Guideline sources The following summarized guidelines for the evaluation and management of COVID-19 infection are prepared by our editorial team based on guidelines from the Infectious Diseases Society of America (IDSA 2023; 2021; 2020), the World Health Organization (WHO 2023), the American College of Physicians (ACP 2022), the International Society on Thrombosis and Haemostasis (ISTH 2022), the International Initiative on Thrombosis and Cancer (ITAC 2022), the National Institutes of Health (NIH 2021), the Society of Critical Care Medicine (SCCM 2021), the American Society of Hematology (ASH 2021), the American College of Chest Physicians (ACCP 2020), the Safe Airway Society (SAS 2020), the International Liaison Committee on Resuscitation (ILCOR 2020), and the Society of Critical Care Medicine (SCCM/APSF 2020). 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 19 20 21 22 22 23 https://web.pathway.md/diseases/rec2UFiNfrEGXdLl0 1/38 6/29/23, 3:24 AM COVID-19 infection Pathway Definition COVID-19 is a severe acute respiratory infection caused by SARS-CoV-2, a positive sense, single- strand enveloped RNA virus belonging to the family Coronaviridae. 19 Epidemiology Person-to-person transmission primarily occurs through droplets generated during coughing and sneezing. Droplets can be transmitted directly through close contact, or via contaminated surfaces, where the virus may remain active for hours to days. Coughing and some airway management procedures can generate aerosols containing suspended viral particles, which can travel greater distances and be inhaled. 20 Pathophysiology The inaugural COVID-19 outbreak was labelled a pandemic by the WHO on March 11, 2020. 19 Disease course The clinical spectrum of SARS-CoV-2 infection appears to be wide, encompassing asymptomatic infection, mild upper respiratory tract illness, and severe viral pneumonia with respiratory failure. Cardiomyopathy has been described in a significant proportion of critically ill patients. Anosmia has been reported in association with presumed neuroinvasive disease. 21 22 23 Prognosis and risk of recurrence Mortality remains high in patients requiring intensive care. 22 Guidelines 1. Screening and diagnosis Indications for screening: screen all persons at the first point of contact with the health system in order to identify patients having suspected or confirmed COVID-19 and allow for early recognition followed by rapid implementation of source control measures. A Diagnosing septic shock: Diagnose septic shock in adult patients with suspected or confirmed COVID-19 meeting the following criteria in the absence of hypovolemia: vasopressors are needed to maintain mean arterial pressure 65 mmHg lactate 2 mmol/L. A Diagnose septic shock in pediatric patients with any hypotension (systolic BP < 5th centile or > 2 SD below normal for age) or two or more of the following: altered mental status bradycardia or tachycardia (HR < 90 bpm or > 160 bpm in infant patients and HR < 70 bpm or > 150 bpm in pediatric patients) https://web.pathway.md/diseases/rec2UFiNfrEGXdLl0 2/38 6/29/23, 3:24 AM COVID-19 infection Pathway prolonged capillary refill (> 2 sec) or feeble pulses tachypnea mottled or cold skin or petechial or purpuric rash increased lactate oliguria hyperthermia or hypothermia. A 2. Classification and risk stratification Triage: As per WHO 2023 guidelines: Triage patients with suspected COVID-19 at a health facility, after screening and isolation, using a standardized triage tool (such as the WHO/IFRC Interagency Integrated Triage Tool), and evaluate for disease severity. A Based on triage: initiate timely care for the acutely ill using a systematic approach, as described in WHO/ICRC Basic emergency care refer patients to appropriate COVID-19 care destination after initial assessment, management and stabilization: within the health facility (critical care unit or ward); to a different health facility; community facility; or home, according to patient medical needs and established COVID-19 care pathways. A As per NIH 2021 guidelines, triage patients with symptoms of COVID-19, when possible, via telehealth visits before receiving in-person care. Refer patients with dyspnea for an in-person evaluation by a healthcare provider and follow-up closely during the initial days after the onset of dyspnea to assess for worsening respiratory status. B 3. Diagnostic investigations Specimen collection: As per WHO 2023 guidelines, obtain at least respiratory specimens in all patients with suspected COVID-19 for NAAT, for example RT-PCR. Consider obtaining repetitive testing of upper respiratory tract and/or lower respiratory tract to establish the diagnosis. A Show 2 more As per NIH 2021 guidelines: Obtain lower respiratory tract specimens, if an initial upper respiratory tract sample is negative, for the diagnosis