In total, 54 studies met eligibility criteria.4-57 Serious adverse events were abstracted from peer-reviewed journal articles, clinicaltrials.gov, and submissions for FDA emergency use authorization.
- In patients with hematologic cancers, there is moderate certainty based on one study that administration of convalescent plasma while hospitalized with COVID-19 may cause elevated risk of serious bleeding events and infection, including sepsis, within 30 days. Certainty of evidence is limited for congestive heart failure within 30 days in this population based on the same study.
- Based on four studies, there is limited certainty that convalescent plasma may be associated with serious thrombotic events within 90 days among patients hospitalized for COVID-19.
- We found insufficient evidence of association of any serious adverse events with the antivirals used for COVID-19 (remdesivir, nirmatrelvir and ritonavir combination, molnupiravir).
- We found insufficient evidence of association of any serious adverse events with the SARS-CoV-2 spike protein receptor binding antibodies bamlanivimab/ etesevimab, bebtelovimab, sotrovimab, casirivimab/ imdevimab, and tixagevimab/ cilgavimab.
- There is limited certainty that the monoclonal antibody tocilizumab, an IL-6 inhibitor, may be associated with elevated risk of neutropenia within four weeks in patients hospitalized with COVID-19, based on one study. There is limited certainty that COVID-19 patients on extracorporeal membrane oxygenation for respiratory support or intravenous infusion of a vasopressor or inotrope for cardiovascular support in the intensive care unit are at elevated risk of bleeding events within 90 days, based on another study.
- No studies of Anakinra for COVID-19 met inclusion criteria. FDA emergency use authorization was based on studies conducted overseas.
Findings
Fifty-four studies published in 66 sources were included; 31 were randomized controlled trials and the remainder were observational studies. No US studies of anakinra for COVID-19 were identified. We found insufficient evidence of association of any serious adverse events with antivirals and spike protein receptor binding antibodies. In patients hospitalized with COVID-19, the monoclonal antibody tocilizumab, an IL-6 inhibitor, may be associated with elevated risk of neutropenia (moderate certainty) and infection (limited certainty). Convalescent plasma may be associated with thrombotic events (limited certainty) as well as bleeding events and infection in patients with hematologic cancers (moderate certainty).
This rapid review will be used by the Health Resources & Services Administration (HRSA) Countermeasures Injury Compensation Program (CICP) to inform a Countermeasures Injury Table. HRSA needs defined the scope of this review; for example, the review was limited to studies that included at least one US site or territory. See the full report and other tabs above for important information on how this report was scoped and conducted.
Background and Purpose
The purpose of this rapid review is to determine if COVID treatments authorized for emergency use by the Food & Drug Administration (FDA) are associated with serious harms. The review will be used by the Health Resources & Services Administration (HRSA) Countermeasures Injury Compensation Program (CICP) to inform a Countermeasures Injury Table. Once a Table and any relevant amendments are published, the Table will be used to make benefits eligibility determinations for covered injuries or deaths. The Agency for Healthcare Research and Quality (AHRQ) commissioned this rapid review using abbreviated methods to provide an assessment of evidence in a compressed timeframe to inform HRSA's work.
The following pharmaceutical interventions to treat or prevent COVID-19 were reviewed:
- Convalescent plasma (from recovered COVID-19 patients);
- Antivirals: Remdesivir (Veklury), Nirmatrelvir and Ritonavir in combination (Paxlovid), Molnupiravir (Lagevrio);
- Monoclonal antibodies: Bamlanivimab and Etesevimab in combination, Bebtelovimab, Casirivimab and Imdevimab in combination (Regeneron), Sotrovimab (Xevudy), Tixagevimab and Cilgavimab in combination (Evusheld), Tocilizumab (Actemra);
- Interleukin-1 receptor antagonist: Anakinra (Kineret).
This rapid review was limited to studies of the above listed interventions when used for treatment or prevention of COVID-19. Studies were required to have a placebo, untreated, or usual care comparison group. Having a comparison group that did not receive the intervention provides important information about the background rate of adverse events in its absence, in particular when adverse events are nonspecific. Numerous serious medical problems occur in patients hospitalized with COVID-19, given patients' advanced age, multiple pre-existing medical conditions, and the natural sequalae of COVID-19 infection. This rate is essential for understanding what would be expected to occur naturally in the absence of any intervention. Thus, no case reports, case series, or uncontrolled surveillance studies were included. Head-to-head comparisons of medications were also excluded.
