Update on myocarditis in children

Marla C. Levinea, Darren Klugmanb and Stephen J. Teacha

a
Division of Emergency Medicine, Children’s National
Medical Center and bDivisions of Critical Care
Medicine and Cardiology, Children’s National Heart
Institute, Children’s National Medical Center,
Washington, District of Columbia, USA
Correspondence to Marla Levine, MD, Division of
Emergency Medicine, Children’s National Medical
Center, 111 Michigan Ave, NW, Washington,
DC 20010, USA
Tel: +1 202 476 4177; fax: +1 202 476 3573;
e-mail: mclevine@cnmc.org
Current Opinion in Pediatrics 2010, 22:278–283
Purpose of review
Myocarditis is an uncommon pediatric illness, and it is frequently missed by medical
personnel. It often masquerades as more common pediatric illnesses such as
respiratory distress or gastrointestinal disease. Given that myocarditis accounts for
12% of sudden cardiac death among adolescents and young adults, the suspicion of
this illness in the differential diagnosis of children presenting with nonspecific
symptomatology and disease progression can be lifesaving.
Recent findings
Historically, the diagnosis of myocarditis required endomyocardial biopsy. More recently
ancillary diagnostic modalities have been used to help make the diagnosis less
invasively. The use of laboratory testing, echocardiography, and cardiac MRI can now
make the diagnosis in the absence of invasive biopsy and can help improve the
diagnostic yield when biopsy is performed. Additionally, with an improved
understanding of the pathophysiology of this disease, research has focused on novel
therapeutic interventions such as immunoglobulin therapy and immunosuppressive
therapy in the care of the patient with myocarditis.
Summary
Myocarditis is a challenging diagnosis to make. With advent of newer diagnostic
modalities and an improved understanding of the disease and its progression, there is a
genuine hope that outcomes of pediatric myocarditis will be improved. The first step,
however, is for medical providers to consider this entity in the differential diagnosis of
patients with concerning presentation or illness history.

Keywords
children, diagnosis, myocarditis, treatment

Curr Opin Pediatr 22:278–283

ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
1040-8703

however, given that the myocardial inflammation in

Introduction
Acute myocarditis continues to be a significant cause of
morbidity and mortality among children and young adults
in the United States [1]. With an estimated annual
incidence of 1 per 100 000 [1–5], this rare disease con-
tinues to be implicated in as many as 12% of sudden
cardiac deaths among adolescents and young adults
[1,6,7,8]. Although myocarditis can be secondary to
both viral and non-viral processes, it is thought that
the majority of cases of pediatric myocarditis in children
in the United States occur due to a viral infection [9–11].
In otherwise healthy patients, the pathophysiology of this
disease process involves invasion of the myocardium by
inflammatory cells, with or without necrosis of myocytes
[9,10,12]. The histological classification, referred to as the
Dallas criteria, necessitates an endomyocardial biopsy
(EMB) for diagnosis [10,12]. EMB, the ‘gold standard’
test for diagnosis of myocarditis, enables the identifi-
cation of lymphocytic invasion of cardiac tissue and
allows detection of the involved virus by PCR [13,14].
The sensitivity and specificity of biopsy remain poor,
1040-8703 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
myocarditis tends to be patchy, making it difficult to
biopsy the diseased area of the myocardium [6,15].
Additionally, there is the potential for substantial inter-
observer variation [6,15].
Myocyte destruction in myocarditis is caused by direct
cellular damage by the infectious agent as well as the
innate host immune response [9,14]. In other words, as an
intact immune system is crucial for clearing the virus-
infected cardiac myocytes, it is also the immune response
that is partially responsible for the myocytes’ destruction
[9]. With persistence of viremia and the accompanying
immune response, acute myocarditis can progress to a
more chronic dilated cardiomyopathy [9].
