In this retrospective study, we described the clinical presentation and diagnostic method findings of 42 children with a clinical diagnosis of myocarditis. Also, we provided clues to improve the early recognition of myocarditis and define possible early predictors for poor outcome in these patients.
The challenges of diagnosing pediatric myocarditis
The identification of pediatric patients with myocarditis in the early phases of the disease is essential in order to start monitoring and supportive treatment in a timely manner. However, the diagnosis may be challenging at initial stages in milder cases before the development of severe adverse events. Our results showed a heterogeneous and unspecific clinical presentation of myocarditis in children. Most patients presented with a preceding viral illness involving the respiratory or gastrointestinal tracts that was not associated with myocarditis initially. Of note, the most common specific cardiac symptom (chest pain) was observed in a similar proportion with shortness of breath and nonspecific respiratory or gastrointestinal symptoms that could mimic the clinical presentation of benign viral infections[2,13-15]. Besides, the physical examination revealed specific cardiac signs only in a minority of cases, and the most common alterations found on physical examination (tachycardia, tachypnea, respiratory distress, and abnormal lung auscultation) were non-specific cardiac signs. Therefore, the early identification of pediatric myocarditis based on clinical presentation and physical examination is challenging. We characterized four specific cardiac presentations in our pediatric myocarditis cohort that included FM, ACS-like, dysrhythmia, and CHF. Remarkably, we observed that the clinical presentation was associated with the age and the time of evolution of symptoms. Thus, older children (> 10-years-old) with ACS-like were diagnosed early after the initial symptoms usually at the time of the first consultation. Conversely, infants (< 2-years-old) were diagnosed late usually after two or more consultations with FM or CHF. This may be explained by the capacity of the older children to describe their symptoms in detail leading to prompt medical consultation and diagnosis. Conversely, younger infants are not able to express their symptoms, and clinicians are more reliant on parents’ observations. Therefore, they only seek medical attention when they observe late symptoms related to heart failure[6,24-26]. Also, the influence of the age on the immunologic response to viral infection of the myocardium might lead to different clinical courses and outcomes[7,29]. Our finding that most patients were consulted to the ED two or more times prior to the final diagnosis and that many patients had a previous diagnosis different from myocarditis, reinforces that a high index of suspicion is needed for infants with prolonged viral infections (overall with respiratory signs or symptoms) that do not improve and lead to multiple medical consultations.
Another reason that diagnosing myocarditis is difficult is the limited diagnostic accuracy of most available noninvasive diagnostic tests. There are no accurate serum biomarkers for the diagnosis of myocarditis. CPR can be elevated in the acute phase, but it is neither sensitive nor specific to determine the presence or absence of active myocardial inflammation. We observed elevated CRP levels only in 16% of our population, so normal values do not exclude a myocardial inflammatory process. Myocytes destruction also occurs in the acute phase of myocarditis; thus serum biomarkers of myocardial damage can be elevated in some cases. However, the sensitivity and negative predictive of elevated troponin I level in patients with biopsy-proven myocarditis were reported to be low[30-32]. We observed elevated troponin T levels in up to 65% of our population. Therefore, increased troponin T levels can reinforce the clinical suspicion of myocarditis in children, but a normal result does not exclude the diagnosis. Natriuretic peptides are secreted by ventricular myocytes in response to volume or pressure overload to counteract the renin-angiotensin-aldosterone and sympathetic nervous system actions in the context of heart failure. Thus, natriuretic peptides can be elevated in myocarditis with LV dysfunction and heart failure. We observed increased NT-proBNP levels only in 40% of patients, and therefore a normal value does not discard the diagnosis of myocarditis. Of note, increased NT-proBNP levels may aid in distinguishing a cardiac from a non-cardiac reason for respiratory symptoms in children[34,35]. This feature seems to be very useful to identify patients with a cardiac process in the context of nonspecific respiratory symptoms, as we observed in our young patients with myocarditis.
ECG and chest X-ray also have limited value for the diagnosis of myocarditis. Although ECG is virtually always abnormal in children with myocarditis, the abnormalities observed were widely variable, and there was not one specific abnormality that occurs with enough frequency to be a specific marker[16-19]. Also, chest X-ray revealed more specific cardiac findings such as cardiomegaly and pulmonary in a minority of patients.
