BRIEF OBSERVATION
Acute Nonrheumatic Streptococcal Myocarditis: STEMI Mimic in Young Adults Gaurav A. Upadhyay, MD,a,b,* Justin F. Gainor, MD,a,* Luisa M. Stamm, MD, PhD,a,c Arnold N. Weinberg, MD,a,c G. William Dec, MD,a,b Jeremy N. Ruskin, MDa,b a
Department of Medicine, bDivision of Cardiology, and cDivision of Infectious Disease, Massachusetts General Hospital, Boston.
ABSTRACT BACKGROUND: Mimicking ST-segment elevation myocardial infarction upon presentation, acute nonrheumatic streptococcal myocarditis is a treatable etiology of myocarditis which has only been infrequently reported. METHODS: Patients were identified through a retrospective query of electronic medical records over a 17-year period (January 1994 to December 2010). We describe a case series of acute nonrheumatic streptococcal myocarditis complicating pharyngitis in young adults. RESULTS: Nine patients were identified; 89% were male, patients had an average age of 28.6 years, and 56% and 22% had confirmed group A and group G streptococcus, respectively. Latency from pharyngitis to chest pain averaged 3.1 ⫾ 1.1 days. No patients met the revised Jones criteria for acute rheumatic fever. All 9 patients (100%) presented with ST-segment elevations on electrocardiography and elevated cardiac biomarkers. Average peak creatine kinase was 934 U/L (normal ⬍ 400 U/L), creatine kinase-MB was 82 ng/mL (normal ⬍ 6.9 ng/mL), and troponin T was 2.30 ng/mL (normal ⬍ 0.03 ng/mL). Six patients underwent coronary angiography, which revealed no obstructive culprit lesions. Cardiac magnetic resonance imaging confirmed myocarditis in 3 patients and was used to document resolution in follow-up for 2 patients. All patients had a complete clinical recovery. CONCLUSIONS: Acute nonrheumatic streptococcal myocarditis is an under-recognized and treatable cause of ST-segment elevation and chest pain in young adults with a history of recent pharyngitis. Etiopathology extends beyond Lancefield group A streptococcus and includes group G streptococcal infection. Cardiac magnetic resonance may be useful in confirming the diagnosis and documenting the resolution. © 2012 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2012) 125, 1230-1233 KEYWORDS: Myocarditis; Pharyngitis; Streptococcal infection; ST-segment elevation myocardial infarction
After epidemics among US service members post-World War II, Dr T. Duckett Jones delivered a schema for the diagnosis of acute rheumatic fever in 1944. What famously became regarded as the “Jones criteria” codified an association between antecedent streptococcal pharyngeal infection and nonsuppurative sequelae, such as carditis, arthralgia, chorea, or rash. Although future iterations of the criteria Funding: None. Conflict of Interest: None. Authorship: All authors had access to the data and played a role in writing this manuscript. *Drs Upadhyay and Gainor contributed equally to the investigation. Requests for reprints should be addressed to Gaurav A. Upadhyay, MD, Massachusetts General Hospital, 55 Fruit St, Gray-Bigelow 109, Boston, MA 02114. E-mail address:
[email protected]
0002-9343/$ -see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2012.06.016
would add echocardiographic and laboratory parameters,1 the fundamental concept of rheumatic disease as a sequel to untreated group A streptococcus infection was established. Contemporaries of Jones, Gore and Saphir,2 conducted an autopsy study of 1402 patients in 1947 in whom they identified 12 cases of myocarditis in the setting of acute streptococcal tonsillitis that did not fit the Jones criteria. They described these cases as nonrheumatic because they occurred during or just days after a streptococcal infection, rather than the 2- to 3-week latency period classically observed with acute rheumatic fever. Since then, acute nonrheumatic streptococcal myocarditis has been identified by a handful of authors as a clinically distinct entity, with different symptoms, time course, and pathophysiology from acute rheumatic fever.3-9 This entity remains infrequently
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reported and is likely under-recognized in clinical practice. We summarize a series of 9 patients.
