Questions Remaining. Clin Infect Dis. Oct 2020.