Coronavirus COVID-19 (SARS-CoV-2)

Updated: October 8, 2023

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 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 has not yet been conclusively demonstrated in an intermediary animal reservoir. However, recent reports have suggested that raccoon dogs (Nyctereutes procyonoides) may be the case based on sampling in/near the Wuhan market. The alternate lab leak theory has its proponents, and a definitive origin may never be known.

CLINICAL

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

Epidemiology

  • COVID-19 cases
    • The virus has established itself as a year-round respiratory pathogen.
      • U.S. Public Health Emergency ceased in May 2023, similar to the WHO for a global health emergency.
      • September 2023, in the U.S., with a rise in infections in late summer + hospitalizations and deaths.
    • The evolution of viral variants and subvariants has slowed due to significant global human immunity. However, reporting cases is less careful or absent in many countries due to antigen testing, which is not captured.
      • Omicron appears at least more transmissible than the Delta variant and is 50-70% more transmissible than earlier variants, including Alpha.
        • This CDC genomic variant surveillance may track circulating Omicron sublineages in the U.S.; XBB subvariants of multiple types dominate in the U.S., with EG.5 and FL.1.5.1 predominating (Sept 2023).
          • Includes NOWCAST projection and modeling of what may happen in real-time since data lag by 2-3+ weeks.
        • Severe infections remain more prevalent in the unimmunized or no prior infection with multiple risk factors and people with poor antibody responses to vaccines or infections.
  • 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 ≥ 50 yrs as the substantial change in increased risk.
    • Risks (per CDC; see link for more complete details): as determined by types of studies, multiple risk factors increase risks further.
      • 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.
      • Racial, ethnic and socioeconomic factors also increased the risk for heightened mortality and poor outcomes due to disparities in and barriers to accessing care.
      • 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 the 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. Viruses 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, but 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 there is 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.
      • It appears to be a tool to predict outbreaks and changes in community viral contours.

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 after the onset of symptoms.
        2. End isolation after 5 full days if fever-free and not using antipyretics and symptoms improve.
          1. Per CDC, 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. 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. CDC no longer advises quarantine (Aug 2022) if entirely up to date on immunization.
        2. If you test negative by antigen testing, this correlates with either no infection or a low possibility for infectivity.
    1. Healthcare worker recommendations:
      1. The CDC updated guidance for HCW (9/23/22), reflecting longer carriage in many with 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 the 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 HCPs, can 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. However, 20-28d is a conservative stance some hospitals use 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, it is 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 is primarily a lower respiratory tract infection in the earlier phases of the pandemic, early and mild cases may have upper respiratory tract viral infection features, especially with Omicron and more so in breakthrough infections 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 less in the Omicron-subvariant era.
    • ~15% require hospitalization.
    • ~5% require ICU care.
    • Lower percentages for those < 50 years, 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 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 and those with comorbidities:
    • If unimmunized or without prior infection/SARS-CoV-2 antibodies, ~50% develop hypoxemia by day 8, 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 5–10 days 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 there is poor lung compliance; ECMO is used in some centers.
  • Greater severity of illness was 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 peak at 10d of illness; resolution begins after day 14 for hospitalized patients.
      • 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 significantly, up to 40% in some series, especially in the critically ill.

