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Prognosis for neonates with enterovirus myocarditis
  1. Matthias W Freund1,
  2. Gitta Kleinveld2,
  3. Tannette G Krediet2,
  4. Anton M van Loon3,
  5. Malgorzata A Verboon-Maciolek2
  1. 1Department of Pediatric Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands
  2. 2Department of Neonatology, University Medical Center Utrecht, Utrecht, The Netherlands
  3. 3Department of Virology, University Medical Center Utrecht, Utrecht, The Netherlands
  1. Correspondence to Dr M A Verboon-Maciolek, Department of Neonatology, University Medical Center Utrecht, KE 04.123.1, Lundlaan 6, 3584 EA Utrecht, The Netherlands; m.verboon-maciolek{at}umcutrecht.nl

Abstract

Objective To assess the severity of the disease and the long-term cardiac prognosis for neonates who developed enterovirus (EV) myocarditis within the first weeks of life.

Design Clinical presentation, echocardiographic and ECG findings and the outcome of seven infants with EV myocarditis admitted to the intensive care unit are reported. Additionally, 28 previously reported cases are described.

Results Seven neonates presented with cardiac failure within 17 days after birth requiring respiratory and circulatory support. Echocardiography showed dilatation and severe dysfunction of the left ventricle in all and mitral regurgitation in six. In six patients the echocardiographic pattern resembled myocardial infarction. ECG showed complete loss of the R-wave and a new Q-wave in the left precordial leads in all. Two infants died and five developed long-term cardiac sequelae requiring medication. In all survivors aneurysm formation in the left ventricular wall was found weeks to months later. One patient is awaiting heart transplantation. Coxsackie virus B was detected in blood, cerebrospinal fluid, nasopharyngeal swab or stool by PCR or culture. The mortality of previously described neonates combined with our seven cases was 31% (11/35). Among the survivors 66% (16/24) developed severe cardiac damage. Only 23% (8/35) of the infants fully recovered.

Conclusions EV myocarditis is a rare but severe disease in the neonatal period, which often leads to death or results in serious chronic cardiac sequelae like chronic heart failure, aneurysm formation within the left ventricle and mitral regurgitation. Chronic cardiac drug therapy is necessary in the majority of these patients.

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Introduction

Enteroviruses (EVs) are a common cause of infection in neonates and infants younger than 3 months of age, especially during the summer and autumn months.1,,3 Severe EV diseases such as meningoencephalitis, severe hepatitis and myocarditis occur mostly in the neonatal period.1 2 4

EV myocarditis occurs sporadically and therefore patients are usually reported as case reports. In 2004, Inwald et al stressed the destructive nature of neonatal EV myocarditis based on short-term outcome of seven infants.5 Coxsackie viruses of group B (CVB) are the predominant causative agents of acute and chronic EV myocarditis which damage the heart primarily via direct lysis of infected myocytes.6 7 Mortality and long-term cardiac prognosis for survivors of EV myocarditis in the neonatal period have not been well studied previously.8

The aim of this study was to describe the clinical presentation, echocardiography and electrocardiogram (ECG) findings and long-term outcome of seven newborn infants with EV myocarditis. In addition, the clinical data and outcome of 28 previously reported cases were analysed to better define the severity of EV myocarditis in the neonatal period.

What is already known on this topic

  • Neonatal enterovirus myocarditis is a rare and devastating disease.

  • Coxsackie B viruses are the predominantly agents of neonatal myocarditis.

What this study adds

  • Majority of survivors of neonatal enterovirus myocarditis develop severe cardiac sequelae like chronic heart disease and aneurysm formation within the left ventricle.

  • Absence of the R-wave and presence of a new Q-wave in I, II and the left precardial leads on ECG may be of value in the diagnosis of neonatal myocarditis.

Patient and methods

Between April 1994 and October 2008, seven full-term neonates with EV myocarditis were treated in the Wilhelmina Children's Hospital, University Medical Center, Utrecht, which is a tertiary referral centre.

