Coronavirus COVID-19 (SARS-CoV-2)

Updated: December 2, 2022

MICROBIOLOGY

  • Coronaviruses
    • Positive sense, single-stranded enveloped RNA virus belongs to the family Coronaviridae.
    • Coronavirus name is derived from the Latin corona, meaning crown. The viral envelope under electron microscopy appears crown-like due to small bulbar projections formed by the viral spike (S) peplomers. Neutralizing antibodies against the S-protein are believed to play an important role in protective immunity.
  • This topic covers the novel coronavirus 2019, SARS-CoV-2.
  • For discussion of other coronaviruses, see individual highlighted modules:
    • Coronavirus for common human respiratory coronavirus infections.
    • SARS for SARS-CoV-1 virus has not been known to circulate since 2002–2003.
    • MERS for the MERS-CoV virus, causing sporadic infections, mainly in the Arabian peninsula since 2012.
    • Coronaviruses also commonly infect birds and mammals, causing gastroenteritis and respiratory diseases.
  • SARS-CoV-2 uncertainty exists regarding whether its emergence into human populations appears to be a zoonotic infection or related to release from a laboratory studying the virus.
    • Origin is uncertain, although bats are implicated as this virus is most closely related by genetic analysis to bat SARS-like coronavirus (genus Betacoronavirus, subgenus Sarbecovirus). Circulating viruses similar to the Wuhan (ancestor strain) of SARS-CoV-2 have not yet been demonstrated in an animal reservoir.

CLINICAL

  • COVID-19 (novel COronaVirus Disease-2019) is the disease, SARS-CoV-2 is the virus.

Epidemiology

  • COVID-19 cases
    • Ongoing pandemic, declared by the WHO. It is unlikely this virus will disappear and likely become part of the repertoire of respiratory viruses that infect humans regularly.
    • Real-time global reports are available through Coronavirus COVID-19 Global Cases Dashboard by Johns Hopkins CSSE.
      • Despite global vaccination efforts and mitigation strategies, including facial masks and social distancing, vaccination, and therapies, millions of cases may be occurring worldwide, many now not documented, including among immunized populations, which allows for continued opportunities for the emergence of variants with immune evasiveness features.
        • Omicron appears at least more transmissible than Delta and the Delta variant and is 50-70% more transmissible than earlier variants, including Alpha.
          • BA.5 sublineage variant of Omicron is predominant in the US, estimated to have a Ro 18.6, which approaches measles contagiousness and appears to have the most evasion of preexisting immunity.
          • BA.4.6 represent a smaller but growing proportion of variants detected in the U.S.
        • Severe infections remain more prevalent in the unimmunized with risk factors and people with poor vaccine responses.
  • Risk groups
    • Older age, especially > 65 yrs, and people with comorbidities appear more likely to develop an infection with severe symptoms and be at risk for death.
      • Age gradient, with > 85 years highest; 81% of U.S. deaths are age > 65 years with 80x greater mortality risk than 18- to 29-year-olds.
      • CDC reports that 95% of COVID-19-related deaths have at least one comorbidity.
      • FDA and CDC have age ≥
    • Risks (per CDC): as determined by types of studies
      • Comorbidities (alphabetical order): age ≥ 50 years, cancer, chronic kidney disease, COPD, chronic lung disease, dementia or other neurological conditions, diabetes (types 1 and 2), Down syndrome, HIV, immunocompromised people, mental health conditions (depression, schizophrenia), BMI ≥ 25 (so overweight or obesity), pregnancy, sickle cell or thalassemia, smoking (current or former), solid organ or blood stem cell transplant, stroke/CVA, substance use disorders, active TB.
        • Multiple comorbidities are additive in risk.
      • Children/Teens: generally at less risk for severe illness; however, underlying medical problems, if present, elevate risk.
        • Younger adults are also hospitalized in the U.S., reflecting increasing percentages in many states. These cases in the later phases of the pandemic account for an increasing percentage of cases.
        • Children < 1 yr at high risk for severe illness
        • Children 1–10 yrs: low risk of disease and transmission
        • Children 10–18 yrs: higher risk of disease compared to 1–10 yr group; however, some studies show a higher risk of transmission than adults.
      • People in congregate settings with disabilities or chronic health problems have worse outcomes and face barriers to care.

Transmission

  • Through respiratory droplets, aerosolization is possible (especially indoors/prolonged exposure, areas with poor ventilation). Acquisition from fomites is likely uncommon. Virus are found in respiratory secretions and saliva.
    • Spread from a fomite, the risk is considered very low.
  • Viral shedding by asymptomatic people may represent a subset of total infections, though some uncertainty remains regarding how much they contribute to totals.
    • Viral shedding may antedate symptoms, usually two days.
    • Viral titers are highest in the earliest phases of infection, 1-2 days before the onset of symptoms, and then in the first 4-6 days of illness in patients without immunosuppression.
  • SARS-CoV-2 continues to evolve rapidly due to the inherent infidelity of RNA viruses that generate random mutations and millions of daily infections.
    • Asymptomatically infected people who shed and spread are part of the explanation.
      • Not-ill people will not as carefully take measures to avoid transmission.
        • Some are super-spreaders, which may be due to inherent characteristics (e.g., their speech generates aerosol, loud speaking, etc.).
      • Mass gatherings enhance transmission, especially indoors in smaller spaces or with poor ventilation.
      • This is essentially the rationale behind universal mask use indoors when community rates are high.
    • Aerosol spread may contribute, especially in some settings.
      • The amount of airborne transmission frequency is debated, and evidence of viral RNA beyond the expected droplet range, especially indoors, if poor ventilation exists.
        • 6-ft distancing remains a routine social distancing recommendation but has largely not been followed in many settings where mitigation strategies are no long advocated; uncovered face/sneezes may generate partial aerosolization with some activities for greater distances.
    • Whether droplet or aerosol, concern for spreading by those ill or not ill but infected is the rationale for the universal wearing of masks while in public or if one cannot maintain social distancing, at least six feet.
    • Stool shedding is also described later in the disease, but uncertain what role, if any, that plays in transmission. Some researchers using as a tool to predict community outbreaks.

