Coronavirus COVID-19 (SARS-CoV-2)

Paul G. Auwaerter, M.D.

MICROBIOLOGY

CLINICAL

Epidemiology

Transmission

Symptoms

Laboratory and imaging findings

  • No laboratory or imaging finding is diagnostic.
  • Severe COVID-19 may be associated with lymphopenia, thrombocytopenia, elevated inflammatory markers (CRP), and mild transaminase elevations.
    • Obtain chest imaging when clinically indicated. CT is not recommended solely to diagnose COVID-19, but CTAs are often obtained to evaluate for PEs.

Differential diagnosis

  • COVID-19 cannot be distinguished from other causes of viral respiratory infections, such as influenza, RSV, other respiratory viruses, or community-acquired pneumonia, based on clinical grounds only.
    • Consider multiplex testing for influenza and RSV, or an expanded respiratory panel, especially in patients with severe illness/immunocompromised or who are hospitalized.

COVID-19 testing:

  • NAATs generally have high sensitivity and very high specificity (>99%); clinical sensitivity varies with assay, timing, specimen type, and collection quality.
    • However, note that viral RNA may remain detectable after the infectious virus is no longer present.
    • A negative NAAT does not completely exclude infection when pretest probability is high, particularly with early testing or suboptimal specimen collection.
    • Cycle-threshold values should not be used as standardized measures of contagiousness, although longitudinal results from the same assay may occasionally help evaluate persistent infection in profoundly immunocompromised patients.
  • Antigen testing provides rapid point-of-care or home diagnosis but is less sensitive (estimated ~45-70% sensitivity compared to PCR; sensitivity depends on sampling and timing, e.g., higher at peak viral burden during early symptomatic illness and high viral burden; specificity ~99%).
    • A negative antigen result is presumptive; repeat testing after 48 hours or obtain a NAAT when clinical suspicion is high.

Isolation/Infectiousness

  • Community settings: CDC uses a symptom-based respiratory-virus approach rather than a fixed COVID-specific isolation period.
    • Remain home until symptoms are improving overall and fever has been absent for ≥24 hours without antipyretics, followed by 5 days of added precautions (eg, masking, ventilation, distancing, and testing when around others).
  • Viral shedding as an infectious risk:
    • Infectious virus is shed for an average of 5–7 days in immunocompetent patients, with a minority remaining culture-positive through day 10.
      • There is no single reliable duration for immunocompromised patients.
        • Profound humoral immune defects, particularly B-cell depletion, hematologic malignancy, CAR-T therapy, or transplantation, may permit replication-competent virus to persist for weeks and occasionally months.
        • PCR positivity alone does not establish infectiousness. Cycle thresholds (Ct) should not be used as validated cutoffs for isolation, but are sometimes used roughly to gauge ongoing replication in immunocompromised patients, especially if values are < 25 Ct. Values are not standardized and vary across platforms; consult ID for guidance.
      • Serial antigen testing may be informative in selected prolonged cases.

SITES OF INFECTION

TREATMENT

General

  • Key issues in COVID care
    • Test promptly if the result will change the approach and treatment, or infection control.
      • Assess risk for disease severity
    • Treat truly high-risk patients early; check for drug interactions.
    • Severe hospitalized disease is increasingly concentrated in elderly/immunocompromised patients.
    • Prolonged replicating infection is primarily an immunocompromised-host problem.
  • Location of care
    • In-hospital care for the seriously ill, those requiring oxygen, or those who are confused.
  • In-hospital supportive care
    • In hospitalized patients with acute respiratory illness, test for influenza or RSV infection when results may alter treatment or infection control.
      • Viral co-infections do occur.
    • Oxygen and mechanical ventilation, if needed.
      • SpO₂ ≤94% on room air is commonly used to define severe COVID-19 and therefore informs treatment decisions such as supplemental oxygen, disease trajectory, timing, and host risks.
        • Pulse oximetry may overestimate arterial oxygen saturation in patients with darker skin pigmentation. Consider investigating a discordant clinical picture with arterial blood gas/co-oximetry when appropriate.
  • Secondary infections, especially in severe/critically ill patients:
    • If bacterial or fungal superinfection is suspected, obtain appropriate cultures and imaging.
      • For suspected CAPA, lower-respiratory sampling and BAL galactomannan are generally more informative. Serum galactomannan and β-D-glucan may provide supportive but imperfect evidence.
      • Often “nosocomial” pathogens (ESBL Gram-negatives, P. aeruginosa, A. baumannii, Aspergillus spp. )
    • Factors to consider
      • Antibiotics are frequently used in hospitalized patients with pneumonia, which may be unnecessary in less severely ill patients with COVID-19 pneumonia.

