Coronavirus COVID-19 (SARS-CoV-2)

Paul G. Auwaerter, M.D.

Updated: October 30, 2024

MICROBIOLOGY

CLINICAL

Epidemiology

Transmission

Symptoms: range from asymptomatic to life-threatening. Most symptomatic illness begins with URTIs. Severe infection is seen chiefly in the elderly, those with multiple comorbidities and the immunocompromised.

Laboratory and imaging findings (severe disease)

  • In COVID-19 pneumonia requiring hospitalization
    • Leukopenia (83%)
    • Thrombocytopenia (36%)
    • Elevated CRP
    • Transaminase elevations
    • Procalcitonin typically normal
    • Chest CT may show ground-glass opacities that may evolve into consolidation or ARDS.
      • Findings peak at 10 days of illness; resolution begins after day 14 for hospitalized patients.
      • CT may show lung findings (such as ground-glass opacities) before developing symptoms.

Differential diagnosis

  • COVID-19 cannot be easily distinguished from other causes of viral respiratory infections, such as influenza, RSV, other respiratory viruses, or community-acquired pneumonia, based only on clinical grounds.
    • Consider multiplex testing, including influenza and RSV, especially with severe illness/hospitalized patients.
    • Anosmia and dysgeusia occur much more frequently than other respiratory viruses, though less so than earlier in the pandemic with Omicron and immunization.

COVID-19 testing: Though testing remains encouraged for all patients, the FDA removed from their EUAs (2/3/23) the requirement for nirmatrelvir/ritonavir or molnupiravir to have a confirmed SARS-CoV-2 infection. Though it is still recommended to test by antigen or molecular assays, there may be circumstances, such as known confirmed household exposure, that clinicians may diagnose COVID without a test in hand.

  • Molecular testing remains the gold standard (PCR, multiplex panels), but outpatient settings often have a longer turnaround time of 48-72 hours unless rapid point-of-care PCR testing is used.
    • The sensitivity for molecular testing is excellent but depends on the sample collection. A small percentage may be missed depending on the technique and timing of illness; a repeat swab is needed if high suspicion exists.
    • Detection of viral RNA ≠ infectious virus necessarily, but is likely valid for up to 8d after onset of illness in the immunocompetent patient.
      • Cycle threshold values are not standardized, vary among platforms, and are not reported as clinical data; however, if values are available in the 30s-40+, then a low likelihood that the viral shedding correlates with an active, replicating virus.
    • A nasopharyngeal (NP) swab specimen is the norm.
      • Other samples include nasal, oropharyngeal, saliva, and lower respiratory samples.
        • Lower tract specimens may yield higher than the upper tract (nasal, oropharyngeal or nasopharyngeal).
        • The false-negative rate in the early phases of the pandemic has been reported to range from 2% to 29%.
          • The specificity of molecular RNA assays is excellent.
  • ANTIGEN
    • Tests detect viral proteins, e.g., SARS-CoV-2 spike protein.
    • Data from 2022-2023 found lower sensitivity of antigen testing than earlier in the pandemic.
      • Overall, 47% when using daily antigen testing compared to PCR. Peak sensitivity was seen on days of reported fever (77%)[3].
        • When no symptoms were present: 18%.
      • Detects high viral loads, typically occurring with the onset of symptoms until day 7, and likely correlates with infectious virus.
      • If negative, repeat testing may yield positive tests.
        • A single negative antigen test does not rule out COVID.
          • To rule out COVID, perform tests 48 hours apart:
            • Symptomatic: two antigen tests
            • Asymptomatic: three antigen test
      • A PCR test can be used to confirm a positive COVID antigen test or test with a method with better sensitivity than antigen.
    • SEROLOGIC
      • Antibody tests do not have a role in determining clinical infectivity, nor are they to be used to assess most patients’ immunity levels.
    • VIRAL CULTURE
      • Not recommended, except for research purposes (requires BSL-3 lab)
  • Incubation period and viral shedding, isolation, quarantine or airborne isolation
    1. Mean incubation with Omicron is 4.3 days, median 3-4d, range 2–14d.
    2. For the general population, the 5-day isolation rule has been dropped by the CDC (3/1/24)
      • Recommendations are now for respiratory viruses (influenza, RSV, COVID, etc.) and are not specific.
        • Return to normal activities when ≥ 24h symptoms are improving; if a fever was present, it is now absent.
        • When back to normal activities, it is recommended that you wear a high-quality mask for the next five days, keep your distance from others, and practice good hygiene (hand and cough).
          • These practices are essential for older adults and people who are immunocompromised.
    3. Viral shedding as an infectious risk
      • Occurs following recovery but does not appear to play a role in transmission in relatively healthy people >10d following the onset of infection (though some variants may be infectious longer, viral RNA may be detected long after for many weeks; hence, why repeated routine testing for negative SARS-CoV-2 RT-PCR not recommended).
      • It may not be so short for severely ill hospitalized patients or those with health problems. However, 20d is a conservative stance hospitals use to remove airborne precautions.
        • Prolonged cultivatable virus was seen in some severely immunocompromised patients.:
          • A low cycle threshold (CT), e.g., < 30 and usually < 25, may indicate an infectious virus is present.
            • However, comparing results using different testing platforms introduces variables that make assessments difficult.
              • The role of CT values is mostly to assess for prolonged shedding.
            • There are no FDA-approved CT values.

SITES OF INFECTION

TREATMENT

General

  • Location of care
    • Most care can be rendered ambulatory, with people remaining at home.
    • In-hospital care is needed for those who are short of breath, require oxygen, and are confused.
  • In-hospital supportive care
    • Consider influenza or RSV co-infection in severe/hospitalized patients.
      • If also infected with influenza, use neuraminidase inhibitors for severe infection (or baloxivir for outpatient use in high-risk patients). There are no drug-drug interactions of concern between influenza and SARS-CoV-2 antivirals.
    • Oxygen and mechanical ventilation, if needed.
      • Oxygen saturation ≤ 94% is a threshold for general consideration for antiviral or immunomodulatory therapy.
        • Occult hypoxemia (arterial blood O2 sat < 88% despite oximetry SpO2 >92%) appears more common in some people of color. Consider this possible limitation of pulse oximetry for appropriate patient presentations.
    • Prone positioning appears helpful if hypoxemia worsens despite intubation and ventilation.
    • ICU patients have high rates of clots (DVT, PE and thrombotic events [CVA, MI]).
    • Anticoagulation is prophylactically often used in ICU patients to avoid thrombotic events.
  • Secondary infections, especially in severe/critically ill patients:
    • ICU patients
      • Evaluate and treat bacterial or fungal superinfection (especially Aspergillus)
        • Sputum culture, beta-D-glucan, and serum or BAL galactomannan are helpful in decision-making.
        • Often “nosocomial” pathogens (ESBL, P. aeruginosa, A. baumannii, Aspergillus spp. )
        • Median time from onset of symptoms: 10–17d
        • The median time to death: 19d
    • Factors to consider
      • Frequent antibacterial use received in 80–100%
      • Antifungals in 7.5–15%

