Background and Purpose

The purpose of this rapid review is to determine if COVID treatments authorized for emergency use by the Food and Drug Administration (FDA) are associated with serious harms. The review will be used by the Health Resources & Services Administration (HRSA) Countermeasures Injury Compensation Program to inform a Countermeasures Injury Table (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.

Methods

The section contains a summary of the project methods; a full description is available as Appendix A. The protocol is registered in PROSPERO (CRD42023467821). 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. A comparison 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.

In August 2023, we searched PubMed (including litCOVID), clinicaltrials.gov, and the FDA submission database with start date January 2020; the Cochrane Database of Systematic Reviews was searched starting at January 2022. We reference mined the Infectious Disease Society of America guidelines, the international COVID Network Meta-analysis database, and systematic reviews published in 2022 and 2023. Researchers screened abstracts and full texts for inclusion using DistillerSR software.

The rapid review was limited to serious adverse events as defined in U.S. statute 42 CFR 110.3(z):

“[P]hysical 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.”¹

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.² For applicability, we abstracted data for the dosage authorized by the FDA when available. Adverse events data were converted to rates for intervention and comparison groups; rates were used to compute risk ratios (RRs) to estimate effects.

We assessed risk of bias with respect to adverse events using two items: whether collection was passive (i.e., whether 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); and whether the authors reported the proportion of patients experiencing each event (e.g., rather than the total number of events because a patient could experience an event more than once, in which case the proportion of patients would lead to an underestimate of the number of events).

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,³ 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.

Evidence Summary

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.

Evidence Base

After full text review of 320 publicly available documents, 54 studies published in 66 publications met eligibility criteria.^4–69 The primary reasons for exclusion were no US study locations (N = 70) and lack of reporting of adverse events (N = 33) in studies of efficacy or effectiveness. A literature flow diagram is included as Appendix B. The number of included studies per intervention ranges from one (tixagevimab and cilgavimab) to 15 (convalescent plasma). Importantly, we identified no US studies of anakinra that met inclusion criteria; US emergency use authorization was based on studies conducted overseas.

Thirty-one randomized controlled trials (RCTs) and 23 controlled observational studies met inclusion criteria. Fifteen studies compared an intervention to no treatment, 26 were placebo-controlled trials, and 12 studies compared an intervention to usual care. One observational study compared patients who received hydroxychloroquine with a group who received hydroxychloroquine plus tocilizumab.²³ Interventions were administered in an outpatient setting in 23 studies; the remainder involved patients hospitalized with COVID-19. Appendix C, the evidence and risk of bias table, displays details such as design, intervention, comparator, age groups, pre-existing conditions, setting, and patient severity for each study.

It was uncommon for studies to report the exact timing of adverse events; we discuss exact timing in the rare cases where it was provided. Published studies usually provided a table listing all serious adverse events that occurred within a specific number of days from administration. Most clinical trials, via clinicaltrials.gov, provided a table which used MedDRA (Medical Dictionary for Regulatory Activities definitions)⁷⁰ terms for adverse events and standard definitions of severity according to the Common Terminology Criteria for Adverse Events (serious being level 3 to 5 on a scale of 1 to 5).⁷¹

Most studies (N = 37) had low overall risk of bias regarding the collection and reporting of adverse events. Because manufacturers sought Emergency Use Authorization from the FDA, clinical trials carefully monitored and reported adverse events, adhering to expected standards. Twelve studies were rated as moderate or unclear risk of bias; most were observational studies with unclear timing or data collection procedures. These were primarily conducted in hospitals where patients presumably were monitored regularly but we did not make assumptions when this was not stated and classified adverse events collection in these cases as unclear. Five observational studies had high risk of bias; they focused on efficacy or effectiveness and included only statement that certain adverse events (e.g., transfusion-related acute lung injury, and transfusion-associated circulatory overload) did not occur during the study period. Risk of bias was incorporated into our certainty of evidence ratings and is discussed in each section describing findings.

Below we describe the serious adverse events reported for each intervention, followed by available data on populations hospitalized with specific COVID-19 sequalae or with specific pre-existing medical conditions. We intended to provide risk ratios for specific age groups such as adolescents and older adults; however, this was not possible. No studies included children under age twelve. Three studies included adolescents (at least age 12) in addition to adults, but adverse events were not reported separately for the adolescents.^{12, 33, 38} All studies but six included adults aged 65 or older; none reported adverse events separately for older adults.

