Report of a Myocarditis Outbreak among Pediatric Patients: Human Herpesvirus 7 as a Causative Agent?

Report of a Myocarditis Outbreak among Pediatric Patients: Human Herpesvirus 7 as a Causative Agent? Abstract Background The etiology of myocarditis in children has not yet been completely elucidated. Objective Medical records of eight pediatric patients diagnosed with acute myocarditis within a 41-day period in a small-town hospital were retrospectively analyzed. Methods We examined antibody titers of adenovirus, Epstein–Barr virus, herpes simplex virus, respiratory syncytial virus, varicella-zoster virus and cytomegalovirus in peripheral blood. We used polymerase chain reaction (PCR) amplification to detect genetic sequences from Human herpesvirus (HHV) 7, HHV 6, enterovirus, measles or parvovirus in peripheral blood. Results The causative agent was HHV 7 in four patients. HHV 7 sequences were detected through PCR in one patient with rapid deterioration. Of four patients with HHV 7, two presented with dilated cardiomyopathy. Conclusion To our knowledge, this is the first report to suggest HHV 7 as a causative agent for acute myocarditis. We believe HHV 7 should be considered as a possible etiologic pathogen for patients with suspected myocarditis. Human herpesvirus 7, outbreak, myocarditis INTRODUCTION Acute myocarditis is an inflammatory disease of the myocardium resulting from various infectious and noninfectious causes, including autoimmune diseases, hypersensitivity reactions, drugs and toxic substances [1–3]. The most common infectious agents that cause acute myocarditis are enteroviruses. Parvovirus B19, adenovirus, cytomegalovirus and Human herpesvirus (HHV) 6 have also been identified as causative agents in patients with myocarditis [3, 4]. Diagnostic techniques include a detailed history, careful physical examination, electrocardiography, chest radiograph, blood tests, noninvasive imaging techniques and endomyocardial biopsy in selected patients [3]. Etiologic agents can be identified through serologic studies, polymerase chain reaction (PCR) analyses and viral cultures of both peripheral blood and myocardial biopsy specimens. Most cases of myocarditis without an identified cause observed in clinical practice are believed to result from undetectable viral infections [3–5]. HHV 7, a member of the family Herpesviridae, has antigenic properties similar to HHV 6 but has never been identified as a causative agent in patients with myocarditis [6]. In this report, we suggest HHV 7 for the first time as the cause of a fatal myocarditis outbreak in pediatric patients. PATIENTS AND METHODS We retrospectively analyzed the cases of eight pediatric patients diagnosed with acute myocarditis within a 41-day period (6 May 6–15 June 2016) in a small-town hospital. Myocarditis was diagnosed based on findings derived from anamnesis, physical examination, cardiac biomarkers (creatinine kinase-MB and troponin I) and electrocardiographic and echocardiographic evaluations. The diagnosis of myocarditis was assumed in patients who presented with a recent history of viral illness, chest pain, palpitation or dyspnea when blood analysis revealed high levels of cardiac biomarkers (both CK-MB and troponin I) and further studies including electrocardiographic and echocardiographic examinations could not suggest another cause for myocardial injury. Patients with any history, sign or symptom of autoimmune diseases, hypersensitivity, high catecholamine states, drug use or exposure to toxic substances were not included in this analysis. To identify the etiologic agent, we examined antibody titers of adenovirus, Epstein–Barr virus, herpes simplex virus, respiratory syncytial virus, varicella-zoster virus and cytomegalovirus in peripheral blood. We also used PCR amplification to detect genetic sequences from HHV 7, HHV 6, enterovirus, measles or parvovirus in peripheral blood. Detection by real-time PCR A multiplex real-time RT-PCR was performed using the Fast Track Diagnostics Fever and Rash Kit (Fast Track Diagnostics, Luxembourg) on ABI® 7500 Instrument (Applied Biosystems, Courtaboeuf, France) according to the manufacturer’s instructions. The assay includes primers/probes for HHV 7 (PCR target: Capsid triplex protein gene), HHV 6 (PCR target: U65/U66 fusion genes), enterovirus (PCR target: 5’ UTR, parts of domain IV and V), measles (PCR target: hemagglutinin protein gene) and parvovirus B19 (PCR target: VP2 gene), a positive control, a negative control, buffer and enzyme mix and uses Streptococcus equi as an extraction control—the internal