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Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19

Published by IDSA,

COVID-19 Guideline, Part 2: Infection Prevention

COVID-19 Guideline, Part 3: Diagnostics

Adarsh Bhimraj*, Rebecca L. Morgan**, Amy Hirsch Shumaker, Valery Lavergne**, Lindsey Baden, Vincent Chi-Chung Cheng, Kathryn M. Edwards, Rajesh Gandhi, Jason Gallagher, William J. Muller, John C. O’Horo, Shmuel Shoham, M. Hassan Murad**, Reem A. Mustafa**, Shahnaz Sultan**, Yngve Falck-Ytter**

*Corresponding Author  **Methodologist


UPDATE (6/25/20): Recommendations on corticosteroids have been revised.

UPDATE (6/22/20): Version 2.0.0 of the guideline has been released and contains:

UPDATE (4/21/20): To the Background section, we added two paragraphs and added hypertension in the risks for severe diseases. To the Methods section, we added information about the criteria used for the certainty of evidence. We changed the titles for the two sections on ACE inhibitors/ARBs and NSAIDS.

UPDATE (4/13/20):  Language has been added to clarify that the guideline panel used the word “only” in recommendations about therapeutic agents with higher uncertainty and/or more potential for harm. See Executive Summary (second paragraph) and Methods section, Evidence to recommendations subsection (third paragraph).

Abstract

Background: There are many pharmacologic therapies that are being used or considered for treatment of coronavirus disease 2019 (COVID-19). There is a need for frequently updated practice guidelines on their use, based on critical evaluation of rapidly emerging literature.

Objective: Develop evidence-based rapid guidelines intended to support patients, clinicians and other health-care professionals in their decisions about treatment and management of patients with COVID-19.

Methods: In March 2020, the Infectious Diseases Society of America (IDSA) formed a multidisciplinary guideline panel of infectious disease clinicians, pharmacists, and methodologists with varied areas of expertise. The process followed a rapid recommendation checklist. The panel prioritized questions and outcomes. Then a systematic review of the peer-reviewed and grey literature was conducted. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the certainty of evidence and make recommendations.

Results: On April 11, 2020, IDSA released online initial treatment recommendations and narrative summaries of other treatments under evaluation. Since that time, the guideline panel and methodologists have continued to monitor the literature and issue updates and addendums to these guidelines in response to evolving research.

Conclusions: Since the inception of its work, the panel has expressed the overarching goal that patients be recruited into ongoing trials, which would provide much needed evidence on the efficacy and safety of various therapies for COVID-19, given that we could not make a determination whether the benefits outweigh harms for most treatments.

Keywords: coronavirus, SARS-CoV-2, COVID, COVID-19, pneumonia

Executive Summary and Background

Executive Summary

Coronavirus disease 2019 (COVID-19) is a pandemic with a rapidly increasing incidence of infections and deaths. Many pharmacologic therapies are being used or considered for treatment. Given the rapidity of emerging literature, the Infectious Diseases Society of America (IDSA) identified the need to develop living, frequently updated evidence-based guidelines to support patients, clinicians and other health-care professionals in their decisions about treatment and management of patients with COVID-19.

Summarized below are the recommendations with comments related to the clinical practice guideline for the treatment and management of COVID-19. A detailed description of background, methods, evidence summary and rationale that support each recommendation, and research needs can be found online in the full text. In brief, per Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, recommendations are labeled as “strong” or “conditional”. The word “recommend” indicates strong recommendations and “suggest” indicates conditional recommendations. In situations where promising interventions were judged to have insufficient evidence of benefit to support their use and with potential appreciable harms or costs, the expert panel recommended their use in the context of a clinical trial. These recommendations acknowledge the current “knowledge gap” and aim at avoiding premature favorable recommendations for potentially ineffective or harmful interventions.

  • Recommendation 1. Among patients with COVID-19, the IDSA guideline panel recommends hydroxychloroquine/chloroquine only in the context of a clinical trial. (Knowledge gap)
  • Recommendation 2. Among patients with COVID-19, the IDSA guideline panel suggests against hydroxychloroquine/chloroquine plus azithromycin outside of the context of a clinical trial. (Conditional recommendation, very low certainty of evidence)
  • Recommendation 3. Among patients who have been admitted to the hospital with COVID-19, the IDSA guideline panel recommends the combination of lopinavir/ritonavir only in the context of a clinical trial. (Knowledge gap)
  • Recommendation 4. Among hospitalized patients with severe* COVID-19, the IDSA guideline panel suggests glucocorticoids rather than no glucocorticoids. (Conditional recommendation, moderate certainty of evidence)
    • *Severe illness is defined as patients with SpO2 ≤94% on room air, and those who require supplemental oxygen, mechanical ventilation, or extracorporeal mechanical oxygenation (ECMO).
  • Recommendation 5. Among hospitalized patients with COVID-19 without hypoxemia requiring supplemental oxygen, the IDSA guideline panel suggests against the use of glucocorticoids. (Conditional recommendation, low certainty of evidence)
  • Recommendation 6. Among patients who have been admitted to the hospital with COVID-19, the IDSA guideline panel recommends tocilizumab only in the context of a clinical trial. (Knowledge gap)
  • Recommendation 7. Among patients who have been admitted to the hospital with COVID-19, the IDSA guideline panel recommends COVID-19 convalescent plasma only in the context of a clinical trial. (Knowledge gap)
  • Recommendation 8. Among hospitalized patients with severe* COVID-19, the IDSA panel suggests remdesivir over no antiviral treatment. (Conditional recommendation, moderate certainty of evidence)
    • Remark: For consideration in contingency or crisis capacity settings (i.e. limited remdesivir supply): 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.
    • *Severe illness is defined as patients with SpO2 ≤94% on room air, and those who require supplemental oxygen, mechanical ventilation, or ECMO.
  • Recommendation 9. Among patients with severe COVID-19 on supplemental oxygen but not on mechanical ventilation or ECMO, the IDSA panel suggests treatment with five days of remdesivir rather than 10 days of remdesivir. (Conditional recommendation, low certainty of evidence)
    • Remark: In patients on mechanical ventilation or ECMO, the duration of treatment is 10 days.
  • Recommendation 10. Among hospitalized patients with severe COVID-19, the IDSA panel suggests against famotidine use for the sole purpose of treating COVID-19 outside of the context of a clinical trial. (Conditional recommendation, very low certainty of evidence)

 

Since the inception of its work, the panel has expressed the overarching goal that patients be recruited into ongoing trials, which would provide much needed evidence on the efficacy and safety of various therapies for COVID-19. The panel has determined that when an explicit trade-off between highly uncertain benefits and known putative harms of these therapeutic agents were considered, a net positive benefit was not reached and could possibly be negative (risk of excess harm). The panel acknowledges that enrolling patients in randomized controlled trials (RCTs) might not be feasible for many frontline providers due to limited access and infrastructure. Should lack of access to clinical trials exist, we encourage setting up local or collaborative registries to systematically evaluate the efficacy and safety of drugs to contribute to the knowledge base. Each clinician can play a role in advancing our understanding of this disease through a local registry or other data collection efforts.

Background

The first cases of COVID-19 were reported from Wuhan, China in early December 2019 [1], now known to be caused by a novel beta-coronavirus, named as Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Within a span of months, COVID-19 has become pandemic due to its transmissibility, spreading across continents with the number of cases and deaths rising daily [2]. Although most infected individuals exhibit a mild illness (80%+), 14% have serious and 5% have critical illness. Approximately 10% will require hospital admission due to COVID-19 pneumonia, of which approximately 10% will require ICU care, including invasive ventilation due to acute respiratory distress syndrome (ARDS) [3]. While mortality appears to be more common in older individuals and those with comorbidities, such as chronic lung disease, cardiovascular disease, hypertension and diabetes, young people with no comorbidities also appear to be at risk for critical illness including multi-organ failure and death.

There has been an expanding number of studies rapidly published online and in academic journals; however, some of these may be of limited quality and are pre-published without sufficient peer-review. Critical appraisal of the existing studies is needed to determine if the existing evidence is sufficient to support currently proposed management strategies.

