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Home , Cardiomegaly, Myocarditis

American Journal of Emergency Medicine (2009) 27, 942–947

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Original Contribution Pediatric : presenting clinical characteristics Yamini Durani MD a,⁎, Matthew Egan MD b, Jeanne Baffa MD c, Steven M. Selbst MD a, Alan L. Nager MD d,e aDivision of Emergency Medicine, Department of Pediatrics, Alfred I. duPont Hospital for Children, Thomas Jefferson University, Wilmington, DE 19899, USA bDivision of Pediatric , Columbus Children's Hospital, Columbus, OH 43205, USA cDivision of Pediatric Cardiology, Alfred I. duPont Hospital for Children, Thomas Jefferson University, Wilmington, DE 19899, USA dDivision of Emergency Medicine and Transport Medicine, Department of Pediatrics, Childrens Hospital Los Angeles, Los Angeles, CA 90027, USA eKeck School of Medicine of the University of Southern California, Los Angeles, CA 90089, USA

Received 23 June 2008; revised 23 July 2008; accepted 24 July 2008

Abstract Objective: The objective of the study was to characterize the clinical profiles of pediatric patients with acute myocarditis and dilated (DCM) before diagnosis. Methods: A retrospective cross-sectional study was conducted to identify patients with myocarditis and DCM who presented over a 10-year span at 2 tertiary care pediatric hospitals. Patients were identified based on the International Classification of , Ninth Revision, diagnostic codes. Results: A total of 693 charts were reviewed. Sixty-two patients were enrolled in the study. Twenty-four (39%) patients had a final diagnosis of myocarditis, and 38 (61%) had DCM. Of the 62 patients initially evaluated, 10 were diagnosed with myocarditis or DCM immediately, leaving 52 patients who required subsequent evaluation before a diagnosis was determined. Study patients had a mean age of 3.5 years, 47% were male, and 53% were female. Common primary complaints were , vomiting, poor feeding, upper respiratory infection (URI), and . Common examination findings were tachypnea, hepatomegaly, respiratory distress, fever, and abnormal examination result. Sixty- three percent had on chest x-ray, and all had an abnormal electrocardiogram results. Conclusions: These data suggest children with acute myocarditis and DCM most commonly present with difficulty breathing. Myocarditis and DCM may mimic other respiratory or viral illnesses, but hepatomegaly or the finding of cardiomegaly and an abnormal electrocardiogram result may help distinguish these diagnoses from other more common pediatric illnesses. © 2009 Elsevier Inc. All rights reserved.

1. Background

Myocarditis, the of the muscular walls of This article was presented, in part, at the Pediatric Academic Societies Meeting in San Francisco, April 2006. the , remains a diagnostic challenge in the clinical ⁎ Corresponding author. Tel.: +1 302 651 4296; fax: +1 302 651 4227. setting because of the variability of presentations in the E-mail address: [email protected] (Y. Durani). pediatric population. It is nonetheless an important

0735-6757/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.ajem.2008.07.032 Pediatric myocarditis: presenting clinical characteristics 943 diagnosis, as it is the most common etiology of The institutional review boards of both participating in previously healthy pediatric patients [1]. The initial hospitals approved the study. diagnosis of myocarditis is highly dependent upon clinical Children up to 18 years old who were identified as having suspicion because diagnosis based on endomyocardial myocarditis or DCM based on the International Classifica- has many inherent risks and is therefore not tion of Diseases, Ninth Revision, codes were eligible for the performed routinely. Unless a high index of suspicion is study. Only patients diagnosed with DCM secondary to acute maintained, acute myocarditis may easily be missed; and the myocarditis were included in the study. Patients with DCM diagnosis may only be obvious in cases when fulminant secondary to other causes such as cardiotoxic drugs, inborn is present. errors of metabolism, malformation syndromes, neuromus- Patients often present with prodromal symptoms that cular disorders, or other familial syndromes were excluded. are not recognized to be associated with myocarditis In all cases, the final diagnosis was based upon expert initially. In a study of 90 patients