Recurrent fulminant non-rheumatic streptococcal myocarditis proven by endomyocardial biopsy and autopsy

Abstract

A 42-year-old man with a history of acute myocarditis after streptococcal pharyngitis developed recurrent fulminant myocarditis. Endomyocardial biopsy revealed myocyte degeneration, interstitial edema, and neutrophil infiltration. The patient's cardiac function deteriorated rapidly, and he died despite mechanical circulatory support. Autopsy revealed neutrophil infiltration, interstitial edema, and micro-abscesses containing masses of streptococci and neutrophilic phagocytosis within the myocardium. The patient did not meet the diagnostic criteria for acute rheumatic fever; thus, he was diagnosed with non-rheumatic streptococcal myocarditis. Non-rheumatic streptococcal myocarditis rarely recurs, but it can be fulminant upon recurrence.

Learning objective

We report a rare case of recurrent fulminant non-rheumatic streptococcal myocarditis. Endomyocardial biopsy and autopsy revealed neutrophil infiltration and micro-abscesses containing bacterial masses of streptococci and neutrophilic phagocytosis in the myocardium. The patient did not meet the diagnostic criteria for acute rheumatic fever; thus, he was diagnosed with non-rheumatic streptococcal myocarditis. Non-rheumatic streptococcal myocarditis rarely recurs, but it can be fulminant upon recurrence.

Introduction

Various viruses and bacteria, such as Chlamydia pneumoniae and Mycobacterium tuberculosis, can cause fulminant myocarditis [1]. The most common complications of group A streptococcus infection are acute rheumatic fever (ARF) and acute glomerulonephritis [2], and the most common cardiac manifestations associated with ARF are valvular inflammation and myocarditis [3]. Non-rheumatic myocarditis, though atypical for ARF, has also been reported. Streptococcal pharyngitis is associated with acute non-rheumatic streptococcal myocarditis [4]. Non-rheumatic streptococcal myocarditis typically affects healthy young men, and is considered to have a good prognosis [5]. However, there have been no reports of recurrent and fulminant non-rheumatic streptococcal myocarditis. In this study, we report a rare case of recurrent and fulminant non-rheumatic streptococcal myocarditis after streptococcal pharyngitis.

Case report

A 42-year-old man was previously diagnosed 4 years previously with streptococcal pharyngitis using a rapid antigen test. A summary of laboratory data collected during this initial episode of myocarditis is shown in Table 1. The patient presented with a temperature of 37.5 °C, which was preceded by sore throat for a few days. No skin rash or erythema, subcutaneous nodules, or arthralgia was noted. Electrocardiography showed a low voltage in all leads with sinus tachycardia (111 beats/min) (Fig. 1A). The patient's blood pressure was 110/75 mm Hg. Echocardiography showed global myocardial edema, a left ventricular ejection fraction (LVEF) of 45%, and pericardial effusion (Video 1). The creatine kinase (CK) (14,478 IU/L; ref. 45–163 IU/L), creatine kinase MB (CK-MB) (64.2 IU/L; ref. <5 IU/L), and cardiac troponin T (1.42 ng/mL; ref. 0.014 ng/mL) concentrations were high. The patient was diagnosed with myocarditis. Four days after admission, cardiac function improved, as indicated by an LVEF of 67%, without the need for inotropic agents or mechanical circulatory support (Video 2). After discharge, cardiac function was maintained with no symptoms of heart failure.

Table 1.

Laboratory data measured during the first and second episodes of myocarditis.

Variable	Episode 1	Episode 2
WBC count (/μL)	22,800	26,000
Neutrophil count (/μL)	19,400	22,400
Lymphocyte count (/μL)	1700	2000
RBC count (×106/μL)	6.2	4.0
Platelet count (×103/μL)	151	58
Hemoglobin (g/dL)	19.2	12.8
Hs-CRP (mg/dL)	5.63	5.83
BUN (mg/dL)	20.7	34.0
Creatinine (mg/dL)	0.84	2.57
AST (IU/L)	190	1862
ALT (IU/L)	58	767
LDH (IU/L)	508	3121
TB (mg/dL)	1.3	1.8
CK (IU/L)	14,478	24,099
CK-MB (IU/L)	64.2	438
Troponin T (ng/mL)	1.42	1.23
Lactate (mmol/L)	2.6	6.5

ALT, alanine transaminase; AST, aspartate transaminase; BUN, blood urea nitrogen; CK, creatine kinase; CK-MB, creatine kinase MB; Hs-CRP, high-sensitivity C-reactive protein; LDH, lactate dehydrogenase; RBC, red blood cell; TB, total bilirubin; WBC, white blood cell.

