Coronavirus COVID-19 (SARS-CoV-2)

Paul G. Auwaerter, M.D.

Updated: January 14, 2022

MICROBIOLOGY

CLINICAL

Epidemiology

Transmission

Incubation period and viral shedding, isolation, quarantine or airborne isolation

  1. Mean incubation 4–5 days, range 2–14
    1. Omicron may be faster.
  2. Quarantine and Isolation: some local health departments may have some variation from CDC guidance below.
    1. For COVID-19 illness, the correct term is isolation.
      1. 10d have passed since symptom AND
        1. At least 24 hours with no fever without fever-reducing medication and
        2. Other symptoms of COVID-19 are improving, e.g., loss of taste and smell may persist for weeks or months after recovery and need not delay the end of isolation.
        3. Healthcare workers (HCWs) only may have shortened isolation requirements in the face of worker shortages and the Omicron variant, see CDC update 12/23/21 for recommendations.
      2. A limited number of persons with severe/critical illness or immunosuppression may produce replication-competent virus beyond 10 days that may warrant extending the duration of isolation and precautions for up to 20 days after symptom onset; consider a consultation with infection control experts.
    2. For close contacts with a person with COVID-19, the correct term is quarantine [CDC defined as at least 15 minutes cumulative over 24h, < 6 ft starting two days before illness onset or positive test result if asymptomatic].
      1. 14d observation remains CDC recommended to exclude infection.
      2. Options to decrease to 10d to enhance compliance or 7d if SARS-CoV-2 testing is negative 5-7 after close exposure.
      3. HCWs may have shortened quarantine requirements in the face of worker shortages and the Omicron variant, see CDC update 12/23/21 for recommendations.
  3. Viral shedding as 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).
      • Exception: HCWs only may have shortened quarantine and isolation requirements in the face of worker shortages and the Omicron variant, see CDC update 12/23/21 for testing recommendations
    • In ill hospitalized patients or those with health problems, it may not be so short, but 20-28d is a conservative stance used by some hospitals to remove airborne precautions rather than the two negative nucleic acid amplification tests (NAAT) rule.
      • Rare reports of cultivatable virus > 60 days especially in severely immunocompromised patients.:
        • Low cycle threshold (CT), e.g., < 30 and usually < 25 may indicate an infectious virus is present.
          • However, difficult to compare results when different testing platforms are used.
  4. Some accumulating data suggest that high viral inoculum may lead to increased risk for disease severity.

Symptoms

Disease spectrum

Laboratory and imaging findings

  • In COVID-19 pneumonia
    • Leukopenia is common among hospitalized patients.
    • LDH may be modestly elevated.
    • LFTs elevated more commonly than in typical community-acquired pneumonia cases
    • Note: the detection of other respiratory viruses in COVID-19 may be as high as 20% (e.g., influenza in spring 2020; however, near-zero for the 2020-2021 respiratory season).
      • Lab detection of viruses such as RSV, influenza, etc. should not result in the conclusion that SARS-2-CoV is not present.
    • Chest CT may show ground-glass opacities that may evolve into consolidation or ARDS.
      • Findings appear to peak at 10d of illness, resolution begins after day 14, for those who are hospitalized.
      • CT may show lung findings (such as ground-glass opacities) before the development of symptoms.
    • Among hospitalized patients, about one-third need to be in the ICU/intubated with an ARDS picture.
      • Elevations in IL-6 (> 40–100), CRP (> 10x normal), ferritin (> 1000) suggested correlating with hyperinflammatory state and may portend the development of ARDS.

Differential diagnosis

  • COVID-19 cannot be easily distinguished from other causes of a viral respiratory infection such as influenza, RSV, other respiratory viruses or community-acquired pneumonia based only on clinical grounds.
    • Anosmia and dysgeusia occur at a much high frequency than with other respiratory viruses; studies have cited ranges from 15-48%.
    • Influenza may be more abrupt onset; COVID-19 often with more perturbations of taste and smell.
    • Increasingly, viral multiplex testing incorporating SARS-CoV-2 is available; however, influenza and RSV rates were very low in the 2020-2021 winter respiratory season.
      • Spring/Summer 2021 saw increasing RSV and other routine respiratory viral infections.
      • Influenza again circulating during the U.S. winter respiratory season 2021-2022.
  • Also, consider pulmonary embolus, acute myocardial infection, chest crisis (sickle cell disease), etc.
    • Thromboses complicate critical COVID-19 patients with significant frequency, in some series up to 40% especially in the critically ill.

