Incidence of Myocarditis Associated with Diphtheria, Tetanus, and Pertussis Vaccine: A Rare Case Series

Abstract

Myocarditis induced by diphtheria–tetanus–pertussis (DTP) vaccination is extremely rare, accounting for only two cases thus far. Hence, to supplement knowledge regarding its pathogenesis and treatment, we reported two cases of myocarditis associated with DTP vaccination in adults. Two patients (a 40-year-old female and a 43-year-old male) presented with mild symptoms and were hemodynamically stable. In both patients, the DTP vaccination was given 4 and 6 days before admission. Both patients had prolonged corrected QT interval (QTc), poor left ventricular function, and high troponin levels at admission. However, numerous ST segment depression was only noted in the first case. Bacteriology and virology study results were negative for any pathogen. No atherosclerotic lesions were observed by coronary angiography. Cardiac magnetic resonance imaging was only performed in the second case, which confirmed the diagnosis of myocarditis. Initial therapy was administered with a beta-blocker, angiotensin-converting enzyme inhibitor, and intravenous methylprednisolone. Nonetheless, in the first case, rapid clinical deterioration and sudden cardiac death occur within 3 days of hospitalization. Learn from the first case, a high-dose intravenous immunoglobulin (IVIG) treatment was initiated in the second case, which resulted in an improvement in left ventricular function and clinical symptoms, as well as a significant reduction in QTc interval and troponin levels. Rapid diagnostic testing and early recognition of the fulminant course is mandatory, allowing clinicians to aggressively treat the patient with high-dose intravenous immune globulin, thus obtaining a better outcome.

Myocarditis is an inflammatory cardiac disease characterized by the inflammation of the myocardium due to several etiologies, including infection, autoimmune, or toxin. ¹ To the best of our knowledge, thus far, only two incidences of myocarditis-related diphtheria–tetanus–pertussis (DTP) vaccination have been reported. ^{2 3} Myocarditis is frequently misdiagnosed owing to a lack of specific clinical signs, with varying clinical conditions ranging from asymptomatic to lethal state, leading to ventricular arrhythmia and sudden cardiac death (SCD). ^{1 3} In the absence of a clear understanding of the underlying mechanism and proper treatment, myocarditis following DTP vaccination remains a controversial topic. Therefore, to prepend additive information regarding this issue, currently, we reported two cases of myocarditis in adults due to DTP vaccination.

Case Report

Case 1

A 40-years-old female presented to the emergency room with atypical chest pain, myalgia, and fatigue within 2 days prior to admission. The patient did not report any viral infection-related symptoms. Neither the patient nor her family had a history of syncope, cardiovascular disease (CVD), and SCD. Four days before, the patient had been vaccinated by DTP and no adverse reactions were reported 1 hour after vaccination. Moreover, the coronavirus disease 19 (COVID-19) vaccination was administered 1 year ago. No remarkable findings were seen in the physical examination except for profound tachycardia. The polymerase chain reactive (PCR) results were negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The electrocardiogram (ECG) showed sinus tachycardia (167 bpm), prolonged QTc interval (510 milliseconds), and ST segment depression in inferolateral leads ( Fig. 1 ).

Fig. 1.

Initial electrocardiogram showed sinus tachycardia (167 bpm), prolonged QTc interval (510 milliseconds), and ST segment depression on inferolateral leads.

Echocardiography revealed normal anatomy of all cardiac chambers with reduced left ventricular ejection fraction (LVEF; 46%), global hypokinetic, and impaired diastolic function. The laboratory examination unveiled a leucocytosis (20,650 cells/µL; normal range (NR): 4,400–11,300 cells/µL), normal potassium levels (3.7 mEq/L; NR: 3.5–5.1 mEq/L), and high troponin I levels (2.36 ng/mL; NR: <0.02 ng/mL). The blood culture and serology test showed no presence of any pathogens. The coronary angiography (CAG) revealed no coronary artery obstruction. Therefore, the diagnosis of myocarditis due to DTP vaccination was established by an exclusion. Moreover, the initial therapy was done with a beta-blocker (BB), angiotensin-converting enzyme inhibitor (ACEi), and intravenous methylprednisolone. The serial ECG on the second day showed a sinus rhythm, improved the ST-T changes, and persisted prolonged QTc interval (500 milliseconds; Fig. 2 ).

Fig. 2.

Serial electrocardiogram revealed sinus rhythm with persisted QTc interval prolongation (500 milliseconds). The ST segment depression was improved compared to the initial ECG.

On the third day of hospitalization, suddenly, the patient experienced SCD due to ventricular tachycardia while waiting for cardiac magnetic resonance (CMR) testing.

Case 2

A 43-year-old male patient attended to the hospital with palpitation and myalgia within 5 days before admission. The patient did not experience any symptoms of viral infection. The patient and his family had no history of syncope, CVD, and SCD. Six days prior to admission, the patient received a DTP vaccination, and the vaccination certificate did not report any adverse reactions 1 hour after the vaccination. The COVID-19 vaccination was given 11 months previously. Upon admission, the vital signs were normal. The patient was SARS-CoV-2 PCR negative. Laboratory investigations revealed leucocytosis (18,050 cells/µL; NR: 4,400–11,300 cells/µL), normal potassium levels (3.6 mEq/L; NR: 3.5–5.1 mEq/L), and increased troponin I levels (2.1 ng/mL; NR: <0.02 ng/mL). Bacteriology and virology studies did not reveal the existence of any pathogen. The ECG revealed a sinus rhythm with a prolonged QTc interval (506 milliseconds; Fig. 3 ).