control—which is introduced by the laboratory into each sample and also the negative control at the lysis buffer stage of the extraction process. The viral RNA is transcribed into complementary DNA using a specific primer-mediated reverse transcription step followed by PCR in the same tube. The presence of specific viral sequences is detected by an increase in fluorescence observed from the relevant dual-labeled probe. Samples with positive results for enterovirus were analyzed through an additional real-time PCR assay for detection of echovirus, coxsachievirus type A and B. RESULTS Median age and weight of the patients were 15 years (10 months–17 years) and 61 kg (8–75 kg). Presenting symptoms were chest pain in three patients, dyspnea in three, palpitation in one and epigastric pain in one. Antibody titers for adenovirus, Epstein–Barr virus, herpes simplex virus, respiratory syncytial virus, varicella-zoster virus and cytomegalovirus all failed to suggest a causative agent. The causative agent was found to be HHV 7 in four patients. Coxsackievirus B and parvovirus B19 were detected in two patients and one patient, respectively, and etiology could not be clarified in the remaining patients. Electrocardiography was normal in three patients but revealed diffuse ST elevation in four patients and diffuse PQ segment depression in one patient. In one patient, ST segment elevation progressed into ST segment depression after the first week before gradually returning to isoelectric line at the end of the second week of disease. Echocardiography revealed severe mitral regurgitation in three patients, pericardial effusion in three patients and pericardial hyperechogenicity in one patient (Table 1). Table 1. Clinical characteristics and follow-up data of patients Patients Age Sex Weight (kg) İnitial symptom Causative agent ECG Echocardiography EF at presentation Status Last EF (%) Case 1 15 years M 57 Chest pain HHV–7 Diffuse ST elevation Severe mitral and tricuspid regurgitation 14 Awaiting transplantation 22 Case 2 15 years M 68 Epigastric pain Coxsackie B N Pericardial effusion 62 Healed completely 66 Case 3 16 years M 74 Chest pain Coxsackie B N N 66 Healed completely 65 Case 4 14 months M 12 Dyspnea Parvovirus B19 Diffuse ST elevation Severe mitral regurgitation 26 Deceased – Case 5 10 months F 8 Dyspnea HHV-7 N Pericardial effusion 60 Healed completely 62 Case 6 2 years F 9 Dyspnea HHV-7 Diffuse ST elevation Pericardial effusion 66 Healed completely 66 Case 7 17 years M 64 Chest pain Unidentified PQ segment depression Pericardial hyperechogenity 65 Healed completely 65 Case 8 16 years M 75 Palpitation HHV–7 Diffuse ST elevation Severe mitral regurgitation 20 Asist device implantation 26 Patients Age Sex Weight (kg) İnitial symptom Causative agent ECG Echocardiography EF at presentation Status Last EF (%) Case 1 15 years M 57 Chest pain HHV–7 Diffuse ST elevation Severe mitral and tricuspid regurgitation 14 Awaiting transplantation 22 Case 2 15 years M 68 Epigastric pain Coxsackie B N Pericardial effusion 62 Healed completely 66 Case 3 16 years M 74 Chest pain Coxsackie B N N 66 Healed completely 65 Case 4 14 months M 12 Dyspnea Parvovirus B19 Diffuse ST elevation Severe mitral regurgitation 26 Deceased – Case 5 10 months F 8 Dyspnea HHV-7 N Pericardial effusion 60 Healed completely 62 Case 6 2 years F 9 Dyspnea HHV-7 Diffuse ST elevation Pericardial effusion 66 Healed completely 66 Case 7 17 years M 64 Chest pain Unidentified PQ segment depression Pericardial hyperechogenity 65 Healed completely 65 Case 8 16 years M 75 Palpitation HHV–7 Diffuse ST elevation Severe mitral regurgitation 20 Asist device implantation 26 N: normal, HHV: human herpesvirus. Table 1. Clinical characteristics and follow-up data of patients Patients Age Sex Weight (kg) İnitial symptom Causative agent ECG Echocardiography EF at presentation Status Last EF (%) Case 1 15 years M 57 Chest pain HHV–7 Diffuse ST elevation Severe mitral and tricuspid regurgitation 14 Awaiting transplantation 22 Case 2 15 years M 68 Epigastric pain Coxsackie B N Pericardial effusion 62 Healed completely 66 Case 3 16 years M 74 Chest pain Coxsackie B N N 66 Healed completely 65 Case 4 14 months M 12 Dyspnea Parvovirus B19 Diffuse ST elevation Severe mitral regurgitation 26 Deceased – Case 5 10 months F 8 Dyspnea HHV-7 N Pericardial effusion 60 Healed completely 62 Case 6 2 years F 9 Dyspnea HHV-7 Diffuse ST elevation Pericardial effusion 66 Healed completely 66 Case 7 17 years M 64 Chest pain Unidentified PQ segment depression Pericardial hyperechogenity 65 Healed completely 65 