Making the diagnosis of myocarditis can be challenging
due to its subtle clinical signs and symptoms. The diag-
nosis of myocarditis should be suspected whenever a child
presents with unexplained shortness of breath or fatigue, a
new arrhythmia, or acute cardiac failure just following a
viral illness [16]. The purpose of this review is to explore
DOI:10.1097/MOP.0b013e32833924d2

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

the recent advances that have been made in the under-
standing, diagnosis and treatment of myocarditis.
Etiology
Myocarditis is defined as an inflammatory disease of the
myocardium [6]. It can be the result of viruses, bacteria
(i.e. Streptococcus), and parasites (i.e. Trypanosoma cruzi),
or drugs such as anthracyclines [6]. As noted earlier, the
majority of cases of myocarditis in children in the United
States are secondary to a viral infection [9–11] Coxsackie
B is the most well known cardiotoxic virus [6]. How-
ever, a number of other viruses have been implicated,
including adenovirus, Epstein Barr virus, influenza A and
B, human herpes simplex virus type 6, cytomegalovirus
and parvovirus [9,17].
Kuhl et al. [17] recently explored the role of parvovirus as
a cause of myocarditis and found that often, when par-
ovovirus was the inciting agent, endomyocardial biopsies
were negative by the Dallas criteria [17]. These speci-
mens were only notable for mild lymphocytic invasion
(<10 cells/mm2). What was noted, however, was the
predominance of macrophages in these viral specimens.
This leads to the postulate that different viruses have
different pathologic mechanisms for myocyte destruction
(macrophage-dependent vs. lymphocyte-dependent, for
example) [13]. Additionally, this lack of lymphocytic
predominance on endomyocardial biopsies may suggest
an inefficient immune response against the viral
pathogen, resulting in ineffective viral clearance [17].
Most recently, Bratincsak and colleagues reported an
association between pandemic novel H1N1 influenza A
and myocarditis [18]. In their single institution retro-
spective review, during October 2009, four children out of
the 80 who were admitted with novel H1N1 infection had
evidence of myocarditis. Of note, three of the affected
children presented with fulminant disease. They con-
cluded, on the basis of this small case series, that novel
H1N1 infection may pose a greater risk for the develop-
ment of myocarditis than other strains of influenza.
The current understanding of myocarditis is that the
disease evolves in three phases. In the acute phase of
the disease, there is histological evidence of inflammatory
cell invasion of the myocardium and subsequent myo-
cardial necrosis and apoptosis [6]. This initiates the
host’s immune cascade, which is described as the sub-
acute phase of the disease. Natural Killer (NK) cells,
macrophages and T cells are all involved in the immune
cascade [9]. NK cells are believed to be cardioprotective
as they are responsible for limiting viral replication [9]. T
cells have been largely implicated in the inflammatory
response that results in myocardial damage [19,20]. In
addition, macrophage activation has been found to lead to
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Update on myocarditis in children Levine et al. 279
the release of cytokines. Murine mouse models of myo-
carditis have demonstrated that these cytokines are both
protective and directly toxic to myocyte [21].
Although the first wave of the immune cascade causes
myocyte destruction, it has been found that the most
destructive phase of infection occurs approximately
7–14 days following the inoculation, the stage of T-cell
invasion [9,22,23]. The proposed mechanism of this
second phase of disease is through molecular mimicry
such that the T cells nonselectively attack the virus and
the virally infected myocytes [9]. This insight has shaped
current treatment options, which have focused on
immunomodulation and immunosuppressive therapy.
These will be further explored below. The third phase
of the disease is the healing phase, which is characterized
by fibrosis of the involved myocardium [6]. However,
with continued inflammation and persistent viremia, left
ventricular dysfunction and dilation may ensue [6,24].
Clinical presentation
The clinical presentation of children with myocarditis
varies from asymptomatic cases to those with complete
cardiovascular collapse (referred to as acute fulminant
myocarditis) [25]. Presentation varies with age [10].