Fig. 3.

Initial electrocardiogram showed prolonged QTc interval (506 milliseconds) with no ST segment deviation.

Echocardiography unveiled a normal cardiac dimension with LVEF being 50%, slightly global hypokinetic, and impaired diastolic function. However, 1 year ago, the echocardiography showed that LVEF was 62%, normokinetic, and normal diastolic function. Hence, we assumed that the LVEF and diastolic function were abnormal compared to the previous one. CAG identified no coronary artery obstruction. CMR examination revealed hypokinetic activity in the apical inferior, mid-, and basal inferior; early gadolinium enhancements in the basal inferior, suggesting myocardial edema; and subendocardial late gadolinium enhancements in the septal, apical, and mid-anterolateral areas, indicating myocardial fibrosis ( Fig. 4 ).

Fig. 4.

Cardiac magnetic resonance imaging showed early gadolinium enhancements in the basal inferior region ( red arrow ), and subendocardial late gadolinium enhancements in the septal, apical, and mid anterolateral areas ( green arrow ).

Several drugs were administered, including BB, ACEi, intravenous methylprednisolone, and intravenous immunoglobulin (IVIG). The IVIG dose was 400 mg/kg daily for 5 days consecutively. The serial ECG on sixth day demonstrated a sinus rhythm with QTc interval improvement (440 milliseconds). On the seventh day, the patient was discharged with normal leucocyte (10,070 cells/µL) and troponin I level (0.02 ng/dL). Two months after discharge, the patient was asymptomatic and had LVEF improvement (60%).

Discussion

To the best of our knowledge, these are the third and fourth cases of myocarditis induced by DTP vaccination. Myocarditis could occur between 1 and 4 days after DTP vaccination. ^{2 3} According to the European Society of Cardiology guideline, the first and second cases were categorized into clinically suspected myocarditis and confirmed myocarditis, respectively. ⁴

Due to its invasive nature and limited availability, endomyocardial biopsy is not routinely performed to diagnose myocarditis. Therefore, CMR examination based on Lake Louise's criteria may be an alternative tool for diagnosing myocarditis. ⁴ In the second case, the CMR results fulfilled Lake Louise's criteria, confirming the myocarditis diagnosis. Otherwise, CMR testing did not utilize in the first case. Hence, despite the absence of coronary artery disease, the diagnosis of myocarditis remains unclear since we were unable to completely exclude the possibility of long QT syndrome. However, owing to no history of syncope, aborted SCD, and any arrhythmia-related symptoms in this patient and her family, the diagnosis of long QT syndrome was less likely.

Several studies demonstrated that QTc interval prolongation, depressed left ventricular function, increased cardiac enzyme, and a higher incidence of ST segment depression in myocarditis patients were correlated with the development of acute fulminant myocarditis and increased the risk of in-hospital mortality. ^{5 6 7 8} Hence, detecting these parameters in myocarditis patients due to DTP vaccination on admission provided important predictive information for early recognition of fulminant myocarditis and may aid in providing a timely aggressive approach to reduce the mortality rate and obtain a better prognosis.

Similar to the case report by Wu et al, in the first case, we acknowledge that mild symptoms did not exclude the progression of acute fulminant myocarditis. The abrupt clinical deterioration and sudden cardiac arrest may still occur in this population, especially when accompanied by QTc interval prolongation, reduced LVEF, high troponin levels, and high incidence of ST segment depression. ³ Interestingly, like the first case, our second patient was also admitted with high troponin levels, decreased LVEF, and prolonged QTc interval, indicating a high risk of developing acute fulminant myocarditis. However, the patient's clinical condition was persistently stable until discharged, followed by normalization of QTc interval, LVEF, and troponin levels. Thus, it concludes that aggressive and appropriate treatment can reduce the progression of the fulminant disease and improve outcomes in patients with myocarditis due to DTP vaccination.

As in two previous cases, blood culture and serology testing in this study also failed to reveal any microorganism, supporting the hypothesis that the autoimmune process is responsible for DTP vaccination-induced myocarditis. In 2017, it was proposed that autoimmune syndrome induced by adjuvants (ASIA syndrome) was responsible for the pathophysiology of immune-mediated myocarditis. Furthermore, DTP is one of the most common vaccines related to ASIA syndrome. ⁹ Thus, it concludes that the most likely etiology of DTP vaccination-induced myocarditis is ASIA syndrome.

According to the pathogenesis mentioned above, immunosuppressive therapy, such as IVIG, may effectively reduce the progression of fulminant myocarditis and resolve the condition. Consistently, a meta-analysis by Huang et al showed that IVIG treatment significantly reduced the risk of in-hospital mortality and increased LVEF in myocarditis patients. ¹⁰ Hence, in contrast to the first case, we add a high dose of IVIG administration in the second case. Subsequently, the improvement of clinical symptoms, QTc interval duration, troponin values, and LVEF were noted, indicating that IVIG was effective in treating the myocarditis induced by DTP vaccination.

The main limitation in this study was the unavailability of CMR data in the first case. Therefore, we could not fully exclude the diagnosis of long QT syndrome.

Conclusion

Although myocarditis patients due to DTP vaccination presented with mild symptoms and relatively stable, early detection of fulminant course, rapid diagnostic testing, and aggressive treatment, especially with high-dose IVIG, are highly required to achieve the most favorable outcome.

Funding Statement

Funding None