The review was limited to studies that included at least one US site or territory, where populations most likely to file a Countermeasures Injury Compensation Program claim would be included.
Discussion
This rapid review found few associations between emergency use authorized pharmaceutical interventions for COVID-19 treatment and serious adverse events.
The associations found included increased risk of infection in one trial of patients with hematologic cancers who received convalescent plasma and in the same trial an increased risk of serious bleeding events. Certainty of evidence was rated moderate. Both increased risk of infection and bleeding events might be expected given the patient population. Adverse events previously reported as associated with convalescent plasma include allergic reactions, transfusion-related acute lung injury, and transfusion-associated circulatory overload. Although those events were reported in the controlled studies we identified, there was no evidence of increased risk. There was limited certainty of the evidence from four studies that convalescent plasma may be associated with serious thrombotic events among patients hospitalized for COVID-19; this is consistent with the product label which notes blood clotting as a potential adverse event.
Our rapid review found no evidence of an association of SARS-CoV-2 antiviral treatment with serious adverse events. This is consistent with a prior network meta-analysis of antiviral agents for COVID-19 treatment which found no increased risk of adverse events when compared with placebo.
While infusion-related reactions ranging from mild to severe are common among recipients of monoclonal antibodies, we found no evidence of elevated risk of these reactions when compared with placebo infusions. The studies of SARS-CoV-2 spike protein receptor binding antibodies (bamlanivimab/estevimab, bebtelovimab, sotrovimab, casirivimab/ imdevimab, and tixagevimab/ cilgavimab) found no association with any serious adverse events. We identified evidence of limited certainty that tocilizumab, an IL-6 inhibitor, may be associated with elevated risk of neutropenia, a previously described adverse effect noted on the product label, and an increased risk of bleeding events. There is also limited certainty that COVID-19 patients on ECMO or intravenous infusion of a vasopressor or inotrope for cardiovascular support in the intensive care unit are at elevated risk of bleeding events within 90 days, based on another study. The tocilizumab label notes the potential for gastrointestinal perforation and thrombocytopenia (reduced platelets which help blood clot) which may be related to our findings on bleeding.
No studies of anakinra for COVID-19 met our inclusion criteria of involving US patients. Due to the prothrombotic effects of anakinra, it was hypothesized that there might be an increase in thrombotic events in patients with COVID-19; however, a meta-analysis of non-US studies found no significant increased risk compared to control.
Limitations
A serious limitation of this review is the inclusion requirement that studies have at least one US site. Inclusion of studies conducted in other regions could potentially change or strengthen the findings. The certainty of evidence for the findings described above could increase if additional studies showed elevated risk but could decrease if those studies showed no elevated risk. Studies from other regions might also report elevated risks for additional serious adverse events. We also limited to studies with a control group to detect elevated rates of events. This excluded uncontrolled studies that may provide signals that should be investigated further. Another limitation is that although most studies included patients with a number of conditions such as chronic obstructive pulmonary disease, obesity, cardiovascular disease, diabetes, chronic kidney disease, and cancer, few were limited to patients with a specific pre-existing condition or reported adverse events data stratified by specific pre-existing conditions.
Conclusions
In conclusion, there were no associations of increased risk of serious adverse events of high certainty. The lack of statistically significant association of most serious adverse events with treatments for COVID-19, when compared with no treatment, placebo, or usual care, supports the hypothesis that such events may be the result of COVID-19 itself. Most patients in the hospital studies had multiple pre-existing chronic conditions; these conditions are known to be associated with multiple adverse clinical outcomes.
Methods
Key Questions
This Rapid Review addresses these Key Questions:
Key Question 1: What are the serious adverse effects or events directly caused by the use or administration of medications authorized by the FDA to prevent or treat COVID-19 infection?
Key Question 2: In what timeframe are the adverse effects or events expected to occur (considering elimination half-life, etc.)?
Inclusion/Exclusion Criteria
The inclusion and exclusion criteria for studies, per the federal Request for Task Order, are listed below.
