Hrev_master [page 104] [Emergency Care Journal 2023; 19:11606] Emergency Care Journal 2023; volume 19:11606 Abstract Pharyngitis and tonsillitis are common reasons for seeking medical care. While mostly viral, Streptococcus pyogenes causes 5-20% of adult cases. Non-rheumatic streptococcal myocarditis is a distinct form of myocarditis associated with streptococcal infec- tion and has clinical features resembling acute coronary syndrome. It mainly affects young men and can lead to significant complica- tions, including sudden cardiac death. We present a case of a young man with non-rheumatic streptococcal myocarditis that developed three days after streptococcal pharyngitis. This is the first docu- mented case in which a treatment approach using a combination of benzathine phenoxymethylpenicillin, perindopril, and bisoprolol, followed by extended therapy with extencillin, resulted in a rapid improvement in the patient’s cardiac function and general health. The insights gained from this case offer valuable guidance for managing similar conditions in the future. Introduction Pharyngitis and tonsillitis are common reasons for seeking care from a general practitioner or at an emergency department. While mostly viral, Streptococcus pyogenes causes 5-20% of adult cases.1 Myocarditis is characterized by inflammation of the heart mus- cle and primarily occurs due to microbial-mediated or autoimmune damage to the heart. It predominantly affects young men and can lead to significant short-term and long-term complications, includ- ing sudden cardiac death or dilated cardiomyopathy.2,3 Other potential causes of this condition include bacteria, parasites, cer- tain medications, systemic diseases, and other factors.1-3 Non-rheumatic streptococcal myocarditis is a unique type of myocarditis associated with streptococcal tonsillitis/pharyngitis or joint abscess/arthritis. It follows a more rapid course and does not occur 2-4 weeks after a streptococcal infection, as seen in acute rheumatic fever.1,4-16 The exact underlying process by which non- rheumatic myocarditis develops after infection with Streptococcus pyogenes is still unclear. Potential factors contributing to its devel- opment include streptococcal toxins and cross-reactivity.1,7 In July 2023, a thorough search of the PubMed/MEDLINE and EMBASE databases using specific search terms (Streptococcus pyogenes, infection, myocarditis, clinical case) found 10 relevant clinical cases from the last five years.7,15 Table 1 gives an overview of these recent cases, all involving young males. Eight cases were linked to tonsillitis/pharyngitis,7-9,12-15 and two with joint abscess/arthritis.10,11 Three of them had severe fulminant myocardi- tis,7,10,11 while the remaining had milder severity. Two cases expe- rienced recurrent episodes.7,8 Most patients showed a favorable clinical response to treatment with antibiotics from the group of penicillin or third-generation cephalosporins, although combina- tions with clindamycin,10 azithromycin,15 and amoxicillin with clavulanic acid9 were also used. One patient with fulminant myocarditis succumbed to the disease,7 while the others had a favorable long-term outcome (Table 1). In this context, we present a case of non-rheumatic streptococ- cal myocarditis in a young man, which emerged three days after the onset of streptococcal pharyngitis. This is the first documented Correspondence: Matic Mihevc, Department of Family Medicine, Faculty of Medicine, University of Ljubljana, Slovenia E-mail: mihevc.matic@zd-tr.si Key words: myocarditis; streptococcus; pharyngitis; treatment; acute coronary syndrome. Conflict of interest: the authors declare no potential conflict of inter- est, and all authors confirm accuracy. Availability of data and material: all data supporting the findings of this study are available upon request from the corresponding author. Ethics approval and consent to participate: ethical approval was not required for this article as it does not involve any studies with human participants or animals. Informed consent was obtained from the patient involved in the case report. Consent for publication: written consent was obtained from the patient, granting permission to use their personal data, including any accompanying