Cardiac evaluation

Echocardiography included morphology, diastolic and systolic diameter of the left ventricle and left atrium, fractional shortening of the left ventricle, presence or absence of mitral and tricuspid regurgitation on admission, during the hospital stay and after discharge every 2–6 months. The normal values for neonates we used were described previously.9 Furthermore, a 12-lead standard ECG, serum cardiac enzymes as creatine kinase-MB were performed on admission and since 2006 troponin and B-type natriuretic peptide were included in the diagnostic work-up of cardiac failure. Cardiac follow-up was performed in all survivors.

Viral diagnosis

Viral diagnosis was confirmed by positive real-time EV polymerase chain reaction (RT-EV PCR) on blood and/or cerebrospinal fluid in five infants and by positive EV culture on nasopharyngeal swab, stool or cerebrospinal fluid in two infants. RT-EV PCR was performed using viral RNA extracted from different specimens as previously described.10 Finally, serologic tests were performed in two infants to show a significant increase of EV-specific antibody titre.

Results

Clinical data

Five of seven infants were born by vaginal delivery and two by caesarean section because of signs of infection of the mother. Three infants presented during the enteroviral season. All infants were full term and birth weight ranged from 2915 to 4040 g. All presented with symptoms suggesting bacterial neonatal infection within the first 17 days of life (table 1). One infant developed hepatitis and in four infants (patient 2, 4, 5 and 6) evidence of cerebral EV infection was found. Two of these four patients developed seizures.

Table 1

The clinical characteristics and extremes of laboratory results of seven infants with EV myocarditis

Cardiac pathology

On admission all infants presented with poor left ventricular function (table 2). An ECG revealed severely decreased left ventricular function and the shortening fraction was 18% or less in all patients. In six patients a moderate to severe mitral regurgitation was present. Hyperechogenity with akinetic or hypokinetic areas of the posterior wall, or the anterolateral papillary muscle of the left ventricle and the ventricular septum were found initially in six infants suggesting myocardial infarction (figure 1). An anomalous origin of the coronary arteries could be excluded by echocardiography in six and by angiography in one. Dilatation of the left ventricle could not be seen on admission but developed during hospital stay in all but one of the patients.

Figure 1

Four chamber view (A) and short axis view (B) of the left ventricle (LV) from patient 5 on admission. Circumscript hyperechogenic area (arrows) of the interventricular septum (IVS) and parts of the anterolateral papillary muscle of the LV. IVS, interventricular septum, LA, left atrium; RA, right atrium; RV, right ventricle.

Table 2

ECG and echocardiography findings on admission and 2 months later and outcome of seven infants with EV myocarditis

On admission all neonates had moderate to severe signs of extensive subendocardial injury (ST-depression) on ECG, but only one (patient #1) showed ST-segment elevation. In all patients a complete loss of the R-wave and the appearance of a new Q-wave was documented (figure 2). In all survivors ECG changes returned to normal within 2 months.

Figure 2

ECG from patient 6 on admission. Depolarisation disturbance and absence of R-wave and deep Q in I, II and V5–V6 (arrows).

Patient #3 developed a supraventricular tachycardia on admission and patient #5 a ventricular tachycardia on day 3 after admission, which both were treated successfully with amiodarone.

Outcome

Two infants (patient #2 and patient #6) died at the age of 3 weeks (10 days after admission) and 7 weeks (5.5 weeks after admission), the latter being on extracorpral membrane oxygenation (ECMO) for 5 weeks, respectively (table 2). None of the survivors fully recovered. All developed dilated cardiomyopathy with mild or severe aneurysm formation within the left ventricle (figure 3) and were followed 13 months to 15.7 years.

Figure 3

Long axis of the left ventricle (LV) from patient 3 at 5 years of age (A) and apical two-chamber view of the LV from patient 4 at 17 months of age (B). Note a large aneurysm in the basal part of the left ventricular posterior wall in both patients. AO, aorta; LA, left atrium; LV-A, left ventricle aneurysm; RA, right atrium; RV, right ventricle.

Virology

The site of isolation of EV and the serotype of EV is given in table 1. In one infant (patient #2) vertical transmission of EV infection was documented.

