Coronavirus COVID-19 (SARS-CoV-2)

Paul G. Auwaerter, M.D.

Updated: February 14, 2021

MICROBIOLOGY

CLINICAL

Epidemiology

Transmission

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

  1. Mean incubation 4–5 days, range 2–14
  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​.
      2. A limited number of persons with severe 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. 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 viral RNA may be detected long after for many weeks; hence, why repeated routine testing for negative SARS-CoV-2 RT-PCR no longer recommended).
    • 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 certainly < 20 may indicate an infectious virus is present.
  4. Some accumulating data suggest that high viral inoculum may lead to increased risk for disease severity.

Symptoms

Less common symptoms:

Disease spectrum

Laboratory and imaging findings

  • In COVID-19 pneumonia
    • Leukopenia in ~70% of 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 ’21-’22 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.
      • 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 a cytokine release syndrome-like picture and impending 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.
    • Multiplex testing will be available for the 2020-2021 respiratory season; however, unclear how many units available to institutions and if used as first-line or tests used in another capacity.
  • 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 remain insufficient in many locations with delays in turnaround for molecular testing. Additional information through CDC.
    • Exact sensitivity not known; however, the general feeling is that they may miss 20–30% depending on technique and timing of illness, so repeat swab needed if high suspicion. Lower respiratory tract samples are noted to have higher yields.
    • 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.
  • 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 may range as high as 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; 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 needed to generate a positive assay.
      • Role is best for quick assessment in situations of congregate living, need for fast identification of an outbreak.
        • Repeated testing will increase the risk of false positives but generally can trust a positive to indicate infection.
      • Symptomatic people who test negative by antigen still require follow-up molecular testing.
    • Use for the screening of asymptomatic people is increasing but data are limited. 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?")
      • 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.
    • Not recommended as the sole basis for diagnosis. Therefore currently available assays do not equate with an "immunity passport" if positive, unclear if they 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, with 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 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).
  • 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 (mostly China, NY hospital reports)
      • Frequent antibacterial use received in 80–100%
      • Antifungals in 7.5–15

Drug Treatment

  • Many types of drugs are under investigation including antivirals, immunomodulators, and surface protein antagonists such as lecithins.
  • Caution is advised as to whether the proposed drugs are effective or safe for COVID-19.
  • If a clinical trial 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) is available with frequent updates for a more complete discussion of risks/benefits of investigational and off-label medications for COVID-19.

Antivirals

  • Remdesivir (RDV)
    • Based on the Adaptive Covid-19 Treatment Trial (ACTT-1[10]), 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.
    • 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.
      • Carrier may accumulate in renal insufficiency, but not judged to be clinically significant.
    • 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 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.[12]
    • 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.
    • Most in the U.S. continue to use RDV.

Other candidate antiviral therapies: only widely discussed drugs listed below

  • Fluvoxamine
    • Phase 2 data suggested benefit, unclear mechanism. Awaiting a larger, well-designed trial to evaluate. Insufficient data to recommend for or against.
  • Ivermectin
    • Phase 2 trial may have benefit, awaiting larger well-desiugned trial to confirm. Insufficient data to recommend for or against.
  • Lopinavir/ritonavir (LPV/RTV)
    • COVID-19 RCT in hospitalized patients (RECOVERY) who also received other medications yielded no benefit but was given relatively late in the disease course
  • Chloroquine (CQ) or hydroxychloroquine (HCQ)
    • Based on the arm of the RECOVERY trial showing no clinical benefit, and other clinical data with cardiotoxicity concerns
  • Among other investigational agents in trials of note: EIDD-2801 (oral), AT-527 (oral).

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[9].