COVID-19 testing

  • Testing capacities have improved but many sites still have a 48-72h turnaround for molecular testing. Additional information through CDC.
    • Sensitivity for molecular testing is excellent but does depend on sample collection. A small percentage depending on technique and timing of illness may be missed, perhaps more so with immunized/boosted people with Omicron in the earliest phases of infection. A repeat swab is needed if high suspicion exists.
      • Lower respiratory tract samples are noted to have higher yields with Delta and earlier variants.
    • Detection of viral RNA ≠ infectious virus, necessarily but is true for the first 10d of symptoms in patients who are not severely ill or immunosuppressed but unimmunized.
      • For immunized, CDC recently issued guidance that 5d after onset, if symptoms have resolved or improving, people can leave isolation as long as wearing masks for days 5-10.
      • Cycle threshold values are not standardized and vary among platforms, and are not reported as clinical data. However, if values are available, if in the 30s-40+, then a low likelihood that the viral shedding correlates with an active, replicating virus.
  • MOLECULAR
    • Nasopharyngeal (NP) swab specimen is the norm, other samples used include nasal, oropharyngeal, saliva, lower respiratory samples.
    • CDC recommends approved assays that detect SARS-CoV-2 nucleic acid or antigen from respiratory tract samples. CDC has further guidance on details for specimen collection, handling, and other aspects.
    • Some assays are point-of-care, others may take 1–2 or more days depending on how they are sent and processed.
    • Lower tract specimens may have a higher yield than the upper tract (nasal, oropharyngeal or nasopharyngeal). The false-negative rate is not well known, but even for molecular assays may range as high as 10-30% and depends on when in the course of the disease the testing is done, with later testing having lower rates of detection. The specificity of molecular RNA assays is excellent.
  • ANTIGEN
    • Tests detect viral proteins, e.g., SARS-CoV-2 spike protein.
    • Sensitivity is lower than molecular tests (ranging from 50-90% in studies); however, the advantage is a quick turnaround time, usually < 15 minutes.
      • Detects high viral loads, typically occurring with the onset of symptoms until day 7.
    • FDA-EUA approval is only for symptomatic early illness of < 1 week as high viral load is needed to generate a positive assay.
      • Its role is best for quick assessment of infectiousness, such as in situations of congregate living, need for fast identification of an outbreak.
        • Home antigen testing is a methodology that is increasingly embraced to lead to a quick diagnosis especially for patients who would benefit from early treatment, e.g., mAbs.
        • Repeated testing will increase the risk of false positives but generally can trust a positive to indicate an infection in a symptomatic patient.
      • Symptomatic people who test negative by antigen still require follow-up molecular testing.
    • Use for the screening of asymptomatic people is increasing. CDC has issued an algorithm with interim recommendations.
      • If high pre-test probability, need to confirm antigen negatives with molecular testing.
      • If low pre-test probability, need to confirm antigen positives with molecular testing.
  • SEROLOGIC
    • Antibody-based tests for COVID-19 may have high rates of false-positive testing if used in low-positive-predicative value scenarios (e.g., screening as in "Have I had COVID-19?"), especially if using anti-nucleoprotein (N) SARS-CoV-2 antibody testing which may cross-react more commonly with common respiratory coronaviruses.
      • Tests have high analytic sensitivity and specificity; however, these are on known or spiked samples. Real-world testing, especially if the low probability of infection, makes these tests much less accurate, prone to false positives.
      • Clinicians should understand if the antibody assessed is against N or S proteins. Many commercial labs use assays against the N protein; these tests will not detect responses to SARS-CoV-2 vaccines (which employ spike protein).
    • Not recommended as the sole basis for diagnosis. Therefore currently available assays do not equate with an "immunity passport" if positive, unclear at what level they may equate with protective immunity.
      • The test may be used to support a clinical diagnosis if a patient has a high likelihood of infection but negative viral RNA testing, e.g., patient with fever, cough, ground-glass infiltrates but negative SARS-CoV-2 NAT testing.
      • FDA has warned not to use these tests yet to implicate authentic infection, protective immunity, or to rule out infection.
        • Cannot rule out infection except with molecular respiratory tests
        • Positive results may be due to past or present infection with non-SARS-CoV-2 coronavirus strains, such as coronavirus HKU1, NL63, OC43, or 229E.
      • In the future, more evaluation against validated banks of sera (positive and negative controls) or multiple antibody-based tests for SARS-CoV-2 may be shown to have higher specificity.
      • Many commercial antibody assays assess for antibodies against the N-protein, so they are not useful for assessing response to COVID-19 immunization, which provokes antibodies against the S-protein.
      • Most helpful for epidemiology.
      • Occasionally helpful to investigate recent illness consistent with COVID-19 but without confirmatory molecular determination.
    • Serologic response to SARS-CoV-2
      • One study found the serologic response to a recombinant SARS-CoV-2 nucleocapsid: IgM 85.4%, IgA 92.7% (median 5d after the onset of symptoms), and IgG 77.9% (14d after onset).[22]
      • Another study from China using IgM and IgG SARS-CoV-2-specific antibodies found < 40% seropositive if illness less than 7d, rising to ~100% 15d or more after onset.
      • Asymptomatically infected individuals produce antibodies to lesser levels and may fall below levels of detection within 2–3 months.[23]
  • VIRAL CULTURE
    • Not recommended, except for research purposes (requires BSL-3 lab)

SITES OF INFECTION

TREATMENT

General

  • Location of care
    • Depending on the capabilities of local health systems, public health officials recommend those with minor symptoms to stay home and not seek care in health clinics or hospitals and monitor symptoms.
    • Medical care is focused on those who are short of breath, have severe symptoms, or require oxygen and supportive care that is only available in a hospital.
  • In-hospital supportive care
    • Oxygen, mechanical ventilation if needed
    • 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 prophylaxis remains unclear in whom and to what level.
  • Secondary infections, especially in severe/critically ill patients:
    • ICU patients: 13–44%
      • Evaluate and treat bacterial or fungal superinfection (especially Aspergillus)
        • Sputum culture, beta-D-glucan and serum or BAL galactomannan are helpful to incorporate into 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, terminal events?
    • Factors to consider
      • Frequent antibacterial use received in 80–100%
      • Antifungals in 7.5–15

Drug Treatment

  • Caution is advised as to whether proposed drugs that are not sufficiently tested are effective or safe for COVID-19.
    • If a clinical trial is available, consider enrolling patients rather than prescribing off-label drug use to assist in understanding whether intervention is efficacious for COVID-19.
  • If considering off-label use of available medication, consider data known, risks of drug therapy. Many limit considerations only to patients at high risk for serious COVID-19 disease.
  • Johns Hopkins Hospital Therapeutic Guidance (PDF document) (updated 1/13/2022) is available with frequent updates for a more complete discussion of the risks/benefits of FDA-approved, investigational and off-label medications for COVID-19.