the revised Jones criteria for acute rheumatic fever. Antistreptolysin O or anti-DNAse B titers were tested in 3 patients, and no significant elevations were noted. Electrocardiograms showed ST-segment elevations of varying disMATERIALS AND METHODS tributions, and cardiac biomarkers were elevated (Table We retrospectively reviewed all 2). Transthoracic echocardiogracases of acute nonrheumatic strepphy was performed in all patococcal myocarditis over a 17-year tients. The average left ventricuCLINICAL SIGNIFICANCE period (January 1994 to December lar ejection fraction was 56% ⫾ 2010). Patients were identified us7.7%, and wall motion abnor● Acute nonrheumatic streptococcal myoing a hospital-wide database conmalities were identified in 3 carditis is an under-recognized cause of taining admission, discharge, and patients. ST-segment elevations in young patients. associated diagnoses. Search terms Most patients (66%) underwent included any combination of tonsil● A history of sore throat preceding chest cardiac catheterization, with no litis, acute tonsillitis, infective tonpain should elicit further workup with culprit coronary lesions identified. sillitis, peritonsillitis, pharyngotoThree patients also underwent cartesting for group A or G streptococcus. nsillitis, suppurative tonsillitis, diac magnetic resonance (CMR) ● Acute nonrheumatic streptococcal myostreptococcal tonsillitis, streptococimaging with results consistent cal sore throat, group A streptococcarditis responds favorably to convenwith myocarditis according to the cal infection, or strep pharyngitis tional antibiotic therapy and has excelLake Louise criteria10 (Figure and chest pain, acute myocarditis, lent long-term clinical prognosis. 1A). All patients made a complete or acute pericarditis. clinical recovery after antibiotic ● Cardiac magnetic resonance imaging is therapy as reported in the limited useful in gauging myocarditis severity RESULTS follow-up (2 patients were lost and documenting resolution. within 3 months, and other paNine patients with acute nonrheutients have been followed 1-8 matic streptococcal myocarditis years). In 2 patients in whom folwere identified; 89% were male, low-up CMR imaging was performed, regression of edema and the average age was 28.6 years. No patients had a and abnormal delayed enhancement was confirmed (Figure history of cardiovascular disease or rheumatic fever. Key 1B). In patients in whom other follow-up imaging (eg, clinical characteristics are presented in Table 1 with a transthoracic echocardiography, treadmill-exercise testing) summary in Table 2. The majority of patients (78%) had was performed, no significant abnormalities were noted. No streptococcal pharyngitis confirmed via microbiologic testpatients required antibiotic prophylaxis for acute rheumatic ing at Massachusetts General Hospital; microbiologic assay fever, and no late sequelae of rheumatic heart disease were results were not available for review in 2 patients who were reported. transferred from outside centers. Two patients (22%) had throat cultures positive for group G streptococcus, whereas the remaining patients had group A streptococcus. DISCUSSION All 9 patients presented with a chief symptom of subWe present the largest single-center case series of acute nonsternal chest pain. The average latency period from pharrheumatic streptococcal myocarditis in the United States. yngitis to onset of chest pain was 3.1 days. No patients met Table 1
Clinical Characteristics of Individual Patients
Age, y
Sex
Throat Culture
Chest Pain
Latency*
ECG Distribution
Peak TnT
16 20 20 22 26 31 37 39 47
M M F M M M M M M
GGS NA GGS GAS GAS GAS (R) GAS (R) NA GAS
⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹
2 3 2 2 3 3 4 5 4
Anterolateral STE Diffuse STE Inferolateral STE Inferior STE Diffuse STE Inferior STE Lateral STE Lateral STE Inferolateral STE
1.06 3.58 1.67 2.01 1.13 2.90 NA† 1.58 4.46
ECG ⫽ electrocardiogram; GAS ⫽ group A streptococcus; GGS ⫽ group G streptococcus; NA ⫽ not available; R ⫽ rapid antigen testing; STE ⫽ ST-segment elevation; TnT ⫽ troponin T. *Latency: days from pharyngitis to onset of chest pain. †Troponin assay not yet commercially available at the time of this patient’s presentation.