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

  1. Mean incubation with Omicron is 4.3 days, median 3-4d, range 2–14d.
  2. Quarantine and Isolation: some local health departments and institutions may vary from CDC guidance.
      1. Isolation: a term used if SARS-CoV-2 is infected with or without symptoms.
        1. If tested positive (antigen or PCR) regardless of vaccine status: isolate at home and from others x 5d.
        2. End isolation after 5 full days if fever-free and not using antipyretics and symptoms improve.
          1. HCW now 7d or two negative serial antigen tests if < 10d.
        3. If severely ill or immunocompromised: isolate x 10d and consult your clinician before ending isolation.
        4. Wear a mask for 10 days inside your home and in public.
          1. Note by author: growing evidence that with the latest Omicron sublineage variants (BA.5), some people with immunity may yield infectious virus through days 10-14, longer if severely immunosuppressed.
        5. Avoid being around people who are at high risk.
      2. Quarantine: a term if potentially exposed.
        1. Quarantine is no longer advised by CDC (Aug 2022) if entirely up to date on immunization.
        2. If exposed (close contact defined as < 6ft from infected person x 15 minutes cumulatively over 24 h) and either unimmunized or not up-to-date (including recommended boosters):
          1. stay home x 5d [the quarantine], wear a well-fitted mask if you cannot be away from others, do not travel, and get tested at least 5d after close contact.
          2. Watch for symptoms x 10d and avoid travel
          3. If you develop symptoms, isolate and get tested
          4. Wear a mask for a full 10 days.
          5. Avoid being around people at high risk
        3. No travel, regardless of immunized status, is recommended x 10 days.
        4. Watch for COVID-19 symptoms x 10 days.
    1. Healthcare worker recommendations:
      1. The CDC updated guidance for HCW (9/22/22), reflecting longer carriage in many infectious virus beyond five days.
        1. Quarantine: in most circumstances, regardless of vaccination status, asymptomatic workers and those who test negative do not need restrictions.
        2. Isolation
          1. HCW with mild to moderate disease (and not immunocompromised) may return to work if:
            • At least 7 days have passed since symptoms first appeared if a negative viral test* is obtained within 48 hours before returning to work (or 10 days if testing is not performed or if a positive test at day 5-7), and
            • At least 24 hours have passed since the last fever without the use of fever-reducing medications, and
            • Symptoms (e.g., cough, shortness of breath) have improved.
          2. HCW with severe/critical infection who are not immunocompromised may return to work if:
            • At least 10 days and up to 20 days have passed since symptoms first appeared, and
            • At least 24 hours have passed since last fever without the use of fever-reducing medications, and
            • Symptoms (e.g., cough, shortness of breath) have improved.
            • The test-based strategy, as described below for moderately to severely immunocompromised HCP, can be used to inform the duration of work restriction.
  3. Viral shedding as an infectious risk
    • Occurs following recovery but does not appear to play a role in transmission in relatively healthy people >10d following the onset of infection (though some variants may be infectious longer, viral RNA may be detected long after for many weeks; hence, why repeated routine testing for negative SARS-CoV-2 RT-PCR not recommended).
    • It may not be so short for ill hospitalized patients or those with health problems, 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.:
        • A 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 an increased risk for disease severity.

Symptoms (in the unimmunized): note symptoms of Omicron infection may be milder, resembling a URTI, in both immunized and unimmunized but still capable of producing a severe infection.

  • Most common
    • Fever
    • Cough (dry)
    • Fatigue
  • Less common
    • Myalgia
    • Pharyngitis (or other respiratory symptoms)
    • Headache
    • GI including diarrhea
    • Conjunctivitis
    • Loss of taste or smell
    • Rash (chilblains, discoloring on fingers/toes)
  • Serious/warning symptoms
    • Shortness of breath
    • Chest pain/pressure
    • Confusion
    • Lethargy
    • Cyanosis