  • Baricitinib: an oral JAK1/JAK2 inhibitor that is FDA approved for the treatment of rheumatoid arthritis.
    • 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.
    • Role in COVID-19 care uncertain, many continue to use dexamethasone for this group.
    • 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 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 agent 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 (preprint) found that patients on high flow oxygen or within the first 24 hours of ICU care contributed most significantly more days of organ free survival (10d compared to placebo) and decreased mortality.
        • RECOVERY (pre-print) found patients who were on oxygen with evidence of systemic inflammation (e.g., CRP > 7.5), had improved survival, and more likely to be discharged by day 28.
      • IDSA and NIH Guidelines not yet recommended use except in a clinical trial.
    • Dosing typically 8 mg/kg x single dose
  • Other potential drugs under discussion or study; some use anecdotally reported:
    • Anakinra (anti-IL1)
    • anti-GM-CSF
    • GM-CSF

Antibody-based therapies

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

  • Proposed as a useful treatment, no large RCT yet to show benefit.
    • NIH Guidelines say there is neither strong data for or against its use.
    • FDA EUA (revised 2/4/21) now approves the use of only high-titer convalescent plasma.
      • See the FDA fact sheet for healthcare providers for detailed information.
      • 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 use of high titer plasma within three days of hospitalization conferred a mortality benefit if received before intibuation[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].
        • Many RCTs published in 20202 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[45].
      • Single-patient eIND (updated 11/16/20) also remains available.
      • This author favors use in patients with risk factors for severe COVID-19 if early in illness course or if patients are immunosuppressed (especially with impaired B-cell responses).
  • RCTs for prophylaxis, early and late COVID-19 treatment are in progress.
  • Prior treatment studies
  • 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 specific to SARS-CoV-2, in U.S. only offered to outpatients with mild-moderate COVID-19. Trials in hospitalized patients have not yielded benefit to date.

  • Three EUAs issued by the FDA for outpatient therapy of COVID-19.
    • Bamlanivimab: single neutralizing IgG1κ mAb directed against the SARS-CoV-2 spike (S) protein, which is described to block viral entry.
      • Only offered to patients ≥ 12 yrs at high risk for COVID-19 hospitalization or complications.
      • Dose: SIngle 700 mg/kg IV infusion of one hour.
      • Benefits cited by the FDA from the BLAZE-1 trial include decreased ED and hospitalizations compared to placebo.
        • NIH Guideline cites insufficient data for a recommendation, IDSA Guideline doesn’t recommend.
    • Bamlanivimab and etesevimab: two neutralizing mAb against the surface spike protein of SARS-CoV-2.
      • Only offered to patients ≥ 12 yrs at high risk for COVID-19 hospitalization or complications.
      • Dose: single infusion of bamlanivimab 700 mg IV and etesevimab 1,400 mg IV
        • Infusion time is decreased to 30 minutes compared to the one hour of other products.
      • Benefits cited by FDA include the BLAZE-1[6] and BLAZE-4 trial showing decreased medical utilization in recipients.
    • Casirivimab and imdevimab: two neutralizing mAb against the surface spike protein of SARS-CoV-2.
      • Only offered to patients ≥ 12 yrs at high risk for COVID-19 hospitalization or complications.
      • Dose: 1200 mg of casirivimab and 1200 mg of imdevimab administered together as a single intravenous infusion over at least 60 minutes.
      • Benefits cited are decreased need for hospitalization or ED visits (6% placebo, 3% in mAb arm)[32].
  • Bamlanivimab (ACTIV-3) and Casirivimab + imdevimab trials in hospitalized patients halted due to a lack of effect.
  • Viral variants, especially B.1.357, existing mAb therapy is not effective due to mutations in the spike protein.
  • Intravenous immunoglobulin (IVIG)
    • Proposed as an intervention in the setting of viral-induced lung injury/ARDS that appears to be due to disordered regulatory T cells with a hyperimmune response
    • Better characterized in influenza-related ARDS, but COVID-19 appears similar.
    • Pooled IVIG reduces immune responses through multiple mechanisms including lessening interrupting complement cascade, lessening activated CD4+ and cytotoxic CD8+ T cells.
    • No large clinical trial data to back use.

Prevention

  • As a newly described virus, much remains to be learned.
    • 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.[13]
    • Difficulty sorting other causes of respiratory illness from the novel coronavirus, especially during influenza season. Co-infections possible (viral, bacterial, fungal).
  • Healthcare workers and health systems in the U.S.
    • Recommend following CDC Guidance for Risk Assessment and Public Health Management of SARS-CoV-2[46]
    • Debate exists whether standard contact and respiratory droplet precautions are sufficient (as with SARS, MERS) versus aerosol/airborne precautions.
      • Current CDC recommendations are for aerosol (e.g., use of negative pressure isolation) airborne precautions.
  • 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 now universally recommended when in public.
    • Don’t touch the face, eyes, etc.
    • Stay home if ill.
    • Cover your sneeze.
    • Disinfect frequently touched household objects.