Case 8 16 years M 75 Palpitation HHV–7 Diffuse ST elevation Severe mitral regurgitation 20 Asist device implantation 26 Patients Age Sex Weight (kg) İnitial symptom Causative agent ECG Echocardiography EF at presentation Status Last EF (%) Case 1 15 years M 57 Chest pain HHV–7 Diffuse ST elevation Severe mitral and tricuspid regurgitation 14 Awaiting transplantation 22 Case 2 15 years M 68 Epigastric pain Coxsackie B N Pericardial effusion 62 Healed completely 66 Case 3 16 years M 74 Chest pain Coxsackie B N N 66 Healed completely 65 Case 4 14 months M 12 Dyspnea Parvovirus B19 Diffuse ST elevation Severe mitral regurgitation 26 Deceased – Case 5 10 months F 8 Dyspnea HHV-7 N Pericardial effusion 60 Healed completely 62 Case 6 2 years F 9 Dyspnea HHV-7 Diffuse ST elevation Pericardial effusion 66 Healed completely 66 Case 7 17 years M 64 Chest pain Unidentified PQ segment depression Pericardial hyperechogenity 65 Healed completely 65 Case 8 16 years M 75 Palpitation HHV–7 Diffuse ST elevation Severe mitral regurgitation 20 Asist device implantation 26 N: normal, HHV: human herpesvirus. Three patients presented with dilated cardiomyopathy (Cases 1, 4 and 8); of these, one died of sudden cardiac arrest within 6 h of hospital admission (Case 4), one required assist device implantation and one patient is on waiting list for heart transplantation with an ejection fraction of 22%. An autopsy could not be performed in the deceased patient owing to parental refusal. HHV 7 sequences were detected through PCR in the patient with rapid deterioration. The remaining five patients have been released for follow-up in a favorable hemodynamic condition without any medication. Of four patients diagnosed with HHV 7, two presented with dilated cardiomyopathy (Cases 1 and 8). DISCUSSION HHV 7 is a relatively new herpesvirus that was first isolated from CD4 T lymphocytes in 1990 by Frenkel et al. [7]. HHV 7 particles are shed from saliva and cause widespread infection in the pediatric population. The virus has been identified as a causal agent for exanthema subitum, coryza, acute infantile hemiplegia and hepatitis in children [7–10]. To our knowledge, HHV 7 has not yet been suggested as a cause of myocarditis. The diagnosis of myocarditis requires a thorough evaluation of clinical and laboratory findings that may include detailed anamnesis, physical examination, blood tests, chest radiograph, electrocardiography, echocardiography, cardiac magnetic resonance imaging (MRI), nuclear imaging and, in selected patients, endomyocardial biopsy [3, 5]. The use of nuclear imaging techniques in patients with myocarditis is restricted owing to low sensitivity, limited availability and the risks of radiation exposure [3]. Scintigraphy has not been used as a diagnostic tool in pediatric patients with myocarditis. Cardiac MRI has emerged as an important diagnostic tool, enabling evaluation of tissue characteristics and ventricular functions and identifying myocarditis with excellent sensitivity and high specificity [3, 11, 12]. However, cardiac MRI was not a diagnostic option for the patients in our study because our facility has no MRI unit. Although endomyocardial biopsy remains the gold standard for diagnosis of myocarditis and enables etiologic investigations through PCR and cultures in children, its use is also limited owing to high interobserver variability in pathologic examinations and the risk of procedural complications, including a non-negligible risk of cardiac perforation [5]. We did not perform endomyocardial biopsies on any of our patients. Instead, the diagnosis of myocarditis was assumed in patients with recent flu-like symptoms, chest pain, palpitation or dyspnea when high levels of CK-MB and troponin I were detected and no other cause of myocardial injury was suggested by electrocardiographic or echocardiographic examinations, physical examination or patient history. Viruses are the most common cause of myocarditis in developed countries. Historically, adenovirus and enteroviruses have been the most commonly identified pathogens causing myocarditis. Relatively new molecular techniques performed on cardiac biopsy specimens, such as PCR and in situ hybridization, have enabled the identification of new agents, such as parvovirus B19 and HHV 6. Viral cultures and identification of viral sequences through PCR using endomyocardial biopsy specimens are the most reliable methods to identify the cause of acute myocarditis [1–5]. Traditional serologic studies, PCR analysis of blood and peripheral viral cultures have also been used to identify the