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Subsections
COVID-19 (Coronavirus Disease 2019): Therapeutics

Infectious Diseases

COVID-19 (Coronavirus Disease 2019): Therapeutics

Management is based on illness severity

Asymptomatic or presymptomatic infections and most with mild illness can self-isolate at home

  • Home Care
    • Appropriate for patients who can adequately isolate at home
    • Steps to implement during home care
      • Avoid public settings; stay home except to get medical care
      • Separate from other people and animals in the household
      • Monitor for clinical deterioration
        • Seek immediate medical care if showing any COVID-19 emergency warning signs
      • Wear a facemask when in the same room/vehicle as other people
      • Frequently wash hands and disinfect touched surfaces
  • CDC Guidelines for Discontinuation of Home Isolation (sxms and severity-based strategy for discontinuing isolation and precautions as opposed to testing based strategies)
    • Isolation
    • For most pts, isolation can be discontinued 5 days after symptom onset, resolution of fever for ≥ 24 hrs (without antipyretics), and improvement in other symptoms
      • Continue wearing well-fitting mask around others (home & public) for 5 additional days; if unable to wear mask, continue isolation through day 10
      • Avoid contact with high-risk populations until after day 10
    • Pts with severe disease or severe immunosuppression, recommend waiting 10-20 days after symptom onset to discontinue isolation
    • Quarantine
    • CDC guidance states individuals with suspected or confirmed COVID-19 exposure are not required to quarantine if they meet following criteria:
      • Are up to date with COVID-19 vaccines, OR
      • Had confirmed COVID-19 within last 90 days
    • Wear well-fitted mask for 10 days; obtain test 5 days post-exposure (not required if confirmed COVID-19 within last 90 days)
  • COVID-19 Vaccines

Mildly ill patients with risk factors for severe disease and moderately ill patients should be closely monitored