1232 Table 2
The American Journal of Medicine, Vol 125, No 12, December 2012 Summary of Clinical Characteristics Across Patients No. (%)
Male gender Chest pain Antibiotics Beta-lactams Macrolides Met revised Jones criteria ST-elevations on ECG
8/9 9/9 9/9 7/9 2/9 0/9 9/9
(89%) (100%) (100%) (78%) (22%) (0%) (100%)
Average ⫾ SD Age (y) Latency period (d) Peak creatine kinase (U/L) Peak CK-MB (ng/mL) Peak TnT (ng/mL) Ejection fraction
28.7 ⫾ 10.5 3.1 ⫾ 1.1 934 ⫾ 238 82 ⫾ 35.3 2.3 ⫾ 1.2 56 ⫾ 7.7
CK-MB ⫽ creatine kinase MB; ECG ⫽ electrocardiogram; standard deviation; TnT ⫽ troponin T.
SD
⫽
Acute nonrheumatic streptococcal myocarditis mimics acute coronary syndrome on presentation and should be considered in the differential of young persons presenting with chest pain. Hallmark features include a history of pharyngitis, ST-segment elevations on electrocardiogram, and an average latency period of 3 days after throat symptoms. Previous reports have suggested the etiopathology to be exclusively due to group A streptococcus; however, we find that group G streptococcus also may lead to acute nonrheumatic streptococcal myocarditis. We find no association between this entity and later cardiomyopathy, although follow-up is limited. The underlying pathophysiologic basis remains unknown. Gore and Saphir2 originally observed a predominant cardiac mononuclear cellular response in acute nonrheumatic streptococcal myocarditis, without evidence of bacteria in situ. Parenchymal necrosis and density of inflammatory response in their study appeared reminiscent of diphtheria toxin-mediated destruction.2 Investigators later postulated that lymphatic channels between the tonsils and the heart might facilitate trafficking.9 The relatively short latency period between tonsillitis and myocarditis seen in our series is consistent with this theory, although we cannot exclude the possibility of secondary exposure and amnestic response. Viral infection might provoke myocarditis independently of concurrent streptococcal pharyngitis. When antigenic complementarity between coxsackievirus and streptococcus was studied, however, coinfection was usually substantially more severe and more likely to lead to future rheumatic heart disease.11 Our patients demonstrated a benign course with no known late sequelae (less indicative of coinfection), although the small size of our study population restricts conclusive assessment. In addition, 2 patients in our study exhibited infection with Lancefield group G streptococcus, as opposed to group
A streptococcus. Although considered commensal, group G streptococci exchange genetic material with group A organisms, occupy the same tissue niche, and cause a similar spectrum of illness.12 We report the first association of group G streptococcal pharyngitis and nonrheumatic myocarditis, raising the possibility of shared virulence factors as a mechanism for etiopathology. Group A and G streptococci are associated with significant disease burden. Acute pharyngitis accounted for 11.6 million US ambulatory care visits in 2007. Furthermore, because streptococcal pharyngitis is predominantly a childhood illness, chest pain symptoms may not be regularly elicited by providers. Of note, pericardial effusion and elevated cardiac biomarkers have been found in acute nonrheumatic streptococcal myocarditis in the absence of chest pain.5 The incidence of asymptomatic presentation may therefore be substantial and would not have been captured in this series. CMR imaging seems useful in confirming the diagnosis of myocarditis.6,10 In patients in whom CMR imaging revealed systolic dysfunction with areas of late gadolinium enhancement, beta-blockers (to suppress ventricular ectopy) and angiotensin-converting enzyme inhibitors (to mitigate adverse ventricular remodeling) were initially used. Follow-up CMR was useful to document resolution and taper ongoing medical therapy.
Study Limitations The results of this series should be interpreted in the context of our study design. Cases were identified through review of admission or discharge diagnoses, and patients may have been missed through omission in documentation. Furthermore, streptococcal assays are not conventionally ordered for patients with myocarditis, and diagnosis may have been missed. Finally, this is a single-center study with limited generalizability, and our results should primarily be considered hypothesis-generating at this time.
