Authors: Zachary Hutchinson, Yuk Law
Categories: Special section on Pediatric Thoracic Transplantation; Edited by Estela Azeka and Christian Benden, Myocarditis, Children, Pediatrics, Heart Failure, Inflammatory heart disease
Source: JHLT Open
Authors: Zachary Hutchinson, Yuk Law
Historically, myocarditis was diagnosed by findings on endomyocardial biopsy. Although still considered to be the reference standard, this approach has become uncommon in pediatrics. Cardiac magnetic resonance imaging can also be used to make a diagnosis, but its use is also limited in pediatrics due to the frequent need for sedation among other logistical and technical requirements. In current practice, the diagnosis of myocarditis in children for the purpose of deciding whether to treat is largely clinical, guided by noninvasive clinical findings. Preceding fever, constitutional, respiratory, and gastrointestinal symptoms, and hepatomegaly are common presenting signs and symptoms that are frequently mistaken for non-cardiac issues. Arrythmias and specific ECG findings can also accompany myocarditis. Cardiac biomarkers including troponin and BNP are frequently elevated and can help provide prognostic information. Infectious workup is an important part of the diagnosis of myocarditis, and recent studies have shown Parvovirus B19 and HHV6 to be the most common causes of viral myocarditis in pediatrics. Echocardiography is key to the clinical diagnosis, yet findings of myocarditis can be quite variable. The hallmark of treatment for myocarditis in children is supportive care including ionotropic support and heart failure therapies, with prompt initiation of mechanical circulatory support for cardiogenic shock or compromising arrhythmias. Some combination of steroids and IVIG are also frequently used to slow the injurious inflammatory response involved with myocarditis, yet this remains an area of debate. Future treatments may include additional immunomodulatory therapies, but further studies are needed.
Myocarditis is defined as inflammation of the myocardium and has a wide range of manifestations that can include heart failure, arrythmia, and death. Historically, myocarditis was defined largely by pathological findings on heart biopsies. In 1995, the WHO defined it as an inflammatory disease of the myocardium caused by different infectious and noninfectious triggers, diagnosed by established histological, immunological, and immunohistochemical criteria.^1^ Prior to this, the Dallas criteria for myocarditis established in 1987 required an inflammatory infiltrate with or without associated myocyte necrosis on heart biopsy to make the diagnosis.^2^ Although a pathologic diagnosis is still considered by some to be the reference standard, there are multiple limitations to routine use of this approach including low sensitivity due to sampling error, inability to biopsy the left ventricle (LV), variation in pathologic interpretation, and the invasive nature of the procedure.^3^
More recently CMRI has been favored as a non-invasive diagnostic tool, while the use of endomyocardial biopsy has decreased.^4^ In 2009, the Lake Louise Criteria were published to establish a consensus approach to the CMRI based diagnosis of myocarditis.^5^ A 2021 AHA Scientific Statement proposed 4 strata to approach the diagnosis of biopsy proven, CMRI-confirmed clinically suspected, clinically suspected, and possible myocarditis.^6^ In current practice, a combination of history, physical exam, lab, ECG (electrocardiography), and echocardiographic findings often guide the decision to treat for presumed myocarditis in children, even in the absence of a definitive diagnosis. In 2017, the global incidence of myocarditis was over 3 million cases, and patients under age 20 had the highest incidence and overall burden of disease.^7^ This review will discuss the current literature related to the diagnosis of pediatric myocarditis with a focus on the clinical, EKG, lab, and imaging findings, along with the approach to treatment with emphasis on cardiac specific treatments (supportive care, MCS, and transplant) as well as the use of antivirals and immunotherapies.