Neonates may present with nonspecific symptoms
suggestive of infection including fever, listlessness and
poor feeding, or they may present with more ominous
signs including apnea, episodic cyanosis, and diaphoresis
[10]. Of note, inflammatory infiltrates on cardiac muscle
biopsies taken at autopsy from cases of sudden infant
death syndrome (SIDS) have demonstrated myocarditis
as a cause of death [26]. Krous et al. [27] studied a series of
infants who had died of SIDS and noted the presence of
scattered inflammatory cells and necrotic cardiomyocytes
even in infants who did not have myocarditis. They
proposed that this histological finding is likely a normal
event in the developing heart exposed to environmental
pathogens. They did, however, note that the degree of
cardiac infiltration by lymphocytes and macrophages was
more extensive in infants who had died of myocarditis.
The clinical presentation of older children and adoles-
cents is also variable. Most children will present with
nonspecific respiratory or gastrointestinal complaints;
only a minority actually reports chest pain [10]. The
nonspecific nature of such symptoms often results in
the misdiagnosis of myocarditis [28]. In fact, Durani
et al. [29] recently noted that the most frequently
reported signs of myocarditis were nonspecific symptoms
such as shortness of breath (69%), vomiting (48%) or poor
feeding (40%). The same analysis also noted that the
diagnosis of myocarditis was not made on the first pres-
entation to a medical provider in 83% of cases [29].
Although providers often consider tachycardia without a
 280 Emergency and critical care medicine
clearly defined cause (fever or dehydration) as a clue to
the presence of myocarditis [14], Durani et al. [29]
found that 66% of patients with myocarditis in their
series actually had normal heart rates at presentation.
Additionally, other signs of congestive heart failure were
absent in the majority of patients; only 50% had hepa-
tomegaly, and only 34% had abnormal lung examination
[28,29].
Diagnosis
Various diagnostic modalities can be used by the medical
provider to arrive at the diagnosis of myocarditis.
Electrocardiogram and chest radiograph
When there is a suspicion of a myocarditis, most providers
will start the evaluation with an electrocardiogram
(EKG) and a chest radiograph. EKG abnormalities are
noted in anywhere from 93–100% of cases of myocarditis
[28,29]. The most common EKG changes are sinus
tachycardia (46%), ST-T wave changes (32–60%), axis
deviation (53%), and ventricular hypertrophy (46%)
[4,10]. Other possible EKG findings that can be noted
are: infarction patterns, decreased ventricular voltages, or
atrial abnormalities [28]. Chest radiographic findings
have been reported in majority of cases of myocarditis
(69–90%), with cardiomegaly being the most commonly
reported radiographic finding (56–60%) [28,29].
Laboratory investigation
Freedman et al. [28] found that the most sensitive marker
for myocarditis was an elevated aspartate aminotransfer-
ase (AST), which was elevated in 85% of definite and
probable cases of myocarditis. Others have looked at
markers of inflammation, including erythrocyte sedimen-
tation rate and C-reactive protein, and have found that
these have been elevated in anywhere from 27–56% of
cases [4,10]. The utility of cardiac troponins in the
investigation of myocarditis has also been examined.
Cardiac Troponin I is a subunit of a thin filament of
the contractile apparatus of the myocardium [30].
Cardiac Troponin T is a contractile protein unique to
cardiac muscle cell [31]. These markers are cardioselec-
tive and will be released into the blood stream within
hours following cardiac muscle cell injury or death
[30,31]. Cardiac Troponin T has been found to be
elevated in children with myocarditis. A level of more
than 0.052 ng/ml has a sensitivity of 71% and specificity of
86% for pediatric myocarditis [32].
A recent study looked at the incidence of elevated cardiac
enzymes among children hospitalized for viral illness.
The aim of the study performed by Renko et al. [30] was
to determine the rate of subclinical myocarditis among
such patients. Their findings revealed that even among
those few patients with elevated cardiac enzymes, these
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
cases were not consistent with myocarditis. Although
cardiac enzymes can be helpful markers when a patient
has signs and symptoms of myocarditis [33], this marker
was not useful in the diagnosis of subclinical myocarditis
[30].