younger than 16 years opinion of a pediatric cardiologist. who died suddenly and unexpectedly, myocarditis was A standardized data collection form was used to abstract found to be a major cause of death in 17%; and 60% of data from hospital medical records. Data were abstracted by these patients had prodromal symptoms [2]. In another 3 investigators. Data collected included demographics, study by Freedman et al of 14 patients seen by a clinical history, physical examination, and results of physician before the diagnosis of myocarditis, 57% were laboratory evaluation. originally diagnosed as having pneumonia or . In The clinical history and physical examination data were addition, 32% of patients presented with respiratory obtained from the first documented encounter at our symptoms, 29% had cardiac symptoms, and 6% had institutions' EDs. If patients were transferred to our facilities gastrointestinal symptoms. from an outside institution and did not have an ED Previous research has shown that acute myocarditis may evaluation, the historical and clinical data were collected progress to (DCM). This occurs as from intensive care unit records or the referring hospital's myocytes are injured by both direct viral injury and by the initial medical evaluation. inflammatory response of the host via the effects of The presence or absence of the following clinical features cytokines, autoantibodies, , natural killer cells, was collected: fever, diaphoresis, lethargy, fatigue, change in and lymphocytic cells [3,4]. Although DCM may result from exercise tolerance, syncope, seizures, difficulty breathing, other etiologies, such as neuromuscular disorders, inborn rapid breathing, cyanosis, wheezing, apnea, cough, rhinor- errors of metabolism, or other familial syndromes, a recent rhea, , , poor feeding, vomiting, study demonstrated that 27% of cases of DCM were , abdominal pain, and decreased urination. Physical secondary to viral myocarditis [5]. In this study, we have examination findings collected included triage or initial vital selected cases of myocarditis and DCM that are only signs and the presence or absence of the following: presumed to be viral in etiology. We also chose to group respiratory distress, evidence of upper respiratory tract the spectrums together because ultimately the support and infection, abnormal lung examination results (wheezing, treatment are the same for both. retractions, rales, decreased air exchange), gallop, murmur, Characterizing of patients with hepatomegaly, perfusion/pulses, and cyanosis. If no doc- acute myocarditis and DCM could possibly facilitate umentation existed regarding a specific sign, symptom, earlier diagnosis of the disease and help prevent , or other aspects of the history, it was recorded misdiagnosis. The primary objective of this study is to as “not documented.” characterize the clinical profiles of pediatric patients with Initial laboratory findings that were abstracted included acute myocarditis and DCM at the time of presentation to complete blood count, C-reactive protein (CRP), erythrocyte the hospital. A secondary objective is to review these sedimentation rate (ESR), , and creatinine kinase patients' initial diagnoses early in the course of their (CK). Microbiology results were also abstracted, such as disease and to analyze cases that were initially diagnosed blood cultures, tracheal aspirate, nasal swab cultures, urine as some other condition before myocarditis or DCM cultures, results, and more specific was considered. viral testing. The findings of the initial chest x-ray (CXR), electrocardiogram (EKG), and echocardiogram were abstracted. The results of these tests were based on reported data in the medical record. 2. Materials and methods If patients had medical evaluations by a physician in the 14 days preceding final diagnosis of myocarditis or DCM, A retrospective cross-sectional study was conducted to the diagnoses given at these encounters were abstracted. identify patients with myocarditis and DCM who presented SPSS for Windows version 14.0 (SPSS Inc, Chicago, IL) over a 10-year span from January 1, 1994, to December 31, [6] was used for data analysis. Descriptive statistics were 2003, at 2 tertiary care pediatric centers with annual used to describe patient characteristics and frequencies of emergency department (ED) visits of 35 000 and 62 000. signs, symptoms, and diagnoses. 944 Y. Durani et al.