Severe and critically ill patients should be hospitalized

  • Inpatient Care
    • Separate triage of patient with respiratory conditions
    • Immediately apply surgical mask on all patients with respiratory conditions
    • Consider
    • If COVID-19 suspected after triage
      • Immediate isolation
      • Transfer to negative pressure room
      • Healthcare personnel use full protective gear and precautions (i.e., contact precautions, airborne precautions, eye protection)
    • If COVID-19 is diagnosed
      • Notify infection control within institution
      • Maintain list of all hospital personnel who may have been in contact
      • Notify County Health Department per local protocol
      • Consult Infectious Disease and Pulmonology services early
    • Supportive therapy
      • IV fluids PRN, Antipyretics PRN, O2 PRN, Monitors
      • Noninvasive ventilatory support as necessary
      • Prevent venous thromboembolism
        • LMWH (contraindications: active bleeding, severe thrombocytopenia)
        • Unknown whether anticoagulation (prophylactic or therapeutic) has any impact on the outcome of COVID-19
    • If undergoing aerosol producing procedures (sputum production, intubation, HFNO, BiPAP/CPAP, etc.)
      • Isolate: single private negative pressure isolation room with HEPA filter
        • If no isolation room available: be cautious when applying airway devices that deliver ≥ 6 L/min O2 (if not intubated) - may generate aerosols
      • High flow nasal oxygen can give fraction of inspired oxygen (FiO2) up to 100% and reduces the need for intubation
        • Apply airborne precautions
      • BiPAP and CPAP should be avoided if possible
        • Use with caution if necessary
      • If private room not possible: keep ≥ 2 ft distance between patients
    • If concomitant asthma or COPD
      • Bronchodilators: use metered dose inhalers with a spacer instead of nebulizers (risk of aerosolization)
      • If severe asthma/COPD: consider epinephrine, early intubation and rapid sequence induction
    • Secondary infections (especially in severely ill and critically ill patients)
      • Occurs in patients in ICU (13-44%)
        • Bacterial or fungal (especially Aspergillus)
        • Often 'nosocomial' pathogens (ESBL, P.aeruginosa, Aspergillus spp)
        • Median time from onset of symptoms:10-17 days
      • Factors to consider (mostly China, NY hospital reports)
        • Frequent antibacterial use received in 80-100%
        • Antifungals in 7.5-15%
        • Steroids in 25-80% of seriously ill patients
    • Inpatient care revolves around supportive management of the most common complications of severe COVID-19
      • Sepsis
        • Empiric antibiotics (CAP vs HCAP) within 1 hr of recognition of sepsis, then work-up source of infection
      • Septic shock
        • Volume support and pressors:
          • Norepinephrine (first line)
          • Vasopressin (second line)
          • Dopamine NOT recommended
      • If flu season or suspect flu
        • Consider oseltamivir
      • ARDS/Respiratory failure (hypercarbic or hypoxic)
        • Strongly consider advanced ventilatory support/intubation
        • DO NOT share ventilators
        • If refractory hypoxemia even with advanced ventilatory support
          • Consider extracorporeal membrane oxygenation (ECMO) if available
      • Hypercoagulability and COVID-19
        • The pathogenesis for COVID-19-associated hypercoagulability remains unknown
          • Hypoxia and systemic inflammation secondary to COVID-19 may lead to high levels of inflammatory cytokines and activation of the coagulation pathway
          • Limited data available to inform clinical management of venous thromboembolism in COVID-19 patients
        • Many institutions adopted an intermediate-intensity (i.e., administering the usual daily LMWH dose BID) or a therapeutic-intensity dose strategy for thromboprophylaxis
        • International Society of Thrombosis and Hemostasis Interim Guidance:
          • LMWH should be considered in all patients (including non‐critically ill) who require hospital admission for COVID‐19, if not contraindicated
        • American Society of Hematology:
          • All hospitalized adults with COVID-19 should receive pharmacologic thromboprophylaxis with LMWH over unfractionated heparin, if not contraindicated
    • Medical/Pharmaceutical
      • Many types of drugs are under investigation including antivirals (protease inhibitors, influenza drugs, nucleoside analogs), immunomodulators, and surface protein antagonists such as lecithin.
        • 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 and IDSA
          • Other corticosteroids shown to also be potentially beneficial in other trials and meta-analyses had a summary OR 0.66 on 28d all-cause mortality
          • Recommend
            • Dexamethasone (6mg/day IV/PO for 10 days) in patients with COVID-19 who are mechanically ventilated or
            • Dexamethasone (6mg/day IV/PO for 10 days) in COVID-19 patients who require supplemental oxygen but are not mechanically ventilated
          • Recommend against
            • Dexamethasone in COVID-19 patients who do not require supplemental O2
        • Remdesivir