Disease spectrum

  • Although severe COVID-19 illness is primarily a lower respiratory tract infection in the earlier phases of the pandemic, early and mild cases may have features of upper respiratory tract viral infection, especially with Omicron and more so in breakthrough infections the immunized.
  • The information below represents knowledge before the Omicron variant.
  • ~80% of infections are not severe, and patients recuperate without special treatment.
    • Especially true for children and younger adults, although the Omicron variants are prompting greater hospitalizations in younger populations.
  • ~20% develop significant infection (higher risk if elderly or comorbidities). Percentages are derived from earlier in the pandemic and appear to be less in the Omicron-subvariant era.
    • ~15% require hospitalization.
    • ~5% require ICU care.
    • Lower percentages for those < 50 yrs, even with comorbidities.
  • Overall mortality risk: varies widely between regions and countries, as well as the variant circulating. Omicron has less pathogenicity than Delta or Alpha variants, notably less pneumonia despite increased growth advantage and transmission.
    • Estimates are difficult as the number of asymptomatic infections and unreported infections if known, would lower rates.
      • Both under- and over-reporting are possible, especially as home antigen testing or undiagnosed URIs are not reported.
      • Rates have changed over time.
      • U.S. COVID fatalities > 1 million, although attributable mortality is estimated to be higher, with more than 3 million deaths.
  • For hospitalized patients with pneumonia, the disease course in people hospitalized with risk factors, especially older patients, those with comorbidities:
    • ~50% develop hypoxemia by day 8 if unimmunized, but this figure is much less in the Omicron era, especially in immunized and boosted.
      • Severe illness and cytokine release syndrome appear to develop primarily within 5–10d after symptom onset in susceptible patients.
      • Markers of a severe infection include regular high fevers (>39°C), RR > 30, worsening oxygen requirements (4–6L nasal cannula), also elevated IL-6 levels (> 40–100), CRP, ferritin, and d-dimer.
      • ARDS develops in 17–29% +/- multiorgan system failure.
    • Patients in the ICU often require mechanical ventilation with prone positions recommended if poor lung compliance; ECMO is used in some centers.
  • Greater severity of illness reported with combined influenza and SARS-CoV-2 infection.

Laboratory and imaging findings

  • In COVID-19 pneumonia
    • Leukopenia is common among hospitalized patients.
    • LDH may be modestly elevated.
    • LFTs are elevated more commonly than in typical community-acquired pneumonia cases.
    • Note: detecting 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 conclude 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 developing 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), and ferritin (> 1000) suggested correlating with a 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.
    • Consider multiplex testing, including influenza and RSV, especially with severe illness/hospitalized patients.
    • Anosmia and dysgeusia occur much more frequently than other respiratory viruses, though less so with Omicron and immunization; studies have cited ranges from 15-48%.
    • Influenza may be more abrupt onset; COVID-19 often with more perturbations of taste, and viral multiplex testing incorporating SARS-CoV-increasingly 2 is available; however, influenza and RSV rates were very low in the 2020-2021 winter respiratory season.
      • Influenza again circulating during the U.S. winter respiratory season 2022-2023.
  • Also, consider pulmonary embolus, acute myocardial infection, chest crisis (sickle cell disease), etc.
    • Thromboses complicate critical COVID-19 patients with significant frequency, up to 40% in some series, especially in the critically ill.

COVID-19 testing

  • Molecular testing remains the gold standard (PCR, multiplex panels), but outpatient settings often have a longer turnaround time of 48-72h.
    • Sensitivity for molecular testing is excellent but does depend on sample collection. Depending on the technique and timing of illness, a small percentage 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 have higher yields with Delta and earlier variants.
    • Detection of viral RNA ≠ infectious virus necessarily, but is valid for the first 8-10d of symptoms in patients who are not severely ill or immunosuppressed.
      • For immunized, CDC issued guidance that 5d after onset, if symptoms have resolved or improved, people can leave isolation as long as wearing masks for days 5-10.
      • Cycle threshold values are not standardized, 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
    • A nasopharyngeal (NP) swab specimen is the norm. Other samples include nasal, oropharyngeal, saliva, and 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 molecular assays may range as high as 10-20% and depend 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, and likely correlates with infectious virus.
      • With abundant home testing ability, many people test with the onset of symptoms. They have negative testing rather than waiting for the ~5d before testing, which was an average earlier in the pandemic. Repeat testing will yield positive tests, or seek molecular testing.
        • To garner sufficient specificity for negative status, CDC recommends three serial antigen tests (compared to one molecular).
    • FDA-EUA approval is only for symptomatic early illness of < 1 week as a high viral load is needed to generate a positive assay.
      • Its role is best for quick assessment of infectiousness, such as in congregate living situations and the need for fast identification of an outbreak.
        • Home antigen testing is now an increasingly embraced methodology to lead to a quick diagnosis, especially for patients who would benefit from early treatment, e.g., mAbs and oral antivirals.
        • Repeated testing will increase the risk of false positives but generally can trust a positive to indicate an infection in a symptomatic patient if SARS-CoV-2 circulating at high rates in the community.
        • Antigen-positive testing is often not reported, so the true incidence of COVID in many countries is now likely undercounted.
      • Use for the screening of asymptomatic people is increasing. CDC has issued an algorithm with interim recommendations.
        • If there is a high pre-test probability, need to confirm antigen negatives with molecular testing or three serial antigen tests.
        • Need to confirm antigen positives with molecular testing if there is a low pre-test probability.
  • 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 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 and 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.
      • 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.
      • Many commercial antibody assays assess for antibodies against the N-protein, so they do not help assess response to COVID-19 immunization, which provokes antibodies against the S-protein.
      • Most helpful for epidemiology.
      • Occasionally helpful to investigate recent illnesses consistent with COVID-19 but without confirmatory molecular determination or for MIS-C or MIS-A consideration.
    • 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).[25]
      • 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.[26]
  • VIRAL CULTURE
    • Not recommended, except for research purposes (requires BSL-3 lab)

SITES OF INFECTION

  • Like many severe viral infections, a growing list of potential associations and complications.
  • Progressive illness, including the hyperinflammatory phase, may cause a multi-organ system failure.
  • Pulmonary
    • Pneumonia with characteristic ground-glass infiltrates, later with evolution to ARDS.
    • Co-infection with other viruses is described as a superinfection with bacteria and molds (especially Aspergillus).
  • GI
    • Some patients have nausea, vomiting, or diarrhea at the onset.
      • May herald more serious disease
    • The virus has been recovered from stool, but the significance is uncertain.
    • Liver: increased LFTs common
  • CNS: encephalopathy is not uncommon, but true encephalitis (abnormal CSF and detection of the virus) appears rare.