Given the rapid global spread of SARS CoV-2 and the difficulty for the overburdened front-line providers and policymakers to stay up to date on emerging literature, IDSA has recognized the necessity of developing a rapid guideline for the treatment of COVID-19. The guideline panel is using a methodologically rigorous process for evaluating the best available evidence and providing treatment recommendations. Two additional guidelines on diagnostic testing and infection prevention also have been developed. These guidelines will be frequently updated as substantive literature becomes available and are accessible on an easy to navigate web and device interface at http://www.idsociety.org/covid19guidelines.

There continue to be several ongoing trials evaluating therapeutic agents for the treatment of COVID-19. As data becomes available from these trials and if there is a preponderance of evidence to suggest the use of a therapeutic agent even in the context of clinical trials is no longer warranted it will be removed from future updates of the guideline (and the removal will be noted in the updated guidelines). If there is emerging evidence on the efficacy or safety of a therapeutic agent not mentioned in the current version of the guideline it will be included in future updates of the guideline.

These recommendations are intended to inform patients, clinicians, and other health professionals by providing the latest available evidence.

Methods and Search Results

This guideline was developed using the GRADE approach for evidence assessment. In addition, given the need for an urgent response to a major public health crisis, the methodological approach was modified according to the Guidelines International Network/McMaster checklist for the development of rapid recommendations [4].

Panel Composition

The initial guideline panel assembled in March 2020 was composed of nine members including infectious diseases specialists as well as experts in public health as well as other front-line clinicians, specializing in pharmacology, pediatrics, medical microbiology, preventive care, critical care, hepatology, nephrology and gastroenterology. Organizational representatives were included from the Society for Healthcare Epidemiology of America (SHEA), and the Pediatric Infectious Diseases Society (PIDS). In May 2020, an additional panel member was included as a representative from the Society of Infectious Diseases Pharmacists (SIDP). The Evidence Foundation provided technical support and guideline methodologists for the development of this guideline.

Disclosure and Management of Potential Conflict of Interest

The conflict of interest (COI) review group for this guideline includes two representatives from IDSA who are responsible for reviewing, evaluating and approving all disclosures. All members of the expert panel have complied with the COI process for reviewing and managing conflicts of interest, which requires disclosure of any financial, intellectual, or other interest that might be construed as constituting an actual, potential, or apparent conflict, regardless of relevancy to the guideline topic. The assessment of disclosed relationships for possible COI is based on the relative weight of the financial relationship (i.e., monetary amount) and the relevance of the relationship (i.e., the degree to which an association might reasonably be interpreted by an independent observer as related to the topic or recommendation of consideration). The COI review group has ensured that the majority of the panel and chair is without potential relevant (related to the topic) conflicts for the duration of their term on the panel. The chair and all members of the technical team have been determined to be unconflicted.

Question Generation

Clinical questions included in this guideline were developed into a PICO format (Population, Intervention, Comparison, Outcomes) [5] and prioritized according to available evidence that met the minimum acceptable criteria (i.e., the body of evidence reported on at least a case-series design, case reports were excluded). Panel members prioritized patient-important outcomes such as mortality, development of ARDS (need for non-invasive or invasive ventilation) and clinical improvement (such as disease-oriented outcomes inferred by radiological findings or virologic cure), and severe adverse events (SAE) leading to treatment discontinuation. Serious adverse events are death, life threatening reactions, those that require hospitalization, result in disability or permanent damage or require an intervention to prevent permanent impairment [6]. Additional drug specific harms were evaluated when clinically relevant, including possible drug-drug reactions, if applicable.

Search Strategy

The National Institute for Health and Care Excellence (NICE) highly-sensitive search was reviewed by the methodologist in consultation with the technical team information specialist and was determined to have high sensitivity [7]. An additional term, COVID, was added to the search strategy used in addition to the treatment terms identified in the PICO questions (Table s1). Ovid Medline and Embase were searched from 2019 through June 18, 2020. Horizon scans have been performed regularly during the evidence assessment and recommendation process to locate additional grey literature and manuscript pre-prints. Reference lists and literature suggested by panelists were reviewed for inclusion. No restrictions were placed on language or study type.

Screening and Study Selection

Two reviewers independently screened titles and abstracts, as well as eligible full-text studies. When acceptable RCTs of effectiveness were found, no additional non-randomized studies or non-comparative evidence (i.e., single arm case series) were sought. Evidence from single arm studies reporting on non-comparative rates of outcomes of interest were included if a historical control event rate could be estimated from the literature. Reviewers extracted relevant information into a standardized data extraction form.

For several interventions, no direct evidence was available other than case reports or mechanistic considerations. The panel either decided to include plausible indirect evidence and make a recommendation (e.g., from studies of SARS-CoV) or to provide a short narrative discussion of the intervention.

Data Collection and Analysis

Data extracted from the available evidence included: mortality, clinical progression or improvement as reported in the studies, virologic clearance, and adverse events. Where applicable, data were pooled using random effects model (fixed effects model for 2 or less trials or pooling of rates) using RevMan [8].

Risk of Bias and Certainty of Evidence

Risk of bias was assessed using the Cochrane Risk of Bias Tool for RCTs and the Risk of Bias Instrument for Non-randomized Studies – of Interventions (ROBINS-I) [9, 10]. The certainty of evidence was assessed using the GRADE approach [11]. Within GRADE, the body of evidence across each outcome is assessed for domains that may reduce or increase one’s certainty in the evidence. Factors that may reduce one’s certainty include risk of bias (study limitations), inconsistency (unexplained heterogeneity across study findings), indirectness (applicability or generalizability to the research question), imprecision (the confidence in the estimate of an effect to support a particular decision) or publication bias (selective publication of studies). One’s certainty in the evidence may be strengthened if the following considerations are present: large or very large magnitude of effect, evidence of a dose-response gradient, or opposing residual confounding. GRADE summary of findings tables were developed in GRADEpro Guideline Development Tool [12].

Evidence to Recommendations

The panel considered core elements of the GRADE evidence in the decision process, including Certainty of evidence and balance between desirable and undesirable effects. Additional domains were acknowledged where applicable (feasibility, resource use, acceptability). For all recommendations, the expert panelists reached consensus. Voting rules were agreed on prior to the panel meetings for situations when consensus could not be reached.

As per GRADE methodology, recommendations are labeled as “strong” or “conditional”. The words “we recommend” indicate strong recommendations and “we suggest” indicate conditional recommendations. Figure 1 provides the suggested interpretation of strong and weak recommendations for patients, clinicians, and healthcare policymakers. For recommendations where the comparators are not formally stated, the comparison of interest is implicitly referred to as “not using the intervention”. These recommendations acknowledge the current “knowledge gap” and aim at avoiding premature favorable recommendations for their use and to avoid encouraging the rapid diffusion of potentially ineffective or harmful interventions. Detailed suggestions about the specific research questions that should be addressed are found in the table (see Table s2).

GRADE Figure

Review Process

This guideline has been rapidly reviewed and approved by the IDSA Board of Directors Executive Committee external to the guideline development panel. SHEA, SIDP and PIDS have reviewed and provided endorsement of its contents.

Updating Process

Regular, frequent screening of the literature will take place to determine the need for revisions based on the likelihood that any new data will have an impact on the recommendations. When necessary, the entire expert panel is reconvened to discuss potential changes.

Changes to these guidelines will fall into one of two categories: update or amendment. An update involves a search for new studies, and if any new studies are found, they will be critically appraisal and the pertinent section will be removed and replaced with the updated section. An amendment involves a change or correction to the document, without any search for new studies and their appraisal. It will also involve changes made to clarify or explain a section based on “living” feedback from the readers.

Guideline revisions may result in major, minor, or “patch” version changes, defined as follows:

  • Major version (e.g., 1.0.0): Synonymous with a newly published version in the journal. This is usually called a "breaking version", i.e. prior recommendations may not be valid anymore.
  • Minor version (e.g., 1.1.0): Includes new information, maybe even added PICOs, but not a breaking version, i.e. existing recommendations are still valid, although new recommendations may be available.
  • Patch version (e.g., 1.0.1): Small changes, i.e., typos, adding words, removing words, but there are no material changes to the document or changes in recommendations.