possible agents causing myocarditis. Despite the low sensitivity and specificity of these techniques and the lack of evidence of a direct relationship between the virus and myocardial inflammation, they can be helpful to detect the etiologic agent, especially in pediatric patients, when endomyocardial biopsy cannot be performed [3–5, 13]. Using PCR performed on peripheral blood, we detected HHV 7 genetic material in four patients (50%) in our study. LIMITATIONS As stated, we did not perform endomyocardial biopsy in any of our patients owing to the risks related to the procedure. Thus, we failed to prove a direct relationship between HHV 7 and myocardial injury. In addition, we were unable to obtain samples from pericardial effusions in our patients owing to insufficient fluid in the pericardial space. CONCLUSION Despite the fact that viral serologic testing and PCR assays of blood are insufficient to prove a direct relationship between a virus and myocardial inflammation, PCR may identify virus sequences in the blood of patients with myocarditis. To our knowledge, this is the first report to suggest HHV 7 as a causative agent for acute myocarditis. We believe HHV 7 should be considered as a possible etiologic pathogen for patients with suspected myocarditis. Funding The study was approved by the institutional review board for clinical research. No funding was received. References 1 Huhn GD , Gross C , Schnurr D , et al. Myocarditis outbreak among adults, illinois, 2003 . Emerg Infect Dis 2005 ; 11 : 1621 – 4 . http://dx.doi.org/10.3201/eid1110.041152 Google Scholar CrossRef Search ADS PubMed 2 Valdés O , Acosta B , Piñón A , et al. First report on fatal myocarditis associated with adenovirus infection in Cuba . J Med Virol 2008 ; 80 : 1756 – 61 . Google Scholar CrossRef Search ADS PubMed 3 Dennert R , Crijns HJ , Heymans S. Acute viral myocarditis . Eur Heart J 2008 ; 29 : 2073 – 82 . http://dx.doi.org/10.1093/eurheartj/ehn296 Google Scholar CrossRef Search ADS PubMed 4 Sinagra G , Anzini M , Pereira NL , et al. Myocarditis in clinical practice . Mayo Clin Proc 2016 ; 91 : 1256 – 66 . http://dx.doi.org/10.1016/j.mayocp.2016.05.013 Google Scholar CrossRef Search ADS PubMed 5 Singh RK , Yeh JC , Price JF. Diagnosis and treatment strategies for children with myocarditis . Prog Pediatr Cardiol 2016 ; 43 : 23 – 30 . http://dx.doi.org/10.1016/j.ppedcard.2016.08.022 Google Scholar CrossRef Search ADS 6 Hall CB , Caserta MT , Schnabel KC , et al. Characteristics and acquisition of Human herpesvirus (HHV)–7 infections in relation to infection with HHV-6 . J Infect Dis 2006 ; 193 : 1063 – 9 . http://dx.doi.org/10.1086/503434 Google Scholar CrossRef Search ADS PubMed 7 Frenkel N , Schirmer E , Wyatt L , et al. Isolation of a new herpesvirus from human CD4+ T cells . Proc Natl Acad Sci USA 1990 ; 87 : 748 – 52 . Google Scholar CrossRef Search ADS PubMed 8 Torigoe S , Kumamoto T , Koide W , et al. Clinical manifestations associated with Human herpesvirus 7 infection . Arch Dis Child 1995 ; 72 : 518 – 19 . http://dx.doi.org/10.1136/adc.72.6.518 Google Scholar CrossRef Search ADS PubMed 9 Torigoe S , Koide W , Yamada M , et al. Human herpesvirus 7 infection associated with central nervous system manifestations . J Pediatr 1996 ; 129 : 301 – 5 . http://dx.doi.org/10.1016/S0022-3476(96)70259-7 Google Scholar CrossRef Search ADS PubMed 10 Hashida T , Komura E , Yoshida M , et al. Hepatitis in association with Human herpesvirus-7 infection . Pediatrics 1995 ; 96 : 783 – 5 . Google Scholar PubMed 11 Abdel-Aty H , Boye P , Zagrosek A , et al. Diagnostic performance of cardiovascular magnetic resonance in patients with suspected acute myocarditis: comparison of different approaches . J Am Coll Cardiol 2005 ; 45 : 1815 – 22 . http://dx.doi.org/10.1016/j.jacc.2004.11.069 Google Scholar CrossRef Search ADS PubMed 12 Friedrich MG , Sechtem U , Schulz-Menger J , et al. International consensus group on cardiovascular magnetic resonance in myocarditis. Cardiovascular magnetic resonance in myocarditis: a JACC white paper . J Am Coll Cardiol 2009 ; 53 : 1475 – 87 . http://dx.doi.org/10.1016/j.jacc.2009.02.007 Google Scholar CrossRef Search ADS PubMed 13 Baughman KL. Diagnosis of myocarditis: death of Dallas criteria . Circulation 2009 ; 113 : 593 – 5 . http://dx.doi.org/10.1161/CIRCULATIONAHA.105.589663 Google Scholar CrossRef Search ADS © The Author [2017]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Tropical Pediatrics Oxford University Press

Report of a Myocarditis Outbreak among Pediatric Patients: Human Herpesvirus 7 as a Causative Agent?