of COVID-19 in intubated and mechanically ventilated adult patients who are suspected to have COVID-19 but who do not have a confirmed diagnosis. B Obtain endotracheal aspirates rather than bronchial wash or BAL specimens when collecting lower respiratory tract samples to establish a diagnosis of COVID-19 in intubated and https://web.pathway.md/diseases/rec2UFiNfrEGXdLl0 3/38 6/29/23, 3:24 AM COVID-19 infection Pathway mechanically ventilated adult patients suspected to have COVID-19 but who do not have a confirmed diagnosis. B As per SCCM 2021 guidelines: Consider obtaining lower respiratory tract samples in preference to upper respiratory tract (nasopharyngeal or oropharyngeal) samples for diagnostic testing in intubated and mechanically ventilated adult patients with suspicion of COVID-19. C Consider obtaining endotracheal aspirates in preference to bronchial wash or BAL specimens for lower respiratory tract sampling in intubated and mechanically ventilated adult patients with suspicion of COVID-19. C Polymerase chain reaction: As per IDSA 2021 guidelines, obtain SARS-CoV-2 NAAT in symptomatic patients in the community suspected of having COVID-19, even when the clinical suspicion for COVID-19 is low. B Show 16 more As per NIH 2021 guidelines, obtain NAAT for the diagnosis of acute SARS-CoV-2 infection with a sample collected from the upper respiratory tract (nasopharyngeal, nasal, or oropharyngeal specimen). B Show 2 more Antigen testing (indications): obtain a single antigen test in symptomatic patients with suspected COVID-19. B Show 7 more Antigen testing, setting: As per IDSA 2023 guidelines: Consider obtaining antigen testing either point-of-care or in a laboratory-based setting. C Consider obtaining either observed or unobserved self-collection of swab specimens for antigen testing if self-collection is performed. C As per WHO 2023 guidelines, offer COVID-19 self-testing, using SARS-CoV-2 antigen rapid diagnostic tests, in addition to professionally obtained testing services. B Serology: As per WHO 2023 guidelines, do not obtain SARS-CoV-2 antibody testing for diagnosis of current infection with COVID-19. D As per NIH 2021 guidelines, do not obtain serologic testing to: diagnose acute SARS-CoV-2 infection, as the sole basis determine whether patients are immune to SARS-CoV-2 infection make decisions about how to group patients in congregate settings (such as schools, dormitories, correctional facilities) determine whether patients may return to the workplace assess for prior infection solely to determine whether to vaccinate an individual assess for immunity to SARS-CoV-2 following vaccination, except in clinical trials. D https://web.pathway.md/diseases/rec2UFiNfrEGXdLl0 4/38 6/29/23, 3:24 AM COVID-19 infection Pathway As per IDSA 2020 guidelines, consider avoiding serologic testing to diagnose SARS-CoV-2 infection during the first 2 weeks following symptom onset. D Show 7 more Coagulation studies: Insufficient evidence to recommend measurement of coagulation markers (such as D-dimers, PT, platelet count, fibrinogen) in nonhospitalized patients with COVID-19. I Insufficient evidence to recommend either for or against using hematologic and coagulation parameters, although commonly measured, to guide management decisions in hospitalized patients with COVID-19. I Evaluation for thromboembolism, asymptomatic: As per NIH 2021 guidelines, insufficient evidence to recommend either for or against routine deep vein thrombosis screening in patients with COVID-19 without signs or symptoms of VTE, regardless of the status of their coagulation markers. I As per ACCP 2020 guidelines, avoid obtaining routine screening for asymptomatic DVT in critically ill patients with COVID-19. D Evaluation for thromboembolism (symptomatic): evaluate the possibility of thromboembolic disease in hospitalized patients with COVID-19 experiencing rapid deterioration of pulmonary, cardiac, or neurological function, or of sudden, localized loss of peripheral perfusion. B Evaluation for other etiologies: As per WHO 2023 guidelines, consider testing for other respiratory viruses and bacteria when clinically indicated according to local guidelines. B Show 2 more As per NIH 2021 guidelines, recognize that only testing can distinguish between SARS-CoV-2 and influenza virus infections and identify SARS-CoV-2 and influenza virus coinfection. Show 3 more 4. Respiratory support Awake prone positioning: As per WHO 2023 guidelines, consider awake prone positioning of severely ill patients hospitalized with COVID-19 requiring supplemental oxygen (includes high-flow nasal cannula) or noninvasive ventilation. C As per NIH 2021 guidelines: Consider offering a trial of awake prone positioning to improve oxygenation in patients with persistent hypoxemia despite increasing supplemental oxygen requirements in