Myocarditis can present with a large spectrum of symptoms from mild chest pain that resolves spontaneously to cardiogenic shock, arrythmia, and sudden death.8, 9 The often nonspecific nature of its presentation frequently delays diagnosis.^10^ One reason is that myocarditis in children is thought to be predominantly secondary to a viral infection, and community acquired infections are highly prevalent in childhood. One study reviewed the symptoms at presentation and initial diagnoses of 62 pediatric patients who were seen in the Emergency Department at two tertiary care children’s hospitals and ultimately diagnosed with myocarditis.^11^ Only 16% of patients were correctly diagnosed at initial presentation, and the remaining patients required at least one more visit within 14 days prior to diagnosis. Most patients had dyspnea as their initial complaint often with a viral prodrome. Nearly two thirds of the patients had cardiomegaly on chest X-ray, and hepatomegaly was also common. Similarly, 62% of patients with myocarditis admitted to a pediatric intensive care unit were initially diagnosed with respiratory illnesses.^12^ Neonatal myocarditis is often mistaken for sepsis.^13^ The presence of fever can favor the diagnosis of myocarditis over cardiomyopathy.^14^ One study found that patients with moderate to severe LV dysfunction related to myocarditis most commonly presented with gastrointestinal symptoms such as abdominal pain and nausea/vomiting in addition to malaise, chest pain, and respiratory distress.^15^ Findings of hepatomegaly or cardiomegaly on chest X-ray in a patient with respiratory distress or gastrointestinal symptoms should raise suspicion for acute heart failure and prompt further workup for possible myocarditis. Many of these signs and symptoms are common in patients seeking acute care. Even after cardiac dysfunction is diagnosed, additional information is needed to differentiate myocarditis from other causes of cardiac dysfunction, given the high background frequency of viral infections in children. See Figure 1 for a framework in the management phases of acute myocarditis.Figure 1Central diagram of the management phases of myocarditis offering diagnostic and therapeutic considerations. After discharge from the hospital, consideration should be given to continue reverse remodeling medications to prevent progression into chronic heart failure.Figure 1
ECG and telemetry monitoring are important in the workup of myocarditis to evaluate for arrythmia and to assess for findings of ischemia such as Q waves that could favor a diagnosis of epicardial coronary artery conditions such as ALCAPA. The presence of ventricular arrythmia favors a diagnosis of acute myocarditis over dilated cardiomyopathy.^14^ However, arrythmias from myocarditis can also include AV block, supraventricular tachycardia, atrial fibrillation, and atrial flutter, and cardiac syncope as the presenting sign is well described.^16^ ECG features of acute myocarditis in children can also include sinus tachycardia, nonspecific T-wave inversions, ST segment elevations either diffusely or in a coronary distribution pattern, PR depressions, low voltage QRS complexes in limb leads, and AV conduction delays.^17^ Pathologic Q waves have also been described with parvovirus B-19 myocarditis and are associated with mortality.^18^ A normal ECG does not rule out myocarditis. One study showed that 28% of patients diagnosed with myocarditis had a completely normal ECG at presentation.^19^
Cardiac biomarkers can be helpful screening labs in the workup of pediatric myocarditis, but they are nonspecific and may be more helpful to trend.6, 20 Troponin I and troponin T are the most used markers of myocardial injury or ischemia and may be elevated in acute myocarditis.^20^ Higher serum levels of troponin I, CK-MB, and NT-pro BNP are associated with fulminant myocarditis and can help identify patients at risk for fulminant myocarditis.^21^ Butts et al. (2017) showed that patients with moderate or severe LV systolic dysfunction and acute heart failure related to myocarditis had higher BNP, higher NT-pro BNP, and lower troponin at admission with associated higher risk of receiving cardiopulmonary resuscitation or mechanical circulatory support.^15^ The use of “liquid biopsies,” blood tests for tissue specific biomarkers such as donor-derived cell-free DNA to monitor for heart transplant rejection, show promise in limiting the need for endomyocardial biopsy.^22^ Several microRNA candidates have been isolated as potential biomarkers for myocarditis, but their specificity and sensitivity need to be further studied.^23^