          • Based on the Adaptive Covid-19 Treatment Trial (ACTT), RDV appears most beneficial if given for severe COVID-19 before mechanical ventilation, reduces the length of hospital stay.
          • Investigators concluded that benefit was accrued to patients prior to the need for mechanical ventilation, highly suggestive that this antiviral yield greater benefit the earlier it is initiated
          • NIH has suggested that this drug will be standard for comparison in adaptive clinical research trials.
          • Recommendations for Hospitalized Patients with Severe COVID-19 (consider concomitant baricitinib):
            • Remdesivir is recommended for treatment of COVID-19 patients hospitalized with SpO2 ≤94% on room air or those who require supplemental O2
            • Remdesivir is recommended for treatment of COVID-19 patients who are on mechanical ventilation or ECMO
            • Remdesivir appears to demonstrate the most benefit in those with severe COVID-19 on supplemental oxygen rather than in patients on mechanical ventilation or ECMO.
          • Recommendation for Duration of Therapy in Patients with Severe COVID-19 Who Are Not Intubated:
            • Hospitalized patients with severe COVID-19 who are not intubated are recommended to receive 5 days of remdesivir
          • Recommendation for Duration of Therapy for Mechanically Ventilated Patients, Patients on ECMO, or Patients Who Have Not Shown Adequate Improvement After 5 Days of Therapy:
            • Insufficient data on optimal duration of therapy for these patients
            • Some experts extend the total remdesivir treatment duration to up to 10 days for these patients
          • Recommended for patients with Mild or Moderate COVID-19:
            • 200 mg IV on day 1, then 100 mg IV daily for days 2 & 3
            • Must be initiated ≤7 days of S/S onset
        • Baricitinib
          • FDA approved for monoTx (consider concomitant remdesivir and/or corticosteroids)
            • Severe pts: 4 mg PO qD x14 days or hospital D/C (whichever is first)
            • Avoid concomitant use with tocilizumab
          • Administration:
            • May be given with/without food
            • If unable to swallow tabs, consider alternative admin:
              • Oral dispersion
              • Gastrostomy tube (G tube)
              • Nasogastric tube (NG tube) or orogastric tube (OG tube)
        • Tocilizumab
          • ≥ 30 kg: 8 mg/kg IV x single dose over 60 mins
          • < 30 kg: 12 mg/kg IV x single dose over 60 mins
          • If no improvement of S/S: may repeat dose once, ≥8 hrs later
            • NMT 800 mg/dose
            • SC admin not authorized
          • Avoid concomitant use with baricitinib
        • Nirmatrelvir/ritonavir
          • FDA approved for COVID-19
          • Dosing based on renal fxn
            • eGFR > 60 mL/min
              • 300 mg/100 mg (nirmatrelvir/ritonavir, co-admin) PO q12hr x5 days
            • eGFR ≤ 60 mL/min and ≥ 30 mL/min
              • 150 mg/100 mg (nirmatrelvir/ritonavir, co-admin) PO q12hr x5 days
            • eGFR < 30 mL/min
              • Not recommended
          • If hospitalization occurs during Tx course
            • May complete Tx per providers discretion
          • Administration:
            • Take with/without food
            • Co-admin nirmatrelvir and ritonavir tabs
            • Swallow whole; do not crush, chew, split tabs
            • Missed dose: if ≤ 8 hrs take dose, otherwise skip
          • IDSA recommendation
            • Recommended for use in ambulatory pts w/ mild-to-moderate COVID-19 at high-risk for
              • Progression to severe disease
                • Nirmatrelvir/ritonavir should be initiated w/in 5 days of symptom onset
                  • Rather than no tx w/ nirmatrelvir/ritonavir
        • Molnupiravir
          • FDA EUA for COVID-19
            • 800 mg PO q12h x5 days
            • Initiate within 5 days of S/S onset
            • Safety/efficacy of >5 days Tx not established
          • If hospitalization occurs during Tx course
            • May complete Tx per providers discretion
          • Administration:
            • Take with/without food
            • Swallow whole; do not open, crush, chew
            • Missed dose: take asap if ≤10 hrs since missed, otherwise skip
        • Anti-SARS-CoV-2 monoclonal antibodies
          • Bebtelovimab (not currently authorized in any US region; not effective against BQ.1 and BQ.1.1 variants)
            • FDA EUA for COVID-19
              • 175 mg IV x1
              • Admin ASAP after positive results and ≤7 days of S/S onset
            • Administration:
              • Admin as single IV injection for ≥30 sec in healthcare setting
              • Monitor for IRRs for ≥1 hr after infusion
            • Authorized for mild-to-moderate COVID-19 in
              • Adults
              • Children (12 years and weighing at least 40 kg)
            • Used to prevent progression to severe COVID-19 and
              • Do not have access or clinically inappropriate for other treatments
          • No longer authorized due to ineffective neutralization of Omicron BA2 subvariant
          • Convalescent Plasma
            • Definition
              • Has been used as passive immunotherapy for infections for > 100 years
              • In recent years, studies derived from people who had recovered from specific infections showed encouraging results