whom endotracheal intubation is not otherwise indicated. C Do not offer awake prone positioning as a rescue therapy for refractory hypoxemia to avoid intubation in patients otherwise meeting the indications for intubation and mechanical ventilation. D https://web.pathway.md/diseases/rec2UFiNfrEGXdLl0 5/38 6/29/23, 3:24 AM COVID-19 infection Pathway Updated evidence: COVI-PRONE In nonintubated adult patients with acute hypoxemia and COVID-19, prone positioning was not superior to usual care with respect to the rate of endotracheal intubation within 30 days. Waleed Alhazzani et al. JAMA. 2022 Jun 7. As per SCCM 2021 guidelines, insufficient evidence to recommend awake prone positioning in nonintubated adult patients with severe COVID-19. I Conventional oxygen therapy: As per WHO 2023 guidelines, administer immediate supplemental oxygen to any patient with emergency signs during resuscitation to target SpO 94% and to any patient without emergency signs and hypoxemia (stable hypoxemic patient) to target SpO > 90%, or 92-95% in pregnant patients. A As per SCCM 2021 guidelines: Consider initiating supplemental oxygen in adult patients with COVID-19 if the SpO is < 92% C , and initiate supplemental oxygen if the SpO is < 90%. C Maintain a SpO 96% in adult patients with COVID-19 and acute hypoxemic respiratory failure on oxygen. B High-flow nasal cannula: As per WHO 2023 guidelines, consider a trial of high-flow nasal cannula in selected patients with COVID-19 and mild ARDS. C As per NIH 2021 guidelines, administer high-flow nasal cannula oxygen rather than noninvasive positive pressure ventilation in adult patients with COVID-19 and acute hypoxemic respiratory failure despite conventional oxygen therapy. B Landmark trials: HiFlo-COVID In adult patients with respiratory distress and a ratio of partial pressure of arterial oxygen to FiO2 < 200 due to COVID-19, high-flow oxygen therapy was superior to conventional oxygen therapy with respect to the rate of intubation within 28 days. Gustavo A Ospina-Tasc n et al. JAMA. 2021 Dec 7. As per SCCM 2021 guidelines, consider using high-flow nasal cannula rather than conventional oxygen therapy in adult patients with COVID-19 and acute hypoxemic respiratory failure despite conventional oxygen therapy. C Show 2 more Noninvasive ventilation: As per WHO 2023 guidelines, consider administering a trial of noninvasive ventilation (CPAP, bi- level positive airway pressure) in selected patients with COVID-19 and mild ARDS. C https://web.pathway.md/diseases/rec2UFiNfrEGXdLl0 6/38 6/29/23, 3:24 AM COVID-19 infection Pathway As per NIH 2021 guidelines, administer a closely monitored trial of noninvasive positive pressure ventilation in adult patients with COVID-19 and acute hypoxemic respiratory failure in the absence of an indication for endotracheal intubation and for whom high-flow nasal cannula is not available. B As per SCCM 2021 guidelines, consider a trial of noninvasive ventilation with close monitoring and short-interval assessment for worsening of respiratory failure in adult patients with COVID- 19 and acute hypoxemic respiratory failure, if high-flow nasal cannula is not available and there is no urgent indication for endotracheal intubation. C Show 2 more Face mask ventilation: Use a 2-person bagging technique in situations where rescue face mask ventilation is required, with the airway assistant squeezing the mask and the airway operator creating a vice (V-E) grip around the mask. E Use ramping and/or an early oropharyngeal airway with low gas flows in order to minimize ventilation pressures. E Supraglottic airways: use a second-generation supraglottic airway devices (such as ProSeal LMA, Supreme LMA, i-gel, SLIPA, and Laryngeal Tube Suction-D) if a supraglottic airway is indicated, as their higher seal pressure during positive pressure ventilation decreases the risk of aerosolization of the virus. E Endotracheal intubation: As per WHO 2023 guidelines, ensure that endotracheal intubation is performed by a trained and experienced provider, using airborne precautions. A As per NIH 2021 guidelines, ensure that endotracheal intubation is performed by a healthcare provider with an extensive airway management experience, if possible. B Show 2 more As per SCCM 2021 guidelines: Consider using video-guided laryngoscopy, if available, instead of direct laryngoscopy for endotracheal intubation of patients with COVID-19. C Ensure that endotracheal intubation in patients with COVID-19 requiring endotracheal intubation is performed by a healthcare professional most experienced with airway management in order to minimize the number of attempts and risk of transmission. E As per SAS 2020 guidelines, use video-guided laryngoscopy, if proficient with its use, as a first- line method for endotracheal intubation of patients with COVID-19. Video-guided