Echocardiography
Echocardiography assesses cardiac muscle function and
associated valvar insufficiency as well as wall motion
abnormalities. Durani et al. [29] recently showed that
in 98% of cases of pediatric myocarditis, the echocardio-
graphy would be abnormal, with segmental wall motion
abnormalities being the most common findings (hypo-
kinesia, akinesia and dyskinesia) [34].
Endomyocardial biopsy
Although EMB is the historical gold standard for the
diagnosis of myocarditis, it is invasive and a potentially
dangerous procedure, especially in the pediatric patient
[35]. The potential complications associated with this
procedure include pneumothorax, hemothorax, dysrhyth-
mia, heart block, perforation and death [35]. As a screen-
ing tool, EMB is insensitive due to the patchy nature of
myocardial inflammation [6,15]. When used with con-
current PCR and in-situ hybridization, it allows rapid
detection and identification of the viral genetic material
[36].
Noninvasive diagnostic modalities
Recent interest has focused on the use of noninvasive
modalities for the diagnosis of myocarditis. Although
echocardiography is helpful in elucidating wall motion
abnormalities, cardiac MRI (CMR) can actually detect
the often subtle patchy myocardial involvement [22,26].
CMR visualizes the whole myocardium, allowing demar-
cation of inflammation from later remodeling [10]. It,
therefore, not only detects myocarditis, but also
quantifies the extent of damage, can be used to guide
the execution of the EMB and can be used to monitor
lesions [15,34]. Gadolinium is the contrast agent that is
used because it penetrates those cells that have lost their
cell membrane integrity and allows diffusion of the
contrast agent into the intracellular space [26]. Signal
enhancement correlates with myocardial blood flow and
edema, which tends to be increased in those tissues that
are inflamed [15,26]. However, on first pass perfusion,
CMR features of myocarditis can be missed [34]. It is the
delayed enhancement images that allow visualization of
the necrotic and fibrotic myocardium [37], which are
largely located in the lateral free wall in cases of myo-
carditis, localized to the subepicardial and intramyocar-
dial regions [15,26,34,38].
In a recent retrospective study that looked at the use of
CMR in children as a predictor of outcome, Vashist et al.
[10,39] found that myocarditis in the pediatric population

is characterized primarily by subepicardial and transmural
enhancement. When CMR has been used to determine
outcome, the findings that have been associated with
poor outcome have been transmural myocardial involve-
ment, global hypokinesia, left ventricular dilatation, and
left ventricular ejection fraction less than 30% [10,39].
On the basis of the strong evidence supporting CMR’s role
in the diagnosis of myocarditis, in April 2009 the Inter-
national Consensus Group on CMR Diagnosis of Myo-
carditis (Lake Louis Consensus Criteria) proposed the
following diagnostic criteria for myocarditis [37]. In
the setting of clinically suspected myocarditis, CMR find-
ings are consistent with myocardial inflammation if at least
two of the following criteria are present: regional or global
myocardial signal increase in T2-weighted images;
increased global myocardial early gadolinium enhance-
ment ratio between myocardium and skeletal muscle in
gadolinium-enhanced T1-weighted images; at least one
focal lesion with nonischemic regional distribution in
inversion recovery-prepared gadolinium-enhanced T1-
weighted images (‘late gadolinium enhancement’).
A CMR study is consistent with myocyte injury and/or
scar caused by myocardial inflammation if Criterion 3 is
present. A repeat CMR study between 1 and 2 weeks
after the initial CMR study is recommended if:
(1) None of the criteria are present, but the onset of
symptoms has been very recent and there is strong
clinical evidence for myocardial inflammation.
(2) Only one of the criteria is present.
Treatment
The cornerstones of treatment for myocarditis in children
remain supportive, and many patients will recover with-
out long-term cardiac sequelae [11]. However, some will
suffer continued cardiac compromise including the devel-
opment of dilated cardiomyopathy and even sudden
cardiac death. In the acute phase of the disease, current
practice is to support the patient to the degree needed with
inotropes, afterload reduction, mechanical ventilation, or
extracorporeal membrane oxygenation (ECMO) as the
condition warrants [10].