Drug Treatments

  • Johns Hopkins Hospital Therapeutic Guidance (PDF document) (updated 1/18/2024) is available to discuss the risks/benefits of FDA-approved, investigational and off-label medications for COVID-19.
  • Criteria for Identifying High-Risk Individuals: treatment for outpatients limited to those with medical conditions or other factors may place adults and pediatric patients (age 12-17 years and weighing at least 40 kg) at higher risk for progression to severe COVID-19:
      • See risk factors in the "Clinical" subheading.
  • Tiered recommendations (in descending order of preference; see individual modules for details) are provided for outpatient treatment of COVID-19 in mild-moderate infection. The recommendations were adapted from the IDSA COVID-19 Outpatient Guidelines and Roadmap.
    • FDA has removed the requirement for nirmatrelvir/ritonavir or molnupiravir to have a confirmed SARS-CoV-2 infection. Though still recommended to test by antigen or molecular assays, there may be circumstances such as known confirmed household exposure that clinicians may diagnose COVID without a test in hand.
    • Antivirals:
      • Nirmatrelvir/ritonavir
        • Preferred, if eligible, and if drug interactions otherwise don’t mean a contraindication.
      • Remdesivir
        • Now, it is often the go-to therapy for patients who cannot take nirmatrelvir/ritonavir due to drug interactions.
        • Daily IV infusion x 3 days is difficult for many organizations due to staffing, space issues, and patient demands.
        • It appears to have similar efficacy to nirmatrelvir/ritonavir for avoiding hospitalization or death in unvaccinated populations.
      • Convalescent plasma
        • This is the sole antibody-based therapy currently used to neutralize the virus.
        • Convalescent plasma (high titer, donated from vaccinated patients) is restricted to immunocompromised patients with COVID per FDA EUA, including outpatient and inpatient administration in immunosuppressed populations.
          • Polyclonal antibodies, more so than a focused mAb, may help avoid the emergence of variants in highly immunosuppressed patients.
          • Convalescent plasma donated within 150 miles of use achieves superior results compared to plasma donated from further distances. This likely has to do with the regionally driven presence of variants at the time of collection and then the speed of use.
          • There was a 54% reduction in hospitalization/death for outpatient use, proving the effectiveness of using convalescent plasma for treating mild-moderate COVID-19 in people with risk factors.[8]
          • Limited supply, as many blood banks do not currently solicit donors.
            • COVID-19 infected AND vaccinated patients (so-called high titer vax convalescent plasma) have the highest neutralizing antibody titers.
            • Standard plasma has antibodies against SARS-CoV-2 but is of unknown titer.
      • Molnupiravir
        • Lower effectiveness (30%) than the above therapies in avoiding hospitalization/death in unimmunized patients.
        • Need pregnancy screen in women of childbearing age, genotoxicity concerns.
        • No meaningful drug interactions are known.

Antivirals

  • Studies for EUA or FDA approval were primarily carried out in the early part of the pandemic in unimmunized individuals. Efficacy is likely less in the population that is now either immunized or previously infected +/- lessening of virulence of recent variants (Omicron).
  • Remdesivir (RDV)
    • Inpatient Use:
      • Based on the Adaptive COVID-19 Treatment Trial (ACTT-1[18]), RDV appears most beneficial for severe COVID-19 before mechanical ventilation, which reduces the length of hospital stay (from median 15d to 10d). Many institutions limit initiation to those who require oxygen but not ICU care. SOLIDARITY and DisCoVeRy trials did not show mortality benefits, but both were open-label, pragmatic trials with no placebo; however, the subgroup needing oxygen, non-critically ill in the DisCoVeRy trial did have a shorter length of stay similar to ACTT-1. Other observational data were used, and the results were similar to those of ACTT-1. U.S. guidelines (NIH, IDSA) continue to endorse the drug is infrequently used overseas.
      • FDA approved (Oct 2020) for COVID-19 hospitalized patients, ages ≥ 12 yrs or 40 kg.
        • EUA is now issued for children < 12 yrs, wt 3.5 – 40 kg.
        • Assess sCr, LFTs and PT INR before use.
      • Dose: 200 mg IV load on day 1, then 100 mg IV q 24 days 2-5
        • Infuse over 30-120 min.
        • If there is no clinical improvement, the treatment may be extended for an additional 5d, especially in patients on mechanical ventilation, ECMO or who are severely immunosuppressed.
        • Carrier (SCED) may accumulate in renal insufficiency but is not judged to be clinically significant despite the warning on the label.
      • Warnings:
        • Don’t use if hypersensitivity reactions ensue.
        • Consider d/c if LFTs 10x ULN.
      • Results of an NIH-sponsored clinical trial (ACTT-1) for COVID-19 patients with evidence of lung involvement:
        • The median time to recovery was reduced by 5d or 31% (10d v 15d).
          • Median days onset of symptoms (9d) before enrollment.
        • The mortality trend was suggested (8% v 11.6%) but was not statistically significant.
        • The benefit appears derived in this trial in patients started on RDV before mechanical ventilation.
          • The NIH COVID-19 Guideline states that the BIIa recommendation for severe COVID-19 requires oxygen but not mechanical ventilation.
        • Investigators concluded that patients received benefits before the need for mechanical ventilation, which suggests that this antiviral yields more significant benefits the earlier it is initiated.
      • Another RCT from China did not show a benefit but did note a mortality trend toward benefit.
      • The Solidarity trial (WHO trial, interim results) had RDV as one of four arms but did not find benefits regarding mortality, LOS or decreasing need for mechanical ventilation.
        • Though a large trial, as a pragmatic trial, there was no placebo comparator. Also, there were problems with selection and assignment bias and missing data.
    • Mild-moderate COVID-19 (usually ambulatory):
      • RDV was studied in the PINETREE study and terminated early due to the availability of monoclonal antibody therapies.
        • Three days of once-daily IV RDV infused as 200mg d1, 100mg d2-3 vs. placebo among unvaccinated, ambulatory patients ≥12 years old with≥1 risk factor for severe COVID-19 and ≤7 days of symptoms.
          • Primary outcome = COVID-19-related hospitalization or death in 28 days.
            • In the RDV arm, 2 (0.7%) participants had a COVID-19-related hospitalization compared to 15 (5.3%) in the placebo arm (p=0.008), for an 87% relative reduction. There were no deaths in either arm, and adverse events were similar in both arms.
        • With the absence of monoclonal antibodies, for patients unable to use Paxlovid due to drug interactions, this is the preferred treatment but logistically challenging to obtain due to IV infusion over three days needed.
    • Outpatient and Inpatient Use:
      • Nirmatrelvir/ritonavir (Paxlovid)
        • Received EUA December 2021.
        • Nirmatrelvir is a SARS-CoV-2 3CLpro protease inhibitor boosted by ritonavir.
          • EPIC-HR RCT enrolled unvaccinated adults with mild COVID-19 as outpatients using five days of PAXLOVID vs. placebo. The primary endpoint was death or hospitalization within 28d.
            • Interim analysis of 2,085 participants showed that 8 (0.8%) in the nirmatrelvir arm vs. 66 (6.3%) in the placebo arm reached the primary endpoint for an impressive relative risk reduction of 88% (p=0.001).
            • No significant safety signals.
        • FDA EUA fact sheet allows for use in people ages ≥ 12 yrs with mild-moderate COVID-19 outpatients OR inpatients (so no severe/critical COVID-19) with risk factors for severe disease AND ≤ 5 days of symptoms.
          • Nirmatrelvir 300 mg (two 150 mg tabs) + ritonavir 100 mg twice daily PO x 5 days
            • Has renal dosing recommendations.
            • Check for drug-drug interactions:
              • Co-administration with CYP3A metabolized drugs may heighten or lessen drug levels and cause potentially life-threatening problems OR lessen levels of nirmatrelvir/ritonavir.
          • It is not to be used for PEP or PrEP.
        • A rebound of symptoms and antigen presence is now frequently described.
          • Trial estimates are ~2% in both treated and untreated but poorly understood and likely higher, with some placing the occurrence at 10-20%. It should be noted that a small percentage of untreated people also suffer rebound symptoms.
          • Mechanism uncertain, but may be due to earlier diagnosis by antigen testing, institution or drug and inhibition of variant-specific immunity, or the consequence of less immunity depending on timing from last immunization or SARS-CoV-2 infection.
          • The drug should not be withheld due to concerns of a rebound in high-risk populations.
      • Molnupiravir
        • Ribonucleoside prodrug with activity against coronaviruses received FDA EUA in December 2021.
        • MOVe-OUT trial in adult outpatients with COVID-19 and ≤ 5 days of symptoms examined 5d of treatment v. placebo. The primary endpoint was hospitalization or death within 29d. Obesity was present in 74% of enrollees.
          • mITT results of 1433 participants, 48 (6.8%) of the molnupiravir arm participants compared to 68 (9.7%) of placebo arm participants were hospitalized or died for a 30% reduction [difference, −3.0 percentage points; 95% CI, −5.9 to −0.1]. Adverse events were comparable.
        • FDA EUA fact Sheet is for adults only with mild-moderate COVID-19 with risk factors for severe disease.
          • 800 mg (200 mg caps) PO q 12 h x 5d
          • Limitations:
            • Benefit has not been shown for use in COVID-19 patients requiring hospitalization.
            • Do not use it in children or adolescents (it may affect bone and cartilage).
            • It is not authorized for PEP or PrEP.
            • Not recommended during pregnancy or if breastfeeding.
            • Men need to use reliable methods of birth control for 3 months, women for 4 days.
        • Lack of evidence of effect in immunized people at high risk for severe illness; therefore, other agents (nirmatrelvir/ritonavir or bebtelovimab) are preferred.