laryngoscopy maximizes the distance between the airway operator's face and the patient, potentially reducing the risk of viral transmission. E Show 3 more Mechanical ventilation: As per WHO 2023 guidelines, promptly recognize progressive acute hypoxemic respiratory failure when a patient with respiratory distress is failing to respond to standard oxygen therapy and ensure adequate preparation to provide advanced oxygen/ventilatory support. A https://web.pathway.md/diseases/rec2UFiNfrEGXdLl0 7/38 6/29/23, 3:24 AM COVID-19 infection Pathway Show 6 more As per NIH 2021 guidelines, use low tidal volume ventilation of 4-8 mL/kg of predicted body weight A and target plateau pressures of < 30 cmH O in mechanically ventilated adult patients with COVID-19 and ARDS. B Show 2 more As per SCCM 2021 guidelines, use low tidal volume ventilation (4-8 mL/kg of predicted body weight) over higher tidal volumes (> 8 mL/kg) in mechanically ventilated adult patients with COVID-19 and ARDS. B Show 7 more Recruitment maneuvers: As per NIH 2021 guidelines, perform recruitment maneuvers in mechanically ventilated adult patients with COVID-19, severe ARDS, and hypoxemia despite optimized ventilation and other rescue strategies. B Show 2 more As per SCCM 2021 guidelines: Consider applying recruitment maneuvers in mechanically ventilated adult patients with COVID-19 and hypoxemia despite optimizing ventilation. C Avoid applying (incremental PEEP) recruitment maneuvers in adult patients with COVID-19. D Multiple persons per ventilator: avoid sharing mechanical ventilators, because it cannot be done safely with current equipment. Allocating the ventilator to the patient who is most likely to benefit is preferable, rather than failing to prevent, or even causing, the demise of multiple patients. D Extracorporeal membrane oxygenation: As per WHO 2023 guidelines, consider referring patients with refractory hypoxemia (including partial pressure of oxygen in arterial blood/FiO of < 50 mmHg for 3 hours, PaO /FiO of < 80 mmHg for > 6 hours) despite lung protective ventilation for ECMO, in settings with access to expertise in ECMO. C As per NIH 2021 guidelines, insufficient evidence to recommend either for or against the use of ECMO in patients with COVID-19 and refractory hypoxemia. I As per SCCM 2021 guidelines, consider venovenous ECMO, if available, in mechanically ventilated adult patients with COVID-19 and refractory hypoxemia despite optimizing ventilation, use of rescue therapies, and proning, or referring the patient to an ECMO center. Use ECMO only for carefully selected patients with COVID-19 and severe ARDS because of the resource- intensive nature of ECMO and the need for experienced centers, healthcare professionals, and infrastructure. C 5. Medical management General principles: https://web.pathway.md/diseases/rec2UFiNfrEGXdLl0 8/38 6/29/23, 3:24 AM COVID-19 infection Pathway As per WHO 2023 guidelines: Use clinical judgment, including consideration of patients' values and preferences and local and national policy if available, to guide management decisions in patients with COVID-19 of any severity assessed in a clinic or hospital, including admission to hospital and to the ICU, rather than currently available prediction models for prognosis. B Identify, in all patients with COVID-19, if they have an advance care plan for COVID-19 (such as desires for intensive care support) and respect their priorities and preferences to tailor the care plan and provide the best care irrespective of treatment choice. A As per NIH 2021 guidelines, plan the management of nonhospitalized patients based on patient's vital signs, physical exam findings, risk factors for progression to severe illness, and the availability of healthcare resources. B Show 2 more Systemic corticosteroids: As per IDSA 2023 guidelines, administer dexamethasone 6 mg IV or PO daily for 10 days or until discharge in hospitalized critically ill patients with COVID-19 (critical illness is defined as patients on mechanical ventilation and extracorporeal mechanical oxygenation; critical illness includes end-organ dysfunction as is seen in sepsis/septic shock; in COVID-19, the most commonly reported form of end-organ dysfunction is ARDS). B Show 4 more Landmark trials: COVID-19-MP In hospitalized patients with COVID-19 pneumonia, pulse methylprednisolone was not superior to placebo with respect to the rate of the percentage of patients who were discharged without oxygen within 30 days. Carlo Salvarani et al. Eur Respir J. 2022 Mar 31. As per WHO 2023 guidelines: Administer systemic corticosteroids for the treatment of patients with severe and critical COVID-19. B Avoid using corticosteroids for the treatment of patients with non-severe COVID-19. D Landmark trials: RECOVERY (lopinavir-ritonavir) In patients admitted to hospital with COVID-19, lopinavir-ritonavir was not superior to usual care with respect to death from all causes at 28 days. Peter W Horby et al. Lancet. 