Search Results

Systematic review and horizon scan of the literature identified 2030 references of which 48 informed the evidence base for these recommendations (Figure s1). Characteristics of the included studies can be found in Tables s3a-3h.

Recommendations 1 and 2: Hydroxychloroquine +/- azithromycin vs. no hydroxychloroquine +/- azithromycin for hospitalized patients

Section last reviewed and updated 6/18/20

Recommendation 1. Among patients with COVID-19, the IDSA guideline panel recommends hydroxychloroquine/chloroquine only in the context of a clinical trial. (Knowledge gap)

Recommendation 2. Among patients with COVID-19, the IDSA guideline panel suggests against hydroxychloroquine/chloroquine plus azithromycin outside of the context of a clinical trial. (Conditional recommendation, very low certainty of evidence)

The last literature search was conducted on June 18, 2020 and we identified three RCTs and two non-randomized studies in OVID. Two new non-indexed RCTs were available.

Why are hydroxychloroquine and hydroxychloroquine plus azithromycin considered for treatment?

Hydroxychloroquine (HCQ) and chloroquine are 4-aminoquinoline drugs developed in the mid-20th century for the treatment of malaria [13]. Hydroxychloroquine differs from chloroquine only in the addition of a hydroxyl group and is associated with a lower incidence of adverse effects with chronic use [13]. These drugs have been used in the treatment of autoimmune diseases for their immunomodulatory effects through effects on several cytokines, including IL-1 and IL-6 [13]. It has been known that they have antiviral properties against many different viruses, including the coronaviruses that cause SARS and Middle Eastern Respiratory Syndrome (MERS) [14, 15]. They have in vitro activity against SARS-CoV-2, and though half maximal effective concentration (EC50) values range considerably between studies, they are generally within the range of predicted achievable tissue concentrations [14, 16-18]. The in vitro activity of HCQ, the history of use for other conditions, and widespread availability of generic versions of the drug made it a potentially attractive option for the treatment of COVID-19. Interest in combinations of HCQ with azithromycin (AZ) began when investigators in a small, uncontrolled study of HCQ use for COVID-19 noticed a higher frequency of patients achieving virologic response in the six subjects who received AZ to prevent bacterial infection [19]. Azithromycin, widely utilized as an antibacterial agent, has been shown to have antiviral activity in vitro against a number of viruses [20-22]. While the exact mechanism of antiviral activity is unknown, possible mechanisms include inhibiting endocytosis thereby limiting viral replication [23] and the ability to induce interferon responses [22, 24]. Macrolides have also been shown to have anti-inflammatory activity [25, 26].

Summary of the evidence

Our search identified three RCTs and six comparative cohort studies of hospitalized patients with confirmed COVID-19 treated with HCQ reporting on mortality, clinical progression or clinical improvement, and adverse events [27-35] (Table s3a) (Table 1).

In addition, we identified three comparative cohort studies and one case-control study reporting adjusted analyses of hospitalized patients with confirmed COVID-19 treated with HCQ plus AZ reporting on the outcomes of mortality, failure of virologic clearance (assessed with polymerase chain reaction [PCR] test), and adverse events (i.e., significant QT prolongation leading to treatment discontinuation) [29, 31, 33, 34] (Table s3a) (Table 2).

Benefits

Hydroxychloroquine

No mortality events were reported from 180 patients receiving either HCQ or no HCQ treatment across two RCTs [27, 29]. Five non-randomized studies failed to identify an association between persons treated with HCQ (compared to those not receiving HCQ) and mortality: Geleris 2020 reported an adjusted hazard ratio (HR) of 1.00 (95% confidence interval [CI]: 0.76, 1.32); Ip 2020 reported an adjusted HR of 1.02 (95% CI: 0.83, 1.27); Magagnoli reported in an adjusted HR in a subset after propensity score adjustment of 0.99 (95% CI: 0.50, 1.92); Mahévas 2020 reported a weighted HR of 1.20 (95% CI: 0.40, 3.30); Rosenberg 2020 reported an adjusted HR of 1.08 (95% CI: 0.63, 1.85) [30-33, 35]. One non-randomized study reported a decrease in mortality among persons treated with HCQ (adjusted HR: 0.36; 95% CI: 0.18, 0.75) [34].

The currently available best evidence failed to demonstrate or to exclude a beneficial effect of HCQ on clinical progression of COVID-19 (as inferred by radiological findings; risk ratio [RR]: 0.61; 95% CI: 0.26, 1.43; see Figure s2a), or on viral clearance by PCR tests (RR: 2.00; 95% CI: 0.02, 20.00; see Figure s2b), although a somewhat higher proportion in the HCQ group experienced clinical improvement (RR: 1.47; 95% CI 1.02, 2.11) (Table 1). However, the certainty in the evidence was rated as very low mainly due to small sample sizes (sparse data), co-interventions, and risk of bias due to methodological limitations.

Hydroxychloroquine + Azithromycin

Three non-randomized studies failed to identify an association between treatment with HCQ + AZ and mortality: Ip reported an adjusted HR of 0.98 (95% CI: 0.75, 1.28); Magagnoli reported an adjusted HR in a subset after propensity score adjustment of 0.89 (95% CI: 0.45, 1.77); Rosenberg 2020 reported an adjusted HR of 1.35 (95% CI: 0.79, 2.40) [31, 33, 35].

Harms

Hydroxychloroquine

Four recent or ongoing RCTs did not show a harm signal among persons with or without COVID-19 receiving treatment with HCQ [37-40], as well as two larger observational studies [30, 33]. Across the body of evidence from three RCTs, treatment with HCQ may increase the risk of experiencing adverse events (RR: 3.14; 95% CI: 1.58, 6.24; Very low CoE); however, the evidence is uncertain [27-29]. Two non-randomized comparative studies suggest increased risk of QT prolongation among patients receiving HCQ compared to those not receiving HCQ (RR: 2.89; 95% CI: 1.62, 5.16; Very low CoE) [32, 33]. In addition, Rosenberg 2020 reported 16% of patients in the HCQ arm experienced arrhythmias compared with 10% in the non-HCQ arm (RR: 1.56; 95% CI: 0.97, 2.50).

In another prospective cohort study in 224 COVID-19 uninfected patients with systemic lupus erythematosus (SLE) who received either chloroquine or HCQ for routine care, gastrointestinal side effects occurred in 7% of patients [41].

While the 4-aminoquinolines, chloroquine and HCQ, have not been demonstrated to cause hemolysis in people with glucose-6-phosphate dehydrogenase (G6PD) deficiency [42, 43], case reports of hemolysis have emerged when these agents have been used for the treatment of COVID-19 [44-46]. It is possible that infection itself, specifically in cases of SARS CoV-2 infection, may trigger hemolysis in G6PD deficient individuals in the absence of a 4-aminoquinolone, however it may be prudent to exercise caution in administering these agents to G6PD deficient individuals with COVID-19, particularly if used for extended durations.

Renal clearance accounts for 15-25% of total clearance of HCQ; however, dose adjustments are not recommended with kidney dysfunction according to package labeling. Chloroquine and HCQ are metabolized by cytochrome P450 isoenzymes 2C8, 2D6, and 3A4 [47], therefore inhibitors and inducers of these enzymes may result in altered pharmacokinetics of these agents.

Hydroxychloroquine + Azithromycin

Two studies described significant QT prolongation in 10 of 95 patients treated with HCQ+AZ, either resulting in an QT increase to over 500 ms or discontinuation of the HCQ+AZ treatment, illustrating the high risk for clinically relevant arrhythmias with this treatment [48, 49]. In addition, several case reports of QT prolongation related to HCQ have also been published [50-53]. A case-control study of persons with COVID-19 treated with HCQ+AZ compared to healthy untreated controls reported higher values of minimum (415 vs 376 ms), mean (453 vs 407 ms) and maximum QTc-interval (533 vs 452 ms) among COVID-19 cases (n=22) than controls (n=34) [36].