                • However, these studies were typically small, non-randomized and largely descriptive
              • Transfusion of COVID-19 virus antibody-rich plasma
            • IDSA recommendation
              • Against the use of COVID-19 convalescent plasma
                • For ambulatory patients w/ mild-to-moderate COVID-19 at high risk for progression
                  • To severe disease and who have no other treatment options
                  • Suggests the use of FDA-qualified high-titer COVID-19 convalescent plasma
                    • Within 8 days of symptom onset, rather than not given
                • For immunocompromised patients hospitalized w/ COVID-19
          • Pre-Exposure Prophylaxis
            • Cilgavimab/Tixagevimab (EUA)
            • Pre-Exposure Prophylaxis
              • Cilgavimab/Tixagevimab (not effective against current dominant variants)
              • Pemivibart (EUA; Premgrada)
                • Adults and adolescents (12 y/o and older weighing at least ~ 88 lbs (40 kgs))
                • Pts who are not currently infected with SARS-CoV-2
                • Pts who have not had a known recent exposure to an individual infected with SARS-CoV-2
                • Moderate-to-severe immune compromise: illness or d/t medications
          • Post-Exposure Prophylaxis
        • COVID-19 Investigational Therapies: (safety and efficacy not yet established)
        • Interferon 1b
          • RCT from Hong Kong found when used with lopinavir/ritonavir and ribavirin (triple therapy) versus LPV/RTV alone, the triple therapy yielded quicker clinical improvement and reduced viral shedding.
          • Suspect most of the benefits derived from interferon; however, many hesitant to use since it tends to make people feel terrible
          • Phase II inhaled formulation trial yielded favorable results.
        • Other potential drugs under discussion or study; some use anecdotally reported:
          • Sarilumab (anti-IL6R)
            • Failed trial, Phase III.
          • Siltuximab (anti-IL6)
            • 11 mg/kg IV x single dose
          • Anakinra (anti-IL1)
            • IDSA guideline panel suggests against routine use in hospitalized patients w/ severe COVID-19
          • anti-GM-CSF
          • GM-CSF
        • Concomitant Therapy Considerations
          • 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 and IDSA.
            • Recommended for patients with severe COVID-19 (requiring oxygen) including those on mechanical ventilation by the NIH and IDSA
            • Supplemental stress-dose steroids may be indicated on a case-by-case basis
            • Patients on chronic corticosteroids (PO or inhaled) for other underlying conditions (e.g., adrenal insufficiency, asthma/COPD) should not discontinue its use
            • In patients w/ severe disease on corticosteroids
              • IDSA suggests baricitinib to be added, rather than no baricitinib
                • Baricitinib 4 mg/day (or appropriate renal dosing)
                  • Up to 14 days or until discharge
                  • Shows most benefit in pts w/
                    • Severe COVID-19 on high-flow O2/non-invasive ventilation
            • Pregnancy Considerations:
              • Since betamethasone and dexamethasone are known to cross the placenta, consider using an equivalent systemic steroid when possible
              • Use of steroids that cross the placenta may be individualized, weighing the neonatal and maternal benefits with the risks
          • ACE inhibitors/ARBs
            • Despite ACE2 being a receptor for SARS-CoV-2, patients taking ACE inhibitors and ARBs for other conditions should continue taking these agents
              • NIH recommends against use of ACE inhibitors or ARBs for treatment of COVID-19 outside of a clinical trial
          • Statins
            • Continue statins in hospitalized patients with COVID-19 who are already taking them
            • Many severe COVID-19 patients have underlying cardiovascular disease, diabetes mellitus, and other indications for use of statins
            • Also, statins are indicated because acute cardiac injury is a reported complication of COVID-19
            • Whether statins could impact the course of SARS-CoV-2 infection is not clear
          • Immunomodulators
            • Immunocompromised patients with COVID-19 are at increased risk for severe disease
            • Decision to terminate immunomodulators must be determined on a case-by-case basis
            • For individuals who require treatment with these agents and DO NOT have COVID-19 infection, there is NO evidence supporting routine discontinuation of the drugs
            • AGA Recommendations for Immunomodulator use in IBD for COVID-19
              • IBD patients with symptomatic COVID-19 (e.g., fever, respiratory symptoms, GI symptoms, etc.) should stop medications after consultation with GI or primary care physicians
              • Drugs to be temporarily discontinued include thiopurines, methotrexate, tofacitinib, and anti-TNFs (i.e., ustekinumab and vedolizumab)
              • However, some drugs may still be continued for IBD (i.e., aminosalicylates, topical rectal therapy, dietary management, oral budesonide and antibiotics)
          • NSAIDs