- COVID-19 convalescent plasma
- Anti-viral medications
- Remdesivir
- Nirmatrelvir and ritonavir
- Molnupiravir
- Monoclonal antibodies
- Tocilizumab
- Bamlanivimab / Etesevimab
- Bebtelovimab
- Sotrovimab
- Casirivimab and Imdevimab
- Tixagevimab and cilgavimab
- Interleukin Antagonist: Anakinra
Use of intervention for reason other than prevention or treatment of COVID-19
- Serious physical injury that warrants hospitalization (whether or not the person was actually hospitalized) or injuries that led to a significant loss of function or disability
- Mortality
Searching for the Evidence: Strategies for Identification of Relevant Studies
To explore adverse events potentially associated with the included pharmaceuticals, we reviewed the product labels and conducted a search on causality of adverse events associated with the interventions, regardless of medical indication. We retrieved the Infectious Disease Society of America guidelines for COVID-19 treatment for context.
In August 2023 we searched the research databases PubMed (including LitCOVID) and the Cochrane Database of Systematic Reviews to identify existing research studies and syntheses on the topic. Identified systematic reviews were screened for relevancy and reference mined for studies of the interventions.
The searches were updated on October 12, 2023. We also downloaded submissions from the FDA database for interventions that received Emergency Use Authorization and reference mined the international COVID Network Meta-analysis database. Finally, we conducted a search of clinicaltrials.gov.
Assessment of Methodological Risk of Bias of Individual Studies
Several study designs were eligible for the review; the evaluation criteria to assess the risk of bias in collection and reporting of adverse events can be applied across all types. We abstracted two items, based on the McHarm instrument. First, if collection was passive (i.e., outpatients contacted researchers if they experienced an event rather than the researchers actively contacting each patient and asking about a pre-determined list of events) rather than active, we rated the study as high risk of bias for collection; if collection/ monitoring methods were not described, we rated as "unclear/moderate." Studies that actively monitored patients were rated as low risk of bias. Secondly, if the authors reported the proportion of patients experiencing each event (e.g., rather than the total number of events) we rated reporting as low risk of bias. If most adverse events were reported this way but some were not, we rated this item as "unclear/moderate" risk of bias. For a study to be rated "overall" as low risk, the study must be rated as low risk on both items.
We incorporated the risk of bias ratings into the rating of evidence certainty.
Serious Adverse Events
The rapid review was limited to serious adverse events as defined in US statute 42 CFR 110.3(z):
"physical biochemical alterations leading to physical changes and serious functional abnormalities at the cellular or tissue level in any bodily function may, in certain circumstances, will be considered serious injuries. As a general matter, only injuries that warranted hospitalization (whether or not the person was actually hospitalized) or injuries that led to a significant loss of function or disability (whether or not hospitalization was warranted) will be considered serious injuries."
Most studies used the Common Terminology Criteria for Adverse Events levels in reporting adverse events. We abstracted those at severity level 3, defined as "severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling" or higher. We abstracted follow up timing and categorized adverse events as occurring within either 45 days of initial pharmaceutical administration or greater than 45 days from administration, per HRSA request. We abstracted exact events except pulmonary embolism and deep vein thrombosis, which were grouped as thrombotic events; arterial or venous bleeding, grouped as bleeding events; and we grouped all serious infections as infection, including sepsis per prior work conducted for AHRQ. For applicability, we abstracted data for the dosage authorized by the FDA when available. Adverse events data was converted to rates for intervention and comparison groups; rates were used to compute risk ratios to estimate effects.
Risk Ratios and Certainty of Evidence
We summarized the risk ratios for each intervention and each event; where possible, we summarized risk ratios for specific populations such as those hospitalized with specific COVID-19 symptoms, pregnant women, and those with pre-existing medical conditions.
Finally, the system below, from the Institute of Medicine 2012 report Adverse Effects of Vaccines: Evidence and Causality was used to assess certainty of evidence.
- High: Two or more studies with negligible methodological limitations that are consistent in terms of the direction of the effect provide high confidence.
- Moderate: One study with negligible methodological limitations, or a collection of studies generally consistent in terms of the direction of the effect, that provides moderate confidence.
- Limited: One study or a collection of studies lacking precision or consistency that provides limited, or low, confidence.
- Insufficient: No epidemiologic studies of sufficient quality.
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