images. Acknowledgments: the author would like to acknowledge the valu- able assistance provided by Marko Medved, MD, and the Cardiology Department of General Hospital Novo Mesto in the preparation of this case report. Received: 23 July 2023. Accepted: 1 September 2023. Early view: 8 September 2023. This work is licensed under a Creative Commons Attribution 4.0 License (by-nc 4.0). ©Copyright: the Author(s), 2023 Licensee PAGEPress, Italy Emergency Care Journal 2023; 19:11606 doi:10.4081/ecj.2023.11606 Publisher's note: all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. When infection strikes the heart: identifying and treating non-rheumatic streptococcal myocarditis in a young man with chest pain and concurrent streptococcal pharyngitis Matic Mihevc Emergency Department, Primary Healthcare Centre Trebnje, Trebnje; Primary Healthcare Research and Development Institute, Community Health Centre Ljubljana; Department of Family Medicine, Faculty of Medicine, University of Ljubljana, Slovenia Non -co mmerc ial us e o nly case in which a treatment approach with a combination of benza- thine phenoxymethylpenicillin, perindopril, and bisoprolol, fol- lowed by one year of therapy with extencillin, resulted in a rapid improvement in the patient’s cardiac function and general health. Case Report A 33-year-old man sought medical attention at the primary health care center due to a two-day history of a sore throat and fever. He had a history of spondylarthritis but was not under cur- rent treatment. The Streptococcus pyogenes infection was con- firmed with the ALLTEST Strep-A rapid test. The patient was pre- scribed peroral benzathine phenoxymethylpenicillin at a dose of 1,500,000 I.U. every 8 hours for 10 days. During the night, the patient experienced chest tightness, which worsened with deep breaths or lying on the stomach. Fearing a possible penicillin allergy, he returned to the primary health care center. Clinical examination revealed signs of pharyn- gitis with no other clinical abnormalities. An electrocardiogram (ECG) showed a sinus rhythm along with non-specific ECG changes, namely elevated ST-segment in lead aVL, T-wave inver- sion in leads III and V1, and a flattened T-wave in lead aVF (Figure 1A). A point-of-care Troponin I test (Stratus® CS Acute Care™ cardiac Tnl) showed an elevated value of 12.05 ng/mL (reference value <0.06 ng/mL). Based on these findings, the patient was referred to a regional hospital for suspected myocarditis (Figure 1). After his referral to the regional hospital, comprehensive assessments were conducted. These revealed an elevated white blood cell count (14.2x109/L) and increased C-reactive protein lev- Case Report Table 1. Overview of the most recent non-rheumatic streptococcal myocarditis case reports in adults. Author, year Gender, Tonsilitis/ Clinical ECG signs Heart (reference) age pharyngitis presentation impairment Treatment Hiraiwa et al., 20227 Male, 42 Yes Sore throat, Precordial Fulminant myocarditis ECMO cardiogenic shock STE (LVEF <10%) Allen et al., 20228 Male, 23 Yes Fever, sore throat, First ECG normal, Myocarditis ASA, ceftriaxone, chest pain subsequent diffuse STE (LVEF 45%) vancomycin, benzathine penicillin, prednisone Kalpakos et al., 20219 Male, 27 Yes Sore throat, fever, Inferior, posterior, Inferior-lateral myocarditis Amoxicillin/ clavulanic hypotension, tachypnoea and lateral STE (LVEF 30%) acid, ACEi, NSAID Kalpakos et al., 20219 Male, 33 Yes Chest pain, nausea, Inferior and posterior Inferior-lateral Amoxicillin epigastric pain STE myocarditis Fox-Levis et al., 202010 Male, 21 No Fever, knee abscess, Inferior STE Fulminant myocarditis Benzylpenicillin, chest pain (LVEF 10-15%) clindamycin, ECMO Ferrero et al., 202011 Male, 35 No Fever, knee swelling, Inferior and lateral Fulminant myocarditis Ampicillin/ chest pain STE (LVEF 10-15%) sulbactam, adrenaline, ACEi Derbas et al., 201912 Male, 25 Yes Chest pain, dyspnoea, Anterior STE Anterior myocarditis NR sore throat, fever (LVEF 53%) Müller, 201913 Male, 31 Yes Fever, chest pain, NR Inferior-posterior NR sore throat myocarditis (LVEF 50%), mitral regurgitation O’Brien et al., 201814 Male, 17 Yes Chest pain, sore throat, Inferior and lateral Septal and apical myocarditis Amoxicillin, fever, dyspnoea