Vaccines

  • Multiple candidate vaccines are in development.
    • Preliminary data from mRNA vaccines are highly promising (94-95% efficacy including avoiding severe COVID-19) and have led to the FDA EUAs for two vaccines: Pfizer/BioNTech and Moderna COVID-19 vaccines.
    • mRNA vaccines in the U.S. with Emergency Use Authorizations (see individual modules for details):
  • 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 viral variant identified in S. Africa (B.1.357).
    • JNJ adenovirus vaccine is furthest along in clinical trials and may have data for analysis in Feb 2021 and FDA consideration.
      • One-dose vaccine
      • Cited as 66% overall effective
        • 72% in U.S., 66% in Latin America, 57% in S. Africa.
        • 85% effective at preventing severe COVID-19.
    • 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 using low-molecular-weight heparin for prevention; others calling against, citing paradoxical clotting.
    • MI, CVA also appear with unusual frequency.
    • Unclear if COVID-19-associated incidence of venous thromboembolism higher than what is reported customarily in ICU populations despite prophylaxis (~8-9%) as only "high incidence" centers reporting.
  • HLH-like changes 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 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

As of Feb 2021, now has EUA approval use in conjunction with a second monoclonal antibody, etesevemab. This combination appears to decrease the need for medical visits and hospitalization. Best if used early, and approved only for high-risk populations over the age of 12 years.

One of the monoclonal antibodies directed against the S protein of SARS-CoV 2. This is a single antibody that has an FDA EUA for mild-moderate COVID-19, but when supplies are exhausted, the manufacturer is not making more, Instead, it is exploring a two-mAb drug noted above. The BLAZE-1 trial as a phase 2 trial did not reach its virological primary endpoint. FDA decided on EUA for a numeric decline in ED visits and hospitalizations compared to placebo. The drug is only for patients at high risk for severe COVID-19. Bamlanivimab is given by IV infusion, usually at limited centers in most states that have a referral or triage system. The drug is not to be used for hospitalized patients as outcomes appear to be worse. Studies for prophylaxis upon close contact are in progress. NIH COVID-19 Guideline states there are insufficient data to make a recommendation.

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). However, place in treatment uncertain and is the focus of the ACTT-4 trial starting in Jan 2021, RDV + barcitinib vs. RDV + dexamethasone. The drug might be considered for use in patients who cannot receive dexamethasone but who require high-flow oxygen or non-invasive ventilation.

Casirivimab imdevimab

Two monoclonal antibodies that have a similar FDA EUA indication for mild-moderate outpatient COVID-19. The published trial suggested a decrease in medical visits with use, which was the basis for emergency approval. In the overall trial population of 275 patients, 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). Adverse reactions were not notably different in the arms. NIH COVID-19 Guideline states there are insufficient data to make a recommendation. The use of the product has similar logistics as bamlanivimab.

COVID-19 Convalescent Plasma

Still waiting for large RCT to confirm 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.

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. Although August FDA EUA expanded use to all hospitalized patients, there is no compelling data to use it in patients without oxygen needs are who are critically ill at the start of therapy.

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 reduced mortality in three studies: EMPACTA, REMAP-CAP and RECOVERY (last two are still in preprint, not yet peer-reviewed)

FOLLOW UP

OTHER INFORMATION

See also

Basis for recommendation

  1. NIH COVID-19 Treatment Guidelines. https://www.covid19treatmentguidelines.nih.gov/ (last updated 2/3/21 accessed 2/10/21)