Fig. 1.

Electrocardiography recordings. (A) The initial episode of myocarditis and (B) recurrent fulminant myocarditis showing ST-segment elevation in the thoracic leads (V1–V4) (black arrows).

Two and a half years after discharge, the patient presented to the emergency room of the local general hospital with a sore throat lasting for 2–3 days. He had no fever and no obvious skin rash/erythema or joint pain. Rapid antigen tests and pharyngeal culture tests were not performed. Electrocardiography showed sinus rhythm (117 beats/min), a low voltage, and slight ST-segment elevation in the chest leads (V1–V4) (Fig. 1B). Echocardiography showed global myocardial edema with an LVEF of 51%. The patient's blood pressure was 90/65 mm Hg, the mean blood pressure was 54 mm Hg, and it was challenging to maintain the systemic circulation. Laboratory tests showed high CK (17,926 IU/L) and cardiac troponin T (0.89 ng/mL) concentrations. The patient was clinically diagnosed with acute pharyngitis and acute myocarditis. A summary of laboratory data collected during the second episode of myocarditis is shown in Table 1.

Echocardiography was repeated 2 h later and showed a decrease in LVEF to <10% with insufficient aortic valve opening. Thus, the patient was diagnosed with fulminant myocarditis with cardiogenic shock (Video 3), with a blood pressure of 64/48 mm Hg. Veno-arterial extracorporeal membrane oxygenation and a pump catheter were used to assist the circulation (Impella CP®; Abiomed, Danvers, MA, USA).

A pathological examination of the right ventricular endomyocardial biopsy revealed myocyte degeneration, interstitial edema, and neutrophil infiltration, indicating bacterial myocarditis (Fig. 2A). Blood culture on admission was positive for Streptococcus pyogenes. Despite administration of ceftriaxone (1.0 g/day) and clindamycin (600 mg/day) on the day of admission, the patient's CK concentration further increased to 24,099 IU/L, CK-MB concentration increased to 438 IU/L, and troponin T concentration increased to 1.23 ng/mL. The patient died of multiorgan failure on the day after admission.

Fig. 2.

Myocardial pathology findings. (A) Right ventricular endomyocardial biopsy specimen stained with hematoxylin & eosin. (B) Black arrows indicate micro-abscesses in the myocardium at the microscopic level (scale bar: 200 μm). (C) Microscopic image of a micro-abscess in the myocardium, showing neutrophil infiltration with nuclear lobulation (scale bar: 20 μm). (D) Gram stain of the myocardial specimen (10 μm), with black arrows indicating phagocytosis of streptococci by neutrophils.

On autopsy, neutrophil infiltration, interstitial edema, and micro-abscesses containing masses of streptococci and neutrophilic phagocytosis were noted within the myocardium (Fig. 2B, C, and D). Valvular and epicardial inflammation were not observed.

The ethics committee of our institution approved this case report, and we obtained permission for publication of this case from the patient's next of kin.

Discussion

We report a rare case of recurrent non-rheumatic myocarditis caused by group A streptococcus that led to fulminant disease. The diagnosis of acute streptococcal myocarditis was based on the pathological diagnosis of neutrophilic myocarditis and autopsy specimen and blood culture positivity for S. pyogenes. Additionally, the autopsy revealed micro-abscesses with masses of streptococci and neutrophilic phagocytosis. The patient was further diagnosed with non-rheumatic streptococcal myocarditis because there was no valvular inflammation or epicarditis. There were no Aschoff bodies noted in the myocardium, which are distinctive of myocarditis associated with ARF [2]. Non-rheumatic streptococcal myocarditis typically occurs in healthy young men and accounts for approximately 3% of myocarditis hospitalizations. The prognosis of affected individuals is good if treated with antibiotics [5].