Several case reports have been published citing the risk of a prolonged QT prolongation, torsades de pointes, and ventricular tachycardia in patients without COVID-19 receiving AZ alone. In a large cohort study, patients taking a five-day course of AZ had an increased risk of sudden cardiac death with a HR of 2.71 (1.58-4.64) vs. 0.85 (0.45-1.60), compared to patients receiving no antibiotic or amoxicillin, respectively [54]. Given the cumulative effect on cardiac conduction seen with HCQ and AZ, if this combination was to be used in the context of a clinical trial, baseline and follow-up echocardiogram (ECG) monitoring would be indicated, as well as careful surveillance for other concomitant medications known to prolong the QT interval.

Providers are encouraged to visit resources such as the newly created website, https://www.covid19-druginteractions.org/, to aid in the evaluation and management of drug interactions with current and emerging investigational agents for COVID-19.

Azithromycin has a low risk for cytochrome P450 interactions [55]; however additional pharmacologic adverse events including gastrointestinal effects and QT prolongation need to be carefully considered particularly in the outpatient setting where frequent ECG monitoring is not feasible.

Other considerations

The panel agreed that the overall certainty of evidence was very low due to concerns with risk of bias, inconsistency, indirectness, imprecision, and publication bias. When considering the addition of AZ, the panel recognized the greater concern with the toxicity.

Conclusions and research needs for this recommendation

The guideline panel recommends that, because of uncertainty regarding its risks and benefits, the use of HCQ should be only in the context of a clinical trial. Because of the potential for toxicity, the panel suggests against HCQ+AZ combination outside of a clinical trial. This recommendation does not address the use of AZ for secondary bacterial pneumonia in patients with COVID-19. Additional RCTs and prospective outcome registries are needed to inform research for treatment with HCQ alone or in combination with AZ for patients with COVID-19 (Table s2).

Table 1.png

 

 

Table 2.png

Recommendation 3: Lopinavir/ ritonavir vs. placebo for confirmed COVID-19 pneumonia

Section last reviewed 6/22/20; no updates made

Recommendation 3. Among patients who have been admitted to the hospital with COVID-19, the IDSA guideline panel recommends the combination of lopinavir/ritonavir only in the context of a clinical trial. (Knowledge gap)

Summary of the evidence

One RCT and two case studies reported on treatment with combination lopinavir/ritonavir for hospitalized patients with COVID-19 [56-58] (Table 3). Cao et al. randomized 199 hospitalized patients with severe COVID-19 to receive treatment with lopinavir/ritonavir in addition to standard of care (n=99) or standard of care alone (n=100) for 14 days. The trial reported on the following outcomes: mortality, failure of clinical improvement (measured using a 7-point scale or hospital discharge), and adverse events leading to treatment discontinuation.

Benefits

Based on a modified intention to treat analysis, treatment with lopinavir/ritonavir failed to show or exclude a beneficial effect on mortality (RR: 0.67; 95% CI: 0.38, 1.17), although failure of clinical improvement was lower in the lopinavir group (RR: 0.78; 95% CI: 0.63, 0.97; ITT analysis).

Harms

Nearly 14% of lopinavir/ritonavir recipients were unable to complete the full 14-day course of administration due primarily to gastrointestinal adverse events, including anorexia, nausea, abdominal discomfort, or diarrhea, as well as two serious adverse episodes of acute gastritis. Two recipients also had self-limited skin eruptions. The risk of hepatic injury, pancreatitis, severe cutaneous eruptions, QT prolongation, and the potential for multiple drug interactions due to CYP3A inhibition, are all well documented with this drug combination.

Other considerations

The panel elected to inform their decision based on the RCT [58]. The panel determined the Certainty of evidence to be very low due to concerns with risk of bias (lack of blinding) and imprecision. In the randomized clinical trial conducted by Cao et al, the group that received lopinavir/ritonavir and the group that did not had similar rates of viral decay. This finding suggests that lopinavir/ritonavir is not having a measurable antiviral effect, its purported mechanism of action.

Conclusions and research needs for this recommendation

The guideline panel recommends the use of lopinavir/ritonavir only in the context of a clinical trial. Additional clinical trials or prospective outcome registries are needed to inform research for treatment with lopinavir/ritonavir and other HIV-1 protease inhibitors for patients with COVID-19 (Table s2).

GRADE Profile 3

Recommendations 4 and 5: Corticosteroids vs. no corticosteroids

Section last reviewed and updated 6/25/20

Recommendation 4. Among hospitalized patients with severe* COVID-19, the IDSA guideline panel suggests glucocorticoids rather than no glucocorticoids. (Conditional recommendation, Moderate certainty of evidence)

  • Remark: Dexamethasone 6 mg IV or PO for 10 days (or until discharge if earlier) or equivalent glucocorticoid dose may be substituted if dexamethasone unavailable. Equivalent total daily doses of alternative glucocorticoids to dexamethasone 6 mg daily are methylprednisolone 32 mg and prednisone 40 mg.

 Recommendation 5. Among hospitalized patients with COVID-19 without hypoxemia requiring supplemental oxygen, the IDSA guideline panel suggests against the use of glucocorticoids. (Conditional recommendation, Low certainty of evidence)

*Severe illness is defined as patients with SpO2 ≤94% on room air, and those who require supplemental oxygen, mechanical ventilation, or ECMO.

 

The last literature search was conducted on June 18, 2020 and we identified one RCT pre-print and seven comparative non-randomized studies.

Why are corticosteroids considered for treatment?

In the early days of the SARS-CoV-2 pandemic, based on experience in both SARS and MERS, recommendations [59] cautioned against the use of systemic corticosteroids due to risk of worsening clinical status, delayed viral clearance, and adverse events [60-62]. Given the hyper-inflammatory state in COVID-19, immunomodulatory approaches, including steroids, continue to be evaluated to address both ARDS and systemic inflammation. ARDS stemming from dysregulated systemic inflammation may translate into prolonged ventilatory requirements and in-hospital mortality. In non-viral ARDS settings there is increasing support for the role of steroids in the management of ARDS [63]. A recent multicenter RCT in patients with moderate-severe ARDS demonstrated a reduced number of ventilatory days and reduction in mortality with use of a 10-day regimen of dexamethasone [64].

Summary of the evidence

Our search identified one RCT, one “partially” randomized trial, one prospective cohort, and five retrospective cohort studies [65-72]. The RCT provided the best available evidence on treatment with corticosteroids for persons with COVID-19 [65] (Table 4, Table 5). Corral-Gudino et al. reported on a study that randomized patients to receive methylprednisolone or standard of care; however, patients expressing a preference for methylprednisolone were assigned to the same treatment arm [66]. Corral-Gudino et al. did not report the disaggregated results from the randomized trial; therefore, succumbing to the same potential for bias as reported subsequently for the non-randomized studies. The non-randomized studies had significant limitations with controlling for multiple co-interventions and disease severity at baseline [67-72]. All non-randomized studies had concerns with risk of bias due to lack of adjustment for critical confounders or potential for residual confounding. Timing of receipt, dose and duration of corticosteroids varied across studies.

The RECOVERY trial is a randomized trial among hospitalized patients in the United Kingdom [65]. In that study, 2104 participants were randomized to receive dexamethasone (6 mg daily for up to 10 days) and 4321 were randomized to usual care. The RECOVERY trial reported on the outcomes of mortality and hospital discharge. Participants and study staff were not blinded to the treatment arms.

Benefits

Among hospitalized patients, 28-day mortality was 17% lower in the group that received dexamethasone than in the group that did not receive dexamethasone (RR 0.83; 0.74-0.92; Moderate certainty of evidence). In addition, at 28 days, patients receiving dexamethasone are more likely to be discharged from the hospital (RR: 1.11; 95% CI: 1.04, 1.19; Moderate certainty of evidence).

In sub-group analyses of patients without hypoxia not receiving supplemental oxygen, there was no evidence for benefit and a trend toward harm with dexamethasone in participants who were not on supplemental oxygen (RR 1.22; 0.86, 1.75; Low certainty of evidence).

Harms

Patients receiving a short course of steroids may experience hyperglycemia, neurological side effects (e.g., agitation/confusion), adrenal suppression, and risk of bacterial and fungal infection [67, 73, 74].

Other considerations

The panel agreed the overall certainty of evidence for treatment with glucocorticoids for patients with severe COVID-19 as moderate due to concerns with indirectness since the evidence was from dexamethasone. The panel agreed that the overall certainty of evidence for patients without hypoxemia requiring supplemental oxygen as low due to concerns with risk of bias (post hoc analysis) and imprecision.