Drug Treatments

  • Criteria for Identifying High-Risk Individuals:
    • Not all comorbidities confer the same risk (see the risk factors section above).
      • Age ≥75 years, immunocompromised states (particularly B-cell dysfunction), and advanced organ disease remain the dominant predictors of severe COVID-19 outcomes in the post-vaccine era.
      • Other conditions act as additive modifiers, with cumulative risk increasing as the number of minor factors rises.
  • Patient considerations for COVID-directed therapies:

    • Clinical scenario

      Antivirals

      Immunomodulators

      High-titer COVID Convalescent Plasma

      Mild-moderate, no oxygen requirement, low risk

      Usually none

      None

      None

      Mild–moderate, no O₂; high risk for progression

      Nirmatrelvir/ritonavir ≤5 d preferred

      Remdesivir IV ×3 d ≤7 d alternative

      Molnupiravir if preferred agents cannot be used

      None

      Not routine; consider in immunocompromised patients, particularly impaired humoral immunity, when active infection is present

      Profoundly immunocompromised / B-cell deficient, early COVID

      Nirmatrelvir/ritonavir or remdesivir

      Individualized longer/additional antiviral courses may be considered for persistent disease

      None unless hypoxemia/inflammatory COVID develops

      Consider early high-titer CCP, particularly in the context of anti-CD20 therapy, B-cell malignancy, CAR-T/HCT, or major antibody deficiency

      Hospitalized, no O₂ requirement

      Consider antiviral therapy for early infection/high risk, especially in immunocompromised patients.

      None

      Consider selectively for profoundly immunocompromised/humoral-deficient patients

      Hospitalized, conventional low-flow O₂

      Remdesivir, particularly early in illness

      Dexamethasone

      Not routine. Consider if there is significant immunocompromise, particularly an absent/poor antibody response or evidence of persistent viral replication.

      Rapidly increasing O₂ requirement / progressive severe COVID

      Remdesivir may still have a role if relatively early; antiviral treatment deserves particular consideration in immunocompromised patients.

      Dexamethasone + baricitinib OR tocilizumab; add an additional immunomodulator (baricitinib or tocilizumab) during progression rather than waiting for corticosteroid failure.

      Consider concurrently whether profound immunocompromise and ongoing replication are plausible.

      HFNC or NIV

      Benefit of starting remdesivir is less certain as inflammatory disease predominates; individualize, especially with immunodeficiency

      Dexamethasone + baricitinib or tocilizumab

      Not routine; consider for significant humoral deficiency/persistent infection

      Mechanical ventilation/ECMO

      Routine initiation of antiviral therapy has limited evidence of benefit this late; consider unusual situations with demonstrated/persistent viral replication.

      Dexamethasone + baricitinib or tocilizumab

      Not routine for critical COVID itself; potentially useful if severe humoral deficiency with persistent viral replication.

      Prolonged/relapsing COVID in B-cell–depleted patient

      Extended/additional remdesivir and/or other antiviral strategies (combination with molnupirivir or nirmatrelvir/ritonavir) may be considered case-by-case

      Avoid, unless there is convincing concomitant inflammatory lung disease

      Important consideration even late in illness; often combined with antiviral therapy

Outpatient

  • Nirmatrelvir/ritonavir(Paxlovid):
    • Begin within 5 days of symptom onset in patients at high risk for progression.
      • Standard dose: nirmatrelvir 300 mg + ritonavir 100 mg twice daily for 5 days.
      • Renal dosing (eGFR):
        • 30–59 mL/min: 150/100 mg twice daily
        • eGFR <30 mL/min, including hemodialysis: 300/100 mg once on day 1, then 150/100 mg once daily on days 2–5; administer after dialysis on dialysis days.
      • Review all medications for clinically important CYP3A interactions.
    • COVID-19 rebound may occur after antiviral therapy or untreated infection and ordinarily should not deter indicated treatment.
  • Remdesivir:
    • Preferred alternative when nirmatrelvir/ritonavir cannot be used.
      • CDC continues to recommend an RDV 200 mg IV on day 1, then 100 mg IV daily on days 2 and 3; initiate within 7 days of symptom onset.
        • At our institution, selected profoundly immunocompromised patients may receive a 5-day outpatient course rather than the 3-day regimen.
      • No dosage adjustment is required for renal impairment, including dialysis.
  • Molnupiravir
    • Alternative only when preferred therapies are unavailable or clinically inappropriate.
      • Adults (only): 800 mg orally every 12 hours for 5 days, to be started within 5 days of symptom onset.
      • Lower efficacy than nirmatrelvir/ritonavir or remdesivir and limited evidence of benefit in vaccinated populations.
      • Avoid during pregnancy; follow current reproductive precautions (see module for details).
  • High-titer COVID-19 convalescent plasma:
    • FDA-licensed for treatment of COVID-19 in patients with immunocompromising disease or receiving immunosuppressive treatment who are at risk for severe progression, in either outpatient or inpatient settings.
    • It may be particularly useful in patients with profound humoral immune defects or persistent viral replication; consider availability and current neutralizing activity.
    • ID consultation is reasonable for prolonged infection or combination treatment.
  • Drugs with no place in SARS-CoV-2 treatment: ivermectin, chloroquine (CQ), or hydroxychloroquine (HCQ).