TREATMENT

General

  • Location of care
    • Those with minor symptoms stay home and do not seek care in health clinics or hospitals but monitor symptoms and consider if antiviral treatment should be used.
    • 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
    • Consider influenza or RSV co-infection in severe/hospitalized patients, as severity appears greater than infection with only SARS-CoV-2.
      • If also infected with influenza, use neuraminidase inhibitors for severe infection (or baloxivir for outpatient use in high-risk patients). There are no drug-drug interactions of concern between influenza and SARS-CoV-2 antivirals.
    • Oxygen, mechanical ventilation if needed
      • Oxygen saturation ≤ 94% used as a threshold for consideration of antiviral or immunomodulatory therapy.
        • Occult hypoxemia (arterial blood O2 sat < 88% despite oximetry SpO2 >92%) appears more common in some people of color. Consider this possible limitation of pulse oximetry for appropriate patient presentations.
    • Prone positioning appears helpful if hypoxemia worsens despite intubation and ventilation.
    • ICU patients have high rates of clots (DVT, PE and thrombotic events [CVA, MI]).
      • Anticoagulation prophylaxis remains unclear in whom and to what level.
  • Secondary infections, especially in severe/critically ill patients:
    • ICU patients
      • Evaluate and treat bacterial or fungal superinfection (especially Aspergillus)
        • Sputum culture, beta-D-glucan, and serum or BAL galactomannan are helpful in decision-making.
        • Often “nosocomial” pathogens (ESBL, P. aeruginosa, A. baumannii, Aspergillus spp. )
        • Median time from onset of symptoms: 10–17d
        • The median time to death: 19d
    • Factors to consider
      • Frequent antibacterial use received in 80–100%
      • Antifungals in 7.5–15%

Drug Treatment

  • Johns Hopkins Hospital Therapeutic Guidance (PDF document)(updated 12/2/2022) 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.
  • For outpatient treatment of COVID-19 in mild-moderate infection, tiered recommendations (in descending order of preference, see individual modules for details)
    • Nirmatrelvir/ritonavir
      • Preferred, if eligible, and if drug interactions otherwise don’t mean a contraindication.
    • Bebtelovimab or convalescent plasma
      • BA.5 and BA.4 subvariants are prevalent, and the mAb remains with excellent in vitro activity neutralizing the virus.
        • Bebtelovimabhas in vitro activity against all known current and past VOCs, including BA.5 and BA.4 and other Omicron subvariants, but limited clinical data exist on efficacy. Granted EUA status by FDA; NIH guideline places at lower-tier below remdesivir (RDV) x 3 days in clinical decision-making (similar to molnupiravir). This author’s opinion is that all known mAbs against the spike protein have worked well if they have good in vitro activity, hence would use similar to how other mAbs were employed, especially if logistical issues prevent early administration of RDV.
        • The federally funded supply is near exhaustion (August 2022), and it is unclear if the drug will be commercialized or if further federal funding will continue to make the mAb drug available.
      • Convalescent plasma (high titer, donated from vaccinated patients) may be preferred in severely immunocompromised and now has EUA for outpatient and inpatient administration in immunosuppressed populations.
        • Polyclonal antibodies may help avoid the emergence of variants in highly immunosuppressed patients, more so than a focused mAb.
        • Convalescent plasma donated within 150 miles of use achieves superior results compared to plasma donated from further distances. This likely has to do with the regionally driven presence of variants at the time of collection and then speed of use.
        • Limited supply as many blood banks no longer solicit donors. COVID-19 infected AND vaccinated patients (so-called high titer vax convalescent plasma) has the highest neutralizing antibody titers.
    • Remdesivir
      • Logistics of 3-day infusion is difficult for many organizations due to staffing and space issues and patient demands.
      • It appears to have similar efficacy to nirmatrelvir/ritonavir or mAb in avoiding hospitalization or death in unvaccinated populations.
    • Molnupiravir
      • Lower effectiveness (30%) than the above therapies in avoiding hospitalization/death in unimmunized patients.
      • Need pregnancy screen in women of childbearing age, genotoxicity concerns.
      • No meaningful drug interactions are known.