Convalescent Plasma

Adverse Events 45 Days or Less

We identified 11 controlled studies of convalescent plasma that reported serious adverse events within 45 days of administration, with timing from 14 to 30 days.^{4, 5, 7, 9, 11, 25, 28, 31, 34, 48, 53} Study data are displayed in Table 1 below.

Six studies reported all-cause mortality; the risk was significantly lower in the intervention group in two studies; one within 28 days from baseline³⁴ (RR 0.51; confidence interval [CI] 0.29, 0.92) with low risk of bias and one within 30 days from baseline⁵³ (RR 0.54; CI 0.35, 0.83) with moderate/unclear risk of bias. In contrast, in another study³¹ mechanically ventilated patients who received convalescent plasma had significantly increased risk of all-cause mortality (RR 1.74; CI 1.49, 2.04) with low risk of bias. The other three studies of patients with severe COVID-19 reported no significant difference. Thus, there is insufficient certainty of evidence for increased mortality in severely ill patients.

Three studies reported serious bleeding events. A study of hematological cancer patients with moderate/unclear risk of bias⁵³ showed significantly increased risk of bleeding within 30 days from baseline (RR 1.96; CI 1.14, 3.36); this is discussed in the section on patients with pre-existing conditions. The other two studies reported no significant difference in risk for bleeding.

Five studies reported serious infection including sepsis; the risk was significantly lower in the intervention group in one study with low risk of bias (RR 0.24; CI 0.09, 0.69).³⁴ In contrast, the study of hematological cancer patients⁵³ reported an increased risk of infection (RR 1.79; CI 1.41, 2.26). The other three studies reported no significant difference. There were no significant differences in risk of acute kidney injury, anaphylaxis, cardiac arrhythmia, fever, hypotension, cerebrovascular accident, transfusion-associated lung injury, seizure, infection, thrombotic events, and transfusion-associated circulatory overload in the other studies.^{4, 9, 11, 28, 48}

Table 1

Serious adverse events, convalescent plasma, 45 days or less.

Adverse Events More Than 45 Days

We identified eight controlled studies of convalescent plasma^{4, 5, 11, 20, 35, 46, 48, 52} that described serious adverse events which occurred between administration and more than 45 days post-intervention, with timing from 60 to 90 days. Data are displayed in Table 2.

Six studies reported all-cause mortality; the risk was significantly lower in the intervention group in two studies; one (RR 0.27; CI 0.08, 0.88) had moderate/unclear risk of bias4 and the other (RR 0.47; CI 0.29, 0.76) had high risk of bias.⁴⁶ The four other studies reported no significant difference in risk.

There were no significant differences in risk for bleeding, cardiac arrhythmia, headache, myocardial infarction, hypertension, hypotension, transfusion associated lung injury, and infection including sepsis in the studies; the direction of risk (elevated vs decreased) varied. One observational study with high risk of bias⁴⁶ reported on serious allergic reaction other than anaphylaxis; risk was elevated but not statistically significant (RR 5.07; CI 0.21, 124.14) based on only one patient experiencing. Certainty of evidence for serious allergic reaction is insufficient due to lack of statistical significance, imprecision, and lack of the event in additional studies.

Results conflicted for risk of acute kidney injury in two studies;^{35, 48} neither result was statistically significant. Four studies reported serious thrombotic events;^{4, 35, 48, 52} three of the these reported elevated risk (one almost five-fold⁵²), but results were not statistically significant. Certainty of evidence is limited due to conflicting results in one of the four studies, lack of statistical significance, and wide confidence intervals. A study of high titer plasma for severe COVID-19⁴⁶ showed an elevated but not statistically significant risk of transfusion associated circulatory overload (RR 5.07; CI 0.21, 124.14) based on only one person experiencing; this study had high risk of bias. Certainty of evidence is insufficient due to risk of bias, lack of statistical significance, extremely wide confidence intervals, and lack of other studies reporting this event. One study reported two cases cerebrovascular accident in the intervention group;³⁵ risk was elevated but not statistically significant (RR 5.05; CI 0.24, 104.97). Risk of bias was low in this clinical trial. Certainty of evidence for cerebrovascular accident is insufficient due to lack of statistical significance, extremely wide confidence intervals, and lack of other studies reporting this event.

Table 2

Serious adverse events, convalescent plasma, more than 45 days.

Antivirals: Remdesivir

Adverse Events 45 Days or Less

We identified three observational studies^{22, 38, 47} and one RCT⁶ of remdesivir that reported serious adverse events within less than 45 days (see Table 3). Remdesivir was administered in an outpatient setting in one observational study which had moderate risk of bias; the other studies were conducted with hospitalized patients and had low risk of bias. Timing ranged from 7 to 29 days. There were no statistically significant risk differences for serious elevated levels of aspartate aminotransferase, hypotension, transfusion associated lung injury, infection, thrombotic events, and transfusion associated circulatory overload. Risk of cardiac arrythmia was elevated in the RCT (RR 4.85; CI 0.57, 41.37) but this was not statistically significant.⁶ There was decreased risk of cardiac arrythmia (also not statistically significant) in an observational study of patients with severe renal disease.⁴⁷ Thus, the evidence of risk of cardiac arrythmia is insufficient due to conflicting results, lack of statistical significance, and lack of precision in the RCT.

In one observational study of patients with severe kidney disease⁴⁷ the risk of alanine aminotransferase increase and seizure were elevated within seven days of administration, but risk ratios were not statistically significant. This is discussed in the later section on patients with pre-existing conditions.

Table 3

Serious adverse events, remdesivir, 45 days or less.

Adverse Events More Than 45 Days

An RCT of remdesivir in patients hospitalized with moderate COVID-19 symptoms reported serious adverse events at more than 45 days;⁵⁰ timing was unclear resulting in moderate/ unclear risk of bias. The differences between groups for risk of both “any serious adverse event” and all-cause mortality were not statistically significant. (Data not displayed.) Specific serious adverse events were not reported.

Antivirals: Nirmatrelvir and Ritonavir

Table 4 displays serious adverse events reported in studies of nirmatrelvir combined with ritonavir. All studies were conducted in an outpatient setting.

Adverse Events 45 Days or Less

We identified one observational study of nirmatrelvir and ritonavir compared with no treatment reporting serious adverse events within 45 days; patients were solid organ transplant recipients.¹⁸ Intervention patients had a significantly lower risk for acute kidney injury (RR 0.13; CI 0.02, 0.90) at 30 days. The risk of bias in collection and reporting of adverse events was moderate/ unclear.

We also identified two placebo controlled trials;^{37, 57} both had low risk of bias. In one trial, intervention patients had a higher risk for cerebrovascular accident (RR 3.02; CI 0.12, 73.96), but this was based on one case and not statistically significant, thus the upper limit of confidence was very high. Thus, the certainty of evidence for cerebrovascular accident is insufficient. The trials reported conflicting non statistically significant results regarding alanine aminotransferase (ALT) increase. Acute kidney injury, bleeding, and serious infection were also reported in the trials; intervention patients had reduced risk that was sometimes statistically significant.

Table 4

Serious adverse events, nirmatrelvir and ritonavir.

Antivirals: Molnupiravir

Adverse Events 45 Days or Less

As displayed in Table 5, we identified four RCTs^{10, 13, 14, 36} and one observational study⁴⁰ of molnupiravir that reported serious adverse events at 45 days or less. Timing ranged from 14 to 30 days; risk of bias was low in three studies, moderate/ unclear in one, and high in one. Route of administration was oral; all studies were conducted in outpatient settings. The differences between groups for risk of all-cause mortality were not statistically significant in any study. Only one study¹⁰ reported specific serious adverse events; there were no statistically significant differences in risk of acute kidney injury, hypertension, infection, or thrombotic events. Risk of bleeding events was elevated but not statistically significant, with wide confidence intervals (RR 2.96; CI 0.12, 72.59). Certainty of evidence for bleeding events is insufficient due to lack of statistical significance, lack of precision (extremely wide confidence intervals) and no report of this adverse event in other studies of the medication.

Adverse Events More Than 45 Days

One RCT that reported at 14 days also reported serious adverse events at 318 days;¹⁰ results are displayed in Table 5. Risk of bias was low. The risk of all-cause mortality was significantly lower in the intervention group; there were no significant differences in risk of acute kidney injury, hypertension, infection, or thrombotic events.

Table 5

Serious adverse events, molnupiravir.

Monoclonal Antibodies: Bamlanivimab and Etesevimab Combination (Anti-Spike Protein Receptor Binding Domain of SARS-CoV-2)

Adverse Events 45 Days or Less

We identified two RCTs of bamlanivimab/ etesevimab^{12, 29} that reported serious adverse events. Both had low risk of bias for adverse events collection and reporting. Data are displayed in Table 6. In an outpatient trial¹² bamlanivimab/ etesevimab patients had a significantly lower risk for all-cause mortality (RR 0.50; CI 0.0, 0.81) within 29 days from baseline. In an inpatient trial patients had elevated but not statistically significant risk of all-cause mortality;²⁹ the dosage administered was much higher than eventually authorized by FDA for emergency use. Elevated but not statistically significant risk for acute kidney injury, cardiac arrythmia, myocardial infarction and infection were detected in the outpatient study.¹² There is insufficient certainty regarding risk of these adverse events due to lack of precision (very wide confidence intervals), lack of statistical significance, and lack of additional studies reporting these events.