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Abstract

Abstract Background The etiology of myocarditis in children has not yet been completely elucidated. Objective Medical records of eight pediatric patients diagnosed with acute myocarditis within a 41-day period in a small-town hospital were retrospectively analyzed. Methods We examined antibody titers of adenovirus, Epstein–Barr virus, herpes simplex virus, respiratory syncytial virus, varicella-zoster virus and cytomegalovirus in peripheral blood. We used polymerase chain reaction (PCR) amplification to detect genetic sequences from Human herpesvirus (HHV) 7, HHV 6, enterovirus, measles or parvovirus in peripheral blood. Results The causative agent was HHV 7 in four patients. HHV 7 sequences were detected through PCR in one patient with rapid deterioration. Of four patients with HHV 7, two presented with dilated cardiomyopathy. Conclusion To our knowledge, this is the first report to suggest HHV 7 as a causative agent for acute myocarditis. We believe HHV 7 should be considered as a possible etiologic pathogen for patients with suspected myocarditis. Human herpesvirus 7, outbreak, myocarditis INTRODUCTION Acute myocarditis is an inflammatory disease of the myocardium resulting from various infectious and noninfectious causes, including autoimmune diseases, hypersensitivity reactions, drugs and toxic substances [1–3]. The most common infectious agents that cause acute myocarditis are enteroviruses. Parvovirus B19, adenovirus, cytomegalovirus and Human herpesvirus (HHV) 6 have also been identified as causative agents in patients with myocarditis [3, 4]. Diagnostic techniques include a detailed history, careful physical examination, electrocardiography, chest radiograph, blood tests, noninvasive imaging techniques and endomyocardial biopsy in selected patients [3]. Etiologic agents can be identified through serologic studies, polymerase chain reaction (PCR) analyses and viral cultures of both peripheral blood and myocardial biopsy specimens. Most cases of myocarditis without an identified cause observed in clinical practice are believed to result from undetectable viral infections [3–5]. HHV 7, a member of the family Herpesviridae, has antigenic properties similar to HHV 6 but has never been identified as a causative agent in patients with myocarditis [6]. In this report, we suggest HHV 7 for the first time as the cause of a fatal myocarditis outbreak in pediatric patients. PATIENTS AND METHODS We retrospectively analyzed the cases of eight pediatric patients diagnosed with acute myocarditis within a 41-day period (6 May 6–15 June 2016) in a small-town hospital. Myocarditis was diagnosed based on findings derived from anamnesis, physical examination, cardiac biomarkers (creatinine kinase-MB and troponin I) and electrocardiographic and echocardiographic evaluations. The diagnosis of myocarditis was assumed in patients who presented with a recent history of viral illness, chest pain, palpitation or dyspnea when blood analysis revealed high levels of cardiac biomarkers (both CK-MB and troponin I) and further studies including electrocardiographic and echocardiographic examinations could not suggest another cause for myocardial injury. Patients with any history, sign or symptom of autoimmune diseases, hypersensitivity, high catecholamine states, drug use or exposure to toxic substances were not included in this analysis. To identify the etiologic agent, we examined antibody titers of adenovirus, Epstein–Barr virus, herpes simplex virus, respiratory syncytial virus, varicella-zoster virus and cytomegalovirus in peripheral blood. We also used PCR amplification to detect genetic sequences from HHV 7, HHV 6, enterovirus, measles or parvovirus in peripheral blood. Detection by real-time PCR A multiplex real-time RT-PCR was performed using the Fast Track Diagnostics Fever and Rash Kit (Fast Track Diagnostics, Luxembourg) on ABI® 7500 Instrument (Applied Biosystems, Courtaboeuf, France) according to the manufacturer’s instructions. The assay includes primers/probes for HHV 7 (PCR target: Capsid triplex protein gene), HHV 6 (PCR target: U65/U66 fusion genes), enterovirus (PCR target: 5’ UTR, parts of domain IV and V), measles (PCR target: hemagglutinin protein gene) and parvovirus B19 (PCR target: VP2 gene), a positive control, a negative control, buffer and enzyme mix and uses Streptococcus equi as an extraction control—the internal control—which is introduced by the laboratory into each sample and also the negative control at the lysis