Antivirals

  • Remdesivir (RDV)
    • Inpatient Use:
      • Based on the Adaptive Covid-19 Treatment Trial (ACTT-1[12]), RDV appears most beneficial if given 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 benefit but both were open-label, pragmatic trials, 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. U.S. guidelines (NIH, IDSA) continue to endorse; the drug is used infrequently overseas.
      • FDA approved (Oct 2020) for COVID-19 hospitalized patients, ages ≥ 12 yrs or 40 kg.
        • EUA now issued for use in children < 12 yrs, wt 3.5 – 40 kg.
        • Assess sCr, LFTs and PT INR prior to use.
      • Dose: 200 mg IV load on day 1, then 100 mg IV q 24 days 2-5
        • Infuse over 30-120 min.
        • May extend for an additional 5d if no clinical improvement, especially in patients on mechanical ventilation, ECMO or severely immunosuppressed.
        • Carrier (SCED) may accumulate in renal insufficiency, but not judged to be clinically significant, despite warning on 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) prior to enrollment.
        • The mortality trend suggested (8% v 11.6%) but not statistically significant.
        • The benefit appears derived in this trial in patients started on RDV prior to mechanical ventilation.
          • NIH COVID-19 Guideline states BIIa recommendation for severe COVD-19 requiring oxygen but not mechanical ventilation.
        • Investigators concluded that benefit was accrued to patients prior to the need for mechanical ventilation, highly suggestive that this antiviral yields greater benefit the earlier it is initiated.
      • Another RCT, from China, did not show a benefit but did note a mortality trend toward benefit.[13]
      • The Solidarity trial (WHO trial, interim results) had RDV as one of four arms but did not find benefit regarding mortality, LOS or decreasing need for mechanical ventilation.
        • Though large trial, as a pragmatic trial there was no placebo comparator. Also, there were problems with selection and assignment bias, missing data.
    • Mild-moderate COVID-19, (usually ambulatory):
      • RDV was studied in the PINETREE study, 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 who had ≥1 risk factor for severe COVID-19 and ≤7 days of symptoms.
          • Primary outcome = COVID-19-related hospitalization or death 28 days.
            • 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. Adverse events were similar in both arms.
        • Discussion of use heightened by lack of effective monoclonal antibody product supplies against Omicron and wait for oral antivirals.
          • Issues include staffing and proper facility logistics to administer, as an FDA-approved drug it can be used off-label, but unclear if insurers will cover the cost.
    • Outpatient and Inpatient Use:
      • Nirmatrelvir/ritonavir (PAXLOVID)
        • Received EUA approval, but will have limited supplies and distribution in early 2022.
        • 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 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) who have risk factors for severe disease AND have ≤ 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 which 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.
      • Molnupiravir
        • Ribonucleoside prodrug with activity against coronaviruses has received FDA EUA, and distribution is expected in January 2022.
        • 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 (may affect bone and cartilage).
            • It is not authorized for PEP or PrEP.
            • Not recommended in pregnancy or if breastfeeding.

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

  • Fluvoxamine: SSRI that may work by inhibiting viral RNA production or interfering with host cell binding, unclear.
    • Phase 2 data suggested benefit (152 adult outpatients with confirmed COVID-19 and symptom onset within 7 days, clinical deterioration occurred in 0 patients treated with fluvoxamine vs 6 (8.3%) patients treated with placebo over 15 days), unclear mechanism.
    • TOGETHER RCT compared fluvoxamine 100 mg x 10d v. placebo, found fewer in the active arm requiring ED or hospitalization.
      • Limitations include study was performed in Brazil, had ED visit > 6h as part of a primary composite endpoint; currently, insufficient data to recommend for or against.
  • Ivermectin
    • Double-blind, RCT of mild COVID-19 treatment x 5d, without efficacy. Not recommended.
  • 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

  • Many agents under consideration in clinical trials or proposed roles
  • Most initial interest regards anti-IL6 agents, to interrupt hyperinflammatory responses that resemble cytokine-release syndromes and cause lung injury.
  • RCTs are in progress to examine the impact on both the early and late use of such drugs.
  • 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[1] and IDSA[2].

Effect of Dexamethasone on 28−day Mortality by Level of Respiratory Support[25]

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 shown to also be potentially beneficial in other trials and meta-analyses had a summary OR 0.66 on 28d all-cause mortality[11].

  • 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 the treatment of rheumatoid arthritis. See tocilizumab section below for recommendations.
    • FDA EUA approved for ages ≥ 2 yrs COVID-19 in hospitalized adults and pediatric patients requiring supplemental oxygen, invasive mechanical ventilation, or ECMO.
    • ACTT-2 trial compared RDV + baricitinib vs. RDV + placebo
      • The primary endpoint was median time to recovery (defined as discharged from hospital or hospitalized but not requiring supplemental oxygen or ongoing medical care)
        • 7 days for baricitinib + remdesivir compared to 8 days for placebo + remdesivir
          [hazard ratio: 1.15 (95% CI 1.00, 1.31); p=0.047].
      • 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 differs from ACTT-2 trial)
      • The composite primary endpoint (death, progression to high flow O2, NIMV, MV or ECMO) not significant.
      • 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 primary endpoint 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.
  • Interferon 1b
    • RCT from Hong Kong found when used with lopinavir/ritonavir and ribavirin (triple therapy) versus LPV/RTV alone, the triple therapy yielded quicker clinical improvement and reduced viral shedding.
    • Suspect most of the benefits derived from interferon; however, many are hesitant to use since it tends to make people feel terrible
    • Phase II inhaled formulation trial yielded favorable results.
  • 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 have not had positive results.
      • More recent studies with high percentages of patients also on dexamethasone have shown benefit.
        • EMPACTA found less progression to ventilation or death if used prior to 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 who were 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 who are 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 in the same way, except for ICU patients where there are no data to support use.
    • Dosing typically 8 mg/kg x single dose, some repeat if 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.