Table 6

Serious adverse events, bamlanivimab/etesevimab.

Monoclonal Antibodies: Bebtelovimab (Anti-Spike Protein Receptor Binding Domain of SARS-CoV-2)

Adverse Events More Than 45 Days

We identified a placebo controlled trial of bebtelovimab that reported serious adverse events;⁵⁵ risk of bias for adverse events collection and reporting was low. Patients with mild or moderate symptoms were administered the medication intravenously in an outpatient setting. We abstracted data for patients who received 175 mg, as this is the dose authorized by the FDA for emergency use. There were no statistically significant differences between groups in risk for anaphylaxis or serious infection. Risk of cerebrovascular accident (RR 2.07; CI 0.08, 50.50 and thrombotic events (RR 2.07; CI 0.08, 50.50) were elevated but not statistically significant based on only one patient experiencing; there is insufficient certainty of evidence due lack of precision (very wide confidence intervals), lack of statistical significance, and lack of additional studies reporting these events. Data are displayed in Table 7.

Table 7

Serious adverse events, bebtelovimab.

Monoclonal Antibodies: Sotrovimab (Anti-Spike Protein Receptor Binding Domain of SARS-CoV-2)

Adverse Events 45 Days or Less

We identified one RCT¹⁶ of sotrovimab and three observational studies^{18, 38, 40} containing a sotrovimab arm that reported serious adverse events at 29 and 30 days post-intervention. All were conducted in an outpatient setting; data are displayed in Table 8. In three studies risk of all-cause mortality was much lower in the intervention group; however, the result was not statistically significant. There was elevated risk of increase in alanine transaminase (RR 3.06; CI 0.12, 74.8) and aspartate aminotransferase (RR 3.06; CI 0.12, 74.8) in the RCT¹⁶ based on only one case of each, so neither were statistically significant. The certainty of evidence is rated insufficient due to lack of precision (very wide confidence intervals), lack of statistical significance, and lack of additional studies reporting these events.

An observational study of organ transplant recipients and showed significant reduction in risk of acute kidney injury¹⁸ in the intervention group (RR 0.35; CI 0.14, 0.87).

Table 8

Serious adverse events, 45 days or less, sotrovimab.

Adverse Events More Than 45 Days

The RCT described immediately above¹⁶ also reported serious adverse events within 168 days post intervention. There were no significant differences in risks for acute kidney injury, cardiac arrhythmia, infection, and thrombotic events. Data are displayed in Table 9.

Table 9

Serious adverse events, more than 45 days, sotrovimab.

Monoclonal Antibodies: Tocilizumab (IL-6 Inhibitor)

Adverse Events 45 Days or Less

Table 10 displays data for two controlled trials^{44, 51} and eight observational studies^{8, 17, 19, 21, 23, 24, 41, 43} of tocilizumab; they reported serious adverse events from five to 28 days post baseline and were conducted with hospital patients. Risk of bias was low in four studies, and moderate/ unclear in six studies. In three observational studies^{8, 17, 21} patients on tocilizumab had a significantly lower risk for all-cause mortality (RR 0.30; CI 0.68, 0.93; RR 0.71; CI 0.61, 0.83; RR 0.40; CI 0.19, 0.85), while difference was not statistically significant in six other studies.

In one trial patients on tocilizumab had a significantly lower risk for serious infection⁵¹ (RR 0.47; CI 0.23, 0.96) while tocilizumab patients were at significantly higher risk (RR 1.72; CI 1.04, 2.83) in an observational study of patients critically ill with COVID-19.²⁴ Differences in risk for serious infection events were not significant in eight other studies. There is insufficient certainty of risk due to conflicting results.

Patients on tocilizumab had a significantly higher risk of neutropenia (RR 11.2; CI 1.54, 81.67) within 28 days of baseline in one low bias trial of 243 patients⁵¹ while a smaller observational study reported no cases.¹⁹ Despite the large effect size, certainty is limited due to lack of precision (extremely wide confidence interval), lack of other controlled studies indicating elevated risk, and conflicting results. Elevated but not statistically significant risk for thrombotic events was found in three studies^{17, 19, 23} while decreased but not statistically significant risk was found in another.⁵¹ Certainty of risk is insufficient due to lack of statistical significance and conflicting results. Three studies found conflicting results for cerebrovascular accident;^{19, 44, 51} none were statistically significant, leading to a rating of insufficient certainty for this event. Other serious adverse events reported in the studies were acute kidney injury, cardiac arrythmia, and myocardial infarction; there were no statistically significant differences in risk of these events in any study.