Several investigators have examined the utility of adju-
vant therapeutic interventions aimed at preventing long-
term cardiac compromise. Intravenous immunoglobulin
(IVIG) has been the most common agent studied [11,40].
As noted earlier, an autoimmune response may be
responsible for the majority of the myocardial damage
[41]; targeting this process should improve outcome [40].
Some reports have demonstrated increased survival
among those managed with IVIG therapy and especially
among children [11,40,42]. Drucker et al. [40] found a
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Update on myocarditis in children Levine et al. 281
statistically significant improvement in survival outcomes
of pediatric patients with myocarditis treated with high-
dose IVIG. McNamara et al. [43] conducted the only
randomized control trial to date, among adults, and failed
to show improved survival or improved left ventricular
function in those patients with myocarditis treated with
high-dose IVIG. Additionally, in a recent multicenter
study that looked at outcomes of pediatric patients with
myocarditis, the use of IVIG did not impart a survival
advantage [44].
Immunosuppressive therapies are possible adjuvants to
therapeutic modalities for myocarditis management [45].
Camargo et al. [46] performed the sole randomized con-
trol trial to date, which looked at immunosuppressive
therapy in children with biopsy proven viral myocarditis.
Patients were randomized to treatment arms, but out-
comes were not blinded. Patients were randomized to
receive prednisone alone, prednisone and azathioprine or
prednisone, azathioprine and cyclosporine. The authors
of this study concluded that combination immunosup-
pressive therapy lead to improvement in cardiac outcome
[46]. Hia et al. [47] performed a meta-analysis evaluating
the current literature on the benefit of immunosuppres-
sive therapy for management of acute viral myocarditis.
They determined that, while the odds of improved out-
come were noted among patients who received immu-
nosuppressive therapy, the results were not statistically
significant [47]. The prevailing consensus is that, in order
to conclude that immunosuppressive therapy does in fact
impart a survival advantage, a large multicenter random-
ized control trial is warranted [47].
Beta blockers, specifically carvedilol, have also been
investigated in terms of their therapeutic benefit in
patients with heart failure. Beta blockers are well known
to improve survival in adult patients with congestive
heart failure [48]. A 2009 Cochrane review examined
the current evidence for the use of beta blockers in
children with congestive heart failure. Three randomized
controlled trials with 20, 22 and 161 patients, respec-
tively, were analyzed. Although a therapeutic benefit was
noted in the two smaller studies, the larger study failed to
demonstrate a statistically significant benefit among
those patients with congestive heart failure who received
beta-blockers [48,49].
Outcome
Although estimates have suggested that the incidence of
myocarditis is approximately 1 per 100 000 [1–5], the true
incidence remains largely unknown due to the significant
number of cases that go undiagnosed [10]. The outcome
of acute myocarditis is, therefore, difficult to characterize
[25,50]. Some children will have complete myocardial
recovery; some will die, whereas others will progress to
 282 Emergency and critical care medicine
dilated cardiomyopathy with an ultimate requirement for
cardiac transplantation [25,51]. According to Greenwood
et al.’s [52] 30-year study of outcomes of 161 children with
primary myocardial disease (myocarditis, nonobstrucu-
tive cardiomyopathy and endomyocardial fibroelastosis),
nearly a third had full recovery, a third died, and a third
had continued cardiac compromise. Patients with acute
fulminant myocarditis have a more clearly defined course.
They often present with abrupt-onset cardiovascular
collapse and require aggressive intensive care manage-
ment [25]. Despite this, they usually have a favorable
long-term survival [25,53]. As Lee et al. [50] noted, those
patients who survived beyond 72 h without the need for
ECMO had a 97% increased likelihood of survival. Kuhn
et al. [16] went on to further describe the clinical features
on presentation that were associated with adverse out-
comes. Ejection fraction less than 30%, a shortening
fraction less than 15% and moderate-to-severe mitral
regurgitation were all associated with ultimate develop-
ment of severe cardiac failure [16].