Antibody-based therapies

Convalescent plasma (CP) or serum-containing neutralizing antibodies against SARS-CoV-2

  • Studies have been mixed regarding effectiveness. Many of the negative RCTs used CP late in the disease course. Positive studies in outpatient and inpatient studies have been used early in the course and used high-titer plasma.
    • FDA EUA (revised 12/28/21) now approves the use of only high-titer convalescent plasma only 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 is found in the FDA letter, using specified test kits.
          • Supply of CP (Jan 2022) very limited, but may improve.
      • Many RCTs remain in progress, but no large trials have yet confirmed benefit although substantial observational data points to subsets of COVID-19 patients who may benefit
        • The subset derived from the expanded access use earlier in 2020 found that the use of high-titer plasma within three days of hospitalization conferred a mortality benefit if received before intubation[4].
        • A small RCT in patients older than 65 years with mild to moderate COVID-19 reduced progression to severe COVID-19 if received within 3 days of onset of illness[5].
        • Retrospective matched cohort study (preprint): 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 were mostly small, underpowered) have not shown mortality benefit to date, although a meta-analysis of observational studies suggests early use does have an impact.
        • RECOVERY trial yielded no 28d mortality benefit; NIH and IDSA Guidance no longer recommends for hospitalized patients.
          • However, positive data suggest early use (< 3d of symptoms or hospitalization), as well as case reports in immunosuppressed illness suggest there remains a role.
      • This author favors use in patients with risk factors for severe COVID-19 if early in illness course and patients are immunosuppressed (especially with impaired B-cell responses).
  • RCTs for prophylaxis, early and late COVID-19 treatment are in progress.[41]
    • RCT (preprint) of 1225 randomized for early COVID, ambulatory high-titer convalescent plasma therapy with the primary endpoint of hospitalization within 28d.
      • 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 appears to have some activity against Omicron (see NIH variant and agent activity chart for latest updates), and Omicron-recovered donors would expect activity to be higher activity.
  • 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 lower if routine donor screening includes HLA antibody screening of female donors with a history of pregnancy

Monoclonal antibodies (mAbs) specific to SARS-CoV-2 against spike protein, in the U.S. are only offered to outpatients with mild-moderate COVID-19. Trials in hospitalized patients have shown benefit in seronegative patients; however, they do not yet have a EUA by the FDA if hospitalized for COVID-19 pneumonia.

  • EUAs issued by the FDA for outpatient therapy of COVID-19, treatment for mild-moderate COVID-19 in outpatients, not hospitalized patients at high risk for complications of COVID-19 (see below for qualifying conditions).
    • Bamlanivimab/etesevimab and Casirivimab and imdevimab have had distribution paused by HHS in the U.S. due to lack of sufficient activity against the Omicron variant.
    • Sotrovimab: single mAb that has activity against VOCs as mab is directed against a highly conserved portion of the spike protein receptor-binding domain. EUA granted 5/21/21 for outpatients with risk factors based on 1% vs 7% placebo hospitalization or death (85% reduction).
      • FDA Fact sheet
      • 500 mg IV infused over 30 minutes.
      • Described as retaining activity against Omicron variant.
        • Supplies are currently limited.
  • Criteria for Identifying High-Risk Individuals: the following 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:
    • Older age (for example, age ≥65 years of age)
    • Obesity or being overweight (for example, BMI >25 kg/m2, or if age 12-17, have BMI ≥85th percentile for their age and gender-based on CDC growth charts).
    • Pregnancy
    • Chronic kidney disease
    • Diabetes
    • Immunosuppressive disease or immunosuppressive treatment
    • Cardiovascular disease (including congenital heart disease) or hypertension
    • Chronic lung diseases (for example, chronic obstructive pulmonary disease, asthma [moderate-to-severe], Interstitial lung disease, cystic fibrosis and pulmonary hypertension)
    • Sickle cell disease
    • Neurodevelopmental disorders (for example, cerebral palsy) or other conditions that confer medical complexity (for example, genetic or metabolic syndromes and severe congenital anomalies)
    • Having a medical-related technological dependence (for example, tracheostomy, gastrostomy, or positive pressure ventilation [not related to COVID-19])

Prevention

  • Data regarding appropriate interventions continue to evolve and generate great debate (e.g., the U.S.).
    • Travel restrictions, quarantines, school/work closings, social distancing are helpful to lower Ro (contagiousness of infection), but the degree of mitigation remains a source of considerable debate among public health officials and politicians.[14]
    • Difficulty sorting other causes of respiratory illness from the novel coronavirus, especially during influenza season. Co-infections are possible (viral, bacterial, fungal).
  • General measures recommended:
    • Avoid sick individuals.
    • Wash hands with soap and water x 20 seconds before eating, after cough/sneezing or bathroom visits.
    • Social distancing maneuvers include keeping spacing >6 feet from other people.
    • Masks are now universally 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: See JHMI Clinical Guidance for COVID-19 Pre- and Post-Exposure Prophylaxis (PDF document) for additional details and data.
    • Post-exposure prophylaxis (PEP):
    • Pre-exposure prophylaxis (PrEP):
      • Tixagevimab/cilgavimab (Evusheld) received FDA EUA for individuals ≥ 12 years of age/≥40 kg AND who are moderate to severely immunocompromised, and not expected to have an adequate response to vaccines. This PrEP mab combination is not a substitute for immunization.
        • Examples: solid-organ transplant pts, active malignancies, bone marrow transplant pts on immunosuppressive or within 2 years of transplant, advanced HIV/AIDS, active treatment with high-dose corticosteroids (i.e., ≥20 mg prednisone or equivalent per day when administered for ≥2 weeks), alkylating agents, antimetabolites, transplant-related immunosuppressive drugs, cancer chemotherapeutic agents classified as severely immunosuppressive, tumor-necrosis (TNF) blockers, and other biologic agents that are immunosuppressive or immunomodulatory (e.g., B-cell depleting agents)
        • AND not expected to mount an adequate response to COVID-19 vaccination OR COVID-19 immunization contraindicated.
      • Given two IM injections, the expected duration of protection is 6 months.
        • Supply is limited in late 2021/early 2022 and allocated by HHS to states for distribution. Check your state health department for details.
      • This monoclonal combination has some in vitro activity against Omicron, but the clinical trial was concluded earlier in 2021.
        • PROVENT trial randomized 5,197 using a 2:1 ratio for one dosing of AZD7442 (Evusheld) 300 mg IM or placebo.
          • At 6 months, preliminary results reported, AZD7442 reduced the risk of symptomatic COVID-19 by 83%. No severe COVID-19 or deaths occurred in the active arm whereas 5 severe cases and 2 deaths were in the placebo group.