    Comment: The most important drug recommendations below but also handles multiple issues arising in patients with COVID-19.
    NIH panel recommends:
    Dexamethasone for mechanically ventilated patients with COVID-19 (A1 recommendation) and those who require oxygen (B1). It is not recommended based on the RECOVERY trial for hospitalized COVID-19 patients who do not need oxygen (A1). Dose 6 mg/kg/d x 10d.
    Remdesivir for hospitalized patients with SpO2 ≤94% on ambient air (at sea level) or those who require supplemental oxygen (BIIa).
    The Panel recommends remdesivir for treatment of COVID-19 in patients who are on mechanical ventilation or extracorporeal membrane oxygenation (ECMO) (BI). Duration of Therapy in Patients with Severe COVID-19 Who Are Not Intubated 5d. For mechanically ventilated or ECMO, 10 d.
    There are insufficient data on the optimal duration of therapy for mechanically ventilated patients, patients on ECMO, or patients who have not shown adequate improvement after 5 days of therapy. Some experts extend the total remdesivir treatment duration to up to 10 days (CIII).
    Recommendation for Patients with Mild or Moderate COVID-19:
    There are insufficient data for the Panel to recommend for or against remdesivir to treat patients with mild or moderate COVID-19.
    Convalescent Plasma: insufficient information for or against use. It should not be a standard of care. RCTs needed.
    IL-6 inhibitors (e.g., tocilizumab): panel had some recommending use based on REMAP-CAP but in combination with dexamethasone.
    Bamlanivimab: insufficient data to recommend.
    Casirivimab plus imdevimab: insufficient data to recommend.
    Baricitinib: insufficient data either for or against the use of baricitinib combined with remdesivir for the treatment of COVID-19 in hospitalized patients in cases where corticosteroids can be used instead. In the rare circumstances where corticosteroids cannot be used, use baricitinib in combination with remdesivir to treat COVID-19 in hospitalized, non-intubated patients who require oxygen supplementation (BIIa).

  2. Bhimraj A, et al. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19 [last updated 2/3/32, accessed 2/10/21]

    Comment: Guidance endorses the use of RDV
    Among hospitalized patients with severe* COVID-19, the IDSA panel suggests remdesivir over no antiviral treatment. (Conditional recommendation, moderate certainty of evidence)
    Remark: For consideration in contingency or crisis capacity settings (i.e., limited remdesivir supply): Remdesivir appears to demonstrate the most benefit in those with severe COVID-19 on supplemental oxygen rather than in patients on mechanical ventilation or extracorporeal mechanical oxygenation (ECMO).
    Recommendation 9. Among patients with severe COVID-19 on supplemental oxygen but not on mechanical ventilation or ECMO, the IDSA panel suggests treatment with five days of remdesivir rather than 10 days of remdesivir. (Conditional recommendation, low certainty of evidence)
    Guidance endorses the use of dexamethasone
    Among hospitalized patients with severe* COVID-19, the IDSA guideline panel suggests glucocorticoids rather than no glucocorticoids. (Conditional recommendation, moderate certainty of evidence)
    Remark: Dexamethasone 6 mg IV or PO for 10 days (or until discharge if earlier) or equivalent glucocorticoid dose may be substituted if dexamethasone is unavailable. Equivalent total daily doses of alternative glucocorticoids to dexamethasone 6 mg daily are methylprednisolone 32 mg and prednisone 40 mg.
    Recommendation 5. Among hospitalized patients with COVID-19 without hypoxemia requiring supplemental oxygen, the IDSA guideline panel suggests against the use of glucocorticoids. (Conditional recommendation, low certainty of evidence)
    *Severe illness is defined as patients with SpO2 ≤94% on room air, and those who require supplemental oxygen, mechanical ventilation, or ECMO.
    Does not recommend the use of tocilizumab except in a clinical trial.\
    Bamlanivimab: recommends against routine use, but considered a "reasonable" option for patients at high risk for COVID-19.
    Casirivimab + imdevimab: recommends against routine use, but considered a "reasonable" option for patients at high risk for COVID-19.

  3. Hanson KE. Infectious Diseases Society of America Guidelines on the Diagnosis of COVID-19, last updated 12/23/20, [accessed 2/10/21]. [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. 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. 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.

  5. 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.

  6. 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.

  7. 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.

