Response to Rezahosseini and Barrella Harboe

To the Editor—We are thankful for the interesting and thoughtful letter regarding our group's study [1] by Rezahosseini and Barrella Harboe [2]. We reported a significantly elevated risk of hospitalization for acute myocardial infarction (AMI) in the time immediately before and after detection of laboratory-confirmed invasive pneumococcal disease (IPD). We discussed our findings in the context of several hypothesized biological mechanisms, including destabilization of atherosclerotic plaques due to the inflammatory response, direct invasion of the myocardium, and formation of microscopic lesions due to Streptococcus pneumoniae infection of the heart tissue and pneumolysin-induced myocardial infarction (MI), among others [3].

However, our discussion did not consider the possible role of antibiotic-induced Kounis syndrome in the development of AMI during an IPD episode. Kounis syndrome, a hypersensitivity disorder, has been described among patients with evidence of allergic reactions or hypersensitivity to prescription drugs, including some antibiotics [4]. It is thought to be relatively rare among patients hospitalized in the United States, even among patients hospitalized primarily for allergic or hypersensitivity reactions (prevalence in 2007–2014, 0.9% [0.2% ST-elevation AMI and 0.7% non–ST-elevation AMI)] [4]. A recent review [5] indicated that the most common cardiac presentation for Kounis syndrome is ST-elevation MI, so it is worth noting that in our study only approximately 10% of patients with AMI had an ST-elevation MI presentation.

As acknowledged in our article’s discussion [1], our data sources did not contain antibiotic use information, limiting our ability to describe or examine the role and timing of antibiotic use in the development of AMI. Yet for completeness, we reanalyzed our secondary analysis with 4 IPD exposure intervals (pre–IPD detection, defined as 7 to 2 days before IPD specimen collection; concurrent with IPD detection, from 1 day before to the day of specimen collection; current IPD, 1–7 days after specimen collection; and post-IPD, 8–28 days after specimen collection), excluding AMI hospitalizations with any evidence of allergic events. We identified potential allergic events using previously reported discharge diagnosis coding algorithms [4, 6]. Of the 338 hospitalizations for AMI among the 324 patients in the analysis, 9 had a secondary diagnosis code for a personal history of allergy to penicillin or other medication, and 1 had a diagnosis code for unspecified shock. Of these 10 hospitalizations, 8 occurred during a control period and 2 occurred in the concurrent IPD period. In the sensitivity analysis excluding these 10 hospitalizations, we observed adjusted incidence rate ratios (IRRs) similar to the findings in our study (pre–IPD detection IRR, 4.12 [95% confidence interval, 1.92–8.84]; IRR concurrent with IPD detection, 331.00 [258.36–424.05]; IRR for current IPD, 10.04 [5.86–17.20]; and post-IPD IRR, 1.82 [.85–3.88]) [1].

Therefore, the low incidence of Kounis syndrome and the rare detection of allergic events documented among AMI hospitalizations in our study, as well as the lack of impact on observed findings when we excluded hospitalizations for AMI among patients with any potential allergic event, demonstrates that Kounis syndrome is unlikely to be a major contributing factor in the substantially increased risk of AMI associated with IPD.

Notes

Financial support. The work was supported by the National Institute on Drug Abuse (grant K01DA051683 to A. D. W.), the National Institute on Aging (grant R01AG043471 to C. G. G.), and the National Institute for Allergy and Infectious Diseases (grant K24AI148459 to C. G. G.), National Institutes of Health; and the Centers for Disease Control and Prevention (grant 1U50CK000491).