STE (LVEF 49%) NSAID, lisinopril Silva et al., 201815 Male, 18 Yes Chest pain, relapse Lateral STE Inferolateral ASA, colchicine, in 2 weeks myopericarditis azithromycin, amoxicillin. STE, ST-segment elevation; ECMO, extracorporeal membrane oxygenation; ECG, electrocardiogram; NR, not reported; LVEF, left ventricular ejection fraction; NSAID, non-steroidal anti-inflammatory drugs; ASA, acetylsalicylic acid; ACEi, angiotensin converting enzyme inhibitor. Figure 1. Electrocardiogram at the onset of myocarditis (A) and after 6 weeks (B). [Emergency Care Journal 2023; 19:11606] [page 105] Non -co mmerc ial us e o nly els of 145.1 mg/L (reference value <5 mg/L). Notably, initial mea- surements of high-sensitive cardiac Troponin T (hs-cTnT) showed a remarkable increase of 982 ng/L (reference value <14 ng/L), while baseline measurement of N-terminal pro-brain natriuretic peptide (NT-proBNP) showed a slight increase of 495.1 ng/L (ref- erence value <450 ng/L). A point-of-care ultrasound examination revealed a normal-sized left ventricle with normal systolic and diastolic function. There was a 0.6 cm right pericardial gap and local pericardial effusion. The next day, ECG changes were recorded. There were ST- segment elevation in lateral ventricular leads and ST-segment depression in leads III and aVF. Coronary angiography was per- formed and showed normal coronary arteries. The patient was treated with bisoprolol 1.25 mg/12h and perindopril 2 mg per day and therapy with benzathine phenoxymethylpenicillin was contin- ued. The markers hs-cTnT and NT-proBNP continued to rise to 1988 ng/L (reference value <14 ng/L) and 711.1 ng/L (reference value <450 ng/L), respectively. On the third day, the patient underwent cardiac magnetic reso- nance imaging (MRI), which showed extensive myocarditis affect- ing the lateral and inferior walls, with preserved left ventricular ejection fraction (LVEF) of 57% and right ventricular ejection fraction (RVEF) of 51% (Figure 2). On day five, both haemocultures and serological tests were negative for cardiotropic viruses, while the patient tested positive for anti-DNAase B antibodies. Remarkably, the patient was no longer experiencing chest pain and had resolved respiratory issues. The levels of hs-cTnT and NT-proBNP decreased to 193 ng/L (ref- erence value <14 ng/L) and 192.1 ng/L (reference value <450 ng/L), respectively. As a result, the patient was discharged home. During the first month of recovery at home, episodes of sinus tachycardia occurred occasionally and eventually subsided. To pre- vent a recurrence, the patient received monthly injections of exten- cillin at a dosage of 2,400,00 I.U. for one year. In addition, the patient continued oral therapy to prevent cardiac remodeling, tak- ing bisoprolol 1.25 mg in the morning and perindopril 2 mg in the evening. Given the severity of the myocarditis, the patient was advised to rest and avoid significant stress for the next six months. Six weeks after myocarditis onset, a follow-up ECG revealed persistent ECG changes. There was ST-segment elevation in lead aVL and ST-segment depression along with biphasic T-waves in leads III and aVF (Figure 1B). After five months, a follow-up car- diac MRI was performed, revealing normalization of cardiac func- tion (RVEF 54%, LVEF 60%) and moderate postmyocardial changes in the lateral wall. After six months, the patient was able to resume work, indicating a successful recovery. Discussion This case report outlines the successful management of a young man with non-rheumatic streptococcal myocarditis and con- current streptococcal pharyngitis, which improved rapidly follow- ing a therapeutic regimen involving benzathine phe- noxymethylpenicillin, bisoprolol, and perindopril. Prior case reports have underscored the heterogeneous clinical presentations of non-rheumatic streptococcal myocarditis, encom- passing symptoms such as chest pain, fever, dyspnoea, dizziness, syncope, nausea, and even signs indicative of cardiac shock. Additionally, signs of the primary infection source, such as sore throat or joint pain, may also be present.7-15 In this context, the patient had the classic triad of symptoms, including fever, sore throat, and chest pain, which is consistent with recent case reports in which the