2020 Oct 5. As per NIH 2021 guidelines, do not use dexamethasone or other systemic corticosteroids in nonhospitalized patients with mild-to-moderate COVID-19 not requiring supplemental oxygen. https://web.pathway.md/diseases/rec2UFiNfrEGXdLl0 9/38 6/29/23, 3:24 AM COVID-19 infection Pathway D Show 12 more As per SCCM 2021 guidelines: Administer a short course of systemic corticosteroids in adult patients with severe or critical COVID-19. B Consider using dexamethasone over other corticosteroids in adult patients with severe or critical COVID-19 who are considered for systemic corticosteroids. C Consider other corticosteroids, if dexamethasone is not available, in doses equivalent to 6 mg daily of dexamethasone for up to 10 days. Remdesivir: As per IDSA 2023 guidelines, consider initiating remdesivir within 7 days of symptom onset in outpatient or hospitalized patients with mild-to-moderate COVID-19 at high risk for progression to severe disease. C Show 4 more Landmark trials: Solidarity (remdesivir) In adult patients hospitalized with COVID-19, remdesivir was not superior to no remdesivir with respect to a in-hospital mortality. WHO Solidarity Trial Consortium. Lancet. 2022 May 21. As per WHO 2023 guidelines: Consider initiating remdesivir in patients with non-severe COVID-19 at the highest risk of hospitalization and in patients with severe COVID-19. C Avoid using remdesivir in patients with critical COVID-19. D As per ACP 2022 guidelines, consider initiating remdesivir for the treatment of ambulatory patients with confirmed mild-to-moderate COVID-19 presenting within 7 days of the onset of symptoms and at high risk for progressing to severe disease. C As per NIH 2021 guidelines, do not continue remdesivir in hospitalized patients being stable enough for discharge and not requiring supplemental oxygen. D Show 9 more As per SCCM 2021 guidelines: Consider administering IV remdesivir in adult patients with severe COVID-19 not requiring mechanical ventilation. C Avoid administering IV remdesivir in adult patients on mechanical ventilation for critical COVID-19. D Inhaled corticosteroids: As per IDSA 2023 guidelines, avoid using ICSs in ambulatory patients with mild-to-moderate COVID-19. D https://web.pathway.md/diseases/rec2UFiNfrEGXdLl0 10/38 6/29/23, 3:24 AM COVID-19 infection Pathway As per ACP 2022 guidelines, do not use ciclesonide for the treatment of ambulatory patients with confirmed mild-to-moderate COVID-19. D Landmark trials: Ciclesonide-COVID In nonhospitalized participants with symptomatic COVID-19 infection, ciclesonide metered dose inhaler was not superior to placebo metered dose inhaler with respect to time to alleviate all COVID-19 related symptoms by day 30. Brian M Clemency et al. JAMA Intern Med. 2022 Jan 1. As per NIH 2021 guidelines, insufficient evidence to recommend either for or against the use of inhaled budesonide for the treatment of patients with COVID-19. I Janus kinase inhibitors: As per IDSA 2023 guidelines, consider administering baricitinib (4 mg daily or appropriate renal dosing, up to 14 days or until discharge from hospital) with corticosteroids in hospitalized adult patients with severe COVID-19 (severe illness defined as patients on high-flow oxygen/noninvasive ventilation at baseline, or requiring mechanical ventilation). C Show 2 more Landmark trials: ATTKPATRASCOVID19 In patients with COVID-19 and the ratio of partial pressure of oxygen to FiO2 < 200, baricitinib was noninferior to tocilizumab with respect to the rate of mechanical ventilation or death by day 28. Theodoros Karampitsakos et al. Clin Microbiol Infect. 2022 Oct 20. As per WHO 2023 guidelines: Administer baricitinib in patients with severe or critical COVID-19. B Avoid using ruxolitinib and tofacitinib in patients with severe or critical COVID-19. D Landmark trials: ACTT-4 In adult patients hospitalized with COVID-19 infection requiring supplemental oxygen by low- flow, high-flow, or non-invasive ventilation, baricitinib was not superior to dexamethasone with respect to the rate of mechanical ventilation-free survival by day 29. Cameron R Wolfe et al. Lancet Respir Med. 2022 May 23. As per NIH 2021 guidelines, do not continue baricitinib in hospitalized patients with COVID-19 being stable enough for discharge and not requiring supplemental oxygen. D https://web.pathway.md/diseases/rec2UFiNfrEGXdLl0 11/38 6/29/23, 3:24 AM COVID-19 infection Pathway Show 10 more Monoclonal antibodies: As per IDSA 2023 guidelines, consider administering anti-SARS-CoV-2 monoclonal antibodies with activity against the predominant regional variants within 7 days of symptom onset in ambulatory patients with mild-to-moderate COVID-19 at high risk for progression to