Antivirals

  • Studies for EUA or FDA approval were primarily carried out in the early part of the pandemic in unimmunized individuals. Efficacy is likely less in the population that is now either immunized or previously infected +/- lessening of virulence of recent variants (Omicron).
  • Remdesivir (RDV)
    • Inpatient Use:
      • Based on the Adaptive Covid-19 Treatment Trial (ACTT-1[15]), 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 benefits, but both were open-label, pragmatic trials with no placebo; however, the subgroup needing oxygen, non-critically ill in the DisCoVeRy trial did have a shorter length of stay similar to ACTT-1. Other observational data back use with results similar to ACTT-1. U.S. guidelines (NIH, IDSA) continue to endorse; the drug is infrequently used overseas.
      • FDA approved (Oct 2020) for COVID-19 hospitalized patients, ages ≥ 12 yrs or 40 kg.
        • EUA is now issued for children < 12 yrs, wt 3.5 – 40 kg.
        • Assess sCr, LFTs and PT INR before use.
      • Dose: 200 mg IV load on day 1, then 100 mg IV q 24 days 2-5
        • Infuse over 30-120 min.
        • May extend for an additional 5d if there is no clinical improvement, especially in patients on mechanical ventilation, ECMO or severely immunosuppressed.
        • Carrier (SCED) may accumulate in renal insufficiency but is not judged to be clinically significant, despite the warning on the label.
      • Warnings:
        • Don’t use if hypersensitivity reactions ensue.
        • Consider d/c if LFTs 10x ULN.
      • Results of an NIH-sponsored clinical trial (ACTT-1) for COVID-19 patients with evidence of lung involvement:
        • The median time to recovery was reduced by 5d or 31% (10d v 15d).
          • Median days onset of symptoms (9d) prior to enrollment.
        • The mortality trend was suggested (8% v 11.6%) but not statistically significant.
        • The benefit appears derived in this trial in patients started on RDV before mechanical ventilation.
          • NIH COVID-19 Guideline states BIIa recommendation for severe COVD-19 requires 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.[16]
      • The Solidarity trial (WHO trial, interim results) had RDV as one of four arms but did not find benefits regarding mortality, LOS or decreasing need for mechanical ventilation.
        • Though a large trial, as a pragmatic trial, there was no placebo comparator. Also, there were problems with selection and assignment bias and missing data.
    • Mild-moderate COVID-19 (usually ambulatory): Each state is responsible for the distribution of drugs available under EUAs. Check with your local health department for how oral antivirals are distributed and where intravenous monoclonal antibodies are available.
      • 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 with≥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 initially and wait for oral antivirals in winter of 2021-2022.
          • 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 December 2021.
        • Nirmatrelvir is a SARS-CoV-2 3CLpro protease inhibitor boosted by ritonavir.
          • EPIC-HR RCT enrolled unvaccinated adults with mild COVID-19 as outpatients using five days of PAXLOVID vs. placebo. The primary endpoint was death or hospitalization within 28d.
            • Interim analysis of 2,085 participants showed that 8 (0.8%) in the nirmatrelvir arm vs. 66 (6.3%) in the placebo arm reached the primary endpoint for an impressive relative risk reduction of 88% (p=0.001).
            • No significant safety signals.
        • FDA EUA fact sheet allows for use in people ages ≥ 12 yrs with mild-moderate COVID-19 outpatients OR inpatients (so no severe/critical COVID-19) 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 may heighten or lessen drug levels and cause potentially life-threatening problems OR lessen levels of nirmatrelvir/ritonavir.
          • It is not to be used for PEP or PrEP.
        • A rebound of symptoms and antigen presence is now frequently described.
          • Trial estimates are ~2% in both treated and untreated but poorly understood and likely higher, with some placing the occurrence at 10-20%.
          • Mechanism uncertain, but may be due to earlier diagnosis by antigen testing, institution or drug and inhibition of variant-specific immunity, or the consequence of less immunity depending on timing from last immunization or SARS-CoV-2 infection.
          • The drug should not be withheld due to concerns of rebound in high-risk populations.
      • Molnupiravir
        • Ribonucleoside prodrug with activity against coronaviruses received FDA EUA in December 2021.
        • MOVe-OUT trial in adult outpatients with COVID-19 and ≤ 5 days of symptoms examined 5d of treatment v. placebo. The primary endpoint was hospitalization or death within 29d. Obesity was present in 74% of enrollees.
          • mITT results of 1433 participants, 48 (6.8%) of the molnupiravir arm participants compared to 68 (9.7%) of placebo arm participants were hospitalized or died for a 30% reduction [difference, −3.0 percentage points; 95% CI, −5.9 to −0.1]. Adverse events were comparable.
        • FDA EUA fact Sheet is for adults only with mild-moderate COVID-19 with risk factors for severe disease.
          • 800 mg (200 mg caps) PO q 12 h x 5d
          • Limitations:
            • Benefit has not been shown for use in COVID-19 patients requiring hospitalization.
            • Do not use it in children or adolescents (it may affect bone and cartilage).
            • It is not authorized for PEP or PrEP.
            • Not recommended during pregnancy or if breastfeeding.
        • Lack of evidence of effect in immunized people at high risk for severe illness; therefore, other agents (nirmtrelavir/ritonavir or bebtelovimab) are preferred.

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

  • 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 and found fewer in the active arm requiring ED or hospitalization.
      • Limitations include the study being performed in Brazil, which had ED visits> 6h as part of a primary composite endpoint; currently, insufficient data to recommend for or against it.
    • Three-arm factorial trial of fluvoxamine, ivermectin or metformin did not any of these agents prevent hypoxemia, emergency department visits, hospitalization, or death.
  • Ivermectin
    • Double-blind RCT of mild COVID-19 treatment x 5d, without efficacy, reinforced by another RCT. 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

  • 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[2] and IDSA[3]

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

Respiratory Support at Randomization

Dexamethasone

Usual Care

*Statistically significant

No oxygen received

17.0%

13.2%

Oxygen only*

21.5%

25.0%

Invasive mechanical ventilation*

29.0%

40.7%

Other corticosteroids were potentially beneficial in other trials, and meta-analyses had a summary OR 0.66 on 28d all-cause mortality[14].