buffer stage of the extraction process. The viral RNA is transcribed into complementary DNA using a specific primer-mediated reverse transcription step followed by PCR in the same tube. The presence of specific viral sequences is detected by an increase in fluorescence observed from the relevant dual-labeled probe. Samples with positive results for enterovirus were analyzed through an additional real-time PCR assay for detection of echovirus, coxsachievirus type A and B. RESULTS Median age and weight of the patients were 15 years (10 months–17 years) and 61 kg (8–75 kg). Presenting symptoms were chest pain in three patients, dyspnea in three, palpitation in one and epigastric pain in one. Antibody titers for adenovirus, Epstein–Barr virus, herpes simplex virus, respiratory syncytial virus, varicella-zoster virus and cytomegalovirus all failed to suggest a causative agent. The causative agent was found to be HHV 7 in four patients. Coxsackievirus B and parvovirus B19 were detected in two patients and one patient, respectively, and etiology could not be clarified in the remaining patients. Electrocardiography was normal in three patients but revealed diffuse ST elevation in four patients and diffuse PQ segment depression in one patient. In one patient, ST segment elevation progressed into ST segment depression after the first week before gradually returning to isoelectric line at the end of the second week of disease. Echocardiography revealed severe mitral regurgitation in three patients, pericardial effusion in three patients and pericardial hyperechogenicity in one patient (Table 1). Table 1. Clinical characteristics and follow-up data of patients Patients Age Sex Weight (kg) İnitial symptom Causative agent ECG Echocardiography EF at presentation Status Last EF (%) Case 1 15 years M 57 Chest pain HHV–7 Diffuse ST elevation Severe mitral and tricuspid regurgitation 14 Awaiting transplantation 22 Case 2 15 years M 68 Epigastric pain Coxsackie B N Pericardial effusion 62 Healed completely 66 Case 3 16 years M 74 Chest pain Coxsackie B N N 66 Healed completely 65 Case 4 14 months M 12 Dyspnea Parvovirus B19 Diffuse ST elevation Severe mitral regurgitation 26 Deceased – Case 5 10 months F 8 Dyspnea HHV-7 N Pericardial effusion 60 Healed completely 62 Case 6 2 years F 9 Dyspnea HHV-7 Diffuse ST elevation Pericardial effusion 66 Healed completely 66 Case 7 17 years M 64 Chest pain Unidentified PQ segment depression Pericardial hyperechogenity 65 Healed completely 65 Case 8 16 years M 75 Palpitation HHV–7 Diffuse ST elevation Severe mitral regurgitation 20 Asist device implantation 26 Patients Age Sex Weight (kg) İnitial symptom Causative agent ECG Echocardiography EF at presentation Status Last EF (%) Case 1 15 years M 57 Chest pain HHV–7 Diffuse ST elevation Severe mitral and tricuspid regurgitation 14 Awaiting transplantation 22 Case 2 15 years M 68 Epigastric pain Coxsackie B N Pericardial effusion 62 Healed completely 66 Case 3 16 years M 74 Chest pain Coxsackie B N N 66 Healed completely 65 Case 4 14 months M 12 Dyspnea Parvovirus B19 Diffuse ST elevation Severe mitral regurgitation 26 Deceased – Case 5 10 months F 8 Dyspnea HHV-7 N Pericardial effusion 60 Healed completely 62 Case 6 2 years F 9 Dyspnea HHV-7 Diffuse ST elevation Pericardial effusion 66 Healed completely 66 Case 7 17 years M 64 Chest pain Unidentified PQ segment depression Pericardial hyperechogenity 65 Healed completely 65 Case 8 16 years M 75 Palpitation HHV–7 Diffuse ST elevation Severe mitral regurgitation 20 Asist device implantation 26 N: normal, HHV: human herpesvirus. Table 1. Clinical characteristics and follow-up data of patients Patients Age Sex Weight (kg) İnitial symptom Causative agent ECG Echocardiography EF at presentation Status Last EF (%) Case 1 15 years M 57 Chest pain HHV–7 Diffuse ST elevation Severe mitral and tricuspid regurgitation 14 Awaiting transplantation 22 Case 2 15 years M 68 Epigastric pain Coxsackie B N Pericardial effusion 62 Healed completely 66 Case 3 16 years M 74 Chest pain Coxsackie B N N 66 Healed completely 65 Case 4 14 months M 12 Dyspnea Parvovirus B19 Diffuse ST elevation Severe mitral regurgitation 26 Deceased – Case 5 10 months F 8 Dyspnea HHV-7 N Pericardial effusion 60 Healed completely 62 Case 6 2 years F 9 Dyspnea HHV-7 Diffuse ST elevation Pericardial effusion 66 Healed completely 66 Case 7 17 years M 64 Chest pain Unidentified PQ segment depression Pericardial hyperechogenity 65 Healed completely 65 Case 8 16 years M 75 Palpitation HHV–7 Diffuse ST elevation Severe