Inpatient

  • Because pivotal trials largely preceded widespread vaccination and infection-derived immunity, absolute treatment effects may be smaller in current populations, although benefit remains greatest in patients at highest risk.
  • Remdesivir (RDV)
    • For hospitalized patients with COVID-19, the greatest benefit is expected when treatment is initiated early in the viral phase, before the need for advanced mechanical ventilatory support.
      • Standard inpatient course is 5 days (200 mg IV on day 1, then 100 mg IV daily)
      • Patients with inadequate clinical response or profound immunocompromise may warrant a longer course.
      • No renal dose adjustment is required, including for patients on dialysis.
  • Dexamethasone
    • 6 mg PO/IV daily for up to 10 days (or until discharge) in patients requiring supplemental oxygen, including those on mechanical ventilation.
      • Do not use corticosteroids solely to treat COVID-19 in patients who do not require supplemental oxygen unless another indication exists
  • Additional immunomodulation: In patients receiving systemic corticosteroids who have rapidly progressive severe or critical COVID-19, add baricitinib or tocilizumab. IDSA Guidance[2] finds that current evidence does not establish clear overall superiority of any single agent; selection may depend on route, renal/hepatic function, cytopenias, infection risk, drug availability, and institutional experience; level of evidence is low (JH favors baricitinib due to potentially fewer adverse events with use compared to tocilizumab).
    • Tocilizumab.
      • 8 mg/kg IV (maximum 800 mg) once; a second dose may be considered occasionally.
    • Baricitinib
      • 4 mg PO daily (renal adjustment required) for up to 14 days or discharge.
    • Alternative immunomodulators:
      • If baricitinib and tocilizumab cannot be used or are unavailable, current IDSA guidance addresses abatacept and infliximab as alternatives.
        • Specialist consultation suggested.
  • COVID convalescent plasma (CCP): for immunocompromised patients only[22]. The optimal dose, frequency, and duration are unknown; the following are expert-guidance approaches rather than FDA-specified regimens

    • Acute COVID-19, immunocompromised

      1–2 units high-titer CCP; typically ~200 mL/unit

      Profound B-cell deficiency / high viral burden

      2 units initially if volume status permits

      Persistent/protracted SARS-CoV-2 infection

      1–2 units initially, with repeat dosing guided by clinical and virologic response

      One proposed regimen for persistent infection

      1 unit every other day × 3 doses, often with remdesivir; expert-opinion regimen, not an FDA-specified schedule

      Repeat course

      Expert guidance suggests considering redosing at ~7 days if persistent infection/high viral burden remains

      Pediatrics

      5–10 mL/kg, up to the adult volume of ~200 mL; evidence is more limited

Special populations

  • Pregnancy and lactation:
    • Do not withhold otherwise indicated COVID-19 therapy solely because of pregnancy or lactation.
    • Nirmatrelvir/ritonavir is the preferred outpatient antiviral for eligible pregnant patients; remdesivir is an alternative.
    • Use corticosteroids for hypoxemic COVID-19 according to usual severity criteria.
  • Renal impairment:
    • Nirmatrelvir/ritonavir now has FDA-labeled dose reductions for moderate and severe renal impairment, including hemodialysis.
    • Remdesivir requires no dosage adjustment for renal impairment or dialysis.
  • Persistent/protracted SARS-CoV-2 infection:
    • Consider in profoundly immunocompromised patients, especially if B-cell depleted, who have persistent or relapsing respiratory symptoms, compatible imaging abnormalities, and continued virologic evidence of infection.
      • Extended antiviral courses, sequential or combination antiviral therapy, and/or high-titer convalescent plasma are used in selected patients, but the optimal regimen and duration remain undefined.
        • Consultation with ID and consideration of antiviral resistance testing or sequencing are appropriate in difficult cases. Ct values are sometimes used to guide, but should not be viewed as a validated treatment endpoint.
      • Serial same-platform molecular or antigen results may occasionally be followed as adjuncts, but clinical response and sustained virologic clearance should not be defined solely by a specific Ct threshold.