Literature review

Data for this review were collected by searching for articles on neonatal EV myocarditis in the PubMed database up to December 2008. We searched only for English literature. Search terms were ‘enterovirus’ in combination with ‘myocarditis’, ‘neonates’, ‘infants’ and ‘dilated cardiomyopathy’. The first review by Kaplan et al on CVB infections in infants with six cases of neonatal EV myocarditis was not included in our analysis because the data of these infants were incomplete.8 In total, 16 articles with 28 sporadic and detailed described cases of EV myocarditis were published between 1989 and 2008.5 11,,25 These 28 cases of neonatal EV myocarditis were included in our analysis of the literature to estimate the severity of the disease (table 3). The clinical signs of EV infection were fever, lethargy, poor feeding, respiratory distress, irritability and poor peripheral perfusion. There were 21 full-term or near term infants and seven preterm infants born <36 weeks of gestation. The median day of onset of symptoms was 6 days (range 1–18 days) after birth. The male/female ratio was 12:10 in the 22 cases for which gender was given. The diagnosis of EV infection in infants was made by EV PCR or virus culture. In 13 patients (46%) the viral strains were typed and CVB1–4 were identified. Seventeen (61%) mothers had a history of viral disease prior to delivery. Twelve patients (43%) developed dysrhythmias. Twelve infants (43%) had signs of disturbed depolarisation on ECG and in two infants the ECG findings were interpreted as myocardial infarction. In one infant, a poor R-wave progression was described.5 Two infants developed extensive areas of bright myocardium (hyperechogenity) suggesting necrosis of the left ventricle and developed calcifications.22 24 In another infant, an aneurysm of the left posterobasal segment of the left ventricle was described at 12-month follow-up.16

Table 3

Characteristics of 28 neonates diagnosed with EV myocarditis previously reported in the English literature 1989–2008

Eight (28%) of the reported patients were treated with pleconaril next to supportive therapy. In addition to pleconaril, four neonates were treated with intravenous immunoglobulin (IVIG). Three of them died and only one survived without sequelae. Another infant who was exclusively treated with IVIG died too. Four patients who were put on ECMO and three of them died.5

The mortality was 32% (9/28) and 58% (11/19) of survivors developed severe cardiac sequelae. None of the preterm infants died and 4/7 (58%) of preterm survivors developed cardiac sequelae similar to 7/12 (58%) of full-term/near term survivors.

Overall analysis (seven own cases and the cases from literature summarised)

The overall mortality among 35 patients with EV myocarditis (7seven cases in this report and 28 from the literature) was 31% (11/35) and 66% (16/24) of survivors developed severe cardiac sequelae. Only 23% (8/35) of all infants fully recovered.

Discussion

Our report highlights the high mortality and high incidence of long-term severe cardiac sequelae among infants with EV myocarditis caused by CVBs. None of our seven patients fully recovered and only 28% (8/28) of previously reported infants survived without sequelae. The majority, 66% (16/24) of survivors, developed sequelae, irrespective of the gestational age.

In contrast to a review on EV infections in infants and children at the end of the 1990s, our study shows a lower overall mortality (31%).3 Interestingly, none of the preterm infants died. This better survival rate may be due to improved neonatal intensive care during the last decade.

Our study demonstrates that this devastating disease predominantly occurs within the first 2 weeks of life and in the majority (61%) of cases maternal disease existed prior to or shortly after the delivery.3 4

It is known that neonatal EV myocarditis may present with arrhythmias, congestive heart failure and cardiogenic shock and can mimic any other neonatal infection.5 The cardiovascular collapse due to myocarditis may occur several days after EV sepsis/meningitis during the second wave of a biphasic pattern of EV infection.