Table 10

Serious adverse events, tocilizumab, 45 days or less.

Adverse Events More Than 45 Days

Three controlled trials of tocilizumab for patients hospitalized for COVID-19 reported serious adverse events at 60 days;^{15, 44, 45} data are displayed in Table 11. The risk of bias was low in two studies, and moderate/unclear in the other. There was no significant difference in risk of all-cause mortality in any study. Elevated but not statistically significant risk of alanine transaminase increase was found in one trial⁴⁵ certainty of evidence for this event is insufficient. Elevated but not statistically significant risk of aspartate aminotransferase increase was found in another trial;⁴⁴ certainty of evidence for this event is also insufficient. Results for bleeding were not statistically significant and in conflicting directions. Intervention patients in one trial⁴⁴ had elevated but not statistically significant risk of cardiac arrythmia and myocardial infarction while another showed reduced risk (not statistically significant) for these serious adverse events.⁴⁵ Lack of statistical significance and conflicting results lead to a certainty rating of insufficient for these events.

Intervention patients in one trial had elevated but not statistically significant risk of infection¹⁵ while patients in the other two^{44, 45} had decreased risk that was not statistically significant. Lack of statistical significance and conflicting results lead to a certainty rating of insufficient for these events. Three studies had non-significant results for thrombotic events in opposing directions. The certainty of evidence is also insufficient for these events. Patients in one trial⁴⁴ had elevated but not statistically significant risk for neutropenia (RR 4.38; CI 0.24, 80.77); certainty of evidence was rated insufficient. Risks for acute kidney injury, hypertension, hypotension, seizure, and transfusion-associated lung injury were lower compared to control but the differences were not statistically significant.

Table 11

Serious adverse events, tocilizumab, more than 45 days.

Monoclonal Antibodies: Casirivimab and Imdevimab Combination (Anti-Spike Protein Receptor Binding Domain of SARS-CoV-2)

Table 12 displays serious adverse events reported in studies of casirivimab and imdevimab.

Adverse Events 45 Days or Less

We identified an observational study of pregnant patients²⁶ and two controlled trials.^{33, 56} All were conducted in an outpatient setting. The results for pregnant patients are discussed in the section on patients with pre-existing conditions. The trials reported serious adverse events at 28 or 29 days, with low risk of bias. Intervention patients had increased risk of myocardial infarction and serious infection in one trial³³ but the results were not statistically significant. Certainty of evidence for these events is insufficient due to lack of report during the first month in other studies and lack of statistical significance.

Adverse Events More Than 45 Days

Three controlled outpatient trials of casirivimab and imdevimab reported serious adverse events within more than 45 days.^{33, 39, 54} Events were reported at 163 and 226 days; risk of bias was low in each study. Serious adverse events reported were acute kidney injury, anaphylaxis, bleeding, cerebrovascular accident, myocardial infarction, infection, seizure, hypertension, hypotension, neutropenia, and thrombotic events. Although there was a non-statistically significant elevated risk for acute kidney injury, all-cause mortality, bleeding events, and myocardial infarction in one trial³³ the other trials reported non-statistically significant reduced risk, leading to a certainty rating of insufficient.

Table 12

Serious adverse events, casirivimab and imdevimab.

Monoclonal Antibodies: Tixagevimab and Cilgavimab Combination (Anti-Spike Protein Receptor Binding Domain of SARS-CoV-2)

Adverse Events More Than 45 Days

We identified one outpatient RCT of tixagevimab and cilgavimab that reported serious adverse events (see Table 13).²⁷ Investigators followed up at 457 days; this long observation period was designed to reflect five half-lives of the medication. Risk of bias was low. Serious adverse events reported were acute kidney injury, bleeding, headache, myocardial infarction, hypertension, joint pain, muscle pain, infection, cerebrovascular accident, and thrombotic events. There were no statistically significant differences between groups in risk for any of these events. However, there was a non-statistically significant trend toward elevated risk of each of these serious events except bleeding and infection. Certainty of evidence is insufficient due to lack of report in other studies, lack of precision (the upper limits of confidence were very high) and lack of statistical significance.

Table 13

Serious adverse events, tixagevimab and cilgavimab.

Anakinra (Interleukin-1 Receptor Antagonist)

We identified no studies of anakinra for COVID-19 conducted in the United States or that included U.S. patients that met our inclusion criteria (comparison group required). Authorization for emergency use was based on studies conducted overseas.