Prevention

  • General measures recommended, especially if at higher risk for severe infection:
    • Be up to date with recommended vaccinations.
    • During periods of increased respiratory virus activity or after exposure, higher-risk patients may benefit from high-quality masks/respirators, improved indoor ventilation/air filtration, distancing from ill household members when feasible, and prompt testing.
    • Stay home when acutely ill and use source control around vulnerable individuals.
  • Healthcare settings:
      • Mild–moderate illness, not moderately/severely immunocompromised: Transmission-Based Precautions for ≥10 days from symptom onset, plus afebrile for ≥24 hours without antipyretics and improving symptoms.
      • Asymptomatic patients: 10 days from first positive test.
      • Severe/critical illness, not significantly immunocompromised:10–20 days, plus clinical improvement and ≥24 hours afebrile.
      • Moderately/severely immunocompromised: Replication-competent virus may persist beyond 20 days; recommend a test-based strategy, plus ID expertise when available.
      • The CDC test-based criterion:
        • Two consecutive negative respiratory specimens collected 48 hours apart, using either antigen testing or NAAT; symptomatic patients should additionally be afebrile and have improving symptoms.
  • Therapeutic Interventions:
    • Post-exposure prophylaxis (PEP):
      • No mAbs are currently available for this indication.
      • Ensitrelvir (FDA approved 2026):
        • First FDA-approved oral COVID-19 post-exposure prophylaxis in adults and adolescents ≥12 years following contact with a person with COVID-19. It is not FDA-approved in the U.S. for treatment of established COVID-19 or for pre-exposure prophylaxis.
          • Timing/dose: Start as soon as possible and within 72 hours after exposure; assess for drug interactions before prescribing.
            • 375 mg orally on day 1, then 125 mg once daily on days 2–5, with or without food.
            • Important:Ensitrelvir is a strong CYP3A inhibitor; review drug interactions before prescribing.
              • Confirm pregnancy status in patients of reproductive potential.
          • Efficacy: In SCORPIO-PEP, symptomatic, PCR-confirmed COVID-19 through day 10 occurred in 2.9% with ensitrelvir vs 9.0% with placebo (67% relative risk reduction; absolute reduction 6.1%; NNT ≈16)[4].
            • Household exposure was the trial setting; however, profound immunocompromise was essentially unrepresented, so efficacy in patients with severe B-cell deficiency, CAR-T therapy, hematologic malignancy, or transplantation is extrapolated.
    • Pre-exposure prophylaxis (PrEP):
      • Pemivibart (PEMGARDA) is available under FDA EUA for PrEP in adults and adolescents ≥12 years and weighing ≥40 kg who are moderately/severely immunocompromised, are unlikely to mount an adequate vaccine response, are not currently infected, and have not had a known recent exposure.
        • The EUA was initially granted biological plausibility for an immunobridging approach rather than clinical outcomes data. The CANOPY Phase 3 trial demonstrated efficacy and safety[15].
          • Anaphylaxis occurred in 4/623 (0.6%); administer where anaphylaxis can be treated immediately and observe during infusion and for ≥2 hours afterward
          • It is not authorized for treatment.
          • Activity is variant-dependent; ongoing genomic surveillance is required.
            • Use only when current FDA susceptibility information indicates activity against circulating variants.
        • Regulatory note: HHS has announced that COVID-19 drug and biologic EUAs will terminate on June 29, 2027, unless the products obtain another regulatory pathway.
        • It is authorized for adults and children ≥ 12 years and >40 kg for pre-exposure prophylaxis in people who are moderately to severely immunocompromised or who are receiving immunosuppressive medications that are unlikely to mount a sufficient immune response to COVID-19 vaccination.

Vaccines

  • See the COVID vaccine module for details.
    • Vaccination remains most clinically important for older adults and people at increased risk for severe disease, particularly immunocompromised patients.
    • 2026–27 U.S. vaccines: FDA selected a monovalent JN.1-lineage XFG antigen for all U.S. 2026–27 COVID vaccines.
      • Current FDA-approved products include Comirnaty, Spikevax, MNEXSPIKE, and Nuvaxovid, with age/risk indications varying by product.
      • Immunocompromised patients: IDSA’s September 2026 guideline strongly recommends age-appropriate 2026–27 vaccination for immunocompromised adults and children; an additional seasonal dose may extend protection, and household contacts should be up to date.

Complications

  • Most COVID-19 is uncomplicated in the current era, but severe disease may cause:
    • Respiratory: Hypoxemic respiratory failure/ARDS; severe cases may progress to sepsis, shock, and multiorgan dysfunction.
    • Thromboembolic: DVT and pulmonary embolism occur predominantly in hospitalized and critically ill patients.
      • VTE: Give standard pharmacologic thromboprophylaxis to hospitalized patients unless contraindicated.
        • In critically ill patients without another indication for therapeutic anticoagulation, prophylactic-intensity dosing is preferred[11].
        • Consider therapeutic-dose heparin in selected non-ICU patients with low bleeding risk; individualize according to institutional/ASH guidance.
        • Routine anticoagulation is not recommended for stable outpatients or after discharge unless another indication exists.
    • Cardiovascular: Myocardial injury, acute coronary events, arrhythmias, heart failure, and pericardial disease may occur, particularly with severe infection. True myocarditis is uncommon but can occasionally be severe.
    • Neurologic: Encephalopathy is the most common neurologic complication of severe illness; ischemic stroke occurs infrequently, but risk is increased during and after acute infection. Encephalitis is rare.
    • Renal: Acute kidney injury occurs principally with severe/critical illness and may require renal replacement therapy.
  • Secondary infection:
    • Bacterial or fungal superinfection is primarily a concern in critically ill, mechanically ventilated, immunocompromised, or prolonged-hospitalization patients.
    • Avoid routine antibacterial therapy for uncomplicated COVID-19 pneumonia.
    • Obtain cultures and other testing when clinical findings suggest superinfection and de-escalate promptly when unsupported.
    • Consider COVID-associated pulmonary aspergillosis (CAPA) in compatible severe/critical illness, particularly in immunocompromised patients.
  • Multi-system Inflammatory Syndromes (children MIS-C; adults MIS-A)

    MIS-C

    MIS-A

    Age

    <21 years by CDC surveillance definition

    ≥21 years

    Typical timing

    ~2-6 weeks post-infection

    Several weeks after

    Key phenotypes

    Fever + marked inflammation + ≥2 organ-system manifestations; GI, cardiac, shock, mucocutaneous and hematologic findings prominent

    Fever + inflammation + prominent cardiac disease, shock, GI and/or mucocutaneous disease

    Respiratory disease

    May occur, but pulmonary disease is not required

    Often less dominated by pneumonitis than acute severe COVID

    Frequency

    Rare (but more common than MIS-A)

    Very rare, incidence poorly established

    • Current CDC MIS-C definition[32]: for surveillance, not diagnostic.
      • The 2023 CSTE/CDC surveillance definition requires age <21 years, no better alternative diagnosis, fever ≥38°C, hospitalization/death, CRP ≥3 mg/dL (30 mg/L), and new manifestations in at least 2 of 5 categories: cardiac involvement, mucocutaneous involvement, shock, GI involvement, or hematologic involvement (platelets <150,000/µL or ALC <1,000/µL). A confirmed case also requires evidence of SARS-CoV-2 infection—NAAT or antigen within 60 days, or compatible serology.
        • Classic presentation is a child who has recovered from COVID and then, weeks later, develops persistent fever, abdominal pain/vomiting/diarrhea, rash/conjunctivitis, hypotension/shock, elevated CRP, lymphopenia/thrombocytopenia, and often elevated troponin/BNP or ventricular dysfunction.
        • MIS-C management[26]: supportive care, plus
          • IVIG 2 g/kg plus low- to moderate-dose glucocorticoids (roughly a prednisone/methylprednisolone equivalent of 1–2 mg/kg/day).
            • Other options include pulse glucocorticoids and anakinra.
            • Fluid status and ventricular function should be assessed before IVIG because some patients have severe myocardial dysfunction and cannot tolerate a rapid 2-g/kg volume load.
          • Low-dose aspirin 3–5 mg/kg/day (maximum 81 mg/day) is generally used unless bleeding risk or marked thrombocytopenia is present, and is continued until platelet counts normalize and coronary arteries are confirmed to be normal at ≥4 weeks. Anticoagulation is not a universal requirement.
        • MIS-A: given rarity, no validated guidelines. Supportive care, and most published series have used systemic corticosteroids.

Selected Drug Comments

Drug

Recommendation

Anakinra

Anakinra is a recombinant human IL-1 receptor antagonist. Although FDA EUA permits use in selected hospitalized adults requiring oxygen who are at risk for progression, IDSA suggests against its routine use for severe COVID-19 because evidence is low certainty and the suPAR-based selection strategy used in SAVE-MORE is not routinely available in the U.S.

Baricitinib

JAK 1/2 inhibitor that may be added to corticosteroids for rapidly progressive severe/critical disease. The drug may also be considered for hypoxemic patients who cannot receive dexamethasone. Due to fewer side effects and similar or better efficacy than tocilizumab (though data for direct comparison are limited), it is now favored at some centers, though robust head-to-head trials comparing the two are lacking.

COVID-19 Convalescent Plasma

FDA-licensed high-titer product for immunocompromised patients, particularly those with profound humoral immune deficiency or persistent infections.

Dexamethasone

Improves outcomes in hypoxemic hospitalized patients; do not use solely for COVID-19 in patients not requiring oxygen.

Ensitrelvir

First FDA-approved oral post-exposure prophylaxis; evidence is based on household exposure, but data are very limited in profoundly immunocompromised contacts.

Molnupiravir

This oral nucleoside antiviral has no significant drug interactions, so it is used as an alternative to RDV or Paxlovid despite trials showing lower efficacy than Paxlovid or RDV. Some have voiced concerns about mutagenesis and the potential to drive new viral variants. The drug should not be used in children, adolescents, pregnant and breastfeeding women.

Nirmatrelvir/ritonavir

A boosted protease inhibitor antiviral, the preferred oral outpatient antiviral for high-risk patients. The greatest practical limitation is CYP3A drug interactions, which require careful checking before prescribing. Renal dosing is now available even for eGFR <30 mL/min/ and those on iHD.

Pemivibart

PrEP for moderately or severely immunocompromised patients while still FDA-authorized and variant-susceptible. Requires redosing every 3 months and has a small anaphylaxis risk. Cost and infusion logistics may limit access.

Remdesivir

When nirmatrelvir/ritonavir cannot be used, regimens include standard 5-day courses for inpatients with severe COVID and 3- or 5-day courses for outpatients, though these are often logistically challenging to coordinate for both clinicians and patients. No renal dose adjustment required.

Tocilizumab

This anti-IL6R mAb may be added to systemic corticosteroids in rapidly progressive severe or critical COVID-19 when an additional immunomodulator is indicated. Baricitinib is an alternative.

FOLLOW UP

OTHER INFORMATION

Basis for recommendation

  1. CDC. Long COVID Clinical Guidance. [updated 3/9/26; accessed 9/16/26].

    Comment: Current U.S. clinical guidance emphasizes that Long COVID is a clinical diagnosis without a definitive laboratory test. Evaluation should address alternative or coexisting diagnoses, with symptom-directed management and attention to post-exertional malaise when recommending rehabilitation.



  2. IDSA. Guidelines on the Treatment and Management of Patients with COVID-19. [last updated 9/26/2026; accessed 10/10/26].

    Comment: With the retirement of NIH Guidelines, these IDSA Guidelines are the lead resource on therapy for COVID-19. One central area where our JH guide differs is in convalescent plasma use, which we at JH believe has a more prominent role in immunosuppressed patients who cannot generate meaningful antibody responses from vaccines. High-titer convalescent plasma is now FDA-approved for treating immunosuppressed patients. For those with advancing severe COVID pneumonia, this GL now states  that either baricitinib or tocilizumab is appropriate, with low levels of evidence. At JH, we feel the same but marginally favor baricitinib because it has fewer potential adverse effects in the critically ill. Pediatric antiviral recommendations are now incorporated.



  3. Belden K, et al. IDSA 2026 Guidelines on the Use of Vaccines for the Prevention of Seasonal COVID-19, Influenza, and RSV Infections in Immunocompromised Patients. (last updated 9/2/26, accessed 10/13/2026)

    Comment: Current evidence-based seasonal respiratory vaccine guidance for immunocompromised patients. Strongly recommends age-appropriate 2026–27 COVID vaccination; an additional seasonal dose may extend protection, and household contacts should remain appropriately vaccinated.

References

  1. Hayden FG, Shinkai M, Clark TW, et al. Ensitrelvir for Covid-19 Postexposure Prophylaxis in Household Contacts. N Engl J Med. 2026;394(19):1905-1915.  [PMID:42127390]

    Comment: Phase 3 household-contact PEP trial supporting FDA approval of ensitrelvir. Symptomatic PCR-confirmed COVID-19 through day 10 occurred in 2.9% with ensitrelvir vs. 9.0% with placebo (67% relative risk reduction). Profound immunocompromise was essentially unrepresented, so efficacy in this population is extrapolated.

  2. Soff SP, Moffitt R, Sharathkumar A, et al. A comprehensive assessment of the impact of COVID variant and vaccination on venous thromboembolism and mortality. Res Pract Thromb Haemost. 2026;10(3):103415.  [PMID:42079673]

    Comment: Large N3C analysis demonstrates the marked decline in COVID-associated VTE over time. During the contemporary Omicron period (May 2022–November 2024), adjusted VTE risk was no longer significantly greater than with other acute respiratory infections. Vaccination was also associated with lower VTE risk.

  3. Farokhnia A, Faro LK, Tian Y, et al. Extended nirmatrelvir-ritonavir for persistent COVID-19: Systematic review with individual patient data. Int J Infect Dis. 2026;167:108558.  [PMID:41856461]

    Comment: Systematic review with individual patient data addressing extended nirmatrelvir/ritonavir for persistent COVID-19. Reports frequent clinical/virologic improvement in selected cases, but evidence is heterogeneous and predominantly observational. Evidence presented here does not establish an optimal regimen or duration.

  4. Baden LR, Shah NS, Liu STH, et al. Nirmatrelvir-ritonavir targeting viral persistence in post-COVID-19 condition (long COVID) in the USA (RECOVER-VITAL): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Infect Dis. 2026.  [PMID:42673984]

    Comment: RECOVER-VITAL randomized 959 adults with Long COVID; 15- or 25-day nirmatrelvir/ritonavir produced no significant benefit in cognitive, autonomic, or exercise phenotypes.

  5. Butler CC, Pinto AD, Harris V, et al. Oral Nirmatrelvir-Ritonavir for Covid-19 in Higher-Risk Outpatients. N Engl J Med. 2026;394(16):1583-1594.  [PMID:42019019]

    Comment: In the largely vaccinated PANORAMIC and CanTreatCOVID populations, hospitalization/death rates were very low, and neither trial demonstrated a significant reduction with nirmatrelvir/ritonavir. This does not overturn the recommendation to treat genuinely high-risk patients—CDC still lists nirmatrelvir/ritonavir as first-line—but it strongly supports the existing theme that contemporary absolute benefit is concentrated in those at highest baseline risk.

  6. Kuo RN, Chen W, Shau WY, et al. Real-World Effectiveness of Nirmatrelvir-Ritonavir Against Severe Outcomes of COVID-19 in Taiwan: A Nationwide Population-Based Cohort Study. Open Forum Infect Dis. 2025;12(9):ofaf553.  [PMID:40988922]

    Comment: A large Omicron-era population cohort in Taiwan supports the continued real-world effectiveness of nirmatrelvir/ritonavir against hospitalization, ICU admission, mechanical ventilation, and death. As an observational study, residual confounding remains possible.

  7. Weinstein E, Paredes R, Gardner A, et al. Extended nirmatrelvir-ritonavir treatment durations for immunocompromised patients with COVID-19 (EPIC-IC): a placebo-controlled, randomised, double-blind, phase 2 trial. Lancet Infect Dis. 2025;25(11):1243-1253.  [PMID:40675169]

    Comment:
    Randomized trial comparing 5-, 10-, and 15-day nirmatrelvir/ritonavir courses in immunocompromised outpatients. Extended courses did not demonstrate a significant advantage for the primary virologic endpoint, although rebound was numerically less frequent; the findings do not support routine extension for every immunocompromised patient.

  8. Siegal DM, Tseng EK, Schünemann HJ, et al. American Society of Hematology living guidelines on use of anticoagulation for thromboprophylaxis for patients with COVID-19: executive summary. Blood Adv. 2025;9(6):1247-1260.  [PMID:39437797]

    Comment: Current ASH evidence-based guidance for anticoagulation in hospitalized patients with COVID-19. For critically ill patients without suspected or confirmed VTE, prophylactic-intensity anticoagulation is favored over empiric intermediate- or therapeutic-intensity dosing. Therapeutic-intensity heparin may be considered in selected acutely ill, non-ICU patients after individualized assessment of thrombosis and bleeding risk. All recommendations are based on low to very low certainty of evidence.

  9. Gupta G, Buonsenso D, Wood J, et al. Mechanistic Insights Into Long Covid: Viral Persistence, Immune Dysregulation, and Multi-Organ Dysfunction. Compr Physiol. 2025;15(3):e70019.  [PMID:40474772]

    Comment: The authors narratively integrate mechanisms relevant to long COVID and viral persistence, as well as immune dysregulation, and lay the groundwork for understanding how antiviral resistance and viral persistence may impact therapy outcomes.

  10. Amstutz A, Schandelmaier S, Ewald H, et al. Effects of Janus kinase inhibitors in adults admitted to hospital due to COVID-19: a systematic review and individual participant data meta-analysis of randomised clinical trials. Lancet Respir Med. 2025;13(6):530-544.  [PMID:40378861]

    Comment: Individual-participant-data meta-analysis of 12 randomized trials (12,902 participants) found lower mortality with JAK inhibitors. Trials largely predated the current immunity/variant era but provide the strongest aggregate randomized evidence supporting baricitinib-class immunomodulation in hospitalized COVID-19.

  11. Mafi JN, Vangala S, Kapral MK, et al. Hospitalizations and Mortality Among Older Adults With and Without Restricted Access to Nirmatrelvir-Ritonavir. JAMA. 2025.  [PMID:39976986]

    Comment: Natural experiment in a highly vaccinated older Ontario population addressing the smaller absolute benefit of nirmatrelvir/ritonavir in patients with substantial background immunity.

  12. Wolfe CR, Cohen J, Mahoney K, et al. Safety and Efficacy of Pemivibart, a Long-Acting Monoclonal Antibody, for Prevention of Symptomatic COVID-19: Interim Results From a Phase 3 Randomized Clinical Trial (CANOPY). Clin Infect Dis. 2025;81(3):439-450.  [PMID:40410927]

    Comment: Phase 3 pemivibart program. The randomized non-immunocompromised cohort demonstrated a substantial reduction in symptomatic COVID-19 at 6 and 12 months. The immunocompromised cohort was evaluated primarily by immunobridging rather than randomized clinical efficacy. Anaphylaxis occurred in 4/623 (0.6%) pemivibart recipients.

  13. Stone EC, Okasako-Schmucker DL, Taliano J, et al. Risk period for transmission of SARS-CoV-2 and seasonal influenza: a rapid review. Infect Control Hosp Epidemiol. 2025;46(3):227-235.  [PMID:39989317]

    Comment: Rapid review of infectious virus shedding in predominantly previously healthy adults. Culture positivity falls substantially during the first week, with most individuals no longer shedding culturable virus by approximately day 10. These estimates should not be extrapolated to profoundly immunocompromised patients.

  14. Zaremba S, Focosi D, Pruter WW, et al. COVID-19 convalescent plasma for B-cell depleted patients: a systematic review and individual patient data meta-analysis. Front Med (Lausanne). 2025;12:1658593.  [PMID:41179884]

    Comment: A systematic review and individual patient data analysis in B-cell-depleted patients found an association between CCP treatment and favorable 60-day survival, particularly with vaccine-boosted contemporary plasma. The evidence is largely observational, so selection bias and residual confounding limit the strength of any causal inference.

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

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

  16. Arevalo-Rodriguez I, Mateos-Haro M, Dinnes J, et al. Laboratory-based molecular test alternatives to RT-PCR for the diagnosis of SARS-CoV-2 infection. Cochrane Database Syst Rev. 2024;10:CD015618.  [PMID:39400904]

    Comment: Cochrane systematic review of 64 studies evaluating laboratory molecular assays for SARS-CoV-2. Performance varied by platform: selected RT-PCR approaches had pooled sensitivity ~95% and specificity ~99.7%, while TMA assays had sensitivity ~98% and specificity ~99%. Results support the high diagnostic accuracy of laboratory NAATs but also emphasize that performance varies by assay, specimen, and study methodology. As such, a single universal sensitivity estimate should not be assumed.

  17. Erlandson KM, Geng LN, Selvaggi CA, et al. Differentiation of Prior SARS-CoV-2 Infection and Postacute Sequelae by Standard Clinical Laboratory Measurements in the RECOVER Cohort. Ann Intern Med. 2024;177(9):1209-1221.  [PMID:39133923]

    Comment: Large RECOVER cohort evaluation found that commonly available laboratory measurements did not reliably distinguish patients with Long COVID from those with prior SARS-CoV-2 infection without post-acute sequelae, supporting the current view that no routine laboratory biomarker establishes the diagnosis.

  18. O'Halloran JA, Ko ER, Anstrom KJ, et al. Abatacept, Cenicriviroc, or Infliximab for Treatment of Adults Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial. JAMA. 2023;330(4):328-339.  [PMID:37428480]

    Comment: Randomized trial informing contingency use of abatacept or infliximab. Abatacept showed a nonsignificant mortality trend, and infliximab showed a mortality signal in secondary analysis. These data support only conditional, low-certainty use when preferred additional immunomodulators are unavailable.

  19. Bloch EM, Focosi D, Shoham S, et al. Guidance on the Use of Convalescent Plasma to Treat Immunocompromised Patients With Coronavirus Disease 2019. Clin Infect Dis. 2023;76(11):2018-2024.  [PMID:36740590]

    Comment: Expert guidance focused on immunocompromised patients, including persistent SARS-CoV-2 infection. Optimal CCP dose, frequency, and duration remain uncertain; suggested 1–2-unit and repeat-dosing strategies are expert-practice approaches rather than FDA-specified regimens.