Other candidate antiviral therapies: only widely discussed drugs are listed below (see Table for a more complete list and references)

  • Ivermectin
    • Double-blind RCT of mild COVID-19 treatment x 5d, without efficacy, reinforced by another RCT and not recommended.
    • Multiple other RCTs without benefit regarding low- or high-dose ivermectin. The drug continues to be used but has no role in treating this viral infection.
  • Chloroquine (CQ) or hydroxychloroquine (HCQ)
    • Based on the arm of the RECOVERY trial showing no clinical benefit and other clinical data with cardiotoxicity concerns

Immunomodulators

  • Dexamethasone
    • Results from the RECOVERY trial showed dexamethasone 6 mg PO or IV daily for up to 10 days reduced 28-day mortality in certain groups of hospitalized COVID-19 patients: recommended for patients with severe COVID-19 (requiring oxygen), including those on mechanical ventilation by the NIH and IDSA.[1]

Effect of Dexamethasone on 28−day Mortality Level of Respiratory Support[12]

Respiratory Support at Randomization

Dexamethasone

Usual Care

*Statistically significant

No oxygen received

17.0%

13.2%

Oxygen only*

21.5%

25.0%

Invasive mechanical ventilation*

29.0%

40.7%

Other corticosteroids were potentially beneficial in other trials, and meta-analyses had a summary OR 0.66 on 28d all-cause mortality[21].

  • Two studies suggest preliminary potential benefits with inhaled budesonide:
    • STOIC: Phase 2 trial found a reduced need for medical care and improved time to recovery.
    • PRINCIPLE (preprint): Early interim analysis suggested shorter illness duration by 3d.
  • Baricitinib: an oral JAK1/JAK2 inhibitor that is FDA-approved for treating rheumatoid arthritis. See the tocilizumab section below for recommendations. Received full FDA approval in May 2022 for treatment of COVID-19 for adults ≥ 18 yrs.
    • FDA approval for adults is for the treatment of COVID-19 in hospitalized adults requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or ECMO.
      • The recommended dose of 4 mg PO once daily for 14 days or until hospital discharge, whichever comes first.
    • FDA EUA remains in place for ages ≥ 2 to 18 years for COVID-19 in hospitalized pediatric patients requiring supplemental oxygen, invasive mechanical ventilation, or ECMO.
    • ACTT-2 trial compared RDV + baricitinib vs. RDV + placebo
      • The primary endpoint was the median time to recovery (defined as discharged from the hospital or hospitalized but not requiring supplemental oxygen or ongoing medical care)
      • Most benefit in patients on high-flow oxygen not requiring mechanical ventilation.
    • COV-BARRIER: RCT with baricitinib vs. standard of care (19% received RDV, 79.3% on corticosteroids which differ from ACTT-2 trial)
      • The composite primary endpoint (death, progression to high-flow O2, NIMV, MV or ECMO) was insignificant.
      • Secondary endpoint 28d all-cause mortality 8.1% v 13.1%, a 38% reduction (HR 0.57 [95% CI 0.41-0.78] was not otherwise explained by the findings specifically, i.e., since the primary endpoint was not reached, no difference in groups regarding clots, MIs, CVA, etc.).
    • Dosing:
      • Adults and pediatric patients 9 years of age and older: 4 mg PO once daily
      • Pediatric patients 2 years to less than 9 years of age: 2 mg PO once daily
    • Duration: 14 days or until hospital discharge.
    • Tofacitinib, a Janus kinase inhibitor, is an alternative that has shown efficacy in severe COVID-19. It should be considered for use if baricitinib is unavailable.
  • Tocilizumab
    • An FDA-approved anti-IL6R monoclonal antibody for CAR-T cell cytokine release syndrome and rheumatoid arthritis.
      • RCTs performed early in the pandemic as monotherapy has not had positive results.
      • More recent studies with high percentages of patients on dexamethasone have shown benefits.
        • EMPACTA found less progression to ventilation or death if used before mechanical ventilation.
        • REMAP-CAP found that for patients on high-flow oxygen or within the first 24 hours of ICU care, tocilizumab contributed most significantly to more days of organ-support-free survival (10d compared to placebo) and decreased mortality.
        • RECOVERY found patients on oxygen with evidence of systemic inflammation (e.g., CRP > 7.5) had improved survival and were more likely to be discharged by day 28.
      • IDSA and NIH Guidelines suggest use in patients in the first 24h of ICU care in combination with dexamethasone alone or with remdesivir for patients on high-flow or NIMV with evidence of progression or increased markers of inflammation.
        • Baricitinib can be used similarly, except for ICU patients with no data to support use.
    • Dosing is typically 8 mg/kg x single dose; some repeat if there is no benefit within 48h
    • Sarilumab (also an anti-IL6R mAb) may be used if tocilizumab is unavailable.
      • Dose: 400 mg IV infused over one hour.
  • Anakinra:
    • EUA (Nov 2022) was granted for treating hospitalized adult COVID-19 patients requiring oxygen with a risk of progression to respiratory failure.
      • 100 mg SQ daily x 10d
      • If GFR < 30 mL/min, 100 mg SQ every other day.
  • Vilobelimab:
    • EUA (4/4/23) was issued for severe COVID-19 infection within 48 hours of starting invasive mechanical ventilation or ECMO.
      • 800 mg IV, potentially repeated up to six times during treatment.
        • Days 2, 4, 8, 15 and 22 as long as hospitalized, including post-ICU.
      • The PANAMO trial showed a mortality benefit; however, most patients did not receive tocilizumab or baricitinib, so it is unclear if this anticomplement C5a drug would work as well in critically ill COVID-19 patients receiving the current standard of care.
        • Survived patients were mainly in Western European trial sites and received either tocilizumab or baricitinib, confounding results.