Conclusions and research needs for these recommendations

The guideline panel suggests glucocorticoids for patients with severe COVID-19. The guideline panel suggests against glucocorticoids for patients with COVID-19 without hypoxemia requiring supplemental oxygen.

Additional research is needed to inform the generalizability of treatment with different glucocorticoids for patients with COVID-19 (Table s2).

Table 4.png

 

Table 5.png

Recommendation 6: Tocilizumab vs. no treatment for severe COVID-19 pneumonia

Section last reviewed 6/22/20; no updates made

Recommendation 6. Among patients who have been admitted to the hospital with COVID-19, the IDSA guideline panel recommends tocilizumab only in the context of a clinical trial. (Knowledge gap)

Summary of the evidence

Studies reporting on the pathogenesis of SARS-CoV-1 and MERS-CoV suggest a release of proinflammatory cytokines including interleukins-6 (IL-6) [75] during the clinical illness. Our search identified one study [75] that reported on 21 severe or critical patients with COVID-19 treated with tocilizumab, an IL-6 blocker (Table 6). This study had no control group. To estimate a control group rate in patients who did not get treatment with tocilizumab, Xu et al. described findings from Yang 2020, which suggested a baseline mortality rate of 60% in critical patients and 11% in severe patients admitted to the ICU [76].

Benefits

We estimate that the patients in Xu 2020 (21 patients, 4 critical and 17 severe) would have a baseline mortality risk of 20% as matched in severity. Therefore, treatment with tocilizumab may have reduced mortality since there were no deaths reported out of 21 patients. However, this conclusion remains highly uncertain given the lack of a contemporaneous control or adjustments for confounding factors. Out of 21 patients, 19 were discharged from the hospital suggesting a 9.5% rate of failure of clinical improvement in the CT scan findings.

Harms

Xu et al. reported no serious adverse events [75]. However, patients receiving tocilizumab are often at an increased risk of serious infections (bacterial, viral, invasive fungal infections, and tuberculosis) and hepatitis B reactivation [77]. Cases of anaphylaxis, severe allergic reactions, severe liver damage and hepatic failure, and intestinal perforation have been reported after tocilizumab administration in patients without COVID-19.

Tocilizumab is not metabolized by the cytochrome P450 isoenzyme system, however elevated IL-6 levels seen in inflammatory states have been shown to inhibit these enzymes, thereby slowing the metabolism of drugs through these pathways. As the 3A4 pathway is responsible for metabolism of many commonly used medications, administration of IL-6 inhibitors like tocilizumab may result in enhanced metabolism in drugs utilizing the cytochrome P450 system [78, 79].

Other considerations

The panel determined that the overall certainty of the evidence was very low due to concerns of high risk of bias due to confounding, indirectness, and imprecision. 

Conclusions and research needs for this recommendation

The guideline panel recommended tocilizumab only in the context of a clinical trial. Additional clinical trials are needed to inform research on the effectiveness of treatment with tocilizumab for patients with COVID-19 (Table s2).

Evidence Profile 6: Tocilizumab vs. no treatment

Recommendation 7: Convalescent plasma vs. no convalescent plasma for hospitalized patients

Section last reviewed and updated on 6/22/20

Recommendation 7. Among patients who have been admitted to the hospital with COVID-19, the IDSA guideline panel recommends COVID-19 convalescent plasma only in the context of a clinical trial. (Knowledge gap)

The last literature search was conducted on June 18, 2020 and we identified one RCT, two comparative cohort studies, and two single-arm registry studies in OVID.

Why is convalescent plasma considered for treatment?

Convalescent plasma (CP) has been used as passive immunotherapy for prevention and treatment of infections for over 100 years [80, 81]. The predominant proposed protective mechanism is thought to be pathogen neutralization, although antibody dependent cellular cytotoxicity and phagocytosis may also play a role. With the advent of effective antimicrobial therapy (i.e., “the antibiotic era”) CP fell out of favor. In recent years, interest in this approach has been revived as a means of addressing viral epidemics such as Ebola, SARS -1 and MERS. Studies of CP derived from people who had recovered from those specific infections showed encouraging results, but were typically small, non-randomized and largely descriptive [82-84]. In the current pandemic, CP obtained from individuals who recovered from COVID-19 has been used in over 20,000 patients with moderate to severe infection as part of an expanded access program.

Many questions remain regarding the minimal antibody titer required for the plasma to provide benefit, the type of antibodies that plasma should contain to be most protective and the optimal timing of therapy. When measurement of neutralizing antibody titers is available, the U.S. Food and Drug Administration (FDA) recommends neutralizing antibody titers of at least 1:160. Such assays have not been widely available and titers in plasma used in the expanded access program have often not been assessed prior to infusion. Multiple prospective clinical trials are in progress utilizing plasma with an IgG ELISA titer cutoff of ≥1:320. Titers at that level are seen in about 80% of donors [85]. The probability of obtaining a neutralizing antibody titer of ≥1:160 is highest (80% or greater) when the ELISA IgG titer is ≥1:1,350 [86]. Regarding timing of treatment: Based on historical experience and emerging data, efficacy is expected to be best when CP is given at earlier stages of the disease and particularly prior to when patients become critically ill [87, 88].

Summary of the evidence

Our search identified one RCT and two comparative cohort studies, as well as one large (n=5000), single-arm registry study among hospitalized patients with COVID-19 receiving COVID-19 CP reporting on the outcomes of mortality, worsening oxygenation, and transfusion-related adverse events [87-90] (Table 7) (Table s3f). We identified an additional small (n=25) single-arm study; however, we excluded it because it did not provide the best available evidence and may have been included in the registry study [86].

All studies had concerns with risk of bias due to lack of adjustment for critical confounders or potential for residual confounding. Timing of receipt of COVID-19 CP during the clinical course of the patients’ illness varied across studies.

Li 2020 randomized 103 patients to receive a transfusion or not in an open-label trial with more than 90% of patients enrolled 14 days after symptom onset (median 30 days). Subjects were propensity score matched on the administration of HCQ and AZ, intubation status and duration, length of hospital stay, and oxygen requirement on the day of transfusion; however, there may have been some residual confounding. Duan 2020 compared 10 CP treated patients to 10 historical control patients matched on age, gender, and severity of illness; however, the study did not adjust for critical confounders including co-treatments, baseline characteristics, disease severity, and timing of plasma delivery. Joyner et al. 2020 reported on 5,000 patients with severe or life-threatening COVID-19 enrolled in the U.S. FDA Expanded Access Program for COVID-19 CP study and found <1% severe adverse events within the first four hours after administration.

Benefits

Convalescent plasma transfusion failed to show or to exclude a beneficial or detrimental effect on mortality; the evidence from both RCT and non-randomized studies is uncertain (RR: 0.65; 95% CI: 0.29, 1.47; very low CoE and HR: 0.34; 95% CI: 0.13, 0.89; very low CoE, respectively). Similarly, receipt of COVID-19 CP may reduce the odds of worsening oxygenation (adjusted odds ratio [OR]: 0.86; 95% CI: 0.75, 0.98; very low CoE); however, the evidence is uncertain because of concerns with risk of bias (Table 7).

Harms

In the largest safety study, there were 15 deaths reported within 4 hours of transfusion in 5,000 patients (0.3%) [90] and four (0.08%) were judged as possibly or probably related to the transfusion of COVID-19 CP. In addition, 21 serious non-fatal adverse events (SAEs) were reported (0.4%): seven cases of transfusion-associated circulatory overload (TACO), 11 cases of transfusion-related acute lung injury (TRALI), and three cases of severe allergic transfusion reactions. Study authors judged all incidences of TACO and TRALI as related to the transfusion of COVID-19 CP. In another smaller study of 52 patients randomized to receive CP transfusions, two subjects developed transfusion-related adverse events (e.g., chills and rash; shortness of breath, cyanosis, and severe dyspnea) within 6 hours of receipt [87].

Other considerations

The panel agreed on the overall certainty of evidence as very low due to concerns with risk of bias and imprecision.

