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RESEARCH LETTER

# Incidence of Immune Checkpoint Inhibitor–Induced Myocarditis During the COVID-19 Pandemic

Alexi Vasbinder ID, PhD, RN; Elizabeth Anderson ID, MPH; Tonimarie Catalan, BS; Anis Ismail ID, MD; Mousumi Banerjee ID, PhD; Ian Pizzo, BS; Kristen Machado ID, BS; Pennelope Blakely ID, BS; Joe-Elie Salem ID, MD, PhD; Salim S. Hayek ID, MD

Immune checkpoint inhibitors (ICIs) have improved the survival of patients with various malignancies; however, they are associated with the development of myocarditis, an increasingly recognized immune-related adverse event.¹ Myocarditis has also entered the clinical spotlight due to the recent COVID-19 pandemic given the increase in myocarditis cases associated with both SARS-CoV-2 infection and mRNA COVID-19 vaccines.² We sought to estimate the incidence of ICI myocarditis throughout the COVID-19 pandemic.

We conducted an observational study of adult (18 years and older) patients who had received at least 1 dose of single or dual ICI therapy at Michigan Medicine between June 2014 and June 2023. Patients taking ICIs were identified through medication administration records of all patients receiving care at Michigan Medicine. ICI myocarditis cases were included from the University of Michigan ICI Cardiotoxicity Registry, a database of all ICI myocarditis cases since 2014.¹ Details of the registry were previously published.¹ In summary, myocarditis was diagnosed by the cardiovascular consult team according to established clinical guidelines.¹ COVID-19 cases were defined as any patient who tested positive at Michigan Medicine.

We compared the cumulative incidence of myocarditis before and after a reference date of March 1, 2020

(month of first documented COVID-19 case in Michigan) and in 6-month intervals beginning January 1, 2019. Using only dates after March 1, 2020, we modeled the relationship between time and count data using a second-order polynomial regression. We included an interaction term between time and an indicator variable for myocarditis versus COVID-19 cases to test whether the trajectories differed. Given the difference in scale magnitude, count data were standardized using z-score normalization. Regression diagnostics were used to check model assumptions. Approval was obtained from the University of Michigan's institutional review board under a waiver of informed consent. The data that support the findings of this study are available from the corresponding author upon reasonable request.

The overall cohort included 4056 patients, of whom 1868 were initiated on ICIs before March 1, 2020, and 2188 from March 1, 2020 to December 8, 2023. A total of 34 cases of ICI myocarditis were diagnosed from June 2014 to December 2023, after a median of 40 days after the first dose of ICI. Of the 34 cases, 25 (74%) were diagnosed after March 1, 2020. Clinical characteristics of patients with ICI myocarditis diagnosed before March 1, 2020, were similar to those diagnosed during the pandemic. Of the 25 cases diagnosed after March 1, 2020, only 1 patient had tested

**Key Words:** coronavirus disease COVID-19 ICI immune checkpoint inhibitor immunotherapy myocarditis

Correspondence to: Salim S. Hayek, MD, Department of Medicine, Division of Cardiology, University of Michigan Frankel Cardiovascular Center, 1500 East Medical Center Drive, CVC #2709, Ann Arbor, MI 48109. Email: [shayek@umich.edu](mailto:shayek@umich.edu)

This article was sent to Tochukwu M. Okwuosa, DO, Associate Editor, for review by expert referees, editorial decision, and final disposition.

For Sources of Funding and Disclosures, see page 3.

© 2024 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

JAHA is available at: [www.ahajournals.org/journal/jaha](https://www.ahajournals.org/journal/jaha)
positive for COVID-19 5months before the diagnosis of ICI myocarditis. Sixteen patients were diagnosed with myocarditis after the COVID-19 vaccines became widely available and, of those, 14 (87.5%) patients received the first dose of vaccine a median of 372 days (minimum, 8 days; maximum: 875 days) before being diagnosed with myocarditis. The remaining 2 patients did not receive the COVID-19 vaccine.