mitral regurgitation 20 Asist device implantation 26 Patients Age Sex Weight (kg) İnitial symptom Causative agent ECG Echocardiography EF at presentation Status Last EF (%) Case 1 15 years M 57 Chest pain HHV–7 Diffuse ST elevation Severe mitral and tricuspid regurgitation 14 Awaiting transplantation 22 Case 2 15 years M 68 Epigastric pain Coxsackie B N Pericardial effusion 62 Healed completely 66 Case 3 16 years M 74 Chest pain Coxsackie B N N 66 Healed completely 65 Case 4 14 months M 12 Dyspnea Parvovirus B19 Diffuse ST elevation Severe mitral regurgitation 26 Deceased – Case 5 10 months F 8 Dyspnea HHV-7 N Pericardial effusion 60 Healed completely 62 Case 6 2 years F 9 Dyspnea HHV-7 Diffuse ST elevation Pericardial effusion 66 Healed completely 66 Case 7 17 years M 64 Chest pain Unidentified PQ segment depression Pericardial hyperechogenity 65 Healed completely 65 Case 8 16 years M 75 Palpitation HHV–7 Diffuse ST elevation Severe mitral regurgitation 20 Asist device implantation 26 N: normal, HHV: human herpesvirus. Three patients presented with dilated cardiomyopathy (Cases 1, 4 and 8); of these, one died of sudden cardiac arrest within 6 h of hospital admission (Case 4), one required assist device implantation and one patient is on waiting list for heart transplantation with an ejection fraction of 22%. An autopsy could not be performed in the deceased patient owing to parental refusal. HHV 7 sequences were detected through PCR in the patient with rapid deterioration. The remaining five patients have been released for follow-up in a favorable hemodynamic condition without any medication. Of four patients diagnosed with HHV 7, two presented with dilated cardiomyopathy (Cases 1 and 8). DISCUSSION HHV 7 is a relatively new herpesvirus that was first isolated from CD4 T lymphocytes in 1990 by Frenkel et al. [7]. HHV 7 particles are shed from saliva and cause widespread infection in the pediatric population. The virus has been identified as a causal agent for exanthema subitum, coryza, acute infantile hemiplegia and hepatitis in children [7–10]. To our knowledge, HHV 7 has not yet been suggested as a cause of myocarditis. The diagnosis of myocarditis requires a thorough evaluation of clinical and laboratory findings that may include detailed anamnesis, physical examination, blood tests, chest radiograph, electrocardiography, echocardiography, cardiac magnetic resonance imaging (MRI), nuclear imaging and, in selected patients, endomyocardial biopsy [3, 5]. The use of nuclear imaging techniques in patients with myocarditis is restricted owing to low sensitivity, limited availability and the risks of radiation exposure [3]. Scintigraphy has not been used as a diagnostic tool in pediatric patients with myocarditis. Cardiac MRI has emerged as an important diagnostic tool, enabling evaluation of tissue characteristics and ventricular functions and identifying myocarditis with excellent sensitivity and high specificity [3, 11, 12]. However, cardiac MRI was not a diagnostic option for the patients in our study because our facility has no MRI unit. Although endomyocardial biopsy remains the gold standard for diagnosis of myocarditis and enables etiologic investigations through PCR and cultures in children, its use is also limited owing to high interobserver variability in pathologic examinations and the risk of procedural complications, including a non-negligible risk of cardiac perforation [5]. We did not perform endomyocardial biopsies on any of our patients. Instead, the diagnosis of myocarditis was assumed in patients with recent flu-like symptoms, chest pain, palpitation or dyspnea when high levels of CK-MB and troponin I were detected and no other cause of myocardial injury was suggested by electrocardiographic or echocardiographic examinations, physical examination or patient history. Viruses are the most common cause of myocarditis in developed countries. Historically, adenovirus and enteroviruses have been the most commonly identified pathogens causing myocarditis. Relatively new molecular techniques performed on cardiac biopsy specimens, such as PCR and in situ hybridization, have enabled the identification of new agents, such as parvovirus B19 and HHV 6. Viral cultures and identification of viral sequences through PCR using endomyocardial biopsy specimens are the most reliable methods to identify the cause of acute myocarditis [1–5]. Traditional serologic studies, PCR analysis of blood and peripheral viral cultures have also been used to identify the possible agents causing