Echocardiography remains the more useful diagnostic test in cases with clinical suspicion of myocarditis. Most children had echocardiographic alterations on admission. The most typical findings associated with myocarditis were LV dilatation and reduced global LVEF. Another echocardiographic sign that can help make the diagnosis is the presence of segmental wall motion abnormalities mimicking ischemic cardiomyopathy, which were observed mostly in older children with ACS-like. This feature can be explained by the focal distribution of areas of inflammation frequently seen in myocarditis. Mitral regurgitation and pericardial effusion may also be observed and help make a diagnosis. Similar to the clinical presentation, echocardiographic findings depend on both the manner and timing of a patient’s presentation. Thus, young patients with FM and more days of evolution presented the most depressed LVEF whereas older patients that were consulted early in the course of the disease with ACS-like usually presented a normal LVEF and segmental wall motion alterations.
cMRI is a promising diagnostic method for myocarditis. The major strength of cMRI is its capacity to detect inflammation, edema, necrosis, and fibrosis within myocardial tissue through several imaging sequences. The use of a mixed cMRI method (Lake Louis criteria) is preferred compared to EMB in clinically stable patients suspected of having myocarditis. Nevertheless, the presence of two of the three characteristics listed in the Lake Louise criteria leads to a low-moderate sensitivity (67%-78%) and negative predictive value (69%), and high specificity (91%) and positive predictive value (91%). Therefore, a negative test does not discard the clinical suspicion of myocarditis. The sensitivity of cMRI for the diagnosis of myocarditis is likely to be limited in patients with less inflammation and a prolonged duration of symptoms; thus cMRI may be more helpful in the diagnosis of acute myocarditis if performed within 14 d of the onset of symptoms. Also, cMRI is not widely available in all centers, and it is difficult to carry out in non-stable patients and infants, which represent the most common clinical picture of myocarditis. Consistent with this, we performed cMRI early in the course of the disease (median of 4 d after admission) in 50% of our population, most of them teenagers with an ACS-like presentation, confirming the diagnosis of suspected myocarditis in 86%. The only cMRI in an infant with FM was performed after 14 d of diagnosis when the patient was stable and was negative. Although cMRI is a promising technology, its sensitivity for the diagnosis of myocarditis must be improved and used timely in the appropriate candidates.
Predictors for poor outcomes
Myocarditis is a significant etiology of CHF, often leading to DCM, need for heart transplantation, and death. Poor outcomes were observed in up to 43% of patients at the time of hospital discharge and 16% after 1 year of follow-up. The mortality rate was 5%, and all cases of death occurred during the initial hospitalization. We observed LV dilation in 43% and LV dysfunction in 50% (14% severe) of cases on admission, reflecting the potential of myocarditis to produce important alterations in the early phases of the disease. Acute myocarditis in patients who present with LV systolic dysfunction can recover in weeks to months. Of note, we found a spontaneous complete recovery rate of initial LV dysfunction or dilation of 69% during the first year of follow-up. These outcomes are similar to those observed in two recent large prospective multicentric studies involving pediatric myocarditis[6,9] and highlight a contemporary good prognosis of acute myocarditis in children that could reflect the advances in the recognition and management of these patients. Also, this reinforces the need for aggressive initial management in the acute phase of the disease waiting for a possible recovery in most patients. Nevertheless, we found that myocarditis in children is still associated with a high rate of CHF, hospitalization, intensive care unit stay, use of cardiac medications, and inotropic support or mechanical circulatory support at the time of diagnosis. Also, 12% still suffered from LV dysfunction or dilation after 1 year. Hence, it would be useful to identify these high-risk patients in the early phase of the disease. The main finding of this study was that a severe depressed LV systolic function (LVEF < 30%) on admission was the only independent predictor for poor outcomes in pediatric myocarditis. However, in the univariate analysis we identified some features that could help clinicians detect these patients on admission. These factors were age < 2-years-old, > 7 d from the initial symptoms, and NT-proBNP > 5000 pg/mL. Of note, LVEF was associated with all these factors. As echocardiography is not widely available at emergency departments and requires some training and expertise, we think that the above mentioned clinical and biochemical factors could be useful to identify high-risk patients. Specifically, NT-proBNP levels seem to be very useful for the screening of LV dysfunction upon admission in children with myocarditis. We found that the diagnostic accuracy of NT-proBNP levels on admission for severe LV dysfunction on echocardiography was high and that those patients with concentrations less than 2000 pg/mL at admission probably will not have a severe LV dysfunction on echocardiography, and therefore they will have a good outcome.
This study had several limitations. The retrospective nature without the establishment of inclusion criteria prior to the beginning of the study and the use of clinically diagnosed myocarditis could lead to the inclusion of patients who did not have myocarditis. The absence of cases of heart transplantation could be because our center does not have a heart transplant program. Therefore, it is possible that more severe cases of myocarditis were referred directly to hospitals with a heart transplant program. Although our mortality rate was low and consistent with the recent literature, it could also be influenced by this fact, and this could limit the risk factors provided. Also, the time of follow-up was short, and this could prevent the analysis of risk factors for long-term outcomes. Finally, none of our patients received immunomodulatory therapy, a promising therapeutic strategy as suggested by several randomized trials. This could impact the outcomes observed in our study, but this kind of therapy remains investigational mainly at this time and requires further elucidation. Of note, despite not using these treatments, our outcomes were similar to those studies that used them.