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

  • Molecular testing remains the gold standard (PCR, multiplex panels), but outpatient settings often have a longer turnaround time of 48-72 hours unless rapid point-of-care PCR testing is used.
    • 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 is necessary but is valid for the first 8-10d of symptoms in patients who are not severely ill or immunosuppressed.
      • Cycle threshold values are not standardized, vary among platforms, and are not reported as clinical data; however, if values are available in the 30s-40+, then a low likelihood that the viral shedding correlates with an active, replicating virus.
  • 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 yield higher 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 the disease is tested, with later testing having lower detection rates. 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, an average earlier in the pandemic. Repeat testing will yield positive tests, or seek molecular testing.
        • The CDC recommends three serial antigen tests (compared to one molecular) to garner sufficient specificity for negative status.
    • 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 to quickly identify 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 circulates 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.
        • With Omicron, many are antigen-positive past 5d of illness, and studies suggest that in immunized, non-immunocompromised people, they are rarely infectious beyond 7-8d despite antigen positivity (which is thought to correlate with higher levels of virus and therefore infectivity)
      • Antigen testing symptomatic people and screening asymptomatics; the CDC has issued an algorithm with recommendations.
        • If a high pre-test probability and testing of symptomatic people is negative, consider alternative diagnoses or perform additional testing (repeat antigen or pursue molecular test).
        • We 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 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 protective immunity, especially as variants evolve.
      • 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.
      • It is occasionally helpful to investigate recent illnesses consistent with COVID-19 if using anti-nucleoprotein antibody tests, 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).
      • Asymptomatically infected individuals produce antibodies to lesser levels and may fall below detection levels within 2–3 months.[17]
  • 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 or superinfection with bacteria and molds (especially Aspergillus).
  • GI
    • Some patients have nausea, vomiting, or diarrhea at the onset.
      • May herald more severe 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 focuses on those who are short of breath, have severe symptoms, or require oxygen, and supportive care 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 and mechanical ventilation, if needed.
      • Oxygen saturation ≤ 94% is a threshold for general consideration for antiviral or immunomodulatory therapy.
        • Occult hypoxemia (arterial blood O2 sat < 88% despite oximetry SpO2 >92%) appears more common in some people of color. Consider this possible limitation of pulse oximetry for appropriate patient presentations.
    • Prone positioning appears helpful if hypoxemia worsens despite intubation and ventilation.
    • ICU patients have high rates of clots (DVT, PE and thrombotic events [CVA, MI]).
    • Anticoagulation is prophylactically often used in ICU patients to avoid thrombotic events.
  • Secondary infections, especially in severe/critically ill patients:
    • ICU patients
      • Evaluate and treat bacterial or fungal superinfection (especially Aspergillus)
        • Sputum culture, beta-D-glucan, and serum or BAL galactomannan are helpful in decision-making.
        • Often “nosocomial” pathogens (ESBL, P. aeruginosa, A. baumannii, Aspergillus spp. )
        • Median time from onset of symptoms: 10–17d
        • The median time to death: 19d
    • Factors to consider
      • Frequent antibacterial use received in 80–100%
      • Antifungals in 7.5–15%

Drug Treatment

  • Johns Hopkins Hospital Therapeutic Guidance (PDF document) (updated 1/18/2024) is available with frequent updates for a complete discussion of the risks/benefits of FDA-approved, investigational and off-label medications for COVID-19.
  • Criteria for Identifying High-Risk Individuals: treatment for outpatients limited to those with medical conditions or other factors may place adults and pediatric patients (age 12-17 years and weighing at least 40 kg) at higher risk for progression to severe COVID-19:
      • 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])
  • For outpatient treatment of COVID-19 in mild-moderate infection, tiered recommendations (in descending order of preference; see individual modules for details).
    • FDA has removed from its EUAs (2/3/23) the requirement for nirmatrelvir/ritonavir or molnupiravir to have a confirmed SARS-CoV-2 infection. Though still recommended to test by antigen or molecular assays, there may be circumstances such as known confirmed household exposure that clinicians may diagnose COVID without a test in hand.
    • Nirmatrelvir/ritonavir
      • Preferred, if eligible, and if drug interactions otherwise don’t mean a contraindication.
    • Remdesivir
      • Now, often the go-to therapy for patients who cannot take nirmatrelvir/ritonavir due to drug interactions.
      • Daily IV infusion x 3 days is difficult for many organizations due to staffing, space issues, and patient demands.
      • It appears to have similar efficacy to nirmatrelvir/ritonavir for avoiding hospitalization or death in unvaccinated populations.
    • Convalescent plasma
      • BQ.1 and BQ1.1 are predominant Omicron sublineages circulating in the U.S., and bebtelovimab has been withdrawn due to lack of activity. This leaves only convalescent plasma as the sole antibody-based therapy as of December 2022 for neutralizing the virus.
      • Convalescent plasma (high titer, donated from vaccinated patients) is restricted to immunocompromised patients with COVID per FDA EUA, including outpatient and inpatient administration in immunosuppressed populations.
        • Polyclonal antibodies 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 the speed of use.
        • There was a 54% reduction in hospitalization/death for outpatient use, proving the effectiveness of using convalescent plasma for treating mild-moderate COVID-19 in people with risk factors.[6]
        • Limited supply, as many blood banks are less routinely soliciting donors.
          • COVID-19 infected AND vaccinated patients (so-called high titer vax convalescent plasma) have the highest neutralizing antibody titers.
    • 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 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) before enrollment.
        • The mortality trend was suggested (8% v 11.6%) but was not statistically significant.
        • The benefit appears derived in this trial in patients started on RDV before mechanical ventilation.
          • NIH COVID-19 Guideline states BIIa recommendation for severe COVID-19 requires oxygen but not mechanical ventilation.
        • Investigators concluded that benefit was accrued to patients before the need for mechanical ventilation, highly suggestive that this antiviral yields more significant benefit the earlier it is initiated.
      • Another RCT from China did not show a benefit but did note a mortality trend toward benefit.
      • The Solidarity trial (WHO trial, interim results) had RDV as one of four arms but did not find benefits regarding mortality, LOS or decreasing need for mechanical ventilation.
        • Though a large trial, as a pragmatic trial, there was no placebo comparator. Also, there were problems with selection and assignment bias and missing data.
    • Mild-moderate COVID-19 (usually ambulatory):
      • RDV was studied in the PINETREE study, terminated early due to the availability of monoclonal antibody therapies.
        • Three days of once-daily IV RDV infused as 200mg d1, 100mg d2-3 vs. placebo among unvaccinated, ambulatory patients ≥12 years old with≥1 risk factor for severe COVID-19 and ≤7 days of symptoms.
          • Primary outcome = COVID-19-related hospitalization or death in 28 days.
            • 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.
        • With the absence of monoclonal antibodies, for patients unable to use Paxlovid due to drug interactions, this is the preferred treatment but logistically challenging to obtain due to IV infusion over three days needed.
    • Outpatient and Inpatient Use:
      • Nirmatrelvir/ritonavir (Paxlovid)
        • Received EUA December 2021.
        • Nirmatrelvir is a SARS-CoV-2 3CLpro protease inhibitor boosted by ritonavir.
          • EPIC-HR RCT enrolled unvaccinated adults with mild COVID-19 as outpatients using five days of PAXLOVID vs. placebo. The primary endpoint was death or hospitalization within 28d.
            • Interim analysis of 2,085 participants showed that 8 (0.8%) in the nirmatrelvir arm vs. 66 (6.3%) in the placebo arm reached the primary endpoint for an impressive relative risk reduction of 88% (p=0.001).
            • No significant safety signals.
        • FDA EUA fact sheet allows for use in people ages ≥ 12 yrs with mild-moderate COVID-19 outpatients OR inpatients (so no severe/critical COVID-19) with risk factors for severe disease AND ≤ 5 days of symptoms.
          • Nirmatrelvir 300 mg (two 150 mg tabs) + ritonavir 100 mg twice daily PO x 5 days
            • Has renal dosing recommendations.
            • Check for drug-drug interactions:
              • Co-administration with CYP3A metabolized drugs may heighten or lessen drug levels and cause potentially life-threatening problems OR lessen levels of nirmatrelvir/ritonavir.
          • It is not to be used for PEP or PrEP.
        • A rebound of symptoms and antigen presence is now frequently described.
          • Trial estimates are ~2% in both treated and untreated but poorly understood and likely higher, with some placing the occurrence at 10-20%. It should be noted that a small percentage of untreated people also suffer rebound symptoms.
          • Mechanism uncertain, but may be due to earlier diagnosis by antigen testing, institution or drug and inhibition of variant-specific immunity, or the consequence of less immunity depending on timing from last immunization or SARS-CoV-2 infection.
          • The drug should not be withheld due to concerns of a rebound in high-risk populations.
      • Molnupiravir
        • Ribonucleoside prodrug with activity against coronaviruses received FDA EUA in December 2021.
        • MOVe-OUT trial in adult outpatients with COVID-19 and ≤ 5 days of symptoms examined 5d of treatment v. placebo. The primary endpoint was hospitalization or death within 29d. Obesity was present in 74% of enrollees.
          • mITT results of 1433 participants, 48 (6.8%) of the molnupiravir arm participants compared to 68 (9.7%) of placebo arm participants were hospitalized or died for a 30% reduction [difference, −3.0 percentage points; 95% CI, −5.9 to −0.1]. Adverse events were comparable.
        • FDA EUA fact Sheet is for adults only with mild-moderate COVID-19 with risk factors for severe disease.
          • 800 mg (200 mg caps) PO q 12 h x 5d
          • Limitations:
            • Benefit has not been shown for use in COVID-19 patients requiring hospitalization.
            • Do not use it in children or adolescents (it may affect bone and cartilage).
            • It is not authorized for PEP or PrEP.
            • Not recommended during pregnancy or if breastfeeding.
        • Lack of evidence of effect in immunized people at high risk for severe illness; therefore, other agents (nirmatrelvir/ritonavir or bebtelovimab) are preferred.

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

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

Immunomodulators

  • Dexamethasone
    • Results from the RECOVERY trial showed dexamethasone 6 mg PO or IV daily for up to 10 days reduced 28-day mortality in certain groups of hospitalized COVID-19 patients: recommended for patients with severe COVID-19 (requiring oxygen), including those on mechanical ventilation by the NIH[1] and IDSA[2]

Effect of Dexamethasone on 28−day Mortality Level of Respiratory Support[9]

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[18].

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

Antibody-based therapies

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

  • Studies have been mixed regarding effectiveness. Many of the negative RCTs used CP late in the disease course. Positive 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 is often limited.
          • Donors who have had COVID-19 and are immunized appear to produce the best titers with activity against known variants.
      • RCTs for inpatients have not confirmed benefit, although substantial observational data point to subsets of COVID-19 patients who may benefit; however, many of these trials administered CP late into the illness (> day 7).
        • The subset derived from the expanded access use earlier in 2020 found that high-titer plasma within three days of hospitalization conferred a mortality benefit if received before intubation[11].
        • 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[12].
        • Retrospective matched cohort study: CP within 3 days after admission, but not 4-7 days, was associated with a significant reduction in mortality risk (aHR = 0.53, 95% CI 0.47-0.60, p< 0.001).
        • Many RCTs published in 2020 primarily small and underpowered) have not shown mortality benefits to date, although a meta-analysis of observational studies suggests early use does have an impact.
        • RECOVERY trial yielded no 28d mortality benefit; NIH and IDSA Guidance no longer recommend it as a therapy for all hospitalized patients.
          • However, positive data suggest early use (< 3d of symptoms or hospitalization) and studies in immunosuppressed illness suggest a role remains and is now with an FDA EUA for immunosuppressed patients.
      • This author favors use in patients with risk factors for severe COVID-19 if patients are immunosuppressed early in the illness course (especially with impaired B-cell responses).
  • RCTs for prophylaxis, early and late COVID-19 treatment.
    • RCT of 1225 randomized for early COVID, ambulatory high-titer convalescent plasma therapy with the primary endpoint of hospitalization within 28d[6].
      • The pre-specified mITT excluded those not transfused. The primary endpoint occurred in 37 of 589 participants (6.3%) who received placebo control plasma and in 17 of 592 participants (2.9%) who received convalescent plasma (RR, 0.46; one-sided 95% upper bound confidence interval 0.733; P=0.004), corresponding to a 54% risk reduction.
        • The study suggests that early administration of high-titer convalescent plasma is effective and would have a similar impact if used in hospitals.
      • Convalescent plasma high titer has activity against Omicron (see NIH variant and agent activity chart for latest updates), and Omicron-recovered donors would expect activity to be higher activity.
  • Patients with prolonged active viral replication (low CT values) may have a response to CP usually combined with directly acting antivirals, e.g., RDV, Paxlovid or molnupiravir.
    • Usually, an immunosuppressed population, such as B-cell deficient, lymphoma or solid organ transplant patients.
      • For example, metaanalysis lymphoma patients found a mortality benefit in RCT and matched cohort studies (RR 0.63 [95% CI 0.50-0.79]}[5].
  • Risks
    • Pathogen transmission (~1 per 2 million transfusions for HIV/HBV/HCV)
    • Allergic transfusion reactions
    • Transfusion-associated circulatory overload (TACO)
    • Transfusion-related acute lung injury (TRALI)
      • Risk < 1 per 5000, potentially higher in COVID-19 due to pulmonary epithelial injury
      • Risk is lower if routine donor screening includes HLA antibody screening of female donors with a pregnancy history.

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

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

Special populations

  • Pregnancy or lactating women (ACOG):
    • Remdesivir: drug is considered safe to use, and women receiving the drug had better outcomes.
    • Dexamethasone: corticosteroid of choice if needed.
    • Nirmatrelvir/ritonavir: similar to HIV-protease antivirals considered safe to use in pregnancy. Experience has not seen safety signals, so it is recommended as the first line for treating COVID in pregnancy for outpatients.
  • Renal failure (GFR < 30 mL/min): despite label caution, many centers have used remdesivir widely, including in renal transplant patients, with safety and good outcomes.