Patients With Pre-existing Conditions or Specific COVID-19 Symptomology

COVID-19 Pneumonia

We identified an RCT of convalescent plasma⁴ and an RCT of tocilizumab⁴⁴ where all subjects were hospitalized with COVID-19 related pneumonia. Other studies included patients with pneumonia but did not stratify adverse events for this specific subset of patients. The risk of bias for adverse events collection and reporting was moderate/unclear in both. Both studies reported adverse events at two months; the tocilizumab trial also reported at four weeks. As displayed in Tables 14 and 15, serious adverse events reported in the convalescent plasma trial were all cause mortality, bleeding events, cardiac arrythmia, acute central nervous system ischemia, headache, hypotension, syncope, and thrombotic events, while the tocilizumab trial reported acute kidney injury, anaphylaxis, transfusion associated lung injury, cardiac arrythmia, aspartate aminotransferase increase, bleeding, infection, neutropenia, hypoglycemia, hypertension, hypotension, thrombotic events, and myocardial infarction. There were no statistically significant differences between intervention and control groups in risk for any of those events. Within 60 days, risk of bleeding events, cardia arrythmia, acute central nervous system ischemia, headache, and thrombotic events were elevated but not statistically significant in the plasma trial leading to insufficient certainty of evidence. Within 60 days, risk of acute kidney injury, cardiac arrythmia, myocardial infarction and thrombotic events were elevated but not statistically significant in the tocilizumab trial leading to insufficient certainty of evidence.

Although not statistically significant, the tocilizumab trial investigators made note of possible risk for neutropenia (RR 4.38; CI 0.24, 80.77) within 60 days of administration in the FDA submission; this serious adverse event occurred in four of 295 (1.4%) of patients in the tocilizumab arm with no occurrences among 143 patients in the placebo arm. Again, certainty is insufficient due to lack of report in other studies, lack of statistical significance, and lack of precision (extremely wide confidence intervals).

Eight intervention patients and thirteen usual care patients in the convalescent plasma trial experienced dyspnea or respiratory distress (not displayed); the authors considered this event related to COVID-19 – related pneumonia rather than any treatment.

Table 14

Serious adverse events, 45 days or less, patients hospitalized with COVID pneumonia.

Table 15

Serious adverse events, more than 45 days, patients hospitalized with COVID pneumonia.

Respiratory or Cardiovascular Organ Support in the Intensive Care Unit

We identified an RCT of tocilizumab administered after COVID-19 patients started organ support in the intensive care unit.^{15, 63} Patients were on extracorporeal membrane oxygenation (ECMO) for respiratory support or intravenous infusion of a vasopressor or inotrope for cardiovascular support. (Other studies included patients on ECMO but did not stratify adverse events results.) Data are displayed in Table 16. The risk of bias for adverse events collection and reporting was low. Within 90 days, there were no statistically significant risk differences between intervention and usual care for bleeding events and thrombotic events. The risk of infection was elevated (RR 3.42; CI 0.14, 83.57) but this was not statistically significant and based on only one of the 353 intervention patients and none of the 402 usual care patients experiencing infection. The certainty of evidence is insufficient due to lack of other studies providing results specifically for organ support patients, lack of statistical significance, and imprecision (very wide confidence intervals). The risk of bleeding events was elevated but not statistically significant (RR 1.42; CI 0.39, 5.26); certainty of evidence was limited due to lack of additional studies providing stratified data for this specific population.

Table 16

Serious adverse events, patients with COVID-19 on organ support in the intensive care unit.

Hematologic Cancers

We identified a propensity score matched observational study of convalescent plasma for patients with hematologic cancers hospitalized with COVID-19.⁵³ The risk of bias for adverse events collection and reporting was moderate/unclear. Data are displayed in Table 17. Within 30 days, convalescent plasma patients had a significantly lower risk for all-cause mortality (RR 0.54; CI 0.35, 0.83), but a significantly higher risk for serious bleeding events (RR 1.96; CI 1.14, 3.36) and infection (RR 1.79; CI 1.41, 2.26) than patients receiving usual care. The risk of certainty was rated moderate due to statistical significance and precision. Other serious adverse events reported were cardiac arrythmia, myocardial infarction, and thrombotic events; there were no statistically significant differences in risk. Congestive heart failure was diagnosed in ten of the 143 plasma patients and less than five of the 143 matched patients who received usual care; unfortunately, the risk ratio was not calculable because the authors did not report patient numbers when less than five experienced an adverse event. Risk would be elevated (RR 2.50; CI 0.79, 7.96) in the most conservative scenario, with four usual care patients diagnosed with congestive heart failure. Certainty of evidence is limited due to lack of statistical significance and risk of bias due to lack of reporting the exact number of patients experiencing the event in the control group.