            • FDA and WHO indicate current epidemiologic evidence is not sufficient to advise against NSAIDs in COVID-19 patients
            • WHO retracted earlier warning against the use of ibuprofen
              • Warning was due to theoretical mechanism suggesting NSAIDs increase expression of ACE2, the receptor by which the coronavirus enters host cells
              • It was unclear whether harm was associated with intermediate or prolonged use of NSAIDs
            • Currently, discontinuation of chronic ibuprofen use is not advised
            • WHO and NHS suggest acetaminophen is preferred to treat pain and fever until there is more evidence
            • Stronger evidence is needed to deduce causation of harmful effect of ibuprofen in COVID-19 patients
          • Avoid nebulized medications
            • Avoid the risk of aerosolization of SARS-CoV-2 through nebulization
            • Use metered dose inhaler for inhaled medications
            • Use appropriate infection control measures
      • Critical Care Guidelines for Adults with COVID-19
        • Infection Control
          • For health care workers who are performing aerosol-generating procedures on COVID-19 patients:
            • Recommended use of N95 masks or powered air-purifying respirators rather than surgical masks
            • Recommended use of PPE (i.e., disposable gloves, gown, and eye protection such as face shield or goggles)
          • Endotracheal intubation should be performed by providers with extensive airway management experience, if possible
          • Intubation should be achieved by video laryngoscopy, if possible
        • Hemodynamic Support
          • Norepinephrine as first-line vasopressor
          • For adults with refractory shock, use low-dose corticosteroid therapy over no corticosteroid
        • Ventilatory Support
          • The following are recommendations for adults with COVID-19 and acute hypoxemic respiratory failure
            • If respiratory failure persists despite conventional O2 therapy:
              • Use HFNC O2 over NIPPV
            • If no indication for endotracheal intubation:
              • Use a trial of NIPPV if HFNC is not available
            • If hypoxemia persists despite increasing supplemental O2 and in whom endotracheal intubation is not indicated:
              • Consider a trial of awake prone positioning
            • The panel recommends against awake prone positioning as a rescue therapy for refractory hypoxemia to avoid intubation
            • For mechanically ventilated adults with ARDS:
              • Low tidal volume ventilation (VT 4-8 mL/kg of predicted BW) is recommended over higher tidal volumes (VT>8 mL/kg)
            • For mechanically ventilated adults with refractory hypoxemia:
              • Prone ventilation for 12-16 hrs/day is recommended over no prone ventilation
            • For mechanically ventilated adults with severe ARDS and hypoxemia despite optimal care:
              • Use an inhaled pulmonary vasodilator as a rescue therapy
                • If no rapid improvement in oxygenation, treatment should be tapered off
            • Insufficient data to recommend for or against routine use of ECMO for COVID-19 patients with refractory hypoxemia
          • Intubation Considerations
            • COVID-19 may cause hypoxemia even in the setting of little respiratory distress
              • May be profoundly hypoxemic without dyspnea (patients may "look" fine)
              • Work of breathing cannot be relied upon to detect patients who are failing on high flow nasal cannula
            • Consider a lower threshold for intubation indications
              • Patients can develop worsening "silent" atelectasis and decline quickly and abruptly without lots of symptoms
              • Oxygenation techniques to maintain saturation during intubation may increase virus aerosolization (e.g., mask ventilation)
                • "Pure" rapid sequence intubation without bagging is preferred
                • Consider viral filter to BMV
              • This will be safer if the patient is starting out with more oxygenation reserve
              • Consider semi-elective intubation over crash intubation (decreases prep time)
            • Intubation procedure can place healthcare workers at risk of acquiring the virus
            • Endotracheal tube confirmation could pose inoculation risk to practitioner
            • Pulmonary complications by COVID-19
              • Atelectasis (consider PEEP, APRV, ARDS)
              • Alveolar fluid filling (drain fluid- prone positioning with ventilation, APRV, coughing or "dumping" breaths to help clear lungs)
            • WHEN TO INTUBATE?
              • Physician clinical decision
              • Consider if
                • Progressively rising FiO2 requirements (e.g., > 75% FiO2 - again, based on patient's status)
                • High flow cannula does not improve oxygenation
                • Comorbid conditions (e.g., COPD, asthma, cardiovascular disease, etc.)
        • AKI and Renal Replacement Therapy
          • For critically ill COVID-19 patients with AKI and indications for RRT:
            • Give continuous RRT, if available
            • If not available, prolong intermittent RRT rather than intermittent hemodialysis