The workup for suspected pediatric myocarditis should involve an investigation into the underlying cause, which includes consideration of infectious (viral, bacterial, fungal, parasitic) and noninfectious (autoimmune, drugs, toxins, genetic) causes.^24^ While most cases of myocarditis are ultimately classified as idiopathic, viruses are the most identified cause in children.24, 25 Infectious workup should always include viral PCRs of blood, and stool, or respiratory secretions if indicated by symptoms in these organ systems, for the most common viruses involved in myocarditis. For blood and tissue viral detection by PCR, the ones well described in the literature include parvovirus B19, adenovirus, enterovirus, EBV, CMV, and HHV-6.^6^ A positive PCR result can serve as a surrogate but not as replacement for myocardial tissue PCR.^6^ A positive viral respiratory or stool PCR can provide indirect support but given the high prevalence of common viral respiratory tract infections in children, they would be further remote evidence than detecting viral nucleic acid from the blood. Additional travel and exposure history should direct the need for further specific testing such as Borrelia burgdorferi (Lyme disease), Trypanosoma cruzi (Chagas disease), or HIV.^1^ Influenza A and B are less common causes of pediatric viral myocarditis, although up to 5% of influenza cases can involve myocarditis that can be fulminant.^26^ SARS-CoV-2 infection can result in fulminant myocarditis, while COVID-19 vaccine-associated myocarditis is usually transient and mild and seen in older children.^27^
Studies that have used myocardial tissue PCR found parvovirus B19 and HHV6 to be the most common causes of pediatric myocarditis, and patients with a combination of the two had higher rates of heart failure and late gadolinium enhancement.^28^ More contemporary studies have corroborated that parvovirus B19 and HHV6 have supplanted adenoviruses and enteroviruses as the most common causes of pediatric viral myocarditis.29, 30, 31 Interestingly, one study using endomyocardial biopsy samples found that parvovirus B19 RNA transcriptional activity, measured via reverse-transcription cDNA and qPCR, was a stronger predictor of poor outcomes than viral DNA load, and active replication combined with inflammation was the strongest predictor of mortality.^32^ Moving beyond identification of a virus or its DNA load to measuring viral transcriptional activity may provide important prognostic information and help guide clinical decision making.
The small amounts of tissue from endomyocardial biopsies can limit the number of pathogens that can be tested for via traditional in-situ staining and PCR approaches. Viral metagenomic approaches, a next generation genetic sequencing technique to analyze an entire community of microorganisms within a sample, without the need to isolate or culture individual organisms, have successfully identified pathogenic profiles in the tissue of a number of conditions in solid organ transplant.^33^ One study of endomyocardial biopsy samples and explanted hearts from patients with fulminant myocarditis or giant cell myocarditis used metagenomic sequencing and identified endogenous retrovirus K, which is ubiquitous in the human genome.^34^ This study showed proof of concept for targeted next-generation sequencing for myocarditis, but future work is needed before clinical use.^33^
Echocardiography is the most used method for evaluating cardiac structure and function for children suspected of having myocarditis. It is crucial that structural causes of diminished LV function must be ruled out, particularly coronary anomalies such as ALCAPA in infants. If echo does not definitively visualize the coronary artery origins, then CTA may be needed. Echo findings of myocarditis can be variable ranging from mild to severe ventricular systolic dysfunction^35^ but perhaps what is telling is the divergence between the severity of remodeling (dilation and sphericity) and severity of systolic dysfunction. Right ventricular dysfunction can be one of the most important predictors of survival and need for transplant.^36^ Myocarditis can resemble patterns of dilated, hypertrophic, restrictive, or ischemic cardiomyopathy. Regional wall motion abnormalities that can mimic myocardial ischemia are common.^37^ Tissue doppler imaging and speckle tracking echocardiography can identify early myocardial dysfunction and be useful to trend for improvement in function.38, 39, 40 Acute myocarditis typically presents with normal or mildly dilated LV cavity size which may include a spherical shaped LV.^41^Increased LVEDD z-score on admission is a significant predictor of morbidity and mortality.^41^ Transient increases in LV wall thickness due to edema have also been suggested.^42^ A relatively thicker LV posterior wall was associated with better prognosis and recovery for children presenting with acute myocarditis.^35^ Fulminant myocarditis typically has near normal LV dimensions and slightly increased LV septal thickness and was associated with excellent survival.^29^ Other echo findings of myocarditis include LV thrombus, LV aneurysm, pericardial effusion, and valvar regurgitation.35, 37 Suthar et al (2018) identified several echo parameters that favor a diagnosis of myocarditis over dilated absence of LV dilation, presence of segmental wall motion abnormalities, lower LV dimension z-score, and less severe LV systolic function.^14^
CMRI can also be helpful in the diagnostic workup of myocarditis. As per the Lake Louise Criteria, the presence of two of three criteria of edema, hyperemia, or necrosis/scar on T2 weighted early gadolinium and late gadolinium enhancement was suggested to assume a high likelihood of myocarditis.^5^ These findings provide evidence of inflammation, which helps differentiate myocarditis from dilated cardiomyopathy. In cases of pediatric myocarditis, the frequent need for sedation in often unstable patients, limited availability of scanners, cost, and differing imaging protocols can limit the use of CMRI^43^ or its utility to change the decision making in the management.