Table 17

Serious adverse events, patients with hematologic cancers hospitalized with COVID-19.

Severe Kidney Disease

We identified a propensity score matched cohort study of patients with severe kidney disease who were hospitalized for COVID-19; patients received remdesivir or no treatment.⁴⁷ The risk of bias for adverse events collection and reporting was low. Data are displayed in Table 18. At one week, there were no statistically significant differences between groups in risk for aspartate aminotransferase increase, cardiac arrythmia, or transfusion associated lung injury. The risk of alanine aminotransferase increase and seizure were elevated for remdesivir patients but neither risk was statistically significant and the upper confidence limits were very high, leading to insufficient certainty.

Table 18

Serious adverse events, patients with severe kidney disease hospitalized with COVID-19.

Organ Transplant

We identified a retrospective cohort study comparing molnupiravir, sotrovimab, and no treatment for COVID-19 outpatients who had undergone solid organ transplant.⁴⁰ Two-thirds were kidney transplant recipients. The risk of bias for adverse events collection and reporting was moderate/unclear. Risk for “any serious adverse event” at 30 days was not statistically significant (data not displayed). Specific serious adverse events were not reported.

Pregnancy

We identified two cohort studies of pregnant patients. Data are displayed in Table 19. One compared those who received no treatment for COVID-19 with those who received casirivimab and imdevimab primarily in the outpatient setting.²⁶ Serious adverse events reported were anaphylaxis, neonatal death, preterm birth, and infection. There were no statistically significant differences between groups in risk for any of these rare events. Timing of adverse events was unclear, resulting in moderate/unclear risk of bias for adverse events collection and reporting. The other observational study³² compared remdesivir with usual care (antibiotics +/- glucocorticoids) for pregant patients hospitalized with moderate symptoms of COVID-19 (data not displayed). Eight of 24 women on remdesivir experienced elevated transaminases during treatment; in 3 of 24, incidental oligohydramnios (too little amniotic fluid around a fetus) was observed within five days of finishing remdesivir. None of these adverse events led to discontinuation of treatment, implying that investigators felt the events were unrelated to the medication (in the case of oligohydramnios) or not serious. The certainty of evidence is insufficient for these events, as no other studies reported these events in pregnant women, investigators did not specifically mention whether these events occurred in the usual care group, and they did not rate severity.

In addition, two of seven pregnant women enrolled in a Phase 2 dose-ranging outpatient study of casirivimab and imdevimab³⁹ experienced miscarriage (not displayed). Both received a higher dose than the 600 mg casirivimab and 600 mg imdevimab combination eventually authorized ed for emergency use. No patients receiving placebo experienced miscarriage. The authors did not report the number of pregnant people in each arm, so risk ratio calculation was not possible. Both miscarriages occurred during the first trimester and were considered unrelated to the study drug or COVID-19 by the investigators. Risk of bias was unclear.

Table 19

Serious adverse events, pregnant patients.

Conclusions

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.⁷² 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.⁷³

While infusion-related reactions ranging from mild to severe are common among recipients of monoclonal antibodies,⁷⁴ 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/etesevimab, 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 effect⁷⁵ 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 studies⁷⁶ found no significant increased risk compared to control.

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.

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.⁷⁷

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Acknowledgments

The authors gratefully acknowledge the following individuals for their contributions to this project: Reed Grimes, M.D., and Vikram Krishnasamy, M.D., of the Health Resources and Services Administration; Mark Helfand, M.D., M.P.H., of Oregon Health & Science University and Director of the Scientific Resource Center for Evidence-based Practice Centers, who served as Associate Editor.

Peer Reviewers

Prior to publication of the final evidence report, EPCs sought input from independent Peer Reviewers without financial conflicts of interest. However, the conclusions and synthesis of the scientific literature presented in this report do not necessarily represent the views of individual reviewers. AHRQ may also seek comments from other Federal agencies when appropriate.

Peer Reviewers must disclose any financial conflicts of interest greater than $5,000 and any other relevant business or professional conflicts of interest. Because of their unique clinical or content expertise, individuals with potential nonfinancial conflicts may be retained. The TOO and the EPC work to balance, manage, or mitigate any potential nonfinancial conflicts of interest identified.