    Special Populations

    • Immunity and Reinfection Risk
      • Individuals who have been infected are normally induced with antibodies
      • Preliminary studies suggest some of the antibodies are protective
        • Evidence is not confirmed
        • Unknown whether immunity in previously infected patients is sufficient for protective purposes and how long immunity will last
      • NOTE: FDA has granted EUA for tests that qualitatively identify antibodies against SARS-CoV-2 in serum or plasma
    • Pregnant Women and Breast Feeding
      • Minimal information available
      • Intrauterine or perinatal transmission has not been identified
      • Pregnant women may be at increased risk for severe illness from COVID-19
      • There may be increased risk of adverse pregnancy outcomes (e.g., preterm birth) among pregnant women with COVID-19
      • Clinical guidelines for pregnant women with suspected COVID-19 should be similar to that in nonpregnant individuals
      • ACOG: decision to separate patients with known or suspected COVID-19 from their infants should be made on a case-by-case basis
      • Breast feeding
        • Unknown whether the virus can be transmitted through breast milk
        • Droplet transmission could occur through close contact during breastfeeding
        • Therefore, breast feeding mothers should use appropriate hand hygiene and a facemask
        • Suspected or confirmed maternal COVID-19 is not a contraindication to breast feeding
    • MIS-C ASSOCIATED WITH COVID-19 in the Pediatric Population
      • Multi-system inflammatory syndrome in children associated with COVID-19 Criteria:
        • An individual aged <21 years of age presenting with:
          • Fever (Fever >38.0°C for ≥24 hours, or report of subjective fever lasting ≥24 hours)
          • Laboratory evidence of inflammation (Including, but not limited to, one or more of the following: an elevated (CRP), (ESR), fibrinogen, procalcitonin, d-dimer, ferritin, lactic acid dehydrogenase (LDH), or interleukin 6 (IL-6), elevated neutrophils, reduced lymphocytes and low albumin
          • and evidence of clinically severe illness requiring hospitalization, with multisystem (>2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological); AND
          • No alternative plausible diagnoses; AND
          • Positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test; or exposure to a suspected or confirmed COVID-19 case within the 4 weeks prior to the onset of symptoms
        • Some individuals may fulfill full or partial criteria for Kawasaki disease but should be reported if they meet the case definition for MIS-C
        • Consider MIS-C in any pediatric death with evidence of SARS-CoV-2 infection.
        • Clinical presentation includes:
          • Fever
          • Red eyes/Red cracked lips
          • Abdominal pain
          • vomiting
          • Diarrhea
          • Skin rash
          • musculocutaneous lesion
          • Swollen Hands and Feet
          • Hypotension, shock (severe cases)
        • Other evaluations include:
          • Echo
          • EKG
          • Cardiac enzymes and troponin testing
          • BNP, NT-proBNP
        • Treatment
          • Fluid Resuscitation
          • Inotropic support
          • Respiratory support
          • Anti-inflammatory measures (Steroids/IVIG )



    Related Topics

    References

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    Contributor(s)

    1. Wedro, Benjamin, MD
    2. Cox, Takema, DO, MBS
    3. Ho, Nghia, MD
    4. Cherian, Geo, MD
    5. Tom, Jubil, MD
    6. Singh, Ajaydeep, MD
    7. Ausi, Michael, MD, MPH

    Updated/Reviewed: March 2024