3. Results Table 2 Identified viral pathogens Specific viral pathogens No. of patients A total of 693 charts were reviewed at the 2 participating (n = 62) institutions. Six hundred twenty-eight patients were excluded because their heart disease was not myocarditis No pathogens identified 42 (68%) or DCM, their heart disease was secondary to another Parainfluenza 8 (13%) Coxsackie 4 (6%) primary diagnosis (eg, muscular dystrophy, metabolic Adenovirus 2 (3%) disorder), or their heart disease was caused by medications. A 2 (3%) Three patients were excluded secondary to incomplete Parvovirus 1 (2%) medical records, resulting in 62 patients available for data Coinfections 3 (5%) analysis: 24 patients from one institution (AI duPont) and 38 Echovirus, coxsackie B 1 (2%) patients from the second institution (Childrens Hospital Los Influenza A and B, adenovirus 1 (2%) Angeles). Twenty-four (38%) patients had a final diagnosis Coxsackie A, adenovirus 1 (2%) of myocarditis, and 38 (61%) had DCM. Patients with known pathogen (%) 32% As depicted on Table 1, study patients had a mean age of 3.5 years and a range from 6 days to 17 years. Forty-seven percent were male, and 53% were female. Regarding race, 29% were African American; 29%, Hispanic; 14%, white; (32%) patients had 2 or 3 evaluations (18 with 2 visits, and 10%, Asian/Pacific Islander; 8%, other; and 10%, not 2 with 3 visits) before myocarditis or DCM was diagnosed. documented. The mean duration of symptoms, before final Table 3 shows data regarding diagnoses for the 52 patients diagnosis, was 7.6 days (SD ± 13 days). Thirty-nine percent at their first evaluation by a physician. A respiratory tract of patients were diagnosed with myocarditis, and 61% were infection was diagnosed in 13 (25%) patients, including diagnosed with DCM. In total, 8 (13%) patients died; and 54 pneumonia, bronchiolitis, and upper respiratory tract (87%) survived. As shown on Table 2, a documented viral infection. Cardiac disease was diagnosed in 8 (15%) pathogen was found in 20 (32%) of study patients, with patients, including cardiomegaly, , myocardial parainfluenza being the most common pathogen found. infarction, and myocarditis. Four patients had combined Sixty-two patients were initially evaluated during this diagnoses, with pneumonia/cardiomegaly in 3 patients and analysis. Ten patients were diagnosed with myocarditis or congenital heart disease/cardiomegaly in 1 patient. Other DCM at the first encounter at our respective institutions, diagnoses were given to 21 (40%) patients, and data were resulting in 52 patients who required subsequent evalua- missing or not available for 6 (12%) patients. All patients tions by a physician before a definitive diagnosis was who were suspected of having cardiac disease at the first determined. Of these 52 patients, 32 (52%) patients had 1 visit were either diagnosed in our EDs or referred to our additional evaluation within 14 days of symptoms. Twenty ED the first day the diagnosis was suspected, and all were admitted to the hospital. Table 4 lists the diagnoses of patients evaluated during the Table 1 Characteristics of study patients second visit to a physician. A respiratory tract infection was Patient characteristics No. of patients diagnosed in 5 (25%) patients, all of whom had pneumonia. (n = 62) Sex Table 3 Diagnoses at first medical evaluation Male 29 (47%) Specific diagnosis No. of patients Female 33 (53%) (n = 52) Mean age (y) 3.5 y (SD ± 5.0) Race Respiratory infection 13 (25%) African American 18 (29%) Pneumonia 3 (6%) Hispanic 18 (29%) Bronchiolitis 5 (10%) White 9 (14%) Upper respiratory tract infection 5 (10%) Asian/Pacific Islander 6 (10%) Cardiac disease 8 (15%) Other 5 (8%) Cardiomegaly 4 (8%) Not documented 6 (10%) Arrhythmia 2 (4%) Mean duration of symptoms (d) 7.6 d (SD ± 13.0) 1 (2%) Final diagnosis Myocarditis 1 (2%) Myocarditis 24 (39%) Combined diagnoses 4 (8%) DCM 38 (61%) Pneumonia/cardiomegaly 3 (6%) Outcome Congenital heart disease/cardiomegaly 1 (2%) Died 8 (13%) Other diagnoses 21 (40%) Survived 54 (87%) Diagnosis not documented 6 (12%) Pediatric myocarditis: presenting clinical characteristics 945