Vaccines

  • Multiple vaccines worldwide. Three used in the U.S. have modules in this guide.
    • Initial high efficacy of 94-95% for the mRNA vaccines are now lower due to the Delta and Omicron variants; however, remain effective in reducing hospitalization or death from COVID-19.
      • Booster doses are recommended for ages ≥ 12 years, which improves vaccine efficacy against the Omicron variant.
        • Efficacy improved in preliminary reports 80-88% for prevention of infection and hospitalization.
    • FDA has fully approved Pfizer/BioNTech for two doses, and Moderna COVID-19 has a EUA.
      • See vaccine modules for details including third-dose information (immunocompromised patients) and booster recommendations.
        • Pfizer now has a EUA for 5- to 11-year-old groups, in addition to 12-15 years.
          • 12-15 years now eligible for booster doses.
      • Both appear to retain excellent protection against variants of concern including P.1, B.1.357, B.1.617.2 (delta).
      • Pfizer/BioNTech vaccine approved for use in ages 16 and older. Ages 12-15 have a EUA, and ages 5-11 also a EUA but using a one-third dose (10 µg).
  • Select other vaccines in use in other countries or under consideration by the FDA
    • AstraZeneca/Oxford ChAD vaccine with inadvertent lower half-dose as dose #1 followed by full dose = 90% efficacy, whereas designed dosing yielded 62% percent efficacy, though recent 1-dose efficacy x 3 months is cited as 76% effective.
      • Appears to not work well against the viral variant identified in S. Africa (B.1.357) but has better protection with the delta variant.
    • JNJ/Janssen adenovirus vaccine with FDA EUA also appears protective against severe COVID-19. It is no longer a recommended vaccine by ACIP except in people who cannot receive one of the mRNA vaccines (e.g., due to anaphylactic reactions).
      • Originally a one-dose vaccine, with a second dose, now recommended.
      • Cited as 66% overall effective
        • 72% in the U.S., 66% in Latin America, 57% in S. Africa.
        • 85% effective at preventing severe COVID-19.
      • Rare clots described, with pause suggested by FDA/CDC (4/12/21, subsequent resumption)
    • Other vaccines have been employed in countries such as China, UAE, Brazil.
      • Multiple sources for updates include WHO and ACIP.

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, CVA also appear with unusual frequency.
    • Unclear if COVID-19-associated incidence of venous thromboembolism is higher than what is reported customarily in ICU populations despite prophylaxis (~8-9%) as only "high incidence" centers reporting.
  • HLH-like changes were described in a subset of patients who died, autopsy findings.
  • CNS: Encephalitis (rare) or encephalopathy (uncommon, more in elderly)
  • Cardiac: myocarditis (transient and also more severe)
  • 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.
    • Wuhan’s experience suggested a 10–20% incidence of bacterial and fungal infections, with a higher percentage in patients who died.
    • Anecdotal experiences growing regarding concern for the development of pulmonary aspergillosis.

Selected Drug Comments

Drug

Recommendation

Bamlanivimab/etesevimab

Distribution paused by HHS due to lack of activity against the Omicron variant.

Baricitinib

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. Recent 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 not significant. 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 primary endpoint not reached, no difference in groups regarding clots, MIs, CVA, etc.). Impressive mortality reduction; however, the study was more international than in the US and only a minority received RDV.

Casirivimab imdevimab

Distribution paused by HHS due to lack of activity against the Omicron variant.

COVID-19 Convalescent Plasma

Still waiting for large RCT to confirm hospital use, however many trials used the agent late (e.g., RECOVERY, others). Convalescent plasma works best as an antiviral. Current FDA EUA for hospitalized patients now enforces the use of high-titer plasma. Best used if within 3 days of illness onset or first three days of hospitalization. May also have a role in immunosuppressed populations.

Dexamethasone

The RECOVERY trial provides the first evidence of therapy that provides a mortality benefit to those who are 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 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 less clear. Also, patients with less than 7d of symptoms appeared to not benefit, suggesting that during the early phase of viral illness there is no impact or potential harm (similar to influenza) but the benefit is seen with 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.

Hydroxychloroquine

The antimalarial and antiinflammatory has not been shown in large randomized trials to yield benefit in the treatment of COVID-19 in hospitalized patients (RECOVERY trial), and concerns raised about cardiotoxicities in critically ill patients. It also appears to not offer prevention after exposure.[24] The drug is not recommended by any mainstream experts or authorities.

Molnupiravir

High hopes for this nucleoside analog; however, 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. Concerns about mutagenesis and driving new viral variants with high levels of use have been voiced as concerns by some, although with only a five-day course, the mutagenesis concern seems lower. Regardless, this drug is clearly in a lower tier than PAXLOVID or sotrovimab; however, it is likely the only outpatient drug easily available in early 2022. The drug should not be used in children, adolescents, pregnant and breastfeeding women.

