Human herpesvirus 6-induced inflammatory cardiomyopathy in immunocompetent children.

Over the last decade, human herpesvirus 6 (HHV-6) has been implicated in the etiology of pediatric myocarditis and subsequent dilated cardiomyopathy (DCM). This review provides an overview of recent literature investigating the pathophysiological relevance of HHV-6 in inflammatory cardiomyopathy. We examined 11 cases of previously published pediatric myocarditis and/or DCM associated with HHV-6 and also our experience of detection of virus particles in vascular endothelium of HHV-6 positive endomyocardial biopsy tissue by electron microscopy. The exact role of the presence of HHV-6 and its load remains controversial as the virus is also found in the heart of healthy controls. Therefore, the question remains open whether and how cardiac HHV-6 may be of pathogenetic importance. Quantitative polymerase chain reaction or mRNA testing allows differentiation between low-level latent virus found in asymptomatic myocardium and active HHV-6 infection. Although only a small number of pediatric cases have been reported in literature, HHV-6 should be considered as a causative agent of inflammatory cardiomyopathy, especially in children under three who might be experiencing a primary infection. Future studies are needed to establish a threshold for determining active infection in biopsy samples and the role of coinfections other cardiotropic viruses.

INTRODUCTION

The current recommendations from an American College of Cardiology Foundation/American Heart Association/European Society of Cardiology scientific statement support a limited role for endomyocardial biopsy (EMB) in the evaluation of patients with dilated cardiomyopathy (DCM). The Class I indications are limited to patients with new-onset heart failure (<2 weeks) associated with a normal or dilated left ventricle with hemodynamic compromise and to patients with new-onset heart failure of 2 weeks to 3 months’ duration with a dilated left ventricle, ventricular arrhythmia, or high degree atrioventricular blockade or to patients whose condition fails to respond to treatment in 1–2 weeks.[1] With the development of new molecular techniques such as electron microscopy, reverse transcriptase-polymerase chain reaction (RT-PCR) and in situ hybridization, the spectrum of most frequently detected viruses in EMB shifted from classic enteroviruses and adenovirus to the two most common pathogens found in EMB biopsies: parvovirus B19 (PVB19) and human herpesvirus 6 (HHV-6).[23] HHV-6 encompasses two closely related herpesviruses, HHV-6A and HHV-6B. Chromosomally integrated HHV-6 (ciHHV-6) is a rare inherited condition affecting 1% of the population, in which the complete genome of the virus is integrated into the chromosome and passed through the germline[45] HHV-6 as a cause of dilated cardiomyopathy has been well recognized in adults.[6] Depending on the localization of cardiotropic viruses in myocardial tissue, it causes different types of myocardial dysfunction, the pathophysiology is summarized in Figure 1. HHV-6A may cause direct infection of cardiomyocytes [Figure 2] whereas HHV-6B infects the vascular endothelium [Figure 3] and subsequently endothelial dysfunction and diastolic dysfunction.[7] We have previously described a practical approach to children presenting with acute systolic heart failure due to acute myocarditis or DCM.[8] This review will primarily focus on the issues specific to cardiac HHV-6 in immunocompetent children.

Figure 1

Possible mechanism of viral myocarditis

Figure 2

Endomyocardial biopsy showing a capillary (C: Capillary lumen; N: Nucleus of endothelial cell) with adjacent myocardium (M). Arrows show herpesvirus particles. Note the myocardial hypoperfusion damage, (×12,000)

Figure 3

Endomyocardial biopsy, higher magnification showing typical human herpesvirus-6A particle (arrow) in an endothelial cell, Bm: Basement membrane, E: Endothelial cells, C: Capillary (×80,000)

LITERATURE REVIEW OF HUMAN HERPESVIRUS-6 MYOCARDITIS AND DILATED CARDIOMYOPATHY IN IMMUNOCOMPETENT CHILDREN

A recent study by Simpson et al. showed 80% of 21 immunocompetent infants with myocarditis were positive for a cardiotropic virus from blood PCR tests, (of which 21 two were positive for HHV-6) compared to <4% of healthy 22 controls.[9] HHV-6 has been detected in 43% of patients from a review of archival tissue specimen from pediatric patients with idiopathic DCM or congenital heart diseases.[10] With these considerations in mind, we conducted this literature review with two specific aims (i) to summarize clinical profile of immunocompetent children with HHV-6 suspected myocarditis or DCM and (ii) to examine HHV-6 as a definite etiological agent for pediatric immunocompetent patients with myocarditis and DCM.

We made a comprehensive literature reviews in the PubMed and Ovid Medline. Standard search terms such as HHV-6 myocarditis and HHV-6 cardiomyopathy were used and references were reviewed to identify additional cases, and they were manually filtered to identify pediatric case studies that fulfilled the criteria of our review [Figure 4]. Our results are summarized in Tables 1 and 2.

Figure 4

PubMed and Ovid Medline review process and outcome summary

Table 1

Clinical profile of immunocompetent patients with suspected myocarditis and dilated cardiomyopathy

Table 2

Examining human herpes virus 6 as an etiological agent for myocarditis and dilated cardiomyopathy in immunocompetent patients

PATIENT-SPECIFIC OBSERVATIONS OF HUMAN HERPESVIRUS-6 INFLAMMATORY CARDIOMYOPATHY

Spotnitz and Lesch describe three distinct pathological stages of viral myocