Background
The first cases of coronavirus disease 2019 (COVID-19) were reported from Wuhan, China in early December 2019, it is now known to be caused by a new beta-coronavirus , named severe acute respiratory syndrome coronavirus 2 (SARS). CoV-2). In a span of months, COVID 19 has become a pandemic due to its transmissibility, spreading across continents with the number of cases and deaths increasing daily.
Although the majority of infected people exhibit mild illness (80%+), 14% have severe illness and 5% have critical illness including invasive ventilation due to acute respiratory distress syndrome (ARDS).
Mortality appears to be more common in older people and in those with comorbidities, such as chronic lung disease, cardiovascular disease and diabetes; young people without comorbidities also appear to be at risk of critical illness, including multiple organ failure and death.
There have been a growing number of studies published rapidly online and in academic journals; however, some of these may be of limited quality and are previously published without sufficient peer review. A critical evaluation of existing studies is needed to determine whether existing evidence is sufficient to support currently proposed management strategies.
Given the rapid global spread of SARS CoV-2 and the difficulty for overstretched frontline providers and policymakers to stay up to date on emerging literature, IDSA has recognized the need to develop rapid guidance for the treatment of COVID -19. The guideline panel used a methodologically rigorous process to evaluate the best available evidence and provide treatment recommendations.
Two additional guidelines on diagnostic testing and infection prevention are also being developed. These guidelines will be updated frequently as substantive literature becomes available and accessible in an easy-to-navigate web and device interface: http://www.idsociety.org/covid19guidelines.
The goal of these recommendations is to inform patients, physicians, and other healthcare professionals by providing the latest available evidence.
Executive Summary
COVID-19 is a pandemic with an increasing incidence of infections and deaths. Many drug therapies are being used or considered for treatment. Given the rapidity of emerging literature, IDSA felt the need to develop updated, evidence-based guidelines to support patients, physicians, and other healthcare professionals in their decisions regarding the treatment and management of patients with COVID-19 infection.
The recommendations are summarized below with comments related to the clinical practice guideline for the treatment and management of COVID-19. A detailed description of the background, methods, summary of evidence and rationale supporting each recommendation, and research needs can be found online in the full text.
In summary, according to the 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 considered 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 recognize the current “knowledge gap” and aim to avoid premature favorable recommendations for potentially ineffective or harmful interventions.
| Recommendation 1. Among patients who have been admitted to hospital with COVID-19, the IDSA guideline panel recommends hydroxychloroquine/chloroquine in the context of a clinical trial . (Knowledge gap). |
| Recommendation 2 . Among patients who have been admitted to hospital with COVID-19, the IDSA guideline panel recommends hydroxychloroquine/chloroquine plus azithromycin only in the context of a clinical trial . (Knowledge gap). |
Summary of the evidence
Two RCTs of confirmed COVID patients with mild pneumonia (e.g., positive CT scan without oxygen requirement) or non-severe infection admitted to hospital treated with hydroxychloroquine (HCQ) reported 14-day mortality, clinical progression ( radiological progression on computed tomography), clinical improvement, failure of virological clearance (CRP) and adverse events (both)
Additionally, we identified four publications describing three trials of combination treatment with HCQ plus azithromycin (AZ) among hospitalized patients with COVID-19 reporting outcomes of mortality, failure of virological clearance (assessed with PCR testing), and adverse events (es i.e., significant prolongation of the QT interval leading to treatment discontinuation).
Benefits
The best currently available evidence could not demonstrate or exclude a beneficial effect of HCQ on the clinical progression of COVID-19 (as inferred by radiological findings; RR: 0.61; 95% CI: 0.26, 1.43; see Figure s2), or in viral clearance by PCR testing, although a slightly higher proportion in the HCQ group experienced clinical improvement (RR: 1.47; 95% CI 1.02, 2.11).
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. Furthermore, the selected outcomes should be considered indirect, as important patient outcomes (e.g., mortality, rate of progression to ARDS, and need for mechanical ventilation) were not available.
Studies evaluating the addition of azithromycin to HCQ provided indirect comparisons of virological clearance failure with historical controls. The observed risk of mortality among patients receiving HCQ + AZ during the hospital stay was 3.4% (6/175 patients). However, an estimated mortality rate in an untreated cohort was not provided in the manuscript.
Compared with lack of viral clearance in historical controls (100% virological failure), 12 symptomatic patients were compared on day 5 or 6 from a separate hospital in France. Patients treated with HCQ + AZ experienced numerically fewer cases of virologic failure (43% combined virologic failure; 29/71 patients).
There is very low certainty in this treatment effect comparison, mainly due to very high risk selection bias, making any claims of effectiveness highly uncertain. Additionally, relying on intermediate outcomes such as viral clearance to determine patient-important outcomes (including a reduction in the development of pneumonia, hospitalization or ICU admission, or the need for intubation) adds another layer of imprecision.
Damage
Two studies described significant QT prolongation in 10 of 95 treated patients, resulting in an increase in the QT interval to greater than 500 ms or discontinuation of HCQ/AZ treatment, illustrating the high risk of clinically relevant arrhythmias. for this treatment. Additionally, several case reports of QT prolongation related to hydroxychloroquine have also been published.
In another prospective cohort study in 224 non-COVID-infected patients with SLE who received chloroquine or hydroxychloroquine for routine care, gastrointestinal side effects occurred in 7% of patients [21].
Several case reports have been published citing the risk of QT prolongation, torsades de pointes , and ventricular tachycardia in patients receiving azithromycin alone . In a large cohort study, patients taking a five-day course of azithromycin had an increased risk of sudden cardiac death with a hazard ratio of 2.71 (1.58-4.64) versus 0.85 (0.45-1.60), compared with patients who did not receive antibiotics or amoxicillin, respectively.
Given the cumulative effect on cardiac conduction observed with hydroxychloroquine and azithromycin, if this combination were used in the context of a clinical trial, baseline and follow-up ECG monitoring would be indicated, as well as careful monitoring of other concomitant medications known to cause prolong the QT interval.
Renal clearance accounts for 15-25% of total hydroxychloroquine clearance, however, no dose adjustments are recommended based on package labeling. Chloroquine and hydroxychloroquine are metabolized by cytochrome P450 isoenzymes 2C8, 2D6 and 3A4 , therefore, inhibitors and inducers of these enzymes may alter the pharmacokinetics of these agents.
Providers are encouraged to visit resources such as the newly created website, https://www.covid19-druginteractions.org/ to assist in the evaluation and management of drug interactions with current and emerging investigational agents for COVID-19.
Azithromycin is low risk for cytochrome P450 interactions; However, additional pharmacological adverse events, including gastrointestinal effects and QT prolongation, should be carefully considered, especially in the outpatient setting, where frequent ECG monitoring is not feasible.
Other considerations
The panel agreed that the overall certainty of the evidence was very low due to concerns with risk of bias, inconsistency, indirectness, imprecision and publication bias.
Conclusions and research needs
The guideline panel recommends that the use of HCQ or the combination HCQ + AZ only be used in the context of a clinical trial.
This recommendation does not address the use of azithromycin for secondary bacterial pneumonia in patients with COVID-19 infection. Additional randomized controlled trials and prospective outcome registries are needed to inform research for treatment with HCQ alone or in combination with azithromycin for patients with COVID-19.
| Recommendation 3 . Among patients who have been admitted to 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 lopinavir/ritonavir combination treatment for hospitalized patients with COVID-19. Cao et al. randomized 199 hospitalized patients with severe COVID-19 to receive treatment with lopinavir/ritonavir in addition to standard care (n = 99) or standard care alone (n = 100) for 14 days. The trial reported the following outcomes: mortality, failure of clinical improvement (measured by 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) or on clinical improvement (RR: 0.78; 95% CI: 0.63, 2.20).
Damage
Nearly 14% of lopinavir/ritonavir recipients were unable to complete the full 14-day dosing course primarily due to gastrointestinal adverse events , including anorexia, nausea, abdominal discomfort, or diarrhea, as well as two serious adverse events of acute gastritis. Two recipients also had self-limited rashes.
The risk of liver injury, pancreatitis, severe skin rashes, QT prolongation, and the potential for multiple drug interactions due to CYP3A inhibition are well documented with this drug combination.
Other considerations
The panel chose to report its decision based on the RCT. The panel determined that the certainty of the evidence is 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 receiving lopinavir/ritonavir and the group not having similar rates of viral caries. This finding suggests that lopinavir/ritonavir is not having a measurable antiviral effect, its putative mechanism of action
Conclusions and research needs
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.
| Recommendation 4 . Among patients who have been admitted to the hospital with COVID-19 pneumonia, the IDSA guideline panel suggests against the use of corticosteroids . (Conditional recommendation, very low certainty of evidence). |
| Recommendation 5 . Among patients who have been admitted to hospital with ARDS due to COVID-19, the IDSA guideline panel recommends the use of corticosteroids in the context of a clinical trial . (Knowledge gap). |
Summary of the evidence
No studies were found that specifically examine the role of steroids for the treatment of acute COVID-19 infection. Corticosteroids were widely used in China to prevent the development of ARDS in patients with COVID-19 pneumonia. Four retrospective cohort studies examined various interventions during the COVID-19 outbreak in the Wuhan area.
Studies show variability in the benefit of corticosteroid use. Limitations of the study include: 1) critical information not reported on baseline risk/severe pneumonia/ARDS; 2) confusion by indication; 3) unadjusted analysis; 4) time of illness not given; 5) great variability in the treatments administered. Due to these limitations, a reasonable joint effort to determine the possible treatment effect was not considered possible.
Benefits and harms
The panel determined that due to the limitation of direct COVID-19 data, indirect evidence from the 2003 SARS outbreak and MERS would also be considered. A systematic review reported on 15 studies, 13 of which were inconclusive about the benefits of corticosteroids. An RCT reported that SARS-CoV-1 viral loads showed delayed viral clearance associated with corticosteroid use.
The same review also reported on a subset of patients with ARDS (three trials). A small RCT in 24 patients using a lower dose of methylprednisolone for two days showed possible improvement in ARDS; However, two larger trials showed little or no effect in critically ill patients with lung failure.
The authors concluded that despite the widespread use of corticosteroids during the SARS outbreak, conclusive evidence of benefit was lacking and that administration of steroids early in the disease process before viral replication is controlled may lead to a delay in viral elimination.
Other considerations
The panel considered the certainty of the direct evidence to be very low due to concerns with the risk of bias, inconsistency and imprecision. The panel based its decision to conditionally recommend the use of corticosteroids among patients admitted to hospital on indirect findings from the systematic review on SARS-CoV.
Conclusions and research needs
As COVID-19 infection is a self-limiting viral disease in most cases, a small subset of patients progresses from COVID-19 pneumonia to develop ARDS. Based on limited data from other coronaviruses, there is no clear benefit and potential harm from corticosteroids .
Carefully designed RCTs and prospective outcome registries are needed to determine the dose, route, timing, and duration of such treatment in preventing clinical deterioration and to better understand the potential harms associated with its use. If a person is taking a steroid (inhaled or systemic) for another indication (for example, asthma), the steroid should be continued.
| 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 the pathogenesis of SARS and MERS-CoV suggest a release of proinflammatory cytokines , including interleukins-6 (IL-6) during clinical disease. Our search identified one study that reported on 21 severe or critically ill patients with COVID-19 infection treated with tocilizumab , an IL-6 blocker. This study did not have a control group. To estimate a control group rate in patients who did not receive tocilizumab treatment, Xu et al. described the findings of Yang 2020, which suggested an initial mortality rate of 60% in critically ill patients and 11% in severely ill patients admitted to the ICU.
Benefits
We estimate that patients in Xu 2020 (21 patients, 4 critical and 17 severe) would have an initial mortality risk of 20% depending on severity. Therefore, tocilizumab treatment may have reduced mortality as no deaths were reported in 21 patients. However, this conclusion remains highly uncertain given the lack of contemporaneous control or adjustments for confounding factors. Of 21 patients, 19 were discharged from the hospital, suggesting a clinical failure rate of 9.5% for clinical improvement in CT scan findings.
Damage
Xu et al. no serious adverse events were reported. However, patients receiving tocilizumab are often at increased risk of serious infections (bacterial, viral, invasive fungal infections, and tuberculosis) and hepatitis B reactivation. Cases of anaphylaxis, severe allergic reactions, severe liver damage, and liver failure, and intestinal perforation after tocilizumab administration in patients without COVID-19 infections.
Tocilizumab is not metabolized by the cytochrome P450 isoenzyme system, however, elevated levels of IL-6 seen in inflammatory states have been shown to inhibit these enzymes, slowing drug metabolism through these pathways. As the 3A4 pathway is responsible for the metabolism of many commonly used drugs, administration of IL-6 inhibitors such as tocilizumab may increase the metabolism of drugs that use the cytochrome P450 system.
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
The guideline panel recommended tocilizumab only in the context of a clinical trial . Additional clinical trials are needed to inform research into the effectiveness of tocilizumab treatment for patients with COVID-19.
| Recommendation 7. Among patients who have been admitted to hospital with COVID-19, the IDSA guideline panel recommends COVID-19 convalescent plasma in the context of a clinical trial . (Knowledge gap). |
Summary of the evidence
Our search identified two case series of a total of 15 patients that reported outcomes of mortality, failure of clinical improvement (as inferred by the need for continuous mechanical ventilation), and treatment-related adverse events among patients. hospitalized with COVID-19 infection.
All five patients in Shen 2020 were mechanically ventilated at the time of treatment compared to three out of 10 patients in the study by Duan et al. Duan 2020 included a comparison of the 10 treated patients with 10 historical control patients with age, sex, and disease severity. Both studies lacked adjustment for critical confounders, including co-treatments, baseline characteristics, disease severity, and timing of plasma delivery.
Benefits
Compared to a 30% mortality rate in the historical control (3/10), no deaths were reported among patients receiving COVID-19 convalescent plasma. Of eight patients in both studies on mechanical ventilation at the time of treatment, 50% (n = 4) were extubated at the time of data collection.
Damage
Among 10 patients, no serious adverse reactions or safety events were recorded after COVID-19 convalescent transfusion.
Other considerations
The panel agreed that the overall certainty of the evidence is very low due to concerns with the risk of bias and imprecision. Continuation of mechanical ventilation was used as a surrogate for failure of clinical improvement; However, the panel recognized the importance of the time frame for extubation by associating it with plasma transfusion. Given the limited information provided on extubation time, the panel recognized an additional knowledge gap with the evaluation of this outcome.
Conclusions and research needs
The guideline panel recommends COVID-19 convalescent plasma in the context of a clinical trial . Additional clinical trials are needed to inform research for COVID-19 convalescent plasma treatment for patients with COVID-19.
The panel expressed the overall goal of having patients recruited for ongoing trials, which would provide much-needed evidence on the effectiveness and safety of various therapies for COVID-19.
The panel determined that when an explicit trade-off between the highly uncertain benefits and presumed putative harms of these therapeutic agents was considered, a net positive benefit was not achieved and could be negative (risk of excessive harm).
The panel recognizes that patient enrollment in RCTs may not be feasible for many frontline providers due to limited access and infrastructure. Where there is a lack of access to clinical trials, we encourage the establishment of local or collaborative registries to systematically evaluate the effectiveness and safety of medicines to contribute to the knowledge base. Every doctor can play a role in advancing our understanding of this disease through a local registry or other data collection efforts.