A previous study reported a patient with non-rheumatic streptococcal myocarditis that was severe enough to require extracorporeal membrane oxygenation (ECMO) [6]. Nakashima et al. [7] also reported a case of fulminant bacterial myocarditis in a 61-year-old woman. The patient was treated with veno-arterial ECMO and antibiotics, but she died. Endomyocardial biopsy showed a bacterial mass, myocardial cell degeneration, and inflammatory cell infiltration. Autopsy revealed bacterial infection around the necrotic cardiac tissue, without vegetation, valve deformation, or endocardial tears. However, infection was caused by group B streptococcus infection. This is different to our case in which myocarditis was associated with group A streptococcus infection.

Kobayashi et al. [8] reported a case of a 71-year-old woman with streptococcal toxic shock syndrome (STSS) due to group A streptococcus infection, which was complicated by acute pericarditis. The patient in Kobayashi et al.'s study had a history of diabetes mellitus and breast cancer, which may have suppressed the immune system, increasing the vulnerability to infection. However, the patient in the present study did not have either of these conditions and was not immunosuppressed. The only relevant history was that of previous streptococcal myocarditis. To our knowledge, the present case report is the first to show a patient with recurrent streptococcal myocarditis. The recurrent nature of this patient's condition may have led the condition to become fulminant.

The patient in Kobayashi et al.'s study was treated with percutaneous cardio-pulmonary support and antibiotic therapy, but she died of multiple organ failure. Autopsy showed abscess formation in part of the myocardium and infiltration of group A streptococcus. However, soft tissue necrosis was also observed, whereas in the present case, endomyocardial biopsy and autopsy findings did not show any soft tissue necrosis or streptococcal infiltration, nor any findings of streptococcal infiltration or micro-abscesses in other organs. In other words, streptococcal infiltration was confined to the heart in the present study.

Given the above observations, the novelty of our study is in the fact that endomyocardial biopsy and autopsy showed that group A streptococcus infection was localized to the heart, indicating organ specificity, and myocarditis associated with group A streptococcal infection recurred and was fulminant at the time of recurrence.

The mechanisms underlying the localization of streptococcal infection in the heart remain unclear. Cross-reactivity between streptococcal M protein and myocardial alpha-helical coiled-coil proteins has been reported as a mechanism underpinning myocarditis development in ARF [9]. Another study showed that human cardiac Ca²⁺ ATPase and a putative group A streptococcal calcium-transporting ATPase have similar peptide sequences, suggesting molecular mimicry and cross-reactivity [10]. The pathophysiology of non-rheumatic streptococcal myocarditis has been discussed as a direct or indirect results of bacterial toxins. However, this mechanism appears to be speculative [4]. In the present case, the gap between the degree of neutrophil infiltration or myocardial damage and the sudden collapse of cardiac function suggests a deleterious secondary autoimmune mechanism in addition to direct myocardial injury.

Some patients transition from heart failure with reduced EF to heart failure with recovered EF after myocarditis. In the present case, cardiac function improved after recovery from the first episode of myocarditis, as indicated by an LVEF of 67%. However, despite an improvement in cardiac function, myocardial damage can persist. During the second episode of myocarditis, cardiac function deteriorated again, as indicated by a decline in LVEF. Unfortunately, cardiac magnetic resonance imaging and left ventricular strain assessment were not performed after the acute phase at first hospitalization. However, we speculate that myocardial damage after the first episode of myocarditis may have been responsible for myocarditis recurrence. Thus, patients with previous streptococcal myocarditis may be at an increased risk of fulminant myocarditis.

In conclusion, it is important to recognize that bacterial myocarditis associated with streptococcal infection can recur. Recurrence can be fulminant, even if the patient does not meet the criteria for ARF.

The following are the supplementary data related to this article.

Video 1

Echocardiography recording during previous myocarditis.

Video 2

Echocardiography recording during recovery of cardiac function.

Video 3

Echocardiography recording during fulminant myocarditis.

Declaration of competing interest

The authors declare that there is no conflict of interest.