Prevention

  • Data regarding appropriate interventions continue to evolve and generate great debate (e.g., the U.S.). Most countries and regions have lifted mandates. Suggestions below can be considered for high-risk or immunosuppressed patients as prudent in public/crowded settings or home environments.
    • 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.[26]
    • 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:
    • Post-exposure prophylaxis (PEP):
      • There are no Mabs currently available for this indication.
    • Pre-exposure prophylaxis (PrEP):
      • Tixagevimab/cilgavimab (Evusheld): EUA removed by FDA/HHS January 2023 due to lack of activity against circulating subvariant

Vaccines

  • Multiple vaccines worldwide, with those below used in the U.S.
    • FDA (Sept 11, 2023) issued an EUA for an updated vaccine. This is a monovalent mRNA spike protein vaccine based on Omicron subvariant XBB.1.5. ACIP has endorsed the FDA EUA with the following:
      • ≥ 5 years: single dose, as long as at least 2 months have passed since last immunization--regardless of prior vaccinations.
      • 6 months-5 years:
        • Previously vaccinated: 1 or 2 doses depending on the vaccine received.
        • Unvaccinated
      • Side effects are likely similar to earlier vaccines.
    • FDA has removed bivalent mRNA vaccines and also has withdrawn the Janssen vaccine.
    • Novavax EUA indications remain unchanged.
    • Interim COVID-19 vaccine recommendations are most easily seen in these CDC tables.
    • Also, see vaccine modules for details.
      • Moderna and Pfizer now have an EUA for children ≥ 6 months of age.
        • Children 6 months and older are now eligible for a booster dose.
      • Novavax subunit vaccine
        • Authorized for ages 12 years and older.
        • FDA gave an EUA (10/3/23) for an updated adjuvanted monovalent vaccine using XXB.1.5. omicron variant lineage.
          • Previous COVID vaccine (any): one dose
          • Unvaccinated: two doses
        • Original monovalent Novavax vaccine is no longer authorized for use in the US.
      • JNJ/Janssen
        • The vaccine supply expired on May 7, 2023.
        • No longer available, those who have received 1 or 2 doses of this vaccine should have a booster mRNA vaccine (Moderna or Pfizer).

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 dying patients.
    • Development of pulmonary aspergillosis. COVID-19-associated pulmonary aspergillosis (CAPA) consideration, especially in severely ill, in ICU or immunosuppressed.

Selected Drug Comments

Drug

Recommendation

Anakinra

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

Baricitinib

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

COVID-19 Convalescent Plasma

We are still waiting for a large RCT to be published to confirm hospital use; however, it is now the only antibody product available to use in people with COVID-19 and high-risk immunosuppressed, especially if vaccine non-responders/pts with B cell disorders. However, many trials used the agent too late (e.g., RECOVERY, others) in hospitalized patients for there to be a chance of helping patients in later phases of infection. Convalescent plasma works best as an antiviral. Current FDA EUA for both outpatients and hospitalized patients now enforces the use of high-titer plasma but is only available for immunosuppressed populations. It is best used within three days of illness onset or the first three days of hospitalization. Now indicated only for immunosuppressed populations. High titer units from people who have recovered from COVID-19 and have been immunized appear to generate the best titers and activity against known circulating variants, including Omicron. An outpatient study of early plasma administration showed a 54% reduction in hospitalization, demonstrating that high-titer units have a role if used early rather than late (in hospital) for average, high-risk patients[6]. NIH guidance has softened slightly with the lack of RCTs and acknowledges use in certain populations.

Dexamethasone

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

Molnupiravir

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

Nirmatrelvir/ritonavir

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

Remdesivir

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

Tocilizumab

This anti-IL6R mAb has had an up-and-down and now up history for COVID-19. The drug appears to not work as monotherapy; however, when combined with dexamethasone 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.