CONCLUSIONS Acute nonrheumatic streptococcal myocarditis should be considered in the differential diagnosis of young patients presenting with ST-segment elevations, chest pain, and a history of sore throat. Rapid antigen testing is sufficient for diagnosing streptococcal infection, and absence of antistreptolysin O and anti-DNAse B elevation confirms acuity. CMR imaging may be used to assess disease severity and document resolution. Of note, unlike many forms of viral myocarditis, acute nonrheumatic streptococcal myocarditis seems to respond favorably to conventional antibiotic therapy and has an excellent clinical prognosis. We have not found an association between acute nonrheumatic streptococcal myocarditis and future acute rheumatic fever or rheumatic heart disease, although our sample size is small and follow-up remains limited. Particularly given the global burden of group A and G streptococcal pharyngitis in adult and pediatric patients, further investigation regarding the symptom-
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Figure 1 Representative lesions seen using late gadolinium-enhanced (LGE) images. (A) Demonstrates abnormal patchy globular delayed enhancement extending along the subepicardial anterolateral and inferolateral left ventricular myocardium from base to mid ventricle. The areas of LGE enhancement shown here corresponded to regions of T2 hyperintensity and early abnormal enhancement, and also exhibited an increased early global myocardial gadolinium enhancement ratio between myocardium and skeletal muscle—together meeting all 3 of the Lake Louise criteria for diagnosis of myocarditis. (B) Near-complete resolution of late gadolinium enhancement with minimal residual, patchy mid-wall to subepicardial late gadolinium enhancement in the mid-anterolateral and mid-inferolateral segments, likely representing a small area of scar.
atic and asymptomatic incidence, underlying pathophysiologic mechanism, and long-term impact seems warranted.
References 1. Guidelines for the diagnosis of rheumatic fever. Jones Criteria, 1992 update. Special Writing Group of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young of the American Heart Association. JAMA. 1992;268:2069-2073. 2. Gore I, Saphir O. Myocarditis associated with acute nasopharyngitis and acute tonsillitis. Am Heart J. 1947;34:831-851. 3. Boruah P, Shetty S, Kumar SS. Acute streptococcal myocarditis presenting as acute ST-elevation myocardial infarction. J Invasive Cardiol. 2010;22:E189-191. 4. Talmon Y, Gilbey P, Fridman N, Wishniak A, Roguin N. Acute myopericarditis complicating acute tonsillitis: beware the young male patient with tonsillitis complaining of chest pain. Ann Otol Rhinol Laryngol. 2008;117:295-297. 5. Talmon Y, Ishai R, Samet A, Sturman A, Roguin N. Acute myopericarditis complicating acute tonsillitis: a prospective study. Ann Otol Rhinol Laryngol. 2009;118:556-558.
6. Mokabberi R, Shirani J, M AH, Go BD, Schiavone W. Streptococcal pharyngitis-associated myocarditis mimicking acute STEMI. JACC Cardiovasc Imaging. 2010;3:892-893. 7. Khavandi A, Whitaker J, Elkington A, Probert J, Walker PR. Acute streptococcal myopericarditis mimicking myocardial infarction. Am J Emerg Med. 2008;26:638 e631-632. 8. Putterman C, Caraco Y, Shalit M. Acute nonrheumatic perimyocarditis complicating streptococcal tonsillitis. Cardiology. 1991;78: 156-160. 9. Karjalainen J. Streptococcal tonsillitis and acute nonrheumatic myopericarditis. Chest. 1989;95:359-363. 10. Friedrich MG, Sechtem U, Schulz-Menger J, et al. Cardiovascular magnetic resonance in myocarditis: a JACC White Paper. J Am Coll Cardiol. 2009;53:1475-1487. 11. Root-Bernstein R, Vonck J, Podufaly A. Antigenic complementarity between coxsackie virus and streptococcus in the induction of rheumatic heart disease and autoimmune myocarditis. Autoimmunity. 2009; 42:1-16. 12. Sriprakash KS, Hartas J. Lateral genetic transfers between group A and G streptococci for M-like genes are ongoing. Microb Pathog. 1996; 20:275-285.