Antibody-based therapies

Convalescent plasma (CP) serum-containing neutralizing antibodies against SARS-CoV-2, preferably using high-titer plasma (defined as a ≥250 titer in the Broad Institute’s neutralizing antibody assay or an S/C cutoff of ≥12 in the Ortho VITROS IgG assay)

  • Studies have been mixed regarding effectiveness. Many of the negative RCTs used CP late in the disease course. Positive outpatient and inpatient studies were used early in the course, and high-titer plasma was used.
    • FDA EUA (revised 12/28/21) now approves using only high-titer convalescent plasma for patients with an immunosuppressive disease or receiving immunosuppressive therapies.
      • See the FDA fact sheet for healthcare providers for detailed information. Compared to earlier EUA, differences now include:
        • CP may be used for either outpatients or inpatients.
        • CP is not authorized for immunocompetent patients (receiving COVID-19 treatments such as dexamethasone or tocilizumab does not qualify).
        • Specifics regarding the qualification of high-titer plasma are found in the FDA letter, using specified test kits.
          • The supply of CP is often limited.
          • Donors who have had COVID-19 and are immunized appear to produce the best titers with activity against known variants.
      • RCTs for inpatients have not confirmed benefit, although substantial observational data point to subsets of COVID-19 patients who may benefit; however, many of these trials administered CP late into the illness (> day 7).
        • The subset derived from the expanded access use earlier in 2020 found that high-titer plasma within three days of hospitalization conferred a mortality benefit if received before intubation[14].
        • A small RCT in patients older than 65 with mild to moderate COVID-19 found that treatment reduced the progression to severe COVID-19 if received within 3 days of the onset of illness[15]
        • Retrospective matched cohort study: CP within 3 days after admission, but not 4-7 days, was associated with a significant reduction in mortality risk (aHR = 0.53, 95% CI 0.47-0.60, p< 0.001).
        • Many RCTs published in 2020, primarily small and underpowered, have not shown mortality benefits to date, although a meta-analysis of observational studies suggests early use does have an impact.
        • The RECOVERY trial yielded no 28d mortality benefit, so the NIH and IDSA Guidance no longer recommend it as a therapy for all hospitalized patients.
          • However, positive data suggest early use (< 3d of symptoms or hospitalization) and studies in immunosuppressed illness suggest a role remains and is now with an FDA EUA for immunosuppressed patients.
      • This author favors use in patients with risk factors for severe COVID-19 if patients are immunosuppressed early in the illness course (especially with impaired B-cell responses).
  • RCTs for prophylaxis, early and late COVID-19 treatment.
    • RCT of 1225 randomized for early COVID, ambulatory high-titer convalescent plasma therapy with the primary endpoint of hospitalization within 28d[8].
      • The pre-specified mITT excluded those not transfused. The primary endpoint occurred in 37 of 589 participants (6.3%) who received placebo control plasma and in 17 of 592 participants (2.9%) who received convalescent plasma (RR, 0.46; one-sided 95% upper bound confidence interval 0.733; P=0.004), corresponding to a 54% risk reduction.
        • The study suggests that early administration of high-titer convalescent plasma is effective and would have a similar impact if used in hospitals.
      • Convalescent plasma high titer has activity against Omicron (see NIH variant and agent activity chart for latest updates), and Omicron-recovered donors would expect activity to be higher activity.
  • Patients with prolonged active viral replication (low CT values) may have a response to CP usually combined with directly acting antivirals, e.g., RDV, Paxlovid or molnupiravir.
    • Usually, an immunosuppressed population, such as B-cell deficient, lymphoma or solid organ transplant patients.
      • For example, metaanalysis lymphoma patients found a mortality benefit in RCT and matched cohort studies (RR 0.63 [95% CI 0.50-0.79]}[7].
  • Risks
    • Pathogen transmission (~1 per 2 million transfusions for HIV/HBV/HCV)
    • Allergic transfusion reactions
    • Transfusion-associated circulatory overload (TACO)
    • Transfusion-related acute lung injury (TRALI)
      • Risk < 1 per 5000, potentially higher in COVID-19 due to pulmonary epithelial injury
      • Risk is lower if routine donor screening includes HLA antibody screening of female donors with a pregnancy history.

Monoclonal antibodies (mAbs) specific to SARS-CoV-2

  • Currently, no such products are available for the treatment of COVID-19.

Special populations

  • Pregnancy or lactating women (ACOG):
    • Remdesivir: The drug is considered safe to use, and women receiving the drug had better outcomes.
    • Dexamethasone: corticosteroid of choice if needed.
    • Nirmatrelvir/ritonavir: similar to HIV-protease antivirals considered safe to use in pregnancy. Experience has not seen safety signals, so it is recommended as the first line for treating COVID in pregnancy for outpatients.
  • Renal failure (GFR < 30 mL/min): The FDA has revised the label based on experience, such that the drug can be given to renal transplant patients with safety and good outcomes.

Prevention

  • General measures recommended:
    • Avoid sick individuals.
    • Wash hands with soap and water x 20 seconds before eating, after coughing/sneezing or during bathroom visits.
    • Social distancing maneuvers
    • Masks are recommended when in public indoors.
    • Don’t touch the face, eyes, etc.
    • Stay home if ill.
    • Cover your sneeze.
    • Disinfect frequently touched household objects.
  • Therapeutic Interventions:
    • Post-exposure prophylaxis (PEP):
      • There are no Mabs currently available for this indication.
    • Pre-exposure prophylaxis (PrEP):
      • Pemivibart (Permgarda) has EUA issued by the FDA (3/22/24) for this human IgG1λ antibody that targets the SARS-CoV-2 spike protein receptor binding domain.
        • EUA granted the biological plausibility of an immunobridging approach rather than clinical outcomes data. CANOPY Phase 3 trial ongoing.
          • It is not authorized for treatment.
        • On 4/3/24, the FDA revised the EUA to request a revised deadline to understand all genotypic and phenotypic resistance data for those failing prophylaxis in the CANOPY clinical trial.
        • It is approved in adults and children ≥ 12 yrs + >40 kg for pre-exposure prophylaxis for moderate to severely immunocompromised people or those receiving immunosuppressive medications unlikely to mount sufficient immune responses to COVID-19 vaccination.
        • Safety data so far in 623 patients with/ at least one dose of the drug
          • Common side effects included headache, fatigue, nausea, local skin reactions at the infusion site, flu-like symptoms
          • Four suffered anaphylaxis

Vaccines

  • See the COVID vaccine module for details.
    • Immunization reduces the risk of severe disease, hospitalization or death.
    • Lessens the chance of developing long COVID.
  • Multiple vaccines worldwide, with those below used in the U.S.
    • Recommended for all ≥ 6 months.
      • Offers protection against severe COVID, hospitalization and death.
      • The 2024- 2025 COVID-19 vaccine is particularly recommended for people 65 and older who are at high risk for severe COVID-19, living in a long-term care facility, are pregnant/breastfeeding or have never received a COVID-19 vaccine. Immunization also lowers the risk of long COVID.
        • mRNA: (KP.2. 2, EUA)
          • Pfizer-BioNTech
          • Moderna
        • Protein subunit vaccine
          • Novavax (JN.1, EUA)
  • Up-to-date with COVID immunization considered if: received 2024-2025 vaccine doses
    • Children 6 mos-4 years
      • Zero prior doses: either 2 doses Moderna or 3 doses Pfizer
      • 1 dose Moderna: need one more dose of Moderna
      • 1 dose Pfizer: need 2 doses, Pfizer
      • 2 doses Pfizer: one more dose Pfizer
    • Children 5-11:
      • Received 1 dose of Moderna or Pfizer
    • People ≥ 12 yrs
      • Received 1 dose of Moderna or Pfizer
    • If age ≥ 65 years, or moderately to severely immunocompromised: CDC recommendation (10/23/24)
      • After 1st dose of the 2024-2025 vaccine, a second dose is recommended (using shared decision-making) six months later.
    • People who recently had COVID
      • May delay immunization x 3 months
      • Could consider sooner if at severe risk of COVID or household member/close contact at risk of COVID-19.

Complications

  • Thrombosis: increasing reports of substantial rates of DVT and PE in critically ill patients. Some centers use low-molecular-weight heparin for prevention; others call against it, citing paradoxical clotting.
    • MI and CVA also appear with unusual frequency.
    • It is unclear if the COVID-19-associated incidence of venous thromboembolism is higher than reported customarily in ICU populations despite prophylaxis (~8-9%), as only "high incidence" centers report.
  • HLH-like changes were described in a subset of patients who died, autopsy findings.
  • CNS: Encephalitis (rare) or encephalopathy (uncommon, more in the elderly)
  • Cardiac: myocarditis (usually transient and mild, but severe cases described)
  • Secondary infection
    • Limited data on incidence because many COVID-19 patients are treated empirically with antibacterials for pneumonia.
    • Appears particularly in critically ill patients and those with prolonged hospitalizations.
    • Loose estimates are a 10–20% incidence of bacterial and fungal infections, with a higher percentage in dying patients.
    • Development of pulmonary aspergillosis. COVID-19-associated pulmonary aspergillosis (CAPA) consideration, especially in severely ill, in ICU or immunosuppressed.

Selected Drug Comments

Drug

Recommendation

Anakinra

Monoclonal inhibitor of IL-1 granted EUA status for treating severe COVID-19 pneumonia with a risk of progressing in hospitalized patients. The SAVE-MORE RCT showed sufficient efficacy (reduction by 11-pt WHO clinical progression at d28, 0.36 (95% confidence interval 0.26–0.50 compared to placebo) and safety, but enrollment was dependent on elevations of soluble urokinase plasminogen activator receptor levels (uPAR ≥6 ng ml−1), a test not routinely available in the US. It can be considered in use similar to the employment of tocilizumab in treating progressive COVID-19 pneumonia in hospitalized patients. It is not currently a recommended treatment for COVID-19, but it is available if shortages of other drugs, such as tocilizumab or JAK inhibitors, exist.

Baricitinib

The second fully FDA-approved treatment for severe COVID-19 (after remdesivir) is a selective inhibitor of Janus kinase (JAK) 1 and 2, FDA-approved for rheumatoid arthritis, studied for COVID-19 in ACTT-2 studying RDV v. RDV + baricitinib. The drug offered a one-day improvement in symptom resolution, which has led to FDA EUA. Upon subgroup analysis, the drug worked based on the ordinal 6 group (high-flow oxygen or non-invasive ventilation). These patients had a time to recovery of 10 days with combination treatment and 18 days with control (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). The drug might be considered for use in patients who cannot receive dexamethasone but who require high-flow oxygen or non-invasive ventilation. COV-BARRIER RCT with baricitinib vs. standard of care (19% received RDV, 79.3% on corticosteroids, which differs from ACTT-2 trial). The composite primary endpoint (death, progression to high flow O2, NIMV, MV or ECMO) was insignificant. The secondary endpoint 28d all-cause mortality 8.1% v 13.1%, a 38% reduction (HR 0.57 (95% CI 0.41-0.78) was not otherwise explained by the findings specifically, i.e., since the primary endpoint was not reached, no difference in groups regarding clots, MIs, CVA, etc.). Impressive mortality reduction; however, the study was more international than the US, and only a minority received RDV. Recent studies (COV-Barrier subset analysis and Recovery) on dexamethasone showed mortality reduction benefits in critically ill patients.

COVID-19 Convalescent Plasma

We are still waiting for a large RCT to be published to confirm hospital use; however, it is now the only antibody product available to use in people with COVID-19 and high-risk immunosuppressed, especially if vaccine non-responders/pts with B cell disorders. However, many trials used the agent too late (e.g., RECOVERY, others) in hospitalized patients for there to be a chance of helping patients in later phases of infection. Convalescent plasma works best as an antiviral. The current FDA EUA for outpatients and hospitalized patients now enforces high-titer plasma, which is only available for immunosuppressed populations. It is best used within three days of illness onset or the first three days of hospitalization. Now indicated only for immunosuppressed populations. High titer units from people who have recovered from COVID-19 and have been immunized appear to generate the best titers and activity against known circulating variants, including Omicron. An outpatient study of early plasma administration showed a 54% reduction in hospitalization, demonstrating that high-titer units have a role if used early rather than late (in hospital) for average, high-risk patients[8]. NIH guidance has softened slightly with the lack of RCTs and acknowledges use in certain populations.

Dexamethasone

The RECOVERY trial provides the first evidence of therapy that provides a mortality benefit to those mechanically ventilated (or who require oxygen, severe COVID-19). In this trial, there was a trend toward increased mortality in those who do not require oxygen, so it was not recommended in this group, usually with early infection. By the numbers, the rate ratio of mortality at 28d was 0.65 (p=0.0003) for those mechanically ventilated, 0.8 (p=0.0021) for severe COVID-19 patients who needed non-invasive supplemental oxygen, but 1.22 (p=0.14; so higher mortality trend) for patients who did not require supplemental oxygen. Some aspects of the RECOVERY trial deserve comment: the UK trial mortality was unusually high if the same benefit would be witnessed in North America is unclear. Also, patients with less than 7d of symptoms appeared not to benefit, suggesting no impact or potential harm during the early phase of viral illness (similar to influenza). Still, the benefit is seen in the later hyperinflammatory phase. This trial was open-label, but the mortality endpoint would tend to discount bias to a substantial degree. Women appeared to benefit less from dexamethasone than men.

Molnupiravir

High hopes for this nucleoside analog; however, the MOVe-OUT trial had only ~ 30% reduction in hospitalization or death within the first month when used in outpatients with fewer than 5 days of symptoms. Some have voiced concerns about mutagenesis and driving new viral variants with high use levels, although with only a five-day course, the mutagenesis concern seems lower. Regardless, this drug is clearly in a lower tier than Paxlovid. The drug should not be used in children, adolescents, pregnant and breastfeeding women. It has few drug interaction issues or side effects from the treatment.

Nirmatrelvir/ritonavir

A combination drug is an oral protease inhibitor that has activity against SARS-CoV-2. Results from the outpatient COVID-19 EPIC trial are impressive for treatment of early COVID-19; if given within the first 3 to 5 days of symptoms, reduced hospitalization or death by 88-89%. The ease of oral administration will make this the preferred route for many compared to injectable monoclonal antibodies. Problems of limited supply in early 2022 have diminished. The use of ritonavir means that prescribers should carefully assess drug-drug interactions. NIH Guidance has suggested this drug is safe to use for pregnant women.

Pemivibart

Similar to Evusheld, it has a long life, thereby requiring 3-month infusions for moderately to severely immunosuppressed people who are unlikely to respond well to immunization. Changing Omicron variants may mean a short lifespan for this monoclonal agent. It is very expensive and poses issues with administration due to the risk of anaphylaxis, prompting prolonged observation times.

Remdesivir

The ACTT1 results showed improved LOS by 4 days in patients receiving RDV. The average duration of symptoms before enrollment was 9d median with a wide range. The key observation from data is that benefit was derived in patients who were started before mechanical ventilation, suggesting that using the drug earlier in the disease course has efficacy--consistent with its mechanism of action as an antiviral. Some argue that SOLIDARITY and DisCoVeRy trials show no mortality benefit, although the latter trial did have a similar benefit for patients on oxygen as ACTT-1. Many US and NIH guidelines favor continued use for patients with severe COVID-19 requiring oxygen but not admitted to the ICU due to improvement in LOS noted by prospective and several retrospective, matched control studies. PINETREE data suggested that early administration (< 5d after symptom onset) in patients at high risk for COVID-19 prevents hospitalization and death. Three-day infusion poses logistical challenges compared to single-dose mAb for outpatients. Still, maybe the treatment of choice for those patients ineligible for Paxlovid and if effective mAb is unavailable. RDV is the first to receive full FDA approval for COVID-19, and use in the outpatient arena often requires financial clearance before receiving since it is now paid by patient insurance; this may slow the time to the first infusion. It has been increasingly used for outpatient treatment since the removal of bebtelovimab.

Tocilizumab

This anti-IL6R mAb has had an up-and-down and now up history for COVID-19. The drug appears to not work as monotherapy; however, when combined with dexamethasone, it reduces the severity and duration of illness and mortality in three studies: EMPACTA, REMAP-CAP, and RECOVERY. Endorsed for use by NIH and IDSA for patients on high-flow 02 or first 24h of ICU care--baricitinib is an alternative. Either should be combined with dexamethasone or another corticosteroid. Baricitinib is an alternative employed by some institutions in the second half of 2021 due to supply shortfalls of tocilizumab.

Vilobelimab

The drug is a chimeric human/mouse immunoglobulin G4 (IgG4) antibody consisting of mouse anti-human complement factor 5a (C5a) monoclonal binding sites (variable regions of heavy and light chain regions) and human gamma 4 heavy chain and kappa light chain constant regions. In the FDA prescribing information, the drug is positioned as an alternative to baricitinib, remdesivir and tocilizumab. Given EUA approval based on Phase 3 RCT severe COVID-19 requiring IMV or ECMO showing reduced mortality with high rates of nonfatal SAEs including pneumonia (18.9% v. 12.8%), sepsis (14.9% v. 7.4%) and septic shock (9.1% v. 7.4%). Place in COVID-19 care is uncertain, and no national guideline (e.g., NIH or IDSA) has yet weighed in.

FOLLOW UP

OTHER INFORMATION

Basis for recommendation

  1. Bhimraj A, et al. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19 [last updated 8/12/24, accessed 9/5/24]

    Comment: Regularly updated and now the lead guideline since the retirement of the NIH panel. One central area where our JH guide differs is in convalescent plasma use, which we at JH believe has a role in early illness in hospitalized patients (< 3d) or in some severely immunosuppressed patients who cannot generate meaningful antibody responses and now has a more significant role that monoclonal antibodies are no longer available. The availability of high-titer convalescent plasma remains limited for many.

References

  1. Erlandson KM, Geng LN, Selvaggi CA, et al. Differentiation of Prior SARS-CoV-2 Infection and Postacute Sequelae by Standard Clinical Laboratory Measurements in the RECOVER Cohort. Ann Intern Med. 2024.  [PMID:39133923]

    Comment: Unfortunately, this large cohort examined did not find any useful combination of commercially available lab tests that could sufficiently identify people with long COVID.