Conclusion
Myocarditis will continue to challenge medical providers
due to its propensity to occur in young and healthy hosts
and to masquerade as benign childhood illness. With the
advent of new diagnostic techniques and continued
research into adjuvant therapeutic strategies, morbidity
and mortality from this disease can hopefully be lessened.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
 of special interest
 of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 370–371).
1 Stiller B. Management of myocarditis in children: the current situation. Adv Exp
Med Biol 2008; 609:196–215.
2 Karjalainen J, Heikkila J. Incidence of three presentations of acute myocarditis
in young men in military service. A 20-year experience. Eur Heart J 1999;
20:1120–1125.
3 Wakafuji S, Okada R. Twenty year autopsy statistics of myocarditis incidence
in Japan. Jpn Circ J 1986; 50:1288–1293.
4 Nugent AW, Daubeney PE, Chondros P, et al. The epidemiology of childhood
cardiomyopathy in Australia. N Engl J Med 2003; 348:1639–1646.
5 Lipshultz SE, Sleeper LA, Towbin JA, et al. The incidence of pediatric
cardiomyopathy in two regions of the United States. N Engl J Med 2003;
348:1647–1655.
6 Sparrow PJ, Merchant N, Provost YL, et al. CT and MR imaging findings in
 patients with acquired heart disease at risk for sudden cardiac death. Radio-
graphics 2009; 29:805–823.
A review of the the utility of computed tomography (CT) and MR as diagnostic
modality in the evaluation of conditions associated with sudden cardiac death.
7 Noren GR, Staley NA, Bandt CM, Kaplan EL. Occurrence of myocarditis in
sudden death in children. J Forensic Sci 1977; 22:188–196.
8 Theleman KP, Kuiper JJ, Roberts WC. Acute myocarditis (predominately
lymphocytic) causing sudden death without heart failure. Am J Cardiol
2001; 88:1078–1083.
9 Kearney MT, Cotton JM, Richardson PJ, Shah AM. Viral myocarditis and
dilated cardiomyopathy: mechanisms, manifestations, and management.
Postgrad Med J 2001; 77:4–10.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
10 Vashist S, Singh GK. Acute myocarditis in children: current concepts and
management. Curr Treat Options Cardiovasc Med 2009; 11:383–391.
11 Robinson J, Hartling L, Vandermeer B, et al. Intravenous immunoglobulin for
presumed viral myocarditis in children and adults. Cochrane Database Syst
Rev 2005:CD004370.
12 Aretz HT, Billingham ME, Edwards WD, et al. Myocarditis. A histopathologic
definition and classification. Am J Cardiovasc Pathol 1987; 1:3–14.
13 Bowles NE, Bowles KR, Towbin JA. Viral genomic detection and outcome in
myocarditis. Heart Fail Clin 2005; 1:407–417.
14 Bohn D, Benson L. Diagnosis and management of pediatric myocarditis.
Paediatr Drugs 2002; 4:171–181.
15 Danti M, Sbarbati S, Alsadi N, et al. Cardiac magnetic resonance imaging:
 diagnostic value and utility in the follow-up of patients with acute myocarditis
mimicking myocardial infarction. Radiol Med 2009; 114:229–238.
This observational study detailed the MRI findings that are consistent with
myocarditis and how this can be used in the evaluation of the patient with signs
and symptoms concerning for myocardial infarction.
16 Kuhn B, Shapiro ED, Walls TA, Friedman AH. Predictors of outcome of
myocarditis. Pediatr Cardiol 2004; 25:379–384.
17 Kuhl U, Pauschinger M, Bock T, et al. Parvovirus B19 infection mimicking
acute myocardial infarction. Circulation 2003; 108:945–950.
18 Bratincsak A, El-Said HG, Bradley JS, Shayan K, Grossfeld PD, Cannavino
 CR. Fulminant Myocarditis Associated With Pandemic H1N1 Influenza A
Virus in Children. J Am Coll Cardiol 2010; 55:928–929.