Very little information is available regarding the long-term cardiac outcome of neonates who survive EV myocarditis. A most recent review on this issue mentioned that the prognosis for survivors of myocarditis is favourable.4 This is in contrast to the results of our study. The pathological changes in the myocardial tissue caused by EV are associated with an unfavourable outcome. EV damages the myocardium primarily via direct lysis and apoptotic degeneration of infected myocytes in the absence of a localised ischaemic event.6 7 26 27 This myocyte necrosis is mimicking myocardial infarction and will be replaced by a scar. Later in life this may turn into an aneurysm of the left ventricle as it frequently occurs in patients with myocardial infarction.15 16 26 Akinetic, hypokinetic and hyperechogenic areas within the left ventricle on echocardiography as shown in figure 1, have been found in all seven infants with EV myocarditis. All of our survivors developed dilated cardiomyopathy with mild or severe aneurysm formation (figure 3) within the left ventricular wall and mild to severe left ventricular dysfunction. Aneurysm formation among infants with EV myocarditis has been reported once previously and its use is limited to short-term cardiopulmonary support.5 31

is probably under-reported due to short follow-up period of described patients.16

ECG changes in neonatal myocarditis are variable and include ST-segment elevation or depression, T wave inversion or flattening, prolonged QTc, QRS widening, abnormalities in atrioventricular conduction and brady or tachyarrhythmia. The dominant and consistent ECG features of subendocardial injury in our seven patients at admission were the development of a new Q-wave and an absence of R-wave in I, II and in the left precordial leads, in addition to other repolarisation abnormalities. Although the sensitivity of ECG findings in myocarditis is low, a pathological Q-wave mimicking myocardial infarction has been described earlier in adults.28,,30 In none of previously described neonatal EV myocarditis cases this ECG feature has been mentioned, even it was visible on a ECG.5 We believe that this uniform ECG feature representing severe myocardial ischaemia has an important additional value in the diagnosis of myocarditis in infants.

The diagnosis of EV myocarditis can be rapidly confirmed by RT-EV PCR in sterile body fluids. No specific antiviral treatment exists for EV myocarditis and in all cases respiratory and circulatory support was required. The value of pleconaril (antipicornavirus drug) in the treatment of patients with neonatal EV myocarditis has not yet been established. None of our patients received pleconaril which at present is not available. Only one patient who was treated with pleconaril previously, fully recovered.17 The possible treatment at this moment is to administer IVIG although there is no clear evidence for its effectiveness. The therapy should be started as early as possible before severe necrosis of the myocytes has occurred.

Treatment with ECMO in neonatal EV myocarditis has been sporadicaly reported. One of our patients and three of the four previously reported patients who were treated with ECMO, died.5 The benefit of ECMO is controversial, because its use is limited to short-term cardiopulmonary support.5 31 32 Another concept of mechanical support in these patients is the use of a left ventricular assist device as Berlin Heart.32 Early heart transplantation in neonatal EV myocarditis is not investigated. One survivor of EV myocarditis after succesful heart transplantation at day 23 of life is described.22 The shortage of donors in this age group limits this therapeutic option.22 33 All patients with neonatal EV myocarditis need long-term cardiac follow-up. Drug therapy for chronic heart failure is required in the majority of survivors and for several of these patients heart transplantation will be necessary.34 35

Our study has several limitations. The follow-up period of several previously reported cases with neonatal EV myocarditis was short. Therefore mortality and morbidity in the long-term cardiac follow-up can only be assumed rather than measured. Knowing that aneurysm formation can occur weeks to months after neonatal EV myocarditis we suspect that several survivors developed cardiac sequelae months after publication and long-term cardiac prognosis for the survivors of neonatal EV myocarditis may even be worse than estimated in our study.

Conclusion

EV myocarditis is a rare and life-threatening disease occurring in the first 2 weeks of life with clinical symptoms suggesting bacterial sepsis, accompanied by congestive heart failure, cardiogenic shock and arrhythmias. Due to extensive myocyte necrosis in the left ventricle symptoms may mimic myocardial infarction. A typical ECG finding with absence of the R-wave and a new Q-wave in I and II and the left precardial leads is an important finding on admission. Even in the presence of sufficient respiratory and circulatory support, the mortality among neonates with EV myocarditis is high. The majority of survivors develop serious cardiac sequelae like chronic heart failure, mitral regurgitation and aneurysm formation within the left ventricle requiring long-term cardiac drug therapy. Since neonatal EV myocarditis is such a devastating disease, more research should be aimed at the development of effective vaccination or antiviral strategies.

References

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Footnotes

  • Competing interests None.

  • Provenance Not commissioned; not externally peer reviewed.

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