Conclusions and research needs for this recommendation

The guideline panel recommends COVID-19 CP only in the context of a clinical trial. Additional clinical trials are needed to inform benefit of treatment with COVID-19 CP for patients with COVID-19 (Table s2).

Table 7.png

Recommendations 8 and 9: Remdesivir vs. no antiviral treatment for severe COVID-10 pneumonia

New section added 6/22/20

Recommendation 8. Among hospitalized patients with severe* COVID-19, the IDSA panel suggests remdesivir over no antiviral treatment. (Conditional recommendation, Moderate certainty of evidence)

  • Remark: For consideration in contingency or crisis capacity settings (i.e., limited remdesivir supply): Remdesivir appears to demonstrate the most benefit in those with severe COVID-19 on supplemental oxygen rather than in patients on mechanical ventilation or extracorporeal mechanical oxygenation (ECMO).

Recommendation 9. Among patients with severe COVID-19 on supplemental oxygen but not on mechanical ventilation or ECMO, the IDSA panel suggests treatment with five days of remdesivir rather than 10 days of remdesivir. (Conditional recommendation, low certainty of evidence)

  • Remark: In patients on mechanical ventilation or ECMO, the duration of treatment is 10 days.

*Severe illness is defined as patients with SpO2 ≤94% on room air, and those who require supplemental oxygen, mechanical ventilation, or ECMO.

 

The last literature search was conducted on 6/18/2020 and we identified three RCTs and two non-randomized studies (NRS) in OVID.

Why is remdesivir considered for treatment?

Remdesivir (GS-5734) is an antiviral drug with potent in vitro activity against a range of RNA viruses including MERS-CoV, SARS-CoV 1 & 2 [91-93]. Remdesivir acts by causing premature termination of viral RNA transcription [93] Its use improved disease outcomes and reduced viral loads in SARS-CoV-1 infected mice [92]. In rhesus macaques therapeutic treatment with remdesivir showed reduction in SARS-CoV-2 loads, pathologic changes and progression of clinical disease [94]. In this animal model, remdesivir treatment initiated 12 hours post-inoculation reduced clinical signs, virus replication in the lungs, and decreased the presence and severity of lung lesions. A case series of 53 patients with severe COVID-19 pneumonia who received remdesivir under a compassionate-use protocol reported clinical improvement in 68% after a median follow-up of 18 days, with 13% mortality and a generally acceptable toxicity profile [95]. However, there was no comparison group of similar patients who received standard care at the participating institutions.

Summary of the evidence

Two RCTs comparing treatment with remdesivir (200 mg day one, 100 mg daily days 2-10) against no remdesivir treatment [96, 97], and one RCT comparing 5 days of treatment (200 mg day one, 100 mg daily days 2-5) against 10 days (200 mg day one, 100 mg daily days 2-10) of treatment [98] served as the best available evidence among hospitalized persons with severe COVID-19. The outcomes assessed were mortality, time to clinical improvement at 14 days, serious adverse events, and adverse events leading to treatment discontinuation (Table 8, Table 9).

The study by Wang et al 2020 was stopped early due to lack of recruitment into the trial due to decreased incidence in China. When comparing treatment with remdesivir to no remdesivir treatment data after 28-days of observation, we did not pool the mortality data from the Wang et al study and 14-day mortality from the Beigel et al study (i.e., Adaptive Covid-19 Treatment Trial [ACTT-1]). This is because the preliminary analysis of the ACTT-1 presented the mortality results appropriately as time-to-event analysis due to possible chance effects at 14 days, as many patients still remained hospitalized, with 28-day mortality data still unavailable at the time of the preliminary analysis.

Randomization performed in Goldman 2020 failed to establish prognostic balance between baseline clinical status among the 397 patients randomized into the treatment arms, with patients in the 10-day arm more severely ill at study entry. Even with the adjusted analysis, residual confounding is possible. In addition, participants, healthcare workers, and outcome assessors were not blinded to the treatment arms.

Benefits

Preliminary evidence in ACTT-1 showed a trend in reduction of mortality by remdesivir over no remdesivir treatment at 14 days (HR: 0.70; 95% CI: 0.47, 1.04; Moderate CoE) [96]. Wang et al. failed to show a mortality benefit at 28 days (RR: 1.09; 95% CI: 0.54, 2.18; Low CoE) [97] but, because the trial was stopped early, the study may have been under-powered to detect an effect. Patients receiving treatment with remdesivir may have greater clinical improvement at 28 days than patients not receiving remdesivir (RR: 1.13; 95% CI: 0.91, 1.41; Low CoE) [97]. In addition, patients receiving treatment with remdesivir had a shorter median time to recovery (median 11 vs. 15 days; HR: 1.32; 95% CI: 1.12, 1.55; High certainty of evidence) [96].

In another study by Goldman et al that compared 5 and 10 days of treatment, the shorter course of remdesivir showed a trend toward decreased mortality (RR: 0.75; 95% CI: 0.51, 1.12; Low CoE) and increased clinical improvement at 14 days (RR: 1.19; 95% CI: 1.01, 1.40; Low CoE); however, the evidence is uncertain because the persons in the 10-day group had more severe disease at baseline and there is the possibility of residual confounding despite the adjusted analysis [98].

Harms

Patients treated with remdesivir do not appear to experience greater SAEs (grade 3/4) than those not receiving remdesivir (RR: 0.88; 95% CI: 0.74, 1.06; Moderate CoE) [96, 97].

Patients receiving five days of remdesivir may experience fewer SAEs and AEs leading to treatment discontinuation than patients receiving 10 days of remdesivir (RR: 0.61; 0.44, 0.85; Low CoE and RR: 0.44; 95% CI: 0.21, 0.95; Low CoE, respectively); however, this evidence is uncertain because of the increased severity of disease among patients in the 10 day arm [98].

Other considerations

The panel agreed that the overall certainty of the evidence for treatment with remdesivir compared to no remdesivir treatment was moderate due to concerns with imprecision. The panel decided to not pool the outcome of mortality as dichotomous data until 28-day data would be released from both trials, due to concerns with 14-day mortality showing a spurious effect. Given the limited evidence across baseline severity, the panel recognized a knowledge gap when assessing whether greater benefit could be attained for patients with less severe disease; however, the panel agreed that the reported data supported the prioritization of remdesivir among persons with severe but not critical COVID-19.

The panel agreed on the overall certainty of the evidence for treatment with a 5-day course compared to a 10-day course of treatment as low due to concerns with risk of bias and imprecision. The panel recognized the benefit of a shorter course of treatment, if providing similar or greater efficacy, on the availability of remdesivir.

Conclusions and research needs for this recommendation

The guideline panel suggests remdesivir rather than no remdesivir for treatment of severe COVID-19 in hospitalized patients. Additional clinical trials are needed to provide increased certainty about the potential for both benefit and harms of treatment with remdesivir, as well as understand the benefit of treatment based on disease severity.

Beigel 2020 reported that the 28-day follow up of the ACTT-1 will be made available. At that time, the outcomes will be reassessed.

Table 8.png

 

 

Table 9.png

Recommendation 10: Famotidine vs. no famotidine for hospitalized patients

New section added 6/22/20

Recommendation 10. Among hospitalized patients with severe COVID-19, the IDSA panel suggests against famotidine use for the sole purpose of treating COVID-19 outside of the context of a clinical trial. (Conditional recommendation, very low certainty of evidence)

The last literature search was conducted on June 18, 2020 and we identified one non-randomized study in OVID. There were no new non-indexed RCTs available.

Why is famotidine considered for treatment?

Anecdotal reports from China suggest that patients infected with coronavirus who were receiving famotidine, a H2 receptor antagonist to treat conditions such as acid reflux and peptic ulcer disease, had improved survival vs. those receiving proton pump inhibitors (PPIs) [99]. This post hoc finding summarized below has led to interest in the drug, though no predominant theory describing a mechanism for its efficacy yet exists. One theory is that famotidine, like many other compounds, binds and therefore inhibits the coronavirus main protease, 3C-like main protease (3CLpro) [100].

Summary of the evidence

Our search identified one cohort study that compared 84 patients treated with famotidine against 1,536 patients not receiving treatment with famotidine [101]. Fifteen percent of patients in the famotidine group (13/84) started famotidine at home before presenting to the hospital. In addition, a subset of 420 patients not treated with famotidine were matched on baseline characteristics to the treated patients.