severe disease. C As per WHO 2023 guidelines: Do not use sotrovimab in patients with non-severe COVID-19. D Do not use casirivimab-imdevimab in any patient with COVID-19. D As per ACP 2022 guidelines, do not use casirivimab-imdevimab, regdanvimab, or sotrovimab for the treatment of ambulatory patients with confirmed mild-to-moderate COVID-19 unless it is considered effective against a SARS-CoV-2 variant or subvariant locally in circulation. D As per NIH 2021 guidelines, administer any of the following anti-SARS-CoV-2 monoclonal antibodies for the treatment of nonhospitalized patients with mild-to-moderate COVID-19 at high risk of clinical progression, as defined by criteria in the FDA Emergency Use Authorizations for the products: bamlanivimab 700 mg plus etesevimab 1,400 mg administered as an IV infusion in regions where the combined frequency of potentially resistant SARS-CoV-2 variants is low casirivimab 600 mg plus imdevimab 600 mg administered as IV infusion or SC injections sotrovimab 500 mg administered as SC infusion. Show 3 more Tocilizumab: As per IDSA 2023 guidelines: Consider administering tocilizumab in addition to standard of care (corticosteroids) in hospitalized adult patients with progressive severe or critical COVID-19 who have elevated markers of systemic inflammation (severe illness is defined as patients with SpO 94% on room air, including patients on supplemental oxygen; critical illness is defined as patients on mechanical ventilation and ECMO; critical illness includes end-organ dysfunction as is seen in sepsis/septic shock; in COVID-19, the most commonly reported form of end-organ dysfunction is ARDS). C Consider administering sarilumab in addition to standard of care (corticosteroids), if tocilizumab is not available, in patients otherwise qualifying for tocilizumab. C As per WHO 2023 guidelines, administer IL-6 receptor blockers (tocilizumab or sarilumab) in patients with severe or critical COVID-19. B As per NIH 2021 guidelines, insufficient evidence to determine which patients requiring supplemental oxygen but not through a high-flow device, noninvasive ventilation, invasive mechanical ventilation, or ECMO would benefit from adding tocilizumab to dexamethasone treatment. Consider adding tocilizumab in patients having rapidly increasing oxygen needs and increased markers of inflammation but not yet requiring high-flow oxygen or noninvasive ventilation. https://web.pathway.md/diseases/rec2UFiNfrEGXdLl0 12/38 6/29/23, 3:24 AM COVID-19 infection Pathway Show 5 more Convalescent plasma: As per IDSA 2023 guidelines, do not use COVID-19 convalescent plasma in immunocompetent patients hospitalized with COVID-19. D Show 2 more As per WHO 2023 guidelines: Do not use convalescent plasma in patients with non-severe COVID-19. D Do not use convalescent plasma in patients with severe or critical COVID-19, except in the context of a clinical trial. As per ACP 2022 guidelines, do not use convalescent plasma for the treatment of ambulatory patients with confirmed mild-to-moderate COVID-19. D As per NIH 2021 guidelines, do not use low-titer COVID-19 convalescent plasma for the treatment of patients with COVID-19. D Show 3 more Landmark trials: SIREN-C3PO In patients who were being treated in an emergency department for COVID-19 symptoms, convalescent plasma was not superior to placebo with respect to the rate of disease progression within 15 days. Frederick K Korley et al. N Engl J Med. 2021 Nov 18. As per SCCM 2021 guidelines, avoid using convalescent plasma in adult patients with severe or critical COVID-19 outside clinical trials. D Other immunomodulators (interferons): Do not use interferons (alfa or beta) for the treatment of severely or critically ill patients with COVID-19. D Insufficient evidence to recommend for or against the use of interferon-beta for the treatment of patients with early (< 7 days from symptom onset) mild-to-moderate COVID-19. I Other immunomodulators (BTK inhibitors): do not use Bruton's tyrosine kinase (such as acalabrutinib, ibrutinib, or zanubrutinib) for the treatment of COVID-19 outside clinical trials. D Other immunomodulators, IL-1R antagonists: As per IDSA 2023 guidelines, avoid using anakinra routinely in hospitalized patients with severe COVID-19. D As per NIH 2021 guidelines, insufficient evidence to recommend for or against the use of anakinra for the treatment of COVID-19. I Other immunomodulators, IVIG: https://web.pathway.md/diseases/rec2UFiNfrEGXdLl0 13/38 6/29/23, 3:24 AM COVID-19 infection Pathway As per NIH 2021 guidelines, do not use IVIG (non-SARS-CoV-2-specific) for the treatment of patients with acute COVID-19 outside clinical trials, unless required for multisystem inflammatory syndrome in children or for other indications. D Updated evidence: ITAC In hospitalized patients with symptomatic COVID-19, hyperimmune IVIG was not superior to placebo with respect to the percentage of patients with favorable clinical categories 1 and 2. ITAC (INSIGHT ) Study Group. Lancet. 