Influenza vaccination and myocarditis among patients receiving immune checkpoint inhibitors.
Awadalla M1, Golden DLA2, Mahmood SS3, Alvi RM2, Mercaldo ND2, Hassan MZO2, Banerji D2, Rokicki A2, Mulligan C2, Murphy SPT2, Jones-O'Connor M2, Cohen JV4, Heinzerling LM5, Armanious M6, Sullivan RJ4, Damrongwatanasuk R6, Chen CL7, Gupta D7, Kirchberger MC5, Moslehi JJ8, Shah SP9, Ganatra S9, Thavendiranathan P10, Rizvi MA11, Sahni G12, Lyon AR13, Tocchetti CG14, Mercurio V14, Thuny F15, Ederhy S16, Mahmoudi M17, Lawrence DP4, Groarke JD18, Nohria A18, Fradley MG6, Reynolds KL4, Neilan TG2,19.
Author information
1
Cardiac MR PET CT Program, Department of Radiology, Massachusetts General Hospital, 165 Cambridge Street, Suite 400, Boston, MA, 02114, USA. mawadalla@mgh.harvard.edu.
2
Cardiac MR PET CT Program, Department of Radiology, Massachusetts General Hospital, 165 Cambridge Street, Suite 400, Boston, MA, 02114, USA.
3
Cardiology Division, New York-Presbyterian Hospital, Weill Cornell Medical Center, New York, NY, USA.
4
Division of Oncology and Hematology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
5
Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nurnberg (FAU), Erlangen, Germany.
6
Cardio-Oncology Program, H. Lee Moffitt Cancer Center & Research Institute and University of South Florida Division of Cardiovascular Medicine, Tampa, FL, USA.
7
Cardiology Division, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA.
8
Cardio-Oncology Program, Vanderbilt University Medical Center, Nashville, TN, USA.
9
Cardiology Division, Lahey Hospital & Medical Center, Burlington, MA, USA.
10
Ted Rogers Program in Cardiotoxicity Prevention, Peter Munk Cardiac Center, Division of Cardiology Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.
11
Division of Oncology and Hematology, Department of Medicine, Lehigh Valley Hospital, Allentown, PA, USA.
12
The Mount Sinai Hospital, New York, NY, USA.
13
Cardio-Oncology Program, Royal Brompton Hospital, London, UK.
14
Department of Translational Medical Sciences, Federico II University, Naples, Italy.
15
Cardiovascular Division, Department of Medicine, Aix-Marseille Universite, Marseille, France.
16
Cardio-Oncology Program, Division of Cardiology, Hopitaux Universitaires est Paris, Paris, France.
17
Division of Cardiology, Department of Medicine, Southampton General Hospital, Southampton, UK.
18
Cardio-Oncology Program, Division of Cardiology, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
19
Cardio-Oncology Program, Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
Abstract
BACKGROUND:
Influenza vaccination (FV) is recommended for patients with cancer. Recent data suggested that the administration of the FV was associated with an increase in immune-related adverse events (irAEs) among patients on immune checkpoint inhibitors (ICIs). Myocarditis is an uncommon but serious complication of ICIs and may also result from infection with influenza. There are no data testing the relationship between FV and the development of myocarditis on ICIs.

METHODS:
Patients on ICIs who developed myocarditis (n = 101) (cases) were compared to ICI-treated patients (n = 201) without myocarditis (controls). A patient was defined as having the FV if they were administered the FV from 6 months prior to start of ICI to anytime during ICI therapy. Alternate thresholds for FV status were also tested. The primary comparison of interest was the rate of FV between cases and controls. Patients with myocarditis were followed for major adverse cardiac events (MACE), defined as the composite of cardiogenic shock, cardiac arrest, hemodynamically significant complete heart block and cardiovascular death.

RESULTS:
The FV was administered to 25% of the myocarditis cases compared to 40% of the non-myocarditis ICI-treated controls (p = 0.01). Similar findings of lower rates of FV administration were noted among myocarditis cases when alternate thresholds were tested. Among the myocarditis cases, those who were vaccinated had 3-fold lower troponin levels when compared to unvaccinated cases (FV vs. No FV: 0.12 [0.02, 0.47] vs. 0.40 [0.11, 1.26] ng/ml, p = 0.02). Within myocarditis cases, those administered the FV also had a lower rate of other irAEs when compared to unvaccinated cases (36 vs. 55% p = 0.10) including lower rates of pneumonitis (12 vs. 36%, p = 0.03). During follow-up (175 [IQR 89, 363] days), 47% of myocarditis cases experienced a MACE. Myocarditis cases who received the FV were at a lower risk of cumulative MACE when compared to unvaccinated cases (24 vs. 59%, p = 0.002).

CONCLUSION:
The rate of FV among ICI-related myocarditis cases was lower than controls on ICIs who did not develop myocarditis. In those who developed myocarditis related to an ICI, there was less myocardial injury and a lower risk of MACE among those who were administered the FV.

KEYWORDS:
Cancer; Cardiovascular disease; Immune checkpoint inhibitors; Immune-related adverse events; Influenza vaccination; Major adverse cardiac events; Myocarditis

PMID: 30795818 PMCID: PMC6387531 DOI: 10.1186/s40425-019-0535-y