  8. Chen P, Nirula A, Heller B, et al. SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19. N Engl J Med. 2020.  [PMID:33113295]

    Comment: Single mAb failed its primary virological endpoint in this dose-ranging trial. However, EUA granted based on less ED and hospitalization in the pooled recipients cared to placebo. Why a low dose (700 mg/kg) selected unclear. Benefits if gained, appear modest.

  9. 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

  10. 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."

  11. 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.

  12. 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.

  13. 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.

  14. CDC COVID-19 Response Team. Severe Outcomes Among Patients with Coronavirus Disease 2019 (COVID-19) - United States, February 12-March 16, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(12):343-346.  [PMID:32214079]

    Comment: US experience to date differs from China’s experience in that a higher proportion of hospitalizations are among the not elderly.

  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. Benvenuto D, Giovanetti M, Salemi M, et al. The global spread of 2019-nCoV: a molecular evolutionary analysis. Pathog Glob Health. 2020.  [PMID:32048560]

    Comment: Strain analysis to date of COVID-19 suggests that they are very similar to bat SAR-like coronavirus.

  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.  [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%]).

  27. 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.

  28. 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.

  29. 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.

  30. 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.

  31. 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.

  32. 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.

  33. 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.

  34. 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.

  35. 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%.

  36. 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.

  37. 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%).

  38. 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.

  39. 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.

  40. Joyner M, et al Effect of Convalescent Plasma on Mortality among Hospitalized Patients with COVID-19: Initial Three-Month Experience; MedRxIV accessed 11/30/20

    Comment:

    In this trial without placebo, a dose-response analysis suggested such that the pooled relative risk of mortality among patients transfused with high antibody level plasma units was 0.65 [0.47-0.92] for 7 days and 0.77 [0.63-0.94] for 30 days compared to low antibody level plasma units.

  41. Joyner M, et al. Evidence favouring the efficacy of convalescent plasma for COVID-19 therapy. Medrxiv (accessed 11/30/20)

    Comment: Aggregating available trial data, authors argue that hospitalized COVID-19 patients transfused with convalescent plasma exhibited a ~57% reduction in mortality rate (10%) compared to matched-patients receiving standard treatments (22%; OR: 0.43, P < 0.001). Note that no RCT performed to date has shown such benefit.

  42. Joyner M, et al. Evidence favouring the efficacy of convalescent plasma for COVID-19 therapy. Medrxiv (accessed 11/30/20)

    Comment:

    Aggregating available trial data, authors argue that hospitalized COVID-19 patients transfused with convalescent plasma exhibited a ~57% reduction in mortality rate (10%) compared to matched-patients receiving standard treatments (22%; OR: 0.43, P < 0.001)

  43. Interim U.S. Guidance for Risk Assessment and Public Health Management of Healthcare Personnel with Potential Exposure in a Healthcare Setting to Patients with Coronavirus Disease 2019 (COVID-19). U.S. Centers for Disease Control and Prevention. [https://www.cdc.gov/coronavirus/2019-ncov/hcp/guidance-risk-assesment-hcp.html] (last updated 12/14/20, accessed 2/10/21]

    Comment: Contact tracing has been shortened from 10d to 2d, for operational reasons, and based on data suggesting lower viral shedding in asymptomatic individuals.

  44. Interim Infection Prevention and Control Recommendations for Patients with Confirmed Coronavirus Disease 2019 (COVID-19) or Persons Under Investigation for COVID-19 in Healthcare Settings. U.S. Centers for Disease Control and Prevention. [https://www.cdc.gov/coronavirus/2019-ncov/infection-control/control-recomm...] last updated 12/14/20, accessed 2/13/21

    Comment: Helpful guidance from the CDC regarding a number of healthcare settings for COVID-related infection control practices.
    Dec 2020: new recs include
    Described recommended IPC practices when caring for patients who have met the criteria for a 14-day quarantine based on prolonged close contact with someone with SARS-CoV-2 infection.

    Added reminders that double gloving is not recommended when providing care to patients with suspected or confirmed SARS-CoV-2 infection
    In general, HCP caring for patients with suspected or confirmed SARS-CoV-2 infection should not wear more than one isolation gown at a time.

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