These findings highlight that myocarditis can be diagnosed non-invasively depending on the differential diagnoses already ruled out and a program’s intention to treat without complete certainty.
Schauer et al. proposed the diagnostic criteria to meet the category of clinically suspected myocarditis. We combine these with other pediatric experience and expert recommendations from adult guidelines to generate a framework for a clinical diagnosis44, 45, 46 when endomyocardial biopsy or CMRI are not obtainable due to patient or feasibility factors (Table 1).Table 1Suggested Clinical Diagnostic Criteria for Pediatric Myocarditis When CMRI or Endomyocardial Biopsy are Not AvailableTable 1CriteriaWithout Another ExplanationA. LV Systolic DysfunctionEF < 55%, FS < 28%, or significant dyskinesisB. LV DimensionsLVEDD Z-score < +3, wall thicknesses >Z-score −3AND supporting evidence from at least one of the following1. Troponin> upper limits of normal2. Ischemic or pericarditic findingsChest pain, pericardial effusion, ECG changes (regional or diffuse ST elevation/depression, PR depression, AV conduction delay)3. Acute heart failureSigns and symptoms of acute heart failureCardiogenic shockHemodynamic instability4. Viral PCR from bloodCommon viruses to consider are Adenovirus, CMV, EBV, Enterovirus, HHV−6, HHV−8, HSV, and Parvovirus*A positive viral PCR/antigen panel from the respiratory tract would be supplemental and can be used to add to borderline criteria above
The mainstay for treatment of acute myocarditis in children is supportive care similar to other forms of acute heart failure.^6^ Close monitoring in an intensive care unit with continuous telemetry, central venous and arterial pressure access is warranted. Ionotropic support with milrinone should be initiated in cases of low cardiac output, with the addition of epinephrine or other vasopressor agents reserved for hypotension or shock due to their higher arrhythmogenic potential.^15^ Following recovery from the acute phase of the illness, patients should be transitioned from ionotropic agents to an oral heart failure regimen for reverse remodeling benefits. The ideal duration of treatment after normalization of function remains unclear.^6^ Registry based and single center studies showed that the majority of pediatric myocarditis patients had normalized LV function, sometimes as early as within a few months of presentation but recovery can also take several years.15, 44, 47
For patients with cardiogenic shock refractory to medical support, MCS should be employed. Pediatric Cardiac Critical Care Consortium registry data from 2014–2021 showed that 21% of patients diagnosed with myocarditis received mechanical circulatory support – ECMO only in 16.7% of patients, ECMO to VAD in 2.4%, extracorporeal cardiac resuscitation in 5%, and VAD only in 1.8%.^42^ Approximately 80% of patients that received MCS survived to discharge.^48^ The need for MCS was associated with mortality, but there was no significant difference in mortality between the above options of MCS.^48^ For patients of adequate size, a percutaneously placed axial pump (Impella) is an attractive option to temporarily support and unload the LV without a septostomy.^49^ Minimum suggested size parameters for placement of the Impella 2.5 device include a minimum LV length of 7.5 cm, which corresponded to a height of 122 cm, weight of 23 kg, and BSA of 0.89 m2 in one study.^50^ One large pediatric heart center study examined outcomes for patients supported with Impella for all conditions and showed 58% survival to recovery, to durable VAD in 14%, and to transplant in 14% of patients by 6 months.^51^ Given the rapid evolution and potential major cardiovascular adverse events, it would be prudent to transfer acute myocarditis patients to a center that offers various forms of MCS and transplantation.