myocarditis. Despite the low sensitivity and specificity of these techniques and the lack of evidence of a direct relationship between the virus and myocardial inflammation, they can be helpful to detect the etiologic agent, especially in pediatric patients, when endomyocardial biopsy cannot be performed [3–5, 13]. Using PCR performed on peripheral blood, we detected HHV 7 genetic material in four patients (50%) in our study. LIMITATIONS As stated, we did not perform endomyocardial biopsy in any of our patients owing to the risks related to the procedure. Thus, we failed to prove a direct relationship between HHV 7 and myocardial injury. In addition, we were unable to obtain samples from pericardial effusions in our patients owing to insufficient fluid in the pericardial space. CONCLUSION Despite the fact that viral serologic testing and PCR assays of blood are insufficient to prove a direct relationship between a virus and myocardial inflammation, PCR may identify virus sequences in the blood of patients with myocarditis. To our knowledge, this is the first report to suggest HHV 7 as a causative agent for acute myocarditis. We believe HHV 7 should be considered as a possible etiologic pathogen for patients with suspected myocarditis. Funding The study was approved by the institutional review board for clinical research. No funding was received. References 1 Huhn GD , Gross C , Schnurr D , et al. Myocarditis outbreak among adults, illinois, 2003 . Emerg Infect Dis 2005 ; 11 : 1621 – 4 . http://dx.doi.org/10.3201/eid1110.041152 Google Scholar CrossRef Search ADS PubMed 2 Valdés O , Acosta B , Piñón A , et al. First report on fatal myocarditis associated with adenovirus infection in Cuba . J Med Virol 2008 ; 80 : 1756 – 61 . Google Scholar CrossRef Search ADS PubMed 3 Dennert R , Crijns HJ , Heymans S. Acute viral myocarditis . Eur Heart J 2008 ; 29 : 2073 – 82 . http://dx.doi.org/10.1093/eurheartj/ehn296 Google Scholar CrossRef Search ADS PubMed 4 Sinagra G , Anzini M , Pereira NL , et al. Myocarditis in clinical practice . Mayo Clin Proc 2016 ; 91 : 1256 – 66 . http://dx.doi.org/10.1016/j.mayocp.2016.05.013 Google Scholar CrossRef Search ADS PubMed 5 Singh RK , Yeh JC , Price JF. Diagnosis and treatment strategies for children with myocarditis . Prog Pediatr Cardiol 2016 ; 43 : 23 – 30 . http://dx.doi.org/10.1016/j.ppedcard.2016.08.022 Google Scholar CrossRef Search ADS 6 Hall CB , Caserta MT , Schnabel KC , et al. Characteristics and acquisition of Human herpesvirus (HHV)–7 infections in relation to infection with HHV-6 . J Infect Dis 2006 ; 193 : 1063 – 9 . http://dx.doi.org/10.1086/503434 Google Scholar CrossRef Search ADS PubMed 7 Frenkel N , Schirmer E , Wyatt L , et al. Isolation of a new herpesvirus from human CD4+ T cells . Proc Natl Acad Sci USA 1990 ; 87 : 748 – 52 . Google Scholar CrossRef Search ADS PubMed 8 Torigoe S , Kumamoto T , Koide W , et al. Clinical manifestations associated with Human herpesvirus 7 infection . Arch Dis Child 1995 ; 72 : 518 – 19 . http://dx.doi.org/10.1136/adc.72.6.518 Google Scholar CrossRef Search ADS PubMed 9 Torigoe S , Koide W , Yamada M , et al. Human herpesvirus 7 infection associated with central nervous system manifestations . J Pediatr 1996 ; 129 : 301 – 5 . http://dx.doi.org/10.1016/S0022-3476(96)70259-7 Google Scholar CrossRef Search ADS PubMed 10 Hashida T , Komura E , Yoshida M , et al. Hepatitis in association with Human herpesvirus-7 infection . Pediatrics 1995 ; 96 : 783 – 5 . Google Scholar PubMed 11 Abdel-Aty H , Boye P , Zagrosek A , et al. Diagnostic performance of cardiovascular magnetic resonance in patients with suspected acute myocarditis: comparison of different approaches . J Am Coll Cardiol 2005 ; 45 : 1815 – 22 . http://dx.doi.org/10.1016/j.jacc.2004.11.069 Google Scholar CrossRef Search ADS PubMed 12 Friedrich MG , Sechtem U , Schulz-Menger J , et al. International consensus group on cardiovascular magnetic resonance in myocarditis. Cardiovascular magnetic resonance in myocarditis: a JACC white paper . J Am Coll Cardiol 2009 ; 53 : 1475 – 87 . http://dx.doi.org/10.1016/j.jacc.2009.02.007 Google Scholar CrossRef Search ADS PubMed 13 Baughman KL. Diagnosis of myocarditis: death of Dallas criteria . Circulation 2009 ; 113 : 593 – 5 . http://dx.doi.org/10.1161/CIRCULATIONAHA.105.589663 Google Scholar CrossRef Search ADS © The Author [2017]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Journal

Journal of Tropical PediatricsOxford University Press

Published: Nov 30, 2017

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