  • 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 the tocilizumab section below for recommendations. Received full FDA approval in May 2022 for treatment of COVID-19 for adults ≥ 18 yrs.
    • FDA approval for adults is for the treatment of COVID-19 in hospitalized adults requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or ECMO.
      • Recommended dose of 4 mg PO once daily for 14 days or until hospital discharge, whichever comes first.
    • FDA EUA remains in place for ages ≥ 2 to 18 yrs for COVID-19 in hospitalized pediatric patients requiring supplemental oxygen, invasive mechanical ventilation, or ECMO.
    • ACTT-2 trial compared RDV + baricitinib vs. RDV + placebo
      • The primary endpoint was the median time to recovery (defined as discharged from the hospital or hospitalized but not requiring supplemental oxygen or ongoing medical care)
      • Most benefit in patients on high-flow oxygen not requiring mechanical ventilation.
    • COV-BARRIER: RCT with baricitinib vs. standard of care (19% received RDV, 79.3% on corticosteroids which differs from ACTT-2 trial)
      • The composite primary endpoint (death, progression to high-flow O2, NIMV, MV or ECMO) was 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 the primary endpoint was not reached, no difference in groups regarding clots, MIs, CVA, etc.).
    • Dosing:
      • Adults and pediatric patients 9 years of age and older: 4 mg PO once daily
      • Pediatric patients 2 years to less than 9 years of age: 2 mg PO once daily
    • Duration: 14 days or until hospital discharge.
  • Tocilizumab
    • An FDA-approved anti-IL6R monoclonal antibody for CAR-T cell cytokine release syndrome and rheumatoid arthritis.
      • RCTs performed early in the pandemic as monotherapy has not had positive results.
      • More recent studies with high percentages of patients also on dexamethasone have shown benefits.
        • EMPACTA found less progression to ventilation or death if used before mechanical ventilation.
        • REMAP-CAP found that for patients on high-flow oxygen or within the first 24 hours of ICU care, tocilizumab contributed most significantly to more days of organ-support-free survival (10d compared to placebo) and decreased mortality.
        • RECOVERY found patients 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 in the first 24h of ICU care in combination with dexamethasone alone or with remdesivir for patients on high-flow or NIMV with evidence of progression or increased markers of inflammation.
        • Baricitinib can be used similarly, except for ICU patients with no data to support use.
    • Dosing is typically 8 mg/kg x single dose; some repeat if there is no benefit within 48h
    • Sarilumab (also an anti-IL6R mAb) may be used if tocilizumab is unavailable.
      • Dose: 400 mg IV infused over one hour.

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 using only high-titer convalescent plasma for patients with an immunosuppressive disease or receiving immunosuppressive therapies.
      • See the FDA fact sheet for healthcare providers for detailed information. Compared to earlier EUA, differences now include:
        • CP may be used for either outpatients or inpatients.
        • CP is not authorized for immunocompetent patients (receiving COVID-19 treatments such as dexamethasone or tocilizumab does not qualify).
        • Specifics regarding the qualification of high-titer plasma are found in the FDA letter, using specified test kits.
          • The supply of CP (Feb 2022) is very limited but may improve.
          • Donors who have had COVID-19 and are immunized appear to produce the best titers with activity against known variants.
      • RCTs for inpatients have not confirmed benefit, although substantial observational data point to subsets of COVID-19 patients who may benefit; however, many of these trials administered CP late into the illness (> day 7).
        • The subset derived from the expanded access use earlier in 2020 found that the use of high-titer plasma within three days of hospitalization conferred a mortality benefit if received before intubation[7].
        • A small RCT in patients older than 65 with mild to moderate COVID-19 reduced progression to severe COVID-19 if received within 3 days of the onset of illness[8].
        • 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 primarily small and underpowered) have not shown mortality benefits to date, although a meta-analysis of observational studies suggests early use does have an impact.
        • 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 the illness course and patients are immunosuppressed (especially with impaired B-cell responses).
  • RCTs for prophylaxis, early and late COVID-19 treatment.[44]
    • RCT of 1225 randomized for early COVID, ambulatory high-titer convalescent plasma therapy with the primary endpoint of hospitalization within 28d[4].
      • 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 benefits 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, casirivimab/imdevimab, and sotrovimab have paused distribution, and EUAs revoked by FDA/HHS or EUA have been revoked been withdrawn by the FDA in the U.S. due to a lack of sufficient activity against the Omicron variants.
    • Bebtelovimab: single mAb that has in vitro activity against all existing variants, including BA.5 and BA.4. Now the sole mAb available for COVID-19 (see author opinion on this drug under the Drug Treatment section for additional details).
      • FDA Fact sheet includes available clinical data known.
      • 175 mg IV infusion
  • 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 ≥50 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, and social distancing were helpful to lower Ro (contagiousness of infection). Still, the degree of mitigation remains a source of considerable debate among public health officials and politicians.[17]
    • 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 coughing/sneezing or during 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) (updated 12/2/2022) 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 that 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.
      • FDA (10/3/22) has revised its EUA fact sheet to note that the drug does not neutralize the BA4.6 variant and lacks activity against other emerging variants, such as BQ.1 and BQ.1.1.