Nirmatrelvir/ritonavir

A combination drug is an oral protease inhibitor that has activity against SARS-CoV-2. Preliminary results from the outpatient COVID-19 trials are impressive; 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 will diminish the potential to help with the Omicron surge. The use of ritonavir means that prescribers should take a careful assessment of drug-drug interactions.

Remdesivir

The ACTT1 results 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. 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. Overall, many in the 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 both prospective and a number of retrospective, matched control studies.

Sotrovimab

Single mAb that preliminary data showing 85% reduction in death or hospitalization for patients receiving it for mild-moderate COVID-19 as outpatients prompted the FDA to issue EUA (5/24/21). Appears to retain activity against delta and omicron variants.

Tixagevimab/cilgavimab

Better known by its trade name Evusheld, and previously called AZD7422, appears effective it reported preliminary results for PrEP with an 83% reduction in symptomatic COVID-19 when alpha and delta variants were commonplace. The monoclonal have an altered Fc that allows for extended half-life and therefore offers protection x 6 months. There is some in vitro activity against Omicron, hence why the distribution is moving ahead, although supply is limited in early 2022. The drug is only for immunosuppressed patients who are expected to not mount adequate vaccine responses or people who cannot receive vaccines due to severe reactions. The drug takes two weeks to have adequate tissue levels and protective effect, so it is not useful for COVID-19 treatment or PEP.

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 appears to have an impact on reducing severity and duration of illness as well as reducing 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.

FOLLOW UP

OTHER INFORMATION

Basis for recommendation

  1. NIH COVID-19 Treatment Guidelines. https://www.covid19treatmentguidelines.nih.gov/ (accessed 1/4/22)

    Comment: Revised regularly with updates. The format now includes updated reference tables for some drugs. Informs much of the basis for RDV, dexamethasone, tocilizumab and baricitinib use discussed. Recent EUAs for mAb casirivimab/imdevimab and bamlanivimab/etesevimab for post-exposure prophylaxis were endorsed.

  2. Bhimraj A, et al. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19 [accessed 1/14/22]

    Comment: Regularly updated, and generally in concert with the NIH GL. One major area where our guide differs is in convalescent plasma use that we believe has a role for early illness in hospitalized patients (< 3d) or in some severely immunosuppressed patients who cannot generate meaningful antibody responses.

  3. Hanson KE. Infectious Diseases Society of America Guidelines on the Diagnosis of COVID-19, last updated 5/27/21, [accessed 1/14/22]. [https://www.idsociety.org/practice-guideline/covid-19-guideline-diagnostic...]

    Comment: Helpful guidance including the suggestion that lower tract specimens (if performed with a validated assay) may be more sensitive than the traditional nasopharyngeal swab, though the evidence is limited. Rapid testing, including antigen and serology also addressed. Also, look at CDC for diagnostic guidance information.

References

  1. 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.  [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 compared to patients who got low titer plasma.

  2. 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.  [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 6 patients who had 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.

  3. Gottlieb RL, Nirula A, Chen P, et al. Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19: A Randomized Clinical Trial. JAMA. 2021.  [PMID:33475701]

    Comment: Interim results from the ongoing BLAZE-1 trial showing that combination therapy of these mAbs resulted in decreased viral load and less need for hospitalization.

  4. Korley FK, Durkalski-Mauldin V, Yeatts SD, et al. Early Convalescent Plasma for High-Risk Outpatients with Covid-19. N Engl J Med. 2021.  [PMID:34407339]

    Comment: The use of 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).

  5. O'Brien MP, Forleo-Neto E, Musser BJ, et al. Subcutaneous REGEN-COV Antibody Combination to Prevent Covid-19. N Engl J Med. 2021.  [PMID:34347950]

    Comment: This RCT enrolled 12 yrs and older with close household contact with COVID-19 within 96h of the index person receiving the COVID-19 diagnosis. SQ dosing was x one at 600 mg/600 mg. Symptomatic infection was seen in 11/753 (1.5%) vs. 59/752 (7.8%) on the placebo group. The relative risk reduction [1 minus the relative risk], 81.4%; P< 0.001). This appears to be an effective intervention for those at high risk with exposure (unimmunized) but would also consider in the immunized in the advanced elderly, immunosuppressed especially.

  6. 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, important 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.

  7. 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.

  8. 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.  [PMID:32876694]

    Comment: 7 randomized trials that included 1703 patients of whom 647 died, 28-day all-cause mortality was lower among patients who received corticosteroids compared with those who received usual care or placebo (summary odds ratio, 0.66). Dexamethasone and hydrocortisone had a similar impact while the single methylprednisolone trial had less effect on mortality.

  9. 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.

  10. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020;395(10236):1569-1578.  [PMID:32423584]

    Comment: Unimpressive trial, but the drug may have been given to late to too ill a population.
    N = 237 patients, halted
    Confirmed infection, 12d or fewer of symptoms, lung involvement
    Remdesivir 200 mg d 1 then 100 mg IV daily vs. placebo
    Findings:
    1. No clinical improvement (subgroup < 10d with trend)
    2. No difference in mortality (subgroup < 10d with trend)
    3. No effect on viral load in upper or lower respiratory tracts

  11. Chinazzi M, Davis JT, Ajelli M, et al. The effect of travel restrictions on the spread of the 2019 novel coronavirus (COVID-19) outbreak. Science. 2020.  [PMID:32144116]

    Comment: Although extraordinary measures may have slowed or stopped COVID-19 in China, questions remain whether this is durable and at what cost to society? It may buy time but effective drugs or vaccines remain in the far future it seems. Authors suggest "the travel quarantine of Wuhan delayed the overall epidemic progression by only 3 to 5 days in Mainland China, but has a more marked effect at the international scale, where case importations were reduced by nearly 80% until mid-February. Modeling results also indicate that sustained 90% travel restrictions to and from Mainland China only modestly affect the epidemic trajectory unless combined with a 50% or higher reduction of transmission in the community."