Table 4 Diagnoses at second medical evaluation Table 6 Major findings on laboratory and radiographic analysis Specific diagnosis No. of patients (n = 20) Mean WBC count ([×1000]/mm3) 11.4 (SD ± 5.4) Respiratory infection 5 (25%) Elevated troponin 7/13 (54%) Pneumonia 5 (25%) Elevated CK 16/22 (73%) Cardiac disease 4 (20%) Elevated ESR 6/16 (38%) Cardiomegaly 2 (10%) Elevated CRP 4/15 (27%) Myocarditis 1 (5%) Abnormal EKG 59/59 (100%) Congenital heart disease 1 (5%) Sinus 27 (46%) Combined diagnoses 2 (10%) 24 (41%) Pneumonia/DCM 1 (5%) ST wave abnormality 19 (32%) abnormality 18 (31%) Pneumonia/cardiomegaly 1 (5%) Other diagnoses 5 (25%) Bundle-branch block 6 (10%) Diagnosis not documented 4 (20%) Arrhythmia 4 (7%) AV block 3 (5%) Prolonged QT interval 3 (5%) Abnormal CXR 53/59 (90%) Cardiac disease was diagnosed in 4 (20%) patients. Two Cardiomegaly 37 (63%) patients had combined diagnoses, with pneumonia/DCM in 1 Pulmonary 9 (15%) patient and pneumonia/cardiomegaly in 1 patient. Other Pulmonary infiltrate 3 (5%) diagnoses were given to 5 (25%) patients, and data were Pleural effusions 1 (2%) missing or not available for 4 (20%) patients. Other abnormality 3 (5%) Of the 52 patients who were seen for their first medical Abnormal echo 60/61 (98%) evaluation before a final diagnosis, 21 (40%) patients were WBC indicates white blood cell; AV, atrioventricular. seen by their primary care provider, 21 (40%) were evaluated in a general ED, 2 (4%) were cared for in a pediatric ED, and 8 (15%) were seen in other settings (clinics, neonatal units, Many of the patients studied had frequent and overlapping etc). Of the 20 patients who were seen at a second medical signs and symptoms at the time they were diagnosed with evaluation (including 18 who had 2 evaluations and 2 myocarditis or DCM. For the 62 patients studied, Table 5 patients who had 3 evaluations) before final diagnosis, 7 lists various common symptoms and clinical findings. At the (35%) were cared for by their primary care provider, 7 (35%) time of presentation to our institutions, 43 (69%) patients had were seen in a general ED, 2 were evaluated in a pediatric a history of shortness of breath, 30 (48%) had vomiting, 25 ED, and 4 (20%) were seen in other areas. (40%) presented with poor feeding, 24 (39%) showed upper respiratory symptoms, 22 (36%) had fever, and 22 (36%) presented with lethargy. On physical examination, 37 (60%) Table 5 Symptoms and physical examination findings patients had clinical evidence of tachypnea, 31 (50%) had hepatomegaly, 29 (47%) patients had respiratory distress, 22 Specific symptoms and physical No. of patients examination findings (n = 62) (36%) patients presented with fever, and 21 (34%) patients had an abnormal lung examination result. Most common presenting symptoms A normal for age [7] was found in 41 (66%) Shortness of breath 43 (69%) patients studied. Of the 20 patients with tachycardia, 9 (45%) Vomiting 30 (48%) Poor feeding 25 (40%) were febrile and 11 (55%) were afebrile. In addition, 1 Upper respiratory symptoms 24 (39%) afebrile patient was bradycardic. Heart rates were based on a Fever 22 (36%) single measurement in triage or the first available vital signs Lethargy 22 (36%) at the time of encounter at our institution. Most common physical examination findings Table 6 shows laboratory data, abnormalities found on Tachypnea 37 (60%) CXR, EKG abnormalities, and results of . Hepatomegaly 31 (50%) The mean white blood cell count of patients was 11 400 (SD ± Respiratory distress 29 (47%) 5.4; range, 4100-34 200). Only 13 patients had a troponin Fever 22 (36%) level checked; and of these, 7 (54%) had an elevated level. Abnormal lung exam 21 (34%) Twenty-two patients had a CK checked; and of these, 16 Heart rate findings (73%) were elevated. Six patients had an elevated ESR, and Normal heart rate 41 (66%) Tachycardia 20 (32%) 4 patients had an elevated CRP. Febrile and tachycardic 9 (45%) An abnormal EKG was documented in 59 of 59 Afebrile and tachycardic 11 (55%) (100%) patients, with no EKG on 3 patients. The most 1 (2%) common abnormal EKG finding was , with the next most common EKG abnormality demon- 946 Y. Durani et al. strating evidence of ventricular hypertrophy followed by diagnoses in patients with mild respiratory symptoms, ST-wave abnormality. An abnormal CXR