Benefits

Famotidine may decrease the composite outcome of death or intubation (HR: 0.42; 95% CI: 0.21, 0.85; Very low CoE); however, the evidence is very uncertain (Table 10).

Harms

Famotidine is well tolerated. Common adverse events include diarrhea or constipation but occur in less than 5% of people. Severe adverse events occur in less than 1% of persons taking famotidine.

Other considerations

The panel determined that the certainty of evidence to be very low due to concerns with risk of bias, imprecision, and possible publication bias. The panel agreed that critically ill patients (i.e., mechanically ventilated) may have been more likely to receive PPIs than famotidine, thus potentially allocating more prognostically favorable patients to the famotidine group; however, the study did not report a protective effect associated with the use of PPIs.

Conclusions and research needs for this recommendation

The guideline panel suggests against famotidine for the sole purpose of treating COVID-19, unless in the context of a clinical trial. Additional clinical trials are needed to inform research for treatment with famotidine for patients with COVID-19 (Table s2).

 

Table 10.png

Narrative summaries of treatments undergoing evaluation

Last reviewed 6/22/20; updates to this section pending

In addition to the clinical questions addressed above, the panel identified several treatments currently undergoing evaluation for which additional data are needed to rate recommendations. Narrative summaries for these treatments are provided below.

HIV antivirals

In vitro antiviral activity of darunavir against SARS-CoV-2 showed no activity at clinically relevant concentrations. Three randomized, open-label clinical trials are currently listed on evaluating darunavir/cobicistat as a potential therapeutic option for COVID-19. Janssen, the manufacturer of darunavir/cobcistat has reported that one of these trials [102] has concluded that darunavir/cobicistat plus conventional treatments was not effective in achieving viral clearance at day seven post randomization, compared to conventional treatments alone. Clinical outcomes of this trial including rate of critical illness and mortality 14 days after randomization, have not been reported to date.

Lopinavir-ritonavir combined with interferon beta or other antivirals

Lopinavir-ritonavir is a combination of protease inhibitors for the treatment of HIV infection. Lopinavir-ritonavir has been shown to have in-vitro antiviral activity against beta-coronaviruses such as SARS-CoV, and MERS-CoV [103-106]. Since lopinavir-ritonavir is not specifically designed for treatment of coronavirus, lopinavir-ritonavir alone may not demonstrate a difference from placebo in reducing viral load when treatment was initiated at a median of 13 days after symptoms onset [105]. In an open label treatment trial, lopinavir-ritonavir with ribavirin reduced the mortality and requirement of intensive care support of hospitalized SARS-CoV-1 patients compared with historical control [105]. Many interferons, especially interferon beta have been shown to have modest in-vitro antiviral activity against SARS-CoV and MERS-CoV [103, 104]. Lopinavir-ritonavir or interferon beta-1b has been shown to reduce viral load of MERS-CoV and improve lung pathology in a nonhuman primate model of common marmoset [106]. Lopinavir/ritonavir and interferon-β1b alone or in combination are being evaluated in clinical trials.

COVID-19 convalescent plasma for prophylaxis

There is a long history of using CP as treatment for infectious diseases, including severe viral lower respiratory tract infections [107]. Individuals who have recovered from SARS-CoV-2 infection may generate neutralizing antibodies [108, 109] that could have application to prevention of infection in certain settings, such as individuals with underlying conditions predisposing to severe disease and those with high-risk exposure. Monoclonal antibodies against other respiratory viruses have been shown to be protective against hospitalization in specific high-risk populations [110, 111] and animal models have suggested utility in prophylaxis against SARS-CoV-1 coronavirus infection [112]. There are some risks associated with the use of CP like transfusion-related acute lung injury or a theoretical risk of antibody-dependent enhancement of infection (ADE). Antibody-dependent enhancement of infection can occur in several viral diseases and involves an enhancement of disease in the presence of certain antibodies [113]. A trial from patients recovered from SARS-CoV-2 infection for use as prophylaxis in adults with a high-risk exposure is expected to begin recruiting shortly [114].

Ribavirin

There are only in vitro data available on the activity of ribavirin on SARS-CoV-2 currently. The EC50 (half maximal effective concentrations) was significantly higher than for chloroquine and remdesivir, so it appears less potent in vitro compared to these agents [16]. There are limited clinical studies in SARS-CoV-1 and MERS-CoV infections. In a systematic review of ribavirin treatment in patients infected with SARS-CoV-1, 26 studies were classified as inconclusive, and four showed possible harm [115]. In a retrospective observational study in patients with MERS-CoV infection, the combination of ribavirin and interferon, compared to no antiviral treatment, was not associated with improvement in the 90-day mortality or more rapid MERS-CoV RNA clearance [116].

Oseltamivir

Oseltamivir is a neuraminidase inhibitor used for prophylaxis and treatment of influenza. Given its specificity for an enzyme not found on coronaviruses, it is unclear what the mechanism of action would be against COVID-19. However, this has been used in combinations of antiviral therapy in Wuhan [117] and continues to be explored as a therapeutic option as part of combination regimens. Two trials evaluating combination regimens are underway in Wuhan [118, 119] as well as a trial in Thailand proposing different combinations [120]. None of the trials or case reports have examined oseltamivir as monotherapy.

Intravenous immunoglobulin

Intravenous immunoglobulin (IVIg) has been used as an adjuvant to treat a variety of pathogens either as a pooled product or in a concentrated more pathogen focused (hyperimmune) form. As the community from which a given batch of IVIg is derived from includes increasing numbers of individuals who have recovered from SARS-CoV-2, the possibility of protective antibodies being present in the pooled product is increased. However, the potential utility of IVIg for the treatment of SARS-CoV-2 is unknown at this time. Its use has been reported in a few patients with COVID-19 [121] , but studies are needed to determine if there may be a role for IVIg in the treatment of SARS-CoV-2.

Should NSAIDS be stopped in patients with COVID-19?

The role of Nonsteroidal anti-inflammatory drugs (NSAIDs) in the management of SARS-CoV2 has been discussed widely. Recent anecdotal reports and subsequent warnings from health officials have suggested against the use of NSAIDs in the care of patients with COVID-19; however, neither FDA, European Medicines Agency, or the World Health Organization have identified evidence linking NSAIDS to COVID-related clinical deterioration. Human coronaviruses, including SARS CoV-2, use ACE2 to bind to human targets and gain entry into target cells [122]. It has been theorized that NSAIDs, due to upregulation in ACE2 in human target cells, may lead to a more severe course of COVID-19 in those taking NSAIDs. While no causal evidence of adverse outcomes with NSAIDs in the management of COVID-19 have been published, there are well known risks of non-steroidal anti-inflammatory agents including cardiovascular, gastrointestinal and renal adverse events [123, 124]. In the setting of bacterial pneumonia, NSAIDs may impair recruitment of polymorphonuclear cells, resulting in a delayed inflammatory response and resolution of infection, however a causal relationship has not been established [125, 126]. RCTs are needed to better understand the safety of NSAIDS in the management of patients with COVID-19. One RCT is currently underway to evaluate the role of naproxen in those critically ill with COVID-19 [127].

Should ACE inhibitors and ARBs for hypertension be stopped in patients with COVID-19?

Angiotensin converting enzyme 2 (ACE2) is the receptor for SARS CoV-2 on human cells. Because angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) may increase ACE2 expression, the possibility has been raised that these drugs may increase the likelihood of acquiring SARS-CoV-2 or may exacerbate the course of COVID-19. To date, however, there are no clinical data to support this hypothetical concern. For this reason, the American Heart Association, the Heart Failure Society of America and the American College of Cardiology all recommend that ACE inhibitors or ARBs be continued in people who have an indication for these medications [128].

Discussion

During epidemics like the COVID-19 pandemic, when there are no clinically proven treatments, the tendency is to use drugs based on in vitro antiviral activity, or on anti-inflammatory effects or based on limited observational studies. It is commendable that observational studies are done during an epidemic, but often they do not have concurrent controls, have a significant risk of bias, and use surrogate outcomes like viral clearance rather than patient-important outcomes. Medications that were thought to be effective based on in vitro studies and observational studies for other diseases were later proven to be ineffective in clinical trials [129].