2022 Feb 5. As per SCCM 2021 guidelines, avoid using standard IVIG routinely in critically ill adult patients with COVID-19. D Other immunomodulators (specific immunoglobulins): insufficient evidence to recommend for or against the use of anti-SARS-CoV-2-specific immunoglobulins for the treatment of COVID-19. I Other immunomodulators (GM-CSF inhibitors): insufficient evidence to recommend for or against the use of GM-CSF inhibitors for the treatment of hospitalized patients with COVID-19. I Nirmatrelvir/ritonavir: As per IDSA 2023 guidelines: Consider initiating nirmatrelvir/ritonavir within 5 days of symptom onset in outpatients with mild-to-moderate COVID-19 at high risk for progression to severe disease. C Administer nirmatrelvir/ritonavir at doses based on renal function: Situation Guidance 300/100 mg every 12 hours for 5 days EGFR > 60 mL/min 150/100 mg every 12 hours for 5 days EGFR 60 and 30 mL/min Do not use nirmatrelvir/ritonavir. EGFR < 30 mL/min Landmark trials: VV116 for COVID-19 In symptomatic adults with mild-to-moderate COVID-19 with a high risk of progression, VV116 was noninferior to nirmatrelvir-ritonavir with respect to time to sustained clinical recovery through day 28. Zhujun Cao et al. N Engl J Med. 2023 Feb 2. As per WHO 2023 guidelines: https://web.pathway.md/diseases/rec2UFiNfrEGXdLl0 14/38 6/29/23, 3:24 AM COVID-19 infection Pathway Initiate nirmatrelvir-ritonavir in patients with non-severe COVID-19 at the highest risk of hospitalization. B Avoid using nirmatrelvir-ritonavir in patients with non-severe COVID-19 at low risk of hospitalization. D As per ACP 2022 guidelines, consider initiating nirmatrelvir/ritonavir for the treatment of ambulatory patients with confirmed mild-to-moderate COVID-19 presenting within 5 days of the onset of symptoms and at high risk for progressing to severe disease. C Molnupiravir: As per IDSA 2023 guidelines, consider initiating molnupiravir (800 mg for 5 days) within 5 days of symptom onset in adult outpatients with mild-to-moderate COVID-19 at high risk for progression to severe disease no other treatment options exist for the patient. C As per WHO 2023 guidelines, consider initiating molnupiravir in patients with non-severe COVID-19 at the highest risk of hospitalization (excluding pregnant, breastfeeding, and pediatric patients). C Landmark trials: PANORAMIC In adult patients with relevant comorbidities with confirmed COVID-19 for 5 days in the community, molnupiravir was not superior to standard care only with respect to hospitalizations or death from all causes at day 28. Christopher C Butler et al. Lancet. 2022 Dec 22. As per ACP 2022 guidelines, consider initiating molnupiravir for the treatment of ambulatory patients with confirmed mild-to-moderate COVID-19 presenting within 5-7 days of the onset of symptoms and at high risk for progressing to severe disease. C Landmark trials: MOVe-OUT In nonhospitalized, unvaccinated adults with mild-to-moderate, laboratory-confirmed COVID- 19 and at least one risk factor for severe COVID-19 illness, molnupiravir was superior to placebo with respect to hospitalization or death at day 29. Ang lica Jayk Bernal et al. N Engl J Med. 2022 Feb 10. Other antivirals, chloroquine/hydroxychloroquine: As per IDSA 2023 guidelines, do not use hydroxychloroquine D or hydroxychloroquine plus azithromycin D in hospitalized patients with COVID-19. D As per WHO 2023 guidelines, do not use hydroxychloroquine or chloroquine in patients with COVID-19, regardless of disease severity. D https://web.pathway.md/diseases/rec2UFiNfrEGXdLl0 15/38 6/29/23, 3:24 AM COVID-19 infection Pathway As per ACP 2022 guidelines, do not use chloroquine or hydroxychloroquine for the treatment of ambulatory patients with confirmed mild-to-moderate COVID-19. D As per NIH 2021 guidelines, do not use chloroquine or hydroxychloroquine (with or without azithromycin) for the treatment of patients with COVID-19. D As per SCCM 2021 guidelines, do not use hydroxychloroquine in adult patients with severe or critical COVID-19. D Other antivirals, lopinavir/ritonavir: As per IDSA 2023 guidelines, do not use lopinavir/ritonavir in ambulatory patients with mild-to- moderate COVID-19 nor in hospitalized patients with COVID-19. D Landmark trials: ACTIV-6 (ivermectin) In patients aged 30 years with confirmed COVID-19, experiencing 2 symptoms of acute infection for 7 days, ivermectin was not superior to placebo with respect to median time to sustained recovery. Susanna Naggie et al. JAMA. 2022 Oct 25. As per WHO 2023 guidelines, do not use lopinavir-ritonavir in patients with COVID-19, regardless of disease severity. D As per ACP 2022 guidelines, do not use lopinavir-ritonavir