  12. Mizumoto K, Chowell G. Estimating Risk for Death from 2019 Novel Coronavirus Disease, China, January-February 2020. Emerg Infect Dis. 2020;26(6).  [PMID:32168464]

    Comment: An early report and these typically have higher rates of infection due to concentrated, very ill patients than later in epidemics. Authors estimate of the risk for death in Wuhan reached values as high as 12% in the epicenter of the epidemic and ≈1% in other, more mildly affected areas. The elevated death risk estimates are probably associated with a breakdown of the healthcare system.

  13. Liu W, Zhang Q, Chen J, et al. Detection of Covid-19 in Children in Early January 2020 in Wuhan, China. N Engl J Med. 2020.  [PMID:32163697]

    Comment: A retrospective look at 366 children hospitalized for respiratory illness. SARS-CoV-2 detected only in 6 (1.6) of patients. Only 1 of the COVID children required ICU care. Of the COVID patients, fever and cough were common and four had pneumonia.

  14. Shen C, Wang Z, Zhao F, et al. Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA. 2020.  [PMID:32219428]

    Comment: A small study of 5 patients who required mechanical ventilation who appeared to benefit from convalescent plasma containing neutralizing antibodies, though also received methylprednisolone and putative antiviral therapies directed against SARS-CoV-2 infection. Authors suggest that many parameters improved including in the 4 ARDS patients.

  15. Bourouiba L. Turbulent Gas Clouds and Respiratory Pathogen Emissions: Potential Implications for Reducing Transmission of COVID-19. JAMA. 2020.  [PMID:32215590]

    Comment: Wading into the aerosol v. droplet debate, the suggestion that forceful uncovered sneezes may cause infectious droplets to go beyond the 6 ft range currently advised by the CDC. This concern has prompted universal mask wear for HCWs, but also for the general public. There may be people who are not ill and therefore sneeze or cough, asymptomatic shedding and dispersing virus.

  16. 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.  [PMID:32213556]

    Comment: Paper suggests that some patients presented with GI symptoms as part of COVID-19, 11.4% of 651 in this study from Zheijiang 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.

  17. Giacomelli A, Pezzati L, Conti F, et al. Self-reported olfactory and taste disorders in SARS-CoV-2 patients: a cross-sectional study. Clin Infect Dis. 2020.  [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.

  18. Lescure FX, Bouadma L, Nguyen D, et al. Clinical and virological data of the first cases of COVID-19 in Europe: a case series. Lancet Infect Dis. 2020.  [PMID:32224310]

    Comment: Series of only five patients from France; however, the descriptions of three potential phenotypes may offer insights into different viral- and Immuno-pathogenesis. 1. Paucisymptom patient: nasopharyngeal high viral titer (and virus in feces), 2. Symptoms then decompensation (~day 10, respiratory decompensation): low viral titer compared to earlier in nasopharyngeal samples and 3. Clinical progression/death: high viral titers in upper and lower respiratory samples plus persisting viremia.

  19. Guo L, Ren L, Yang S, et al. Profiling Early Humoral Response to Diagnose Novel Coronavirus Disease (COVID-19). Clin Infect Dis. 2020.  [PMID:32198501]

    Comment: Authors used a nucleocapsid-based antibody for the detection of antibodies against SARS-CoV-2. IgM and IgA antibodies were found 5 days (IQR 3-6) after symptom onset, while IgG was detected on 14 days (IQR 10-18). Positive responses overall were seen as IgM 85.4%, IgA 92.7% and IgG 77.9% respectively. Considering both confirmed and probable cases, the positive rates of IgM antibodies were 75.6% and 93.1%, respectively. The detection efficiency by IgM ELISA is higher than that of qPCR method after 5.5 days of symptom onset. The positive detection rate is significantly increased (98.6%) when combined IgM ELISA assay with PCR for each patient compare with a single qPCR test (51.9%).

  20. Long QX, Tang XJ, Shi QL, et al. Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections. Nat Med. 2020.  [PMID:32555424]

    Comment: 37 asymptomatic individuals displayed longer viral shedding, less cytokine generation and less serological responsiveness.
    Asymptomatic 93.3% (28/30) and 81.1% (30/37) had less IgG and neutralizing Abs
    ‒In comparison , 96.8% (30/31) and 62.2% (23/37) of symptomatic patients.
    -40% asymptomatic seronegative vs. 12.9% of the symptomatic group during convalescence
    §Protective immunity may not be long-lived

  21. Boulware DR, Pullen MF, Bangdiwala AS, et al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N Engl J Med. 2020.  [PMID:32492293]

    Comment: HCQ did not appear to prevent illness consistent with COVID-19 in patients with moderate or high-risk exposure to the virus when started within four days of the exposure.

  22. RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report. N Engl J Med. 2020.  [PMID:32678530]

    Comment: Pragmatic trial and also important 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 greatest absolute reductions in 28-day mortality were seen in the sickest patients, and subgroup analysis suggests in those > 7d of symptoms which would correlate with the inflammatory phase. Dexamethasone improves 28d mortality compared to placebo in patients requiring IMV (NNT = 8.5) and those patients requiring oxygen therapy (NNT = 29). There was no benefit to patients not requiring oxygenation support and even a signal for harm.

  23. Zhu N, Zhang D, Wang W, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020.  [PMID:31978945]

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

  24. Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020.  [PMID:32015507]

    Comment: Authors have sequenced what is now termed SARS-2-CoV. Its genome 79.5% sequence identify to SARS-CoV. Furthermore, it was found that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus.