  2. Smith-Jeffcoat SE, Mellis AM, Grijalva CG, et al. SARS-CoV-2 Viral Shedding and Rapid Antigen Test Performance - Respiratory Virus Transmission Network, November 2022-May 2023. MMWR Morb Mortal Wkly Rep. 2024;73(16):365-371.  [PMID:38668391]

    Comment: Antigen testing is now in the sensitivity range similar to influenza RIDTs. The overall sensitivity of daily antigen testing was only 47% but rose to 77% on days of fever. If people were asymptomatic, it was only 18%.

  3. Xie Y, Choi T, Al-Aly Z. Association of Treatment With Nirmatrelvir and the Risk of Post-COVID-19 Condition. JAMA Intern Med. 2023.  [PMID:36951829]

    Comment: This cohort study suggests that those with at least one risk factor for COVID-19 had a reduced risk of ~ 25% for long COVID if they took the antiviral protease inhibitor.

  4. Deyoe JE, Kelly JD, Grijalva CG, et al. Association of Culturable-Virus Detection and Household Transmission of SARS-CoV-2, California and Tennessee, 2020-2022. J Infect Dis. 2023;227(12):1343-1347.  [PMID:36705269]

    Comment: An elegant study including viral cultures, done first early in the pandemic and then later on, but not in a well-immunized population, found that while 61% remained with culturable virus ≥ 6 days after symptom onset, household transmission mainly occurred < 6d. This is to keep in mind that high viral load is a factor in viral transmission, often when people are asymptotic.

  5. Alwine JC, Casadevall A, Enquist LW, et al. A Critical Analysis of the Evidence for the SARS-CoV-2 Origin Hypotheses. mSphere. 2023;8(2):e0011923.  [PMID:36897078]

    Comment: One of many articles written on this subject. Without surprise now 4 years (2024) from the pandemic onset, it is doubtful we’ll know for sure without more disclosure from the Chinese government.

  6. Senefeld JW, Franchini M, Mengoli C, et al. COVID-19 Convalescent Plasma for the Treatment of Immunocompromised Patients: A Systematic Review and Meta-analysis. JAMA Netw Open. 2023;6(1):e2250647.  [PMID:36633846]

    Comment: Many academic centers employ CP +/—other agents such as RDV for their immunodeficient, hospitalized COVID patients. This population has not been as well studied, and CP has been unfairly maligned due to negative trials in other populations that probably would not benefit from late administration. This meta-analysis shows a mortality benefit, suggesting that some populations benefit from antibodies against the virus.

  7. Sullivan DJ, Gebo KA, Shoham S, et al. Early Outpatient Treatment for Covid-19 with Convalescent Plasma. N Engl J Med. 2022;386(18):1700-1711.  [PMID:35353960]

    Comment: Though convalescent plasma is now limited by the FDA to immunosuppressed patients, this RCT of early administration of high-titer convalescent plasma showed a 54% reduction in hospitalization within 28d of symptom onset.

  8. Hammond J, Leister-Tebbe H, Gardner A, et al. Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19. N Engl J Med. 2022;386(15):1397-1408.  [PMID:35172054]

    Comment: A trial in unimmunized patients with mild-moderate COVID-19 found an 87-88% reduction in hospitalization or death compared to placebo. The drug is relatively well-tolerated. Its Achilles heel is co-packaging with ritonavir to boost nirmtrelavir levels, the SARS-CoV-2 specific protease inhibitor. Ritonavir, with its suicide inhibitor impact on CYP3A4, knocks out many patients who are on medications such as tacrolimus. We need to check for drug interactions. Patients on statins can have the drug held for the 5-day course.

  9. Jayk Bernal A, Gomes da Silva MM, Musungaie DB, et al. Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients. N Engl J Med. 2022;386(6):509-520.  [PMID:34914868]

    Comment: It was disappointing that the efficacy fell to 30% from the preliminary 50% impact at reducing hospitalization or death in this study of mild-moderate COVID-19 in unimmunized patients. The drug has a clean slide effect profile. Much has been made of genotoxicity concerns, but the impact is not clear from a 5d course. Check for pregnancy in women of childbearing age. Notably, fewer deaths in the molnupiravir arm, but not statistically significant. Probably worthwhile in patients at high risk for disease progression, and at least in early 2022 is the easiest to procure and take compared to other outpatient medications for COVID-19.

  10. Takahashi H, Ichinose N, Okada Y. False-negative rate of SARS-CoV-2 RT-PCR tests and its relationship to test timing and illness severity: A case series. IDCases. 2022;28:e01496.  [PMID:35402162]

    Comment: Experience from early in the pandemic (2020) found some false positives, usually either procurement error or low viral levels, often at later stages of the illness.

  11. RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021;384(8):693-704.  [PMID:32678530]

    Comment: Pragmatic trial, and it is also essential to note the extraordinarily high background mortality in the U.K. at the time (~40%). 28-day mortality in the usual care group was highest in those patients receiving IMV (40.7%), intermediate in those receiving oxygen only (25.0%), and lowest among those who were not receiving respiratory support at randomization (13.2%). The most significant absolute reductions in 28-day mortality were seen in the sickest patients, and subgroup analysis suggests in those > 7d of symptoms that would correlate with the inflammatory phase. Dexamethasone improves 28d mortality compared to placebo in patients requiring IMV (NNT = 8.5) and those requiring oxygen therapy (NNT = 29). There was no benefit to patients not requiring oxygenation support and even a signal for harm.

  12. Korley FK, Durkalski-Mauldin V, Yeatts SD, et al. Early Convalescent Plasma for High-Risk Outpatients with Covid-19. N Engl J Med. 2021;385(21):1951-1960.  [PMID:34407339]

    Comment: High-titer convalescent plasma was not helpful in this trial of 511 patients who received it < 7d from the onset of symptoms. The average duration of symptoms in the active arm was 4 days (median IQR).

  13. Joyner MJ, Carter RE, Senefeld JW, et al. Convalescent Plasma Antibody Levels and the Risk of Death from Covid-19. N Engl J Med. 2021;384(11):1015-1027.  [PMID:33523609]

    Comment: A subset of patients in the expanded access use of COVID-19 convalescent plasma found that high titer recipients who received units before critical illness had a lower risk of death than those with low titer plasma.

  14. Libster R, Pérez Marc G, Wappner D, et al. Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults. N Engl J Med. 2021;384(7):610-618.  [PMID:33406353]

    Comment: Small but well-done double-blind RCT of patients > 65 yrs with mild COVID-18 and less than three days of symptoms. A total of 160 patients found that severe respiratory disease developed in 13 of 80 patients (16%) who received convalescent plasma and 25 of 80 patients (31%) who received placebo (relative risk, 0.52; 95% confidence interval [CI], 0.29 to 0.94; P = 0.03), with a relative risk reduction of 48%. A modified intention-to-treat analysis that excluded six patients with a primary end-point event before infusion of convalescent plasma or placebo showed a larger effect size (relative risk, 0.40; 95% CI, 0.20 to 0.81). No solicited adverse events were observed. The study is the best evidence that you need high titer units and early administration to have an effect.