for the treatment of ambulatory patients with confirmed mild-to-moderate COVID-19. D As per NIH 2021 guidelines, do not use lopinavir/ritonavir or other human immunodeficiency virus protease inhibitors for the treatment of ambulatory patients with COVID-19. D Landmark trials: LOTUS China In hospitalized adult patients with confirmed COVID-19 infection, lopinavir-ritonavir was not superior to standard care with respect to time to clinical improvement. Cao B et al. N Engl J Med. 2020 May 7. Other antivirals, ivermectin: As per IDSA 2023 guidelines: Avoid using ivermectin for the treatment of hospitalized patients with COVID-19. D Do not use ivermectin for the treatment of ambulatory patients with COVID-19. D Landmark trials: COVID-OUT (ivermectin) https://web.pathway.md/diseases/rec2UFiNfrEGXdLl0 16/38 6/29/23, 3:24 AM COVID-19 infection Pathway In nonhospitalized adults aged between 30 to 85 years with a confirmed diagnosis of COVID- 19 within the past 3 days, ivermectin was not superior to placebo with respect to the composite outcome of hypoxemia, emergency department visit, hospitalization, or death. Carolyn T Bramante et al. N Engl J Med. 2022 Aug 18. As per WHO 2023 guidelines, do not use ivermectin in patients with COVID-19, regardless of disease severity, except in the context of a clinical trial. As per ACP 2022 guidelines, do not use ivermectin for the treatment of ambulatory patients with confirmed mild-to-moderate COVID-19. D As per NIH 2021 guidelines, insufficient evidence to recommend for or against the use of ivermectin for the treatment of COVID-19. I Other antivirals, nitazoxanide: As per ACP 2022 guidelines, do not use nitazoxanide for the treatment of ambulatory patients with confirmed mild-to-moderate COVID-19. D Landmark trials: COVID NT-300 In patients presenting within 72-hour onset of mild or moderate COVID-19, nitazoxanide was not superior to placebo with respect to time to sustained clinical recovery. Jean-Fran ois Rossignol et al. EClinicalMedicine. 2022 Feb 28. As per NIH 2021 guidelines, do not use nitazoxanide for the treatment of COVID-19 outside clinical trials. D Antibiotics: As per WHO 2023 guidelines, do not use antibiotic therapy or prophylaxis in patients with suspected or confirmed mild COVID-19. D Show 2 more As per ACP 2022 guidelines, do not use azithromycin for the treatment of ambulatory patients with confirmed mild-to-moderate COVID-19. D As per NIH 2021 guidelines, do not use antibiotics (such as azithromycin, doxycycline) in patients with COVID-19 in the absence of another indication. D Show 2 more Antipyretics: As per WHO 2023 guidelines, prescribe antipyretics for fever and pain in patients with mild COVID-19. A As per NIH 2021 guidelines, use strategies for antipyretic therapy (such as acetaminophen, NSAIDs) in patients with COVID-19 similar to the approaches used in other patients. B As per SCCM 2021 guidelines, consider administering acetaminophen for temperature control in critically ill adult patients with COVID-19. C https://web.pathway.md/diseases/rec2UFiNfrEGXdLl0 17/38 6/29/23, 3:24 AM COVID-19 infection Pathway Thromboproprophylaxis, indications: As per NIH 2021 guidelines, do not initiate anticoagulant or antiplatelet therapy for the prevention of VTE or arterial thrombosis in nonhospitalized patients (or in the emergency department if the patient is not being admitted to the hospital) with COVID-19, unless the patient has other indications for the therapy or is participating in a clinical trial. D Show 3 more As per SCCM 2021 guidelines: Initiate pharmacologic VTE prophylaxis in adult patients with severe or critical COVID-19. B Consider avoiding the routine use of therapeutic anticoagulation outside of clinical trials in adult patients with severe or critical COVID-19 and no evidence of VTE. D As per ACCP 2020 guidelines, consider initiating anticoagulant thromboprophylaxis, if not contraindicated, in acutely ill or critically ill hospitalized patients with COVID-19. E Thromboproprophylaxis, choice of agent: As per ISTH 2022 guidelines, consider initiating oral sulodexide therapy within 3 days of symptom onset to reduce the risk of hospitalization in nonhospitalized patients with COVID-19 at higher risk of disease progression. C Show 9 more Landmark trials: COVID-PACT (antiplatelet therapy) In adult patients with COVID-19 infection requiring ICU-level of care, clopidogrel was not superior to no clopidogrel with respect to the rate of death due to venous and arterial thrombotic events through hospital discharge or 28 days. Erin A Bohula et al. Circulation. 2022 Nov. As per NIH 2021 guidelines: Prefer LMWH or UFH over OACs in hospitalized critically ill patients with COVID-19 because the two types of heparin have shorter half-lives, can be administered IV or SC, and have fewer drug-drug interactions. B