The list of Peer Reviewers follows:

• David R. Boulware, M.D., M.P.H.
  Professor of Medicine, Division of Infectious Diseases and International
  Medicine, Department of Medicine
  University of Minnesota Medical School
  Minneapolis, MN
• Gerald Dal Pan, M.D., M.H.S.
  Director, CDER Office of Surveillance and Epidemiology
  U.S. Food and Drug Administration
  Silver Spring, MD

Afterword

Recognized for excellence in conducting comprehensive systematic reviews, the Agency for Healthcare Research and Quality (AHRQ) Evidence-based Practice Center (EPC) Program is developing a range of rapid evidence products to assist end-users in making specific decisions in a limited timeframe.

The AHRQ EPC Program recognizes that people are struggling with urgent questions on how to address the COVID-19 pandemic. To shorten timelines, reviewers make strategic choices about which review processes to abridge. The adaptations made for expediency may limit the certainty and generalizability of the findings from the review, particularly in areas with a large literature base. Transparent reporting of the methods used and the resulting limitations of the evidence synthesis are extremely important.

Given the rapidly evolving field, the AHRQ EPC Program will update these reviews on a regular basis to keep the medical community and public up to date as more studies are published. If you have comments or have unpublished data to share related to this report, they may be sent by mail to the Task Order Officer named below at: Agency for Healthcare Research and Quality, 5600 Fishers Lane, Rockville, MD 20857, or by email to vog.shh.qrha@cpe and will be considered in the next version of the report.

• Robert Otto Valdez, Ph.D., M.S.H.A.
  Director
  Agency for Healthcare Research and Quality
• Christine Chang, M.D.
  Director
  Evidence-based Practice Center Program
  Center for Evidence and Practice Improvement
  Agency for Healthcare Research and Quality
• Therese Miller, Dr.P.H.
  Director
  Center for Evidence and Practice Improvement
  Agency for Healthcare Research and Quality
• Meghan Wagner, Pharm. D., M.B.A
  Task Order Officer
  Evidence-based Practice Center Program
  Center for Evidence and Practice Improvement
  Agency for Healthcare Research and Quality

Appendixes

Appendix B. Literature Flow Diagram

Figure B.1Literature flow diagram

Version 19.0

Suggested citation:

Maglione M, Klausner JD, Wirnkar PK, Fallarme I, Lak R, Sysawang K, Fu N, Yagyu S, Motala A, Tolentino D, Hempel S. Adverse Events Associated With COVID-19 Pharmaceutical Treatments. Rapid Evidence Product. (Prepared by the Southern California Evidence-based Practice Center under Contract No. 75Q80120D00009). AHRQ Publication No. 24-EHC011. Rockville, MD: Agency for Healthcare Research and Quality; March 2024. DOI: https://doi.org/10.23970/AHRQEPCRAPIDCOVID. Posted final reports are located on the Effective Health Care Program search page.

Disclaimers: This report is based on research conducted by the University of Southern California Evidence-based Practice Center under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 75Q80120D00009). The findings and conclusions in this document are those of the authors, who are responsible for its contents; the findings and conclusions do not necessarily represent the views of AHRQ. Therefore, no statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services.

None of the investigators have any affiliations or financial involvement that conflicts with the material presented in this report.

The information in this report is intended to help healthcare decision makers—patients and clinicians, health system leaders, and policymakers, among others—make well-informed decisions and thereby improve the quality of healthcare services. This report is not intended to be a substitute for the application of clinical judgment. Anyone who makes decisions concerning the provision of clinical care should consider this report in the same way as any medical reference and in conjunction with all other pertinent information, i.e., in the context of available resources and circumstances presented by individual patients.

This report is made available to the public under the terms of a licensing agreement between the author and the Agency for Healthcare Research and Quality. Most AHRQ documents are publicly available to use for noncommercial purposes (research, clinical or patient education, quality improvement projects) in the United States, and do not need specific permission to be reprinted and used unless they contain material that is copyrighted by others. Specific written permission is needed for commercial use (reprinting for sale, incorporation into software, incorporation into for-profit training courses) or for use outside of the U.S. If organizational policies require permission to adapt or use these materials, AHRQ will provide such permission in writing.

AHRQ or U.S. Department of Health and Human Services endorsement of any derivative products that may be developed from this report, such as clinical practice guidelines, other quality enhancement tools, or reimbursement or coverage policies, may not be stated or implied.

AHRQ appreciates appropriate acknowledgment and citation of its work. Suggested language for acknowledgment: This work was based on an evidence report, Adverse Events Associated with COVID-19 Pharmaceutical Treatments, by the Evidence-based Practice Center Program at the Agency for Healthcare Research and Quality (AHRQ).