Discussion
During epidemics such as the current COVID-19 pandemic, when there are no clinically proven treatments, the trend is to use drugs based on in vitro antiviral activity , or anti-inflammatory effects, or limited observational studies. It is advisable that observational studies be conducted during an epidemic, but they often do not have concurrent controls, have a significant risk of bias, and use surrogate outcomes such as viral clearance instead of patient-important outcomes.
Subsequently, drugs that were considered effective based on in vitro studies and observational studies for other diseases were shown to be ineffective in clinical trials.
Due to the understandable urgency in data production, synthesis, and dissemination during the current pandemic, there has been a notable increase in accelerated 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 reliability of that evidence, including:
1) The avoidance of the usual research steps, inclusion of the same patients in several studies.
2) Limited peer review process (the usual due diligence of editors and reviewers is pushed aside, which can lead to inadvertent errors in data and calculations, incomplete reporting of methods and results, as well as an underestimation of the limitations of the study).
3) Greater potential for publication bias (in the interest of showing promising data and in the race for recognition, there may be a greater inclination to publish positive results and ignore negative ones). The scope and impact of these considerations remain uncertain, but were recognized in the development of this guidance.
Despite these limitations , the recommendations were based on evidence from the best available clinical studies with patient-important endpoints. The panel determined that when considering an explicit trade-off between highly uncertain benefits (e.g., the panel could not confirm that HCQ increases viral cure or reduces mortality) and putative harms (QT prolongation and interactions pharmacological), a net positive benefit was not achieved and could possibly be negative (risk of excessive harm).
The safety of medications used to treat COVID-19 has also not been studied , especially in patients with cardiovascular disease, immunosuppressive conditions, or those who are severely ill with multiple organ failure.
Drugs such as azithromycin and hydroxychloroquine can cause QT prolongation and life-threatening arrhythmias.
Steroids and IL-6 inhibitors may be immunosuppressive and potentially increase the risk of secondary infections. Steroids can cause long-term side effects, such as osteonecrosis.
Since the panel could not determine whether the benefits outweigh the harms for these treatments, it would be ethical and prudent to enroll COVID-19 patients in clinical trials, rather than using clinically unproven therapies. There are multiple trials underway, some with adaptive designs, that can potentially quickly answer pressing questions about the efficacy and safety of medications in treating patients with COVID-19.
We recognize that patient enrollment in RCTs may not be feasible for many frontline providers due to limited access and infrastructure. Where there is a lack of access to clinical trials, we encourage establishing local or collaborative registries to systematically evaluate the efficacy and safety of medicines to contribute to the knowledge base.
Without such assessments, we often attribute success to medications and failure to the disease (COVID-19).
During such a pandemic, barriers to conducting studies and enrolling patients in trials for already overburdened frontline providers must be minimized while ensuring patient rights and safety.
For clinical trials and observational studies, it is critical to determine standardized and practical a priori 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 , it is important to clearly distinguish between asymptomatic carriage, upper respiratory tract infection, and lower respiratory tract infection.
Disease severity should be reasonably defined using readily available clinical criteria for end-stage organ failure, such as the degree of respiratory failure using the Sa02 or Fi02:Pa02 ratios for lower respiratory tract infection, as opposed to severity determinations based on location, such as ICU admission, which may lead to biases based on resource limitations (i.e., bed availability) or regional/institutional practice patterns.
For outcomes of prophylaxis trials , the primary objective should be prevention of infection and for therapeutic trials patient-centered outcomes such as reduction in mortality (both short and long term).
Trials should also study treatments in high-risk populations or special populations such as immunocompromised patients, people with HIV, patients with cardiovascular comorbidities, and pregnant women.
The panel expressed the overall goal of having patients recruited for ongoing trials, which would provide much-needed evidence on the effectiveness and safety of various therapies for COVID-19.
This is a "living" guideline that will be updated frequently as new data emerge. Updates and changes to the guidance will be posted on the IDSA website.