The incidence of ICI myocarditis was greater after March 1, 2020, compared with the prepandemic period (1.2% versus 0.46%, *P*=0.015). The incidence of ICI myocarditis peaked between July 2021 and December 2022 (2.1%) and declined precipitously, with the lowest incidence reported between January 2023 and June 2023 (0.32%) (Figure). The rise and descent in ICI myocarditis cases tracked that of COVID-19 cases (Figure), with similar slopes and a Fréchet distance of 1.15 between the curves, metrics used to assess the similarity between COVID-19 and ICI myocarditis curves.³ In addition, there were no significant differences between the coefficients of the polynomial regression modeling for ICI myocarditis and COVID-19 cases (*P* interaction=0.19). Of note, there was no difference in the proportion of dual ICI use among 6-month intervals (*P*=0.25).

This is the first observation of a possible relationship between the COVID-19 pandemic and ICI myocarditis, with similar incidence trajectories. The incidence of ICI myocarditis increased during the COVID-19 pandemic, then rapidly declined after the Delta surge, despite a growing number of patients taking ICIs, implementation of routine monitoring protocols,¹ and similar rates of dual ICI use. While the reason for this observation is unclear, several large studies have identified a substantial increase in the incidence of various autoimmune diseases after SARS-CoV-2 infection.⁴ The association between COVID-19 and autoimmune diseases is thought to be due to the virus’s ability to disrupt self-tolerance and trigger autoimmune reactions via cross-reactivity.⁴ Immunoinflammatory responses can persist for months after SARS-CoV-2 infection (an effect more prominent with the earlier viral variants) and could increase the risk of aberrant immune activations in patients receiving ICIs.⁵ While the increased vigilance and screening for ICI myocarditis may have influenced its higher detection rates after March 2020, the subsequent decline in incidence to prepandemic levels after 2022 suggests other factors are at play.

<figure><img src="image_1.png" /><figcaption>**Figure.** Incidence of immune checkpoint inhibitor (ICI) myocarditis before and during the COVID-19 pandemic.</figcaption></figure>

The red line depicts the incidence of myocarditis expressed as the percentage of myocarditis cases per total number of ICI recipients for each 6-month interval beginning January 1, 2019. The blue bars represent patients taking single-agent ICI therapy, and the yellow bars denote those taking combination ICI therapy for each 6-month interval. Before 2019, these bars reflect the average number of patients taking single and dual ICIs, respectively, from June 14, 2014 to December 31, 2018. The green line depicts the total number of COVID-19 cases. The timing of COVID-19 variants is approximated based on the predominance of the circulating COVID-19 variants in the United States.
The strengths of this study include the system-
atic collection of data of all patients taking ICIs at
the University of Michigan, allowing for accurate as-
sessment of the incidence of myocarditis. Despite its
large sample size, this remains a single-center obser-
vational study in which the findings warrant external
validation and cannot establish causation, especially
since COVID-19 exposure of patients with ICI myo-
carditis could not be confirmed, and unknown con-
founders could not be accounted for. Nevertheless,
these findings are supported by several observa-
tions supporting a link between autoimmunity and
COVID-19 and has important implications for ongoing
and future clinical trials on therapeutic strategies for
ICI myocarditis.

ARTICLE INFORMATION

Received September 13, 2023; accepted February 23, 2024.

Affiliations

Department of Internal Medicine, Division of Cardiology (A.V., E.A., T.C., A.I., I.P., K.M., P.B., S.S.H.) and Department of Biostatistics, School of Public Health (M.B.), University of Michigan, Ann Arbor, MI and Department of Pharmacology, Sorbonne Université, INSERM, AP-HP, CIC-1901, Pitié-Salpêtrière Hospital, Paris, France (J.-E.S.).

Sources of Funding

A.V. is supported by a National Heart, Lung, and Blood Institute-funded postdoctoral fellowship (T32HL007853).

Disclosures

None.

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