Due to the understandable urgency in producing, synthesizing and disseminating data during the current pandemic, there has been a noticeable increase in fast track publication of studies. In addition to well-established concerns that may decrease our certainty in the available evidence, there may be additional issues that will ultimately influence the trustworthiness of that evidence, including: 1) Circumvention of usual research steps (delay of IRB approval [130], inclusion of same patients in several studies); 2) Limited peer-review process (the usual due diligence from editors and reviewers is side-stepped, potentially leading to unnoticed errors in data and calculations, incomplete reporting of methods and results, as well as underestimation of study limitations); 3) Increased potential for publication bias (in the interest of showing promising data and in the race to achieve recognition, there may be added inclination to publish positive results and disregard negative ones). The extent and impact of these considerations remain currently uncertain but were acknowledged in the development of this guideline. 

Despite these limitations, the recommendations in this guideline are based on evidence from the best available clinical studies with patient-important endpoints. The panel determined that when an explicit trade-off between the highly uncertain benefits (e.g., the panel was unable to confirm that HCQ increases viral cure or reduces mortality) and the known putative harms (QT prolongation and drug-drug interactions) were considered, a net positive benefit was not reached and could possibly be negative (risk of excess harm). The safety of drugs used for the treatment of COVID-19, especially in patients with cardiovascular disease, immunosuppressive conditions, or those who are critically ill with multi-organ failure has also not been studied. Drugs like AZ and HCQ can cause QT prolongation and potentially life-threatening arrhythmias. Steroids and IL-6 inhibitors can be immunosuppressive and potentially increase risk of secondary infections. Steroids may produce long term side effect such as osteonecrosis [131]. In instances where the panel could not make a determination whether the benefits outweigh harms, it is be ethical and prudent to enroll patients with COVID-19 in clinical trials, rather than use clinically unproven therapies [132]. There are multiple ongoing trials, some with adaptive designs, which potentially can quickly answer pressing questions on efficacy and safety of drugs in the treatment of patients with COVID-19.

We acknowledge that enrolling patients in RCTs might not be feasible for many frontline providers due to limited access and infrastructure. Should lack of access to clinical trials exist, we encourage setting up local or collaborative registries to systematically evaluate the efficacy and safety of drugs to contribute to the knowledge base. Without such evaluations we often attribute success to drugs and failure to disease (COVID-19) [129]. During such a pandemic, barriers to conducting studies and enrolling patients in trials for already overburdened front line providers should be minimized while ensuring the rights and safety of patients [133].

For clinical trials and observational studies, it is critical to determine a priori standardized and practical definitions of patient populations, clinical syndromes, disease severity and outcomes. Observational and non-experimental studies can sometimes answer questions not addressed by trials, but there is still a need for standardized definitions. For clinical syndromes clearly distinguishing between asymptomatic carrier state, upper respiratory tract infection and lower respiratory tract infection is important. Illness severity should be reasonably defined using readily available clinical criteria of end organ failure, like the degree of respiratory failure using SpO2 (percentage of oxyhemoglobin saturation) or PaO2:FiO2 ratios (partial pressure of oxygen in arterial blood: fractional percentage of inspired oxygen) for lower respiratory tract infection, as opposed to location-based severity determinations such as ICU admission, which can lead to bias based on resource limitations (i.e., bed availability) or regional/institutional practice patterns [134]. For outcomes of prophylaxis trials, the primary endpoint should be prevention of infection and for therapeutic trials patient centered outcomes like reduction of mortality (both short term and long term) [135]. Trials should also study treatments in high risk populations or special populations like immunosuppressed patients, people with HIV, patients with cardiovascular comorbidities and pregnant women. The panel expressed the overarching goal that patients be recruited into ongoing trials, which would provide much needed evidence on the efficacy and safety of various therapies for COVID-19.

This is a living guideline that will be frequently updated as new data emerges. Updates and changes to the guideline will be posted to the IDSA website.

Notes

Acknowledgement

The expert panel thanks the Infectious Diseases Society of America for supporting guideline development, and specifically Cindy Sears, Dana Wollins, Genet Demisashi, and Rebecca Goldwater for their continued support throughout the guideline process. The panel would also like to acknowledge Haya Waseem and Kapeena Sivakumaran for supporting the evidence base for this guideline.

Financial Support

This project was funded by IDSA.

COI Summary

The following list is a reflection of what has been reported to the IDSA. To provide thorough transparency, the IDSA requires full disclosure of all relationships, regardless of relevancy to the guideline topic. Evaluation of such relationships as potential conflicts of interest is determined by a review process which includes assessment by the Board of Directors liaison to the Standards and Practice Guideline Committee and, if necessary, the Conflicts of Interest (COI) and Ethics Committee. The assessment of disclosed relationships for possible COI is based on the relative weight of the financial relationship (i.e., monetary amount) and the relevance of the relationship (i.e., the degree to which an association might reasonably be interpreted by an independent observer as related to the topic or recommendation of consideration). The reader of these guidelines should be mindful of this when the list of disclosures is reviewed. L.B. receives research funding from the National Institutes of Health/National Institute of Allergy and Infectious Diseases, Bill and Melinda Gates Foundation, and Wellcome Trust, and serves as chair of the Antimicrobial Drug Advisory Committee of the Food and Drug Administration. V.C. receives research funding from the Health and Medical Research Fund. K. E. serves as a scientific advisor for Merck, Bionet, IBM, Sanofi, X4 Pharmaceuticals, Inc., Seqirus, Inc., Moderna, Inc. and Pfizer, and receives research funding from the Centers for Disease Control and Prevention and the National Institutes of Health. R. G. has served on a scientific advisory board for Gilead Sciences, Inc., serves on a scientific advisory board for Merck, and receives research funding from the NIH. J.G. serves in an advisory role for Qpex and Shionogi; receives research funding from Merk; previously served in an advisory role for Acceletrate, Achaogen, Astellas, Melinta, Nabriva, Paratek, scPharmaceutic, Spero and Tetraphase; and previously served on the speakers bureau for Astellas, Melinta, Merck and Shiongi. M.H.M receives research funding from the Agency for Healthcare Research and Quality, the Endocrine Society, the Society for Vascular Surgery and The American Society of Hematology and is a Board member for the Evidence Foundation. W.J.M. serves in an advisory role for Seqirus, Inc. and receives research funding Ansun BioPharma, Astellas Pharma, Inc, AstraZeneca, Janssen Pharmaceutica, Karius, Melinta, Merck, Roche and Tetraphase. S.S. serves as an advisory board member for Amplyx Pharmaceuticals, Inc.; as an advisor/consultant to ReViral Ltd.; receives research funding from Ansun BioPharma, F2G, Shire (now Takeda), University of Nebraska, Cidara Therapeutics; and has served as an advisor for Janssen Pharmaceutica and Acidophil. A.H.S. receives research funding from the U.S. Department of Veterans Affairs. Y.F.Y. receives honoraria for evidence reviews and teaching from the Evidence Foundation, honoraria for evidence reviews for the American Gastroenterological Association, and serves as a Director for the Evidence Foundation and for the U.S. GRADE Network. All other authors: no disclosures reported. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. All other authors: no disclosures reported.

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It is important to realize that guidelines cannot always account for individual variation among patients. They are assessments of current scientific and clinical information provided as an educational service; are not continually updated and may not reflect the most recent evidence (new evidence may emerge between the time information is developed and when it is published or read); should not be considered inclusive of all proper treatments methods of care, or as a statement of the standard of care; do not mandate any particular course of medical care; and are not intended to supplant physician judgment with respect to particular patients or special clinical situations. Whether and the extent to which to follow guidelines is voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient’s individual circumstances. While IDSA makes every effort to present accurate, complete, and reliable information, these guidelines are presented “as is” without any warranty, either express or implied. IDSA (and its officers, directors, members, employees, and agents) assume no responsibility for any loss, damage, or claim with respect to any liabilities, including direct, special, indirect, or consequential damages, incurred in connection with these guidelines or reliance on the information presented.

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