Vilobelimab

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

FOLLOW UP

  • For the immunized, the 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.
    • The CDC has revised this for healthcare personnel to 7 days or two serial negative antigen tests within 48 hours.
  • 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.
  • Quarantine and Isolation: (CDC, updated 5/11/23):
    • Transmission to others correlated with viral load and was often highest when asymptomatic and in the first days after the onset of symptoms.
    • Serial viral cultures of infected patients (early in the pandemic and Delta/early Omicron) were found to be 61% positive after d6 of symptom onset; however, secondary household transmission occurred primarily in < 6d[4].
    • Advice for COVID-19 (+) patients remains self-isolation/quarantine:
      • 5d isolation at home, staying away from others (as this is the most infectious period).
      • After d5, wear a high-quality mask around others at home or in public.
  • Long COVID, post-COVID Conditions
    • A wide range of symptoms that WHO defines as the continuation or development of new symptoms 3 months after the initial SARS-CoV-2 infection, with these symptoms lasting for at least 2 months with no other explanation.
    • Occurrence is greater in those who have had severe COVID-19.
    • Unimmunized and untreated people with risk factors appear more predisposed.
    • Common symptoms:
      • Fatigue (often post-exertional) interfering with usual activities
      • Brain fog, neurocognitive dysfunction
      • Dyspnea and chest pain
      • Headaches
      • Sleep problems
      • Depression or anxiety
      • Joint or muscle pain
    • Diagnosis and treatment: as the mechanism of disease is not understood, this impairs the ability to manage.
      • No current diagnostic tests secure the diagnosis, and some patients may lack a history of COVID-19. Alternatively, anchoring to COVID may be a bias that delays the investigation into other causes.
        • Studies are ongoing to understand the condition. Incidence estimates widely vary from < 5% to 20% or more.
      • Patient management currently needs to be individualized relating to patient complaints.

OTHER INFORMATION

  • Severe illness strikes the same populations at high risk for seasonal influenza complications (e.g., elderly, immunosuppressed, obese and those with comorbidities).
  • The case fatality rate remains higher than seasonal influenza, especially in advanced elderly and those with multiple comorbidities transplant patients.

Basis for recommendation

  1. NIH COVID-19 Treatment Guidelines. https://www.covid19treatmentguidelines.nih.gov/ (last updated 4/20/2023, accessed 10/9/23)

    Comment: Comprehensive GL is revised regularly with updates. Recent additions include two studies suggesting the safety of using the protease inhibitor Paxlovid during pregnancy (similar to the HIV protease inhibitor experience.

  2. Bhimraj A, et al. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19 [last updated 6/23/23, accessed 10/9/23]

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

References

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

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

  2. Deyoe JE, Kelly JD, Grijalva CG, et al. Association of culturable-virus detection and household transmission of SARS-CoV-2 - California and Tennessee, 2020-2022. J Infect Dis. 2023.  [PMID:36705269]

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

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

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

  4. 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.

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

    Comment: 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 co-packaging with ritonavir to boost nirmtrelavir levels, the SARS-CoV-2 specific protease inhibitor. Ritonavir, with its suicide inhibitor impact on CYP3A4, knocks out many patients who are on meds such as tacrolimus. Need to check for drug interactions. Patients on statins can have the drug held for the 5-day course.

  6. 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.

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

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

  8. 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).

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

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

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

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

  11. 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.

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

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

  13. 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.

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

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

  15. 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

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

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

  17. Spinner CD, Gottlieb RL, Criner GJ, et al. Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial. JAMA. 2020;324(11):1048-1057.  [PMID:32821939]

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

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

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

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

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

  20. Kam KQ, Yung CF, Cui L, et al. A Well Infant With Coronavirus Disease 2019 With High Viral Load. Clin Infect Dis. 2020;71(15):847-849.  [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, well known for regular coronavirus infections, influenza and others.

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

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

  22. Mizumoto K, Chowell G. Estimating Risk for Death from Coronavirus Disease, China, January-February 2020. Emerg Infect Dis. 2020;26(6):1251-1256.  [PMID:32168464]

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

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

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

  24. 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;368(6489):395-400.  [PMID:32144116]

    Comment: Although extraordinary measures may have slowed or stopped COVID-19 in China, questions remain about whether this is durable and at what cost to society. It may buy time, but effective drugs or vaccines remain in the future. 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."

  25. 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;382(14):1370-1371.  [PMID:32163697]

    Comment: A retrospective look at 366 children hospitalized for respiratory illness. SARS-CoV-2 was 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.

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

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

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

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

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Last updated: January 24, 2024