was documen- respiratory distress, or unexplained . ted in 53 of 59 (90%) patients. In addition, 6 (10%) had a Although many clinicians believe resting tachycardia is a normal CXR and 3 patients had no CXR. The most common finding in patients with myocarditis, this study common abnormal CXR finding was cardiomegaly in 37 found that 66% of patients had a normal heart rate for age. In (60%) patients, followed by pulmonary edema and addition, the heart rate did not appear to be related to fever. It pulmonary infiltrate. An abnormal echocardiogram was is our speculation that sequential vital signs to measure found in 60 of 61 (97%) patients. One patient had a trends in the heart rate may be more helpful in future studies. normal echocardiogram, and 1 patient died in the ED and A single heart rate measurement, therefore, may not be a had no echocardiogram performed. The patient with a useful objective marker of myocarditis. normal echocardiogram result was diagnosed with Most cases of myocarditis or DCM were not initially myocarditis by a cardiologist based on a clinical picture recognized by either a primary care provider or a general of respiratory distress, upper respiratory tract infection, emergency medicine health care provider. Of the 62 patients positive viral culture, and cardiac arrhythmia consisting initially analyzed, 52 (84%) required more than 1 visit to a of premature atrial contractions. The patient who died and physician within 14 days before the diagnosis of myocarditis had no echocardiogram performed was diagnosed with a or DCM was made. Overall, most patients were initially probable myocarditis because of evidence of heart failure diagnosed with a respiratory illness. on CXR and cardiac arrhythmia that progressed to cardiac Although myocarditis and DCM may mimic other arrest. The patient's cardiac rhythm was obtained from a respiratory or viral illnesses, findings on physical cardiorespiratory monitor tracing; and the patient initially examination such as hepatomegaly should not be over- had a narrow QRS complex with peaked T waves that looked; and the finding of cardiomegaly on CXR should changed to a widened QRS complex, resulting eventually help distinguish these diagnoses from other more common in . pediatric respiratory illnesses. In addition, although not A myocardial biopsy was performed in 6 patients, and apparent in our study, several case reports have included findings consistent with myocarditis were found in 5; 1 seizures as the inciting event, along with other cardiac patient had an insufficient sample. signs and symptoms that led to the diagnosis of myocarditis [10,11]. Therefore, this variability in signs and symptoms, especially when they are associated with cardiac or radiographic findings, should alert the clinician 4. Discussion to assess for myocarditis or DCM. Our study is similar to a previously published study by This study has identified prodromal symptoms and signs Freedman et al, who examined signs and symptoms along associated with myocarditis and DCM in a diverse pediatric with CXR and EKG findings in patients with myocarditis. population. Myocarditis and DCM may vary from mild to Although the 2 studies were similar with regard to the fulminant disease. In milder cases, diagnosis at initial predominance of respiratory and gastrointestinal symptoms, presentation may be challenging. However, because of the our study had a higher percentage of patients with potential for severe and fatal disease, it is important to respiratory complaints. In addition, our study demonstrated identify myocarditis and DCM early, so that monitoring and that 50% of patients at the time of diagnosis had supportive treatment can be timely. hepatomegaly vs 36% in the study of Freedman et al. Most patients in this study population presented with Regarding CXR evaluation, our study demonstrated that complaints of shortness of breath and were found to have 60% of patients had evidence of cardiomegaly (vs 55%); tachypnea with associated respiratory distress and an and 95% of patients with myocarditis in our study had an abnormal lung examination result. This is consistent with abnormal EKG (vs 93%) [3]. a case series of 7 myocarditis patients who all presented