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Flu Vaccination May Protect Against Myocarditis Related to Checkpoint Inhibitors

Key findings

  • 25% of 101 patients who developed myocarditis had been vaccinated against influenza within six months of starting immune checkpoint inhibitor (ICI) therapy, or during therapy, compared with 40% of 201 controls who did not develop myocarditis
  • Lower vaccination rates among myocarditis cases were also noted when using a three-month cut-off or when restricting the time frame to vaccination only during ICI therapy
  • Supporting a protective effect of vaccination among patients on an ICI, serum troponin was three times higher among unvaccinated myocarditis cases than among vaccinated cases
  • During follow up, the cumulative rate of major adverse cardiac events among unvaccinated cases was more than double that noted among vaccinated cases

Myocarditis is an uncommon but serious complication of the immune checkpoint inhibitors (ICIs) that have revolutionized cancer treatment. Influenza vaccination has been linked to reduced risk of cardiovascular events in broad populations, and it is recommended for cancer patients. However, there are no influenza vaccination guidelines specific to cancer patients receiving immunotherapy.

Tomas G. Neilan, MD, MPH, director of the Cardio-Oncology Program at Massachusetts General Hospital, and colleagues conducted a retrospective case–control study to test the association between influenza vaccination and development of myocarditis among patients on ICI therapy. In the Journal for ImmunoTherapy of Cancer, they report evidence of a protective effect of influenza vaccination that they say warrants further investigation.

Deriving the Study Population

Dr. Neilan's group identified 101 cases of ICI-related myocarditis from a 16-center registry. These patients were diagnosed between November 2013 and October 2018. The average age was 67, and 72% were male.

The 201 controls were derived from a Mass General registry of all patients started on ICI during the same time period who did not develop myocarditis.

Rates of Influenza Vaccination

The researchers used three time frames to define influenza vaccination. Regardless of definition, the vaccination rate was significantly higher among cases (those who stayed free of myocarditis) than among controls (those who developed the complication):

  • Within six months prior to starting ICI therapy or during therapy: 25% of cases vs. 40% of controls, = .01
  • Within three months prior to starting ICI therapy or during therapy: 17% of cases vs. 34% of controls, = .002
  • Only during ICI therapy: 8% of cases vs. 17% of controls, = .04

Analysis of Patients Who Developed Myocarditis

Dr. Neilan's team compared the myocarditis patients who received influenza vaccination within six months before starting ICI to those who had not been vaccinated. There were no differences between groups in age, sex, cardiovascular risk factors, use of monotherapy versus combination ICI therapy or the particular ICI agents used. Neither was there any difference in left ventricular ejection fraction according to vaccination status.

However, the median admission level of serum troponin, a measure of myocardial injury, was three times higher among patients with myocarditis who had not been vaccinated against influenza (0.12 vs. 0.40 ng/mL, = .02).

The researchers note that in a previous study of theirs, the degree of elevation of serum troponin was a predictor of adverse cardiovascular events among patients who developed myocarditis while on an ICI.

Major Adverse Cardiac Events (MACE)

The median follow-up of patients who developed myocarditis was 175 days. During this period, 47% of the cases experienced a MACE: cardiovascular death, cardiac arrest, cardiogenic shock or complete heart block requiring a temporary pacemaker. Compared with unvaccinated cases, myocarditis cases who had been vaccinated against influenza were at significantly lower risk of cardiovascular death (72% vs. 36%, = .04) and cumulative MACE (59% vs. 24%, = .002).

Research Implications

There is a clear need to establish the safety of influenza vaccination among cancer patients treated with ICIs and whether it does protect against myocarditis. Prospective studies will be difficult, though, because the incidence of ICI-related myocarditis is estimated to be only 0.5%-1%.

How influenza vaccination might protect against cardiovascular events is unclear and also needs to be investigated, the researchers say. Direct involvement of influenza in the myocardium is uncommon, although influenza infection can cause myocarditis by direct cytolysis of myocytes. In addition, host immune response to the virus may have an important role.

Refer a patient to the Mass General Heart Center

Learn more about the Cardio-Oncology Program at Mass General


Myocarditis related to immune checkpoint inhibitors may be identified early through EKG and Troponin tests and treated with high dose steroids


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