  15. Parr JB. Time to Reassess Tocilizumab's Role in COVID-19 Pneumonia. JAMA Intern Med. 2021;181(1):12-15.  [PMID:33079980]

    Comment: Helpful data synthesis of major tocilizumab trials. Data overall is mixed; there may be efficacy but nothing like that suggested from observational trials--at least for immunomodulatory monotherapy tocilizumab. The author suggests waiting for more RCT data to determine if the drug is helpful for COVID-19 patients. This paper included EMPACTA; however, not RECOVERY or REMAP-CAP, which has defined a difference between dexamethasone + tocilizumab vs. tocilizumab monotherapy.

  16. Salama C, Han J, Yau L, et al. Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia. N Engl J Med. 2021;384(1):20-30.  [PMID:33332779]

    Comment: Called a positive trial for tocilizumab, essential points are that 1) statistical significance only when the rate of progressing to mechanical ventilation is included (not just mechanical ventilation and death as hard endpoints) and 2) > 80% of patients also received dexamethasone, suggesting that the two drugs need to work together to help patients.

  17. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of Covid-19 - Final Report. N Engl J Med. 2020.  [PMID:32445440]

    Comment: The ACTT1 results that showed improved LOS by 4 days in patients receiving RDV. The average duration of symptoms prior to enrollment was 9d median with a wide range. The key observation from data is that benefit was derived in patients who were started prior to mechanical ventilation, suggesting that the use of the drug earlier in the disease course has efficacy--consistent with its mechanism of action as an antiviral. Final results are now available.

  18. Kim D, Quinn J, Pinsky B, et al. Rates of Co-infection Between SARS-CoV-2 and Other Respiratory Pathogens. JAMA. 2020;323(20):2085-2086.  [PMID:32293646]

    Comment: A series of 1217 specimens analyzed for respiratory viruses found 116/1217 specimens (9.5%) were positive for SARS-CoV-2, and 318 (26.1%) were positive for one or more non–SARS-CoV-2 pathogens. Within the SARS-CoV-2 positive specimens, 24 (20.7%) were positive for one or more additional pathogens. The most commonly detected co-infections were rhinovirus/enterovirus (6.9%), respiratory syncytial virus (5.2%), and non–SARS-CoV-2 Coronaviridae (4.3%). This report yielded higher viral co-pathogen rates than earlier COVID-19 studies but similar to the co-infection rates of many standard respiratory viral illnesses. Finding a virus other than SARS-CoV-2 should not be grounds for concluding that COVID-19 is not present.

  19. Woloshin S, Patel N, Kesselheim AS. False Negative Tests for SARS-CoV-2 Infection - Challenges and Implications. N Engl J Med. 2020;383(6):e38.  [PMID:32502334]

    Comment: Notes that false negatives were very common in the early phases of the pandemic (reports of 27% early Chinese experience) and ranged from 2-29% in five other studies.

  20. WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Sterne JAC, Murthy S, et al. Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis. JAMA. 2020;324(13):1330-1341.  [PMID:32876694]

    Comment: Seven randomized trials included 1703 patients, of whom 647 died. 28-day all-cause mortality was lower among patients who received corticosteroids than those who received usual care or placebo (summary odds ratio, 0.66). Dexamethasone and hydrocortisone had similar impacts, while the single methylprednisolone trial had less effect on mortality.

  21. 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. JAMA. 2020;324(11):1048-1057.  [PMID:32821939]

    Comment: Though the open-label trial was cited as a reason to use 5-day instead of 10-d RDV for severe COVID-19, the fact that the 10-d course did worse without notably more side effects is concerning that the 5d data are perhaps not as solid. Also, the FDA cites this trial as a reason (along with ACTT-1) to expand RDV use to those hospitalized but not needing oxygen; however, NNT =~100, and limited patients not requiring oxygen at randomization are included.

  22. Ai T, Yang Z, Hou H, et al. Correlation of Chest CT and RT-PCR Testing for Coronavirus Disease 2019 (COVID-19) in China: A Report of 1014 Cases. Radiology. 2020;296(2):E32-E40.  [PMID:32101510]

    Comment: Chest CT shows early ground-glass infiltrates, which may offer a speedier "diagnosis" than PCR studies in an epidemic setting as a first finding if molecular assays were not readily available.

  23. Giacomelli A, Pezzati L, Conti F, et al. Self-reported Olfactory and Taste Disorders in Patients With Severe Acute Respiratory Coronavirus 2 Infection: A Cross-sectional Study. Clin Infect Dis. 2020;71(15):889-890.  [PMID:32215618]

    Comment: Authors report on patients in earlier phases of COVID-19 infection; 20 (33.9%) reported at least one taste or olfactory disorder and 11 (18.6%) both. This is not unique, though, as other viral respiratory infections may also cause these symptoms.

  24. Jin X, Lian JS, Hu JH, et al. Epidemiological, clinical and virological characteristics of 74 cases of coronavirus-infected disease 2019 (COVID-19) with gastrointestinal symptoms. Gut. 2020;69(6):1002-1009.  [PMID:32213556]

    Comment: The paper suggests that some patients presented with GI symptoms as part of COVID-19, 11.4% of 651 in this study from Zhejiang University in Hangzhou. A caveat is their definition of GI included nausea only in addition to diarrhea and vomiting, as they only needed one of the three to qualify for GI symptoms. They also suggested that patients who had GI had more severe COVID infection.

  25. Wölfel R, Corman VM, Guggemos W, et al. Virological assessment of hospitalized patients with COVID-2019. Nature. 2020;581(7809):465-469.  [PMID:32235945]

    Comment: A small but well-conducted study looks at 9 cases, with most patients on day 1 having mild or prodromal symptoms. Key findings include finding the virus in upper respiratory tissues with no difference between nasopharyngeal and oropharyngeal speeding, which was very high during the first week of illness but not in the stool. Viral RNA remained in the sputum beyond the resolution of symptoms. Seroconversion occurred by day 7 in 50% of patients but by day 14 in 100%. Despite the knowledge gained about viral kinetics, this paper proves that illness may also present as a routine upper respiratory tract infection without pneumonia or lower tract symptoms.

  26. Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020;323(11):1061-1069.  [PMID:32031570]

    Comment: One of the initial significant reports of the Wuhan COVID-19 epidemic. In this series, the median age was 56 and slightly more men (54%) were affected. Predominant symptoms include fever, fatigue and dry cough. Leukopenia was seen in ~70%. Thirty-six patients (26.1%) were transferred to the intensive care unit (ICU) because of complications, including acute respiratory distress syndrome (22 [61.1%]), arrhythmia (16 [44.4%]), and shock (11 [30.6%]).

  27. Zhu N, Zhang D, Wang W, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020;382(8):727-733.  [PMID:31978945]

    Comment: An early report includes electron microscopy photomicrographs and sequence analysis of what is now termed COVID-19 disease and SARS-2-CoV virus.

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