Although the results of our studies differ to a small with respiratory distress, including tachypnea and inter- degree regarding clinical signs and symptoms (respiratory costal retractions. In this series of patients, initial and gastrointestinal), such symptoms along with CXR and diagnoses included asthma, pneumonia, congestive heart EKG findings ultimately led to the same cardiac diagnosis failure, rule-out sepsis, and shock [8]. Although all of the in both studies. patients in the study progressed and developed worsening As demonstrated in our study, several laboratory tests symptoms, they nonetheless all started out with respiratory were obtained in a relatively small proportion of patients. symptoms, similar to most of the patients in our study It has been postulated that troponin levels may provide the population. In another case series of 4 patients, all best evidence of myocyte injury in patients with presented with the acute onset of severe respiratory myocarditis [12]. Our study, however, demonstrated that distress, leading to shock; and all were subsequently only 7 of 13 patients tested had a positive result. This diagnosed with myocarditis [9]. Therefore, a cardiac small sample size does not allow us to draw the conclusion etiology should be considered among the differential that this should be a mandatory laboratory test in the Pediatric myocarditis: presenting clinical characteristics 947 evaluation of patients with suspected myocarditis or DCM References until further large-scale studies are completed that may conclusively determine its utility. In addition, of 22 [1] Calabrese F, Rigo E, Milanesi O, et al. Molecular diagnosis of patients who had CK levels drawn, 73% had an elevated myocarditis and dilated cardiomyopathy in children: clinicopathologic features and prognostic implications. Diagn Mol Pathol 2002;11:212-21. level. Although this is a relatively high percentage (based [2] Lipshultz SE, Sleeper LA, Towbin JA, et al. The incidence of pediatric on a small sample size), this is a nonspecific marker of cardiomyopathy in two regions of the United States. N Engl J Med muscle breakdown and is not predictive or diagnostic of 2003;348:1647-55. myocarditis or DCM. [3] Freedman SB, Haladyn JK, Floh A, et al. Pediatric myocarditis: This study has several limitations. It is a retrospective emergency department clinical findings and diagnostic evaluation. Pediatrics 2007;6:1278-85. chart review that is limited by the available data in the [4] Kawai C. From myocarditis to cardiomyopathy: mechanisms of medical record. Particularly, in patients who had prior inflammation and cell death. Circulation 1999;99:1091-100. medical evaluations, details of the clinical history and [5] Leonard E. Viral myocarditis. Pediatr Infect Dis J 2004;23:665-6. physical examination at that time were not available. In [6] SPSS for Windows version 14.0 (SPSS, Inc., Chicago, IL), 2005. addition, most diagnoses of myocarditis and DCM were [7] Garson A. . In: Garson A, Bricker JT, Fisher DJ, Neish SR, editors. The science and practice of pediatric cardiology. based on expert opinion of a cardiologist and not biopsy- 2nd ed. Baltimore (Md): Williams and Wilkins; 1998. p. 735-6. proven disease, a reality in clinical practice. Long-term [8] Press S, Lipkind RS. Acute myocarditis in infants. Initial presentation. follow-up of patients who survived was not analyzed. Clin Pediatr 1990;29:73-6. [9] Bonadio WA, Losek JL. Infants with myocarditis presenting with severe respiratory distress and shock. Pediatr Emerg Care 1987;3:110-3. [10] Chavda KK, Dhuper S, Madhok A, et al. Seizures secondary to a high- Acknowledgment grade as a presentation of acute myocarditis. Pediatr Emerg Care 2004;20:387-90. The authors wish to thank wholeheartedly Linda Quzts, [11] Cunningham R, Silbergleit R. Viral myocarditis presenting with seizure and electrocardiographic findings of acute myocardial infarc- Administrative Secretary, for her invaluable assistance and tion in a 14-month-old child. Ann Emerg Med 2000;35:618-22. Ronald Tsai for his diligence and dedication regarding data [12] Lippi G, Salvagno G, Guidi G. Cardiac troponin in pediatric support throughout the study. myocarditis. Pediatrics 2008;121:864-5 [Letter].