This important letter to the editor reports on a case series of children who
developed myocarditis in association with novel H1N1 infection.
19 Bohn D. Acute viral myocarditis. Pediatri Crit Care Med 2006; 7:3–24.
20 Shekerdemian L, Bohn D. Acute viral myocarditis:Epidemiology and Patho-
physiology. Pediatr Crit Care Med 2006; 7:6.
21 Matsumori A. Molecular and immune mechanisms in the pathogenesis of
cardiomyopathy: role of viruses, cytokines, and nitric oxide. Jpn Circ J 1997;
61:275–291.
22 Goitein O, Matetzky S, Beinart R, et al. Acute myocarditis: noninvasive
evaluation with cardiac MRI and transthoracic echocardiography. AJR Am
J Roentgenol 2009; 192:254–258.
23 Kishimoto C, Kuribayashi K, Masuda T, et al. Immunologic behavior of
lymphocytes in experimental viral myocarditis: significance of T lymphocytes
in the severity of myocarditis and silent myocarditis in BALB/c-nu/nu mice.
Circulation 1985; 71:1247–1254.
24 Kawai C. From myocarditis to cardiomyopathy: mechanisms of inflammation
and cell death: learning from the past for the future. Circulation 1999;
99:1091–1100.
25 Amabile N, Fraisse A, Bouvenot J, et al. Outcome of acute fulminant myo-
carditis in children. Heart 2006; 92:1269–1273.
26 Friedrich MG, Strohm O, Schulz-Menger J, et al. Contrast media-enhanced
magnetic resonance imaging visualizes myocardial changes in the course of
viral myocarditis. Circulation 1998; 97:1802–1809.
27 Krous HF, Ferandos C, Masoumi H, et al. Myocardial inflammation, cellular
death, and viral detection in sudden infant death caused by SIDS, suffocation,
or myocarditis. Pediatr Res 2009; 66:17–21.
28 Freedman SB, Haladyn JK, Floh A, et al. Pediatric myocarditis: emergency
department clinical findings and diagnostic evaluation. Pediatrics 2007;
120:1278–1285.
29 Durani Y, Egan M, Baffa J, et al. Pediatric myocarditis: presenting clinical
 characteristics. Am J Emerg Med 2009; 27:942–947.
This descriptive study detailed the clinical profiles of patients associated with
acute myocarditis and describes how these can be used to distinguish myocarditis
from other diseases in the pediatric patient.
30 Renko M, Leskinen M, Kontiokari T, et al. Cardiac troponin-I as a screening tool
 for myocarditis in children hospitalized for viral infection. Acta Paediatr 2009.
[Epub ahead of print]
This observational study aimed to ascertain the number of patients with viral illness
who have subclinical myocarditis using Troponin I (TnI) as a diagnostic tool.
31 Franz WM, Remppis A, Kandolf R, et al. Serum troponin T: diagnostic marker
for acute myocarditis. Clin Chem 1996; 42:340–341.
32 Soongswang J, Durongpisitkul K, Ratanarapee S, et al. Cardiac troponin T:
its role in the diagnosis of clinically suspected acute myocarditis and
chronic dilated cardiomyopathy in children. Pediatr Cardiol 2002; 23:531–
535.
33 Lippi G, Salvagno GL, Guidi GC. Cardiac troponins in pediatric myocarditis.
Pediatrics 2008; 121:864; author reply 864–865.
34 Skouri HN, Dec GW, Friedrich MG, Cooper LT. Noninvasive imaging in
myocarditis. J Am Coll Cardiol 2006; 48:2085–2093.

35 Pophal SG, Sigfusson G, Booth KL, et al. Complications of endomyocardial
biopsy in children. J Am Coll Cardiol 1999; 34:2105–2110.
36 Checchia PA, Kulik TJ. Acute viral myocarditis: Diagnosis. Pediatr Crit Care
Med 2006; 7:4.