primary source of infection was tonsillitis or pharyn- gitis.7-9,12-15 While male gender, family history of heart disease, and preceding episodes of non-rheumatic streptococcal myocarditis have emerged as risk factors,7-15 it is noteworthy that instances involving female patients have also been documented.17 In the pre- sent case, the patient had underlying spondylarthritis, which is known to increase the risk of cardiovascular comorbidity (18). This suggests that chronic autoimmune diseases may serve as addi- tional risk factors due to their involvement in the immune response and tissue cross-reactivity.7,18 In terms of clinical and diagnostic findings, most patients exhibited ECG changes such as ST-segment elevations, T-wave inversions, and biphasic T-waves along with elevated cardiac markers, especially Troponin I and Creatine Kinase-MB, whereas no hs-cTnT has been reported so far.7-15 However, there were also cases where the initial ECG appeared non-specific, but subsequent ECGs showed changes.8 This pattern was also observed in our patient, underscoring the risk that the disease may be missed if only the initial ECG is considered. Furthermore, we identified per- sistent ECG changes even in the post-myocarditis phase, thus emphasizing the enduring impact of myocarditis on cardiac electri- cal activity, possibly attributable to structural changes or irregular- ities in cardiac motion.2,3 Transthoracic echocardiography showed regional wall motion abnormalities in about 25% of patients, pericardial effusion in <10%, and mitral regurgitation with an accessory mass in one case.1,7-15 The LVEF varied, with some patients having preserved LVEF,12,13 mildly reduced LVEF,8,14 or reduced LVEF.7,9-11 In our case, we found minor pericardial effusion with preserved LVEF. The therapeutic approach to myocarditis hinges upon several factors, encompassing the acuteness, severity, clinical manifesta- tion, and underlying causative factors.2,3 Supportive care remains a cornerstone, while guidelines for heart failure management are applicable when dealing with cases featuring reduced LVEF.2 The utilization of β-blockers or angiotensin-converting enzyme inhibitors to mitigate inflammation, counteract adverse remodel- Case Report Figure 2. Cardiac magnetic resonance imaging on the third day showing extensive myocarditis involving the lateral and inferior walls. [page 106] [Emergency Care Journal 2023; 19:11606] Non -co mmerc ial us e o nly ing, and potentially limit scar formation remains an area of ongo- ing debate, particularly in scenarios where LVEF is preserved.2 Notably, both these classes of drugs have demonstrated efficacy in animal models of myocarditis, addressing both necrotic and fibrot- ic aspects.19 While some authors have reported the utilization of non-steroidal anti-inflammatory drugs,8,9,14,15 their application in myocarditis is discouraged due to their potential interference with the production of anti-inflammatory prostaglandins, which could hinder the cardiac healing process. In instances of severe myocarditis, interventions such as inotropic support, mechanical circulatory support, or cardiac transplantation might be needed.2,3 The specific therapeutic strategies for myocarditis are tailored to the underlying etiology. For non-rheumatic streptococcal myocarditis, antibiotics from the penicillin group, such as benza- thine penicillin,8 benzylpenicillin,10 ampicillin,11 and amoxi- cillin,9,14,15 have exhibited favorable outcomes in various clinical cases. These treatment approaches align with the guidelines set for managing streptococcal pharyngitis established by CDC/AAFP/ACP-ASIM.20 However, the optimal duration of antibiotic therapy remains a subject of discourse, driven by the potential risk of myocarditis recurrence, necessitating further com- prehensive investigation. In contrast, current guidelines for patients with rheumatic fever with carditis but no residual heart disease recommend 10-year prophylaxis with benzylpenicillin after the last attack.16 In the present case, a prolonged one-year course with extencillin was selected, and no recurrence transpired within the one-year follow-up period. Conclusions Non-rheumatic streptococcal myocarditis is a serious compli- cation arising from streptococcal