  25. 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.  [PMID:32031570]

    Comment: One of the initial major reports of the Wuhan COVID-19 epidemic. In this series, the median age was 56 and slightly more men (54%) 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%]).

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

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

  27. Kam KQ, Yung CF, Cui L, et al. A Well Infant with Coronavirus Disease 2019 (COVID-19) with High Viral Load. Clin Infect Dis. 2020.  [PMID:32112082]

    Comment: No surprise, here an infant sheds high levels of the virus but is without symptoms. Children are well known "vectors" of viral infection often without significant disease is well known for regular coronavirus infections, influenza and others.

  28. Weinreich DM, Sivapalasingam S, Norton T, et al. REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19. N Engl J Med. 2020.  [PMID:33332778]

    Comment: Interim analysis of the mAb product studied among 275 outpatients with mild-moderate COVID-19. In the overall trial population, 6% of the patients in the placebo group and 3% of the patients in the combined REGN-COV2 dose groups reported at least one medically attended visit; among patients who were serum antibody–negative at baseline, the corresponding percentages were 15% and 6% (difference, −9 percentage points; 95% CI, −29 to 11). No differences were seen in the active arm compared to placebo for adverse reactions.

  29. 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.  [PMID:32821939]

    Comment: Though the open-label trial 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 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 included.

  30. Wölfel R, Corman VM, Guggemos W, et al. Virological assessment of hospitalized patients with COVID-2019. Nature. 2020.  [PMID:32235945]

    Comment: A small but well-conducted study looking at 9 cases with most patients on day 1 having mild or prodromal symptoms. Key findings include finding 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 stool. Viral RNA remained in 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 offers proof that illness may also present as a routine upper respiratory tract infection without pneumonia or lower tract symptoms.

  31. Grein J, Ohmagari N, Shin D, et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med. 2020.  [PMID:32275812]

    Comment: Early experience with this antiviral in severe COVID-19 illness, found that there was an improvement in 36 of 53 patients (68%). Seven patients (13%) died; mortality was 18% (6 of 34) among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation. The lack of a control arm makes this number difficult to understand whether the drug is helpful. As authors indicate, there is a need to await RCT data.

  32. Kim D, Quinn J, Pinsky B, et al. Rates of Co-infection Between SARS-CoV-2 and Other Respiratory Pathogens. JAMA. 2020.  [PMID:32293646]

    Comment: 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 1 or more non–SARS-CoV-2 pathogens. WIthin the SARS-CoV-2 positive specimens, 24 (20.7%) were positive for 1 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 seen with many standard respiratory viral illnesses. Importantly, this means that finding a virus other than the SARS-CoV-2 should not be grounds for concluding that COVID-19 is not present.

  33. Chow EJ, Schwartz NG, Tobolowsky FA, et al. Symptom Screening at Illness Onset of Health Care Personnel With SARS-CoV-2 Infection in King County, Washington. JAMA. 2020.  [PMID:32301962]

    Comment: Syndromic screening that used fever and respiratory symptoms failed to detect SARS-CoV-2 infection (often at high titer) in 17% of HCWs presenting for assessment. While limited testing has forced decisions to screen people at a higher likelihood of infection, the wide range of potential COVID-19 infection means that some may unknowingly work and spread the virus. This no doubt is one reason the virus has spread so rapidly.

  34. Grasselli G, Zangrillo A, Zanella A, et al. Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy. JAMA. 2020.  [PMID:32250385]

    Comment: A large critical care experience derived from Northern Italy had 1591 patients who 68% had 1 comorbidity and 82% were male. Mortality as of the 3/25/20 writing date was 26%.

  35. Liu Y, Ning Z, Chen Y, et al. Aerodynamic analysis of SARS-CoV-2 in two Wuhan hospitals. Nature. 2020.  [PMID:32340022]

    Comment: An entry into the PRO potential for routine aerosolization of SARS-CoV-2. Viral RNA (unclear if infectious) found in toilet areas but not in ventilated isolation words. Levels also seen in areas prone to crowing including medical staff areas.

  36. Borba MGS, Val FFA, Sampaio VS, et al. Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial. JAMA Netw Open. 2020;3(4):e208857.  [PMID:32339248]

    Comment: High dose CQ suggested to contribute to mortality. 440 patients, 81 were enrolled (41 [50.6%] to a high-dosage group and 40 [49.4%] to low-dosage group). Enrolled patients had a mean (SD) age of 51.1 (13.9) years, and most (60 [75.3%]) were men. Older age (mean [SD] age, 54.7 [13.7] years vs 47.4 [13.3] years) and more heart disease (5 of 28 [17.9%] vs 0) were seen in the high-dose group. Viral RNA was detected in 31 of 40 (77.5%) and 31 of 41 (75.6%) patients in the low-dosage and high-dosage groups, respectively. Lethality until day 13 was 39.0% in the high-dosage group (16 of 41) and 15.0% in the low-dosage group (6 of 40). The high-dosage group presented more instances of QTc interval greater than 500 milliseconds (7 of 37 [18.9%]) compared with the low-dosage group (4 of 36 [11.1%]). Respiratory secretion at day 4 was negative in only 6 of 27 patients (22.2%).

  37. Chen T, Wu D, Chen H, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ. 2020;368:m1091.  [PMID:32217556]

    Comment: Patients in this Chinese retrospective study were older (median 68 yrs), male (73%) and had cardiovascular disease, including hypertension. While ARDS was common, acute cardiac injury and heart failure were also felt to contribute to high mortality.

  38. Cheng Y, Wong R, Soo YO, et al. Use of convalescent plasma therapy in SARS patients in Hong Kong. Eur J Clin Microbiol Infect Dis. 2005;24(1):44-6.  [PMID:15616839]

    Comment: SARS paper that may inform COVID-19 infection. Benefit from convalescent plasma for treatment suggested by earlier discharge.

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