37 Friedrich MG, Sechtem U, Schulz-Menger J, et al. Cardiovascular magnetic
 resonance in myocarditis: a JACC White Paper. J Am Coll Cardiol 2009;
53:1475–1487.
Consensus guidelines that delineate the indications, protocols and diag-
nostic criteria for the use of cardiac MR in the patient with suspected myo-
carditis.
38 Mahrholdt H, Goedecke C, Wagner A, et al. Cardiovascular magnetic
resonance assessment of human myocarditis: a comparison to histology
and molecular pathology. Circulation 2004; 109:1250–1258.
39 Vashist S, Woodard PK, Grady M, Singh G. MRI characteristics of acute
myocarditis in pediatric patients: patterns and predictors of outcomes
[abstract]. St Louis Washington University School of Medicine; 2009.
40 Drucker NA, Colan SD, Lewis AB, et al. Gamma-globulin treatment of
acute myocarditis in the pediatric population. Circulation 1994; 89:252–
257.
41 Kishimoto C, Abelmann WH. In vivo significance of T cells in the development
of Coxsackievirus B3 myocarditis in mice. Immature but antigen-specific T
cells aggravate cardiac injury. Circ Res 1990; 67:589–598.
42 Camargo PR, Okay TS, Yamamoto L, et al. Myocarditis in children and
 detection of viruses in myocardial tissue: implications for immunosuppressive
therapy. Int J Cardiol 2009. [Epub ahead of print]
This observational study evaluated the outcomes of children with chronic myo-
carditis treated with immunosuppressive therapy.
43 McNamara DM, Holubkov R, Starling RC, et al. Controlled trial of intravenous
immune globulin in recent-onset dilated cardiomyopathy. Circulation 2001;
103:2254–2259.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Update on myocarditis in children Levine et al. 283
44 Klugman D, Berger JT, Sable CA, et al. Pediatric patients hospitalized with
 myocarditis: a multi-institutional analysis. Pediatr Cardiol 2009. [Epub ahead
of print]
This descriptive study aimed to assess hospital and patient level variables that
could help predict myocarditis outcomes. Considerable variability was noted
among the cases, resulting in an inability to predict outcome based on character-
istics of the patient or level of severity on presentation.
45 Feltes TF, Adatia I. Immunotherapies for acute viral myocarditis in the pediatric
patient. Pediatr Crit Care Med 2006; 7:S17–S20.
46 Camargo PR, Snitcowsky R, da Luz PL, et al. Favorable effects of immuno-
suppressive therapy in children with dilated cardiomyopathy and active
myocarditis. Pediatr Cardiol 1995; 16:61–68.
47 Hia CP, Yip WC, Tai BC, Quek SC. Immunosuppressive therapy in acute
myocarditis: an 18 year systematic review. Arch Dis Child 2004; 89:580–584.
48 Frobel AK, Hulpke-Wette M, Schmidt KG, Laer S. Beta-blockers for congestive
 heart failure in children. Cochrane Database Syst Rev 2009:CD007037.
This Cochrane Review evaluated the outcomes of children with congestive heart
failure who received beta-blockers as part of the treatment regimen. The result of
this meta-analysis was that there continues to be a lack of evidence to support or
discourage this form of therapeutic management in pediatric patients with CHF.
49 Shaddy RE, Boucek MM, Hsu DT, et al. Carvedilol for children and adolescents
with heart failure: a randomized controlled trial. JAMA 2007; 298:1171–1179.
50 Lee KJ, McCrindle BW, Bohn DJ, et al. Clinical outcomes of acute myocarditis
in childhood. Heart 1999; 82:226–233.
51 Feldman AM, McNamara D. Myocarditis. N Engl J Med 2000; 343:1388–1398.
52 Greenwood RD, Nadas AS, Fyler DC. The clinical course of primary myo-
cardial disease in infants and children. Am Heart J 1976; 92:549–560.
53 Daubeney PE, Nugent AW, Chondros P, et al. Clinical features and outcomes
of childhood dilated cardiomyopathy: results from a national population-based
study. Circulation 2006; 114:2671–2678.