infection, displaying clinical and diagnostic features like acute coronary syndrome. The condition manifests with various symptoms, including instances of sudden and severe heart failure. The long-term forecast is favorable, with complete restoration of heart function and overall well-being. To avoid cardiac remodeling, it is advised that individuals refrain from participating in competitive sports or engaging in strenuous exercise for a period of 3-6 months following diagnosis. Additionally, a minimum of 12-month regimen with extencillin may be considered to prevent the recurrence of the disease. References 1. Schmutzler L, Mirna M, Hoppe UC, Lichtenauer M. From streptococcal pharyngitis/tonsillitis to myocarditis: a systemat- ic review. J Cardiovasc Dev Dis 2022;9:170. 2. Tschöpe C, Ammirati E, Bozkurt B, et al. Myocarditis and inflammatory cardiomyopathy: current evidence and future directions. Nat Rev Cardiol 2021;18:169-93. 3. Lampejo T, Durkin SM, Bhatt N, Guttmann O. Acute myocarditis: aetiology, diagnosis and management. Clin Med (Lond) 2021;21:505-10. 4. Zühlke LJ, Beaton A, Engel ME, et al. Group A streptococcus, acute rheumatic fever and rheumatic heart disease: epidemiol- ogy and clinical considerations. Curr Treat Options Cardiovasc Med 2017;19:15. 5. Talmon Y, Gilbey P, Fridman N, et al. Acute myopericarditis complicating acute tonsillitis: beware the young male patient with tonsillitis complaining of chest pain. Ann Otol Rhinol Laryngol 2008;117:295-7. 6. Aguirre JL, Jurado M, Porres-Aguilar M, et al. Acute non- rheumatic streptococcal myocarditis resembling ST-elevation acute myocardial infarction in a young patient. Proc (Bayl Univ Med Cent) 2015;28:188-90. 7. Hiraiwa H, Morimoto R, Ando R, et al. Recurrent fulminant non-rheumatic streptococcal myocarditis proven by endomy- ocardial biopsy and autopsy. J Cardiol Cases 2022;26:62-5. 8. Allen J, Munoz C, Byakova A, Pachulski R. Acute fulminant group A beta-hemolytic streptococcus-associated carditis: a case report and literature review. Cureus 2022;14:e27282. 9. Kalpakos T, Wilgenhof A, Michiels V, et al. Streptococcal pharyngitis associated myocarditis (SPAM): the perfect ST- segment elevation myocardial infarction (STEMI) mimic in young individuals. A case series. Acta Cardiol 2021;76:449-54. 10. Fox-Lewis A, Merz TM, Hennessy I. Severe non-rheumatic streptococcal myocarditis requiring extracorporeal membrane oxygenation support. Lancet Infect Dis 2020;20:1481. 11. Ferrero P, Piazza I, Lorini LF, Senni M. Epidemiologic and clinical profiles of bacterial myocarditis. Report of two cases and data from a pooled analysis. Indian Heart J 2020;72:82-92. 12. Derbas LA, Samanta A, Potla S, et al. Separating acute rheumatic fever from nonrheumatic streptococcal myocarditis. Case Rep Med 2019:4674875. 13. Müller C. 31-year old male with fever, chest pain and tonsilli- tis. Dtsch Med Wochenschr 2019;144:201-2. 14. O’Brien CE, Coulson JD, Sekar P, et al. Non-rheumatic strep- tococcal myocarditis mimicking acute myocardial infarction in an adolescent male. Cardiol Young 2018;28:454-7. 15. Silva R, Puga L, Teixeira R, et al. Acute non-rheumatic myopericarditis: a rare complication of pharyngitis. Eur J Case Rep Intern Med 2018;5:000987. 16. Al-Jazairi A, Al-Jaser R, Al-Halees Z, et al. Guidelines for the secondary prevention of rheumatic heart disease: endorsed by Saudi Pediatric Infectious Diseases Society (SPIDS). Int J Pediatr Adolesc Med 2017;4:47-50. 17. Talmon Y, Ishai R, Samet A, et al. Acute myopericarditis com- plicating acute tonsillitis: a prospective study. Ann Otol Rhinol Laryngol 2009;118:556-8. 18. Liew JW, Ramiro S, Gensler LS. Cardiovascular morbidity and mortality in ankylosing spondylitis and psoriatic arthritis. Best Pract Res Clin Rheumatol 2018;32:369-89. 19. Silverblatt JA, Ziff OJ, Dancy L, et al. Therapies to limit myocardial injury in animal models of myocarditis: a system- atic review and meta-analysis. Basic Res Cardiol 2019;114:48. 20. Mustafa Z, Ghaffari M. Diagnostic methods, clinical guide- lines, and antibiotic treatment for group A streptococcal pharyngitis: a narrative review. Front Cell Infect Microbiol 2020;10:563627. Case Report [Emergency Care Journal 2023; 19:11606] [page 107] Non -co mmerc ial us e o nly