Vaccines

  • Multiple vaccines worldwide. Three used in the U.S. have modules in this guide.
    • The initial high efficacy of 94-95% for the mRNA vaccines is now lower due to the Delta and Omicron variants; however, they 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 preliminary reports by 80-88% for infection prevention and hospitalization.
    • FDA has fully approved Pfizer/BioNTech for two doses and Moderna COVID-19 for two doses. Booster doses are also approved for Pfizer ages ≥ 12 yrs.
      • See vaccine modules for details, including third-dose information (immunocompromised patients) and booster recommendations.
        • FDA has authorized a second booster mRNA vaccine (dose #4) for ages ≥ 50 years, solid organ transplant recipients or those with similar immune risk.
        • Pfizer now has a EUA for children ≥ 6 months of age.
          • Children 5 years and older are now eligible for a booster dose (one).
      • Both, if boosted, appear to retain excellent protection against Omicron subvariants for avoiding severe COVID-19, although protection wanes 9 months or more after the last vaccination (or infection).
        • Vaccine efficacy (protection against infection): declining with BA.5 and BA.4 subvariants.
      • 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).
      • JNJ/Janssen adenovirus vaccine 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).
        • FDA (May 5, 2022) limited authorized to use to individuals 18 years of age and older for whom other authorized or approved COVID-19 vaccines are not accessible or clinically appropriate and to individuals 18 years of age and older who elect to receive the Janssen COVID-19 vaccine because they would otherwise not receive a COVID-19 vaccine.
          • The rare occurrence of TTS syndrome, which tends to occur 1-2 weeks post-immunization, prompted suggested restriction.
          • Use remains appropriate as the benefits outweigh the risks if no other vaccine is recommended.
        • Originally a one-dose vaccine with additional dosing was recommended as an mRNA vaccine (based on superior immune response) in people capable of receiving these vaccines. Otherwise, the second dose of JNJ/Janssen is recommended.
        • Cited as 66% overall effective in the pivotal trial, now less without mRNA booster in the face of Omicron, with 2x risk of death compared to mRNA vaccines.
          • 72% in the U.S., 66% in Latin America, 57% in S. Africa.
          • 85% effective at preventing severe COVID-19.
        • Rare clots in the setting of thrombocytopenia (TTS) are described.
        • Other vaccines have been employed in countries such as China, UAE, and Brazil.
          • Multiple sources for updates include WHO and ACIP.
      • Novavax subunit vaccine, with EUA for primary series. EUA for booster under consideration.
        • It offers an alternative for people who are hesitant to obtain mRNA vaccines or are contraindicated for them.

Complications

  • Thrombosis: increasing reports of substantial rates of DVT and PE in critically ill patients. Some centers use low-molecular-weight heparin for prevention; others call against it, citing paradoxical clotting.
    • MI, and CVA also appear with unusual frequency.
    • Unclear if COVID-19-associated incidence of venous thromboembolism is higher than 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 the 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.
    • Loose estimates are a 10–20% incidence of bacterial and fungal infections, with a higher percentage in patients who died.
    • Development of pulmonary aspergillosis. COVID-19-associated pulmonary aspergillosis (CAPA) consideration, especially in severely ill, in ICU or immunosuppressed.

Selected Drug Comments

Drug

Recommendation

Bamlanivimab/etesevimab

No longer available as HHS withdrew EUA due to lack of activity against the Omicron variant.

Baricitinib

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

Bebtelovimab

Received EUA in Feb ’22 based on limited clinical data. However, in vitro data suggest it has the most reliable activity against known variants, including Omicron’s BA.5 and BA.4 subvariants. However, most recent subvariants, BQ.1, BQ.1.1 and others, may evade this therapeutic. COVID guideline places a lower tier below remdesivir (RDV) x 3 days in clinical decision-making (similar to molnupiravir). This author’s opinion is that all known mAbs against the spike protein have worked well if they have good in vitro activity, hence would use similar to how other mAbs were employed primarily if logistical issues prevent early administration of RDV.

Casirivimab imdevimab

HHS halted distribution due to a lack of activity against the Omicron variant.

COVID-19 Convalescent Plasma

Still waiting for a large RCT to be published 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 both outpatients and hospitalized patients now enforces the use of high-titer plasma but is only available for immunosuppressed populations. Best used if within 3 days of illness onset or first 3 days of hospitalization. Now indicated only for immunosuppressed populations. High titer units from people who have recovered from COVID-19 and who have been immunized appear to generate the best titers and activity against known circulating variants, including Omicron. Outpatient study of early plasma administration showed 54% reduction in hospitalization, demonstrating that high-titer units have a role if used early rather than late (in hospital) for average, high-risk patients[4].

Dexamethasone

The RECOVERY trial provides the first evidence of therapy that provides a mortality benefit to those mechanically ventilated (or who require oxygen, severe COVID-19). In this trial, there was a trend toward increased mortality in those who do not require oxygen, so 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 not to benefit, suggesting that during the early phase of viral illness, there is no impact or potential harm (similar to influenza). Still, the benefit is seen in the later hyperinflammatory phase. This trial was open-label, but the mortality endpoint would tend to discount bias to a substantial degree. Women appeared to benefit less from dexamethasone than men.

Hydroxychloroquine

Antimalarial and anti-inflammatory have not been shown in large randomized trials to yield benefits in the treatment of COVID-19 in hospitalized patients (RECOVERY trial), and concerns have been raised about cardiotoxicities in critically ill patients. It also appears not to offer prevention after exposure.[27] Any mainstream experts or authorities do not recommend the drug.

Molnupiravir

High hopes for this nucleoside analog; however, the MOVe-OUT trial had only ~ 30% reduction in hospitalization or death within the first month when used in outpatients with fewer than 5 days of symptoms. 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. The drug should not be used in children, adolescents, pregnant and breastfeeding women. It has few drug interaction issues or side effects from the treatment.