Despite supportive care, roughly one fourth of children either die or undergo cardiac transplantation within three years of diagnosis.^47^ Of the patients listed for transplant in the PHTS database, 3.3% are for myocarditis. They have higher acuity at listing and worse post- transplant survival when compared to patients listed for dilated cardiomyopathy, and their outcomes have not changed in the last three decades.^52^
Additional treatment for pediatric myocarditis is aimed at quelling the injurious viral infection and/or inflammatory response. If a viral source is identified, it is reasonable to treat if there is an available antiviral agent, ideally with consultation from a Pediatric Infectious Disease specialist. Antivirals available in the US include acyclovir and valacyclovir for herpes and varicella, ganciclovir/valganciclovir for CMV, oseltamivir and baloxavir for influenza, remdesivir for COVID, and multiple antivirals for HIV and Hepatitis C.^6^ Cidofovir has been used for adenovirus and ganciclovir for HHV-6, but off-label and primarily in immunocompromised hosts.53, 54 While antivirals have not been thoroughly tested specifically for pediatric myocarditis, the expert opinion of the authors is that the potential benefit of preventing further myocyte damage likely outweighs the risk of side effects.
Studies examining the efficacy of immunomodulators such as IVIG and immunosuppression such as steroids have shown conflicting results with some studies showing no improvement in outcomes, but commonly hampered by small sample sizes. A recent meta-analysis studying the use of corticosteroids for pediatric myocarditis included 604 pediatric patients and showed statistically significant improvement in LV ejection fraction but no statistically significant improvement in survival.^55^ A meta-analysis examining the efficacy of IVIG for pediatric myocarditis included 812 patients treated with IVIG and 592 not treated with IVIG. There was improvement in survival in the IVIG group, but this difference became statistically insignificant when controlling for heterogeneity of the studies.^56^ A 2019 meta-analysis of the use of corticosteroids or IVIG showed improvement in LVEF and survival with IVIG while no change with steroids.^57^ A single-center study of a protocol using high dose steroids with a 10–12-week taper and IVIG for acute myocarditis (modeled after their transplant rejection protocol) showed recovery of ventricular function in 70% of patients and 92.5% transplant free survival at a median follow up of 1 year, with no significant infections or long-term side effects of therapy.^44^
Additional immunomodulatory therapies have been studied in small case studies. Piccininni et al described a case of fulminant myocarditis caused by influenza B that improved with anti- thymocyte globulin.^58^ The use of Anakinra, an IL-1 receptor antagonist, was associated with improvement in myocardial function and myocardial enzymes in 8 patients with acute fulminant myocarditis due to either MISC (7 patients) or parvovirus B19 myocarditis (1 patient).^59^ Four patients over age one year and two patients under age one year with Parvovirus B19 associated myocarditis treated with interferon beta 1B recovered ventricular function.^60^ The immunosuppressive agent muronomab-CD3 was added to a regimen of steroids and IVIG for 15 pediatric myocarditis patients, and 9 patients made a recovery with LVEF of at least 45% within 17 days, one patient recovered after 60 days, 4 died from ECMO complications or gastrointestinal illness, and one patient underwent transplantation.^61^ These cases hold promise for additional targeted immunotherapies for pediatric myocarditis, but more rigorous studies and inclusion of controls is needed to demonstrate benefit.
In summary, it remains difficult to ascertain the diagnosis of myocarditis in children. There is utility in using CMRI and or endomyocardial biopsy to improve the diagnostic certainty when it is feasible. If a clinically based diagnosis is required, either because the biopsy or CMRI is negative or not feasible, then a synthesis of the presenting features (Table 1) can help guide further decision making. For example, a child with a normal sized LV, slightly thick LV walls, LVEF of 35%, troponin and BNP markedly elevated and with signs and symptoms of acute heart failure without any anatomic defects or detectable viral infection would have presumed myocarditis even if the CMRI or biopsy were negative, especially if the intent is to treat myocarditis by immunotherapy by that center.
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.