  20. Peterson JH, Paranjape NS, Grundlingh N, et al. Outcomes and Adverse Effects of Baricitinib Versus Tocilizumab in the Management of Severe COVID-19. Crit Care Med. 2023;51(3):337-346.  [PMID:36729439]

    Comment: A retrospective analysis of outcomes and adverse effects, which included 956 participants from 11 hospitals in the state of Georgia (U.S.) who received either TCZ or BAR, found no differences in mortality following propensity-score matching. However, adverse effects were significantly higher in the TCZ group compared with the BAR group: secondary infections (32% vs 22%; p < 0.01); thrombotic events (24% vs 16%; p < 0.01); and acute liver injury (8% vs 3%; p < 0.01). These two studies suggest fewer adverse outcomes and lower mortality with BAR.

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

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

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

    Comment: A randomized trial of early high-titer outpatient CCP found a 54% relative reduction in hospitalization when administered within 9 days of symptom onset, with greater biologic plausibility for early antiviral use. The trial enrolled a broader outpatient population than the current FDA-licensed indication, which is restricted to patients with immunocompromising disease or immunosuppressive treatment.

  23. Henderson LA, Canna SW, Friedman KG, et al. American College of Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children Associated With SARS-CoV-2 and Hyperinflammation in Pediatric COVID-19: Version 3. Arthritis Rheumatol. 2022;74(4):e1-e20.  [PMID:35118829]

    Comment: Multidisciplinary consensus guidance for diagnosis and management of MIS-C. Supports IVIG 2 g/kg plus low-to-moderate-dose glucocorticoids as first-line immunomodulatory therapy for most hospitalized patients; assessment of ventricular function and volume status before IVIG; low-dose aspirin in appropriate patients; and escalation with high-dose corticosteroids or anakinra for refractory disease. Although published in 2022, these principles remain consistent with current CDC clinical-care guidance.

  24. 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: Pivotal randomized trial establishing the efficacy of 5-day nirmatrelvir/ritonavir in unvaccinated high-risk outpatients, with an ~88% relative reduction in hospitalization or death. Conducted before Omicron and widespread background immunity, so the magnitude of absolute benefit should not be extrapolated directly to contemporary populations. Clinically important CYP3A drug interactions remain its principal practical limitation.

  25. 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:
    Pivotal unvaccinated outpatient trial demonstrating substantially less efficacy than nirmatrelvir/ritonavir or outpatient remdesivir. Conducted before Omicron and widespread background immunity. The drug remains an alternative when preferred therapies cannot be used.

  26. Gottlieb RL, Vaca CE, Paredes R, et al. Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients. N Engl J Med. 2022;386(4):305-315.  [PMID:34937145]

    Comment: Performed early in the pandemic, before vaccination or background immunity, and provided rationale for 3 days of RDV for treat early COVID and prevent progression. Many still use 3 days of therapy for those who cannot take Paxlovid; however, the relevance now in the larger population with background immunity is difficult to reconcile and continue to believe its relevance

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

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

  28. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of Covid-19 - Final Report. N Engl J Med. 2020;383(19):1813-1826.  [PMID:32445440]

    Comment: The foundational randomized remdesivir trial showed a shorter time to recovery, with the clearest benefit before invasive mechanical ventilation. Conducted before vaccination and Omicron, its principal relevance now is support for earlier antiviral treatment rather than an estimate of current absolute benefit.

  29. CDC. Multisystem Inflammatory Syndrome (MIS) [updated 2/19/26; accessed 9/16/26].

    Comment: Current CDC surveillance definitions and reporting criteria for MIS-C and MIS-A. The surveillance definition should not be used as a rigid bedside diagnostic rule. See CDC clinical-care guidance/ACR guidance for treatment. Provides CDC case definitions, reporting, and links to clinical and lab criteria.

  30. CDC. Appendix A: Type and Duration of Precautions Recommended for Selected Infections and Conditions [updated 9/11/26; accessed 10/13/2026].

    Comment: Current CDC healthcare infection-control guidance. Uses time- and symptom-based discontinuation of transmission-based precautions for most patients (≥10 days for mild/moderate disease; 10–20 days for severe/critical disease) and recommends a test-based approach for moderately/severely immunocompromised patients because replication-competent virus may persist beyond 20 days.


  31. CDC. COVID-19 Treatment Clinical Care for Outpatients. Updated October 8, 2026.

    Comment: Current practical U.S. treatment framework: nirmatrelvir/ritonavir is preferred when feasible; 3-day IV remdesivir started within 7 days is the preferred alternative; molnupiravir is reserved for situations in which preferred therapies cannot be used. Longer/additional remdesivir courses may be considered in selected immunocompromised patients with persistent symptoms.



  32. FDA. EUA transition notice. [updated 7/1/26; accessed 9/16/26].

    Comment: All remaining COVID drug/biologic EUAs terminate on June 29, 2027, unless another pathway intervenes.


  33. WHO. Therapeutics and COVID-19: living guideline, August 2025. Accessed 10/13/2026.

    Comment: Current COVID guidance from the WHO that has some distinctions from US medication availability and practices.


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