Nirmatrelvir/ritonavir

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

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 studies, matched control studies. PINETREE data suggested that early administration (< 5d after symptom onset) in patients at high risk for COVID-19 prevents hospitalization and death. Three-day infusion poses logistical challenges compared to single-dose mAb for outpatients. Still, maybe the treatment of choice for those patients ineligible for Paxlovid and if effective mAb is unavailable. RDV is the first to receive full FDA approval for COVID-19, and use in the outpatient arena often requires financial clearance before receiving since now paid by patient insurance; this may slow the time to first infusion.

Sotrovimab

Distribution was halted, and EUA withdrawn due to reduced activity against the BA.2 subvariant (4/5/22).

Tixagevimab/cilgavimab

Better known by its trade name Evusheld and previously called AZD7422, it appears to have effective PrEP with a 76.7% reduction in symptomatic COVID-19 when alpha and delta variants were commonplace in the PROVENT trial (which was among the unvaccinated with few immunosuppressed in the trial). The monoclonal has an altered Fc that allows for extended half-life and therefore offers protection x 6 months. With BA.2 now dominant in the U.S, the cilgavimab retains significant activity, more so than against early Omicron variants and subvariants. The drug is only for immunosuppressed patients who are expected not to 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 effects, so it is not helpful for COVID-19 treatment or PEP. There was a signal that administration caused more cardiac events (0.6%) compared to placebo (0.2%) in those with known cardiovascular disease only. More recent concerns are lack of in vitro activity against variants BA.4.6, BQ.1, BQ.1.1 and others.

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 the severity and duration of illness and mortality in three studies: EMPACTA, REMAP-CAP, and RECOVERY. Endorsed for use by NIH and IDSA for patients on high-flow 02 or first 24h of ICU care--baricitinib is an alternative. Either should be combined with dexamethasone or another corticosteroid. Baricitinib is an alternative employed by some institutions in the second half of 2021 due to supply shortfalls of tocilizumab.

FOLLOW UP

  • Case fatality rates are highly variable in regions and different countries. Unclear why, and it may be multifactorial.
  • Recovery from COVID-19 produces antibodies, but the response is heterogeneous, significantly lower in asymptomatic infected patients, and measurable responses such as antibody levels may diminish significantly in as little as 2–3 months. The protective immunity duration is unclear. T-cell responses are also likely critical.
  • Advice for COVID-19 (+) patients and self-isolation/quarantine: recent changes have included decreasing isolation from 10 to 5d for further details, see the CDC link for a table with recommendations.

OTHER INFORMATION

  • Testing for viral RNA may include asymptomatic in addition to symptomatic patients; however, if not molecular tests, see the CDC algorithm for proper interpretation and follow-up testing (if needed) when using antigen-based tests.
  • Severe illness strikes much the same populations at high risk for seasonal influenza complications (e.g., elderly, immunosuppressed, obesity and comorbidities).
  • The case fatality rate is probably higher than seasonal influenza (≤0.1%) but may be lower than initially reported (~ 2–4%), but careful epidemiology surveys in progress and changes with each new variant; may be different in some countries as social distancing interventions and other factors differ.

Basis for recommendation

  1. Hanson KE. Infectious Diseases Society of America Guidelines on the Diagnosis of COVID-19, last updated 12/20/20, [accessed 8/29/2022]. [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.

  2. NIH COVID-19 Treatment Guidelines. https://www.covid19treatmentguidelines.nih.gov/ (last updated 9/30/2022, accessed 10/18/22)

    Comment: Revised regularly with updates. The format includes updated reference tables for some drugs. Informs much of the basis for RDV, dexamethasone, tocilizumab and baricitinib use discussed. Also rates outpatient COVID-19 therapies for early disease. The panel places the only remaining mAb bebtelovimab as a third line (along with molnupiravir) due to limited clinical data to support use while having excellent in vitro activity against Omicron and subvariants.

  3. Bhimraj A, et al. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19 [last updated 8/30/22, accessed 10/18/2022]

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

References

  1. Sullivan DJ, Gebo KA, Shoham S, et al. Early Outpatient Treatment for Covid-19 with Convalescent Plasma. N Engl J Med. 2022.  [PMID:35353960]

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

  2. Hammond J, Leister-Tebbe H, Gardner A, et al. Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19. N Engl J Med. 2022.  [PMID:35172054]

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

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

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

  4. 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.

  5. 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.

  6. 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.

  7. 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).

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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

  14. 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."

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  21. 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.

  22. 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%).

  23. 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

  24. 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.

  25. 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.

  26. 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.

  27. 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.

  28. 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%]).

  29. 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.

  30. 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.

  31. 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.

  32. 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.

  33. 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.

  34. 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.

  35. 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.

  36. 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.

  37. 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%.

  38. 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.

  39. 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%).

  40. 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.

  41. 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.

  42. Barnette, GK et al. Oral Sabizabulin for High-Risk, Hospitalized Adults with Covid-19: Interim Analysis. NEJM July 2022

    Comment:
    Interim analysis of this multinational trial of a colchicine-like drug that binds to alpha and beta microtubules that may interfere with both viral assembly and inflammatory drivers was halted early by the DSMB because of mortality benefit. The drug was part of 150 randomized patients that yielded a 24.9% absolute reduction or 55.2% relative reduction in deaths compared to the standard of care, which mainly was dexamethasone, with about one-third receiving RDV and about half immunized. Conducted during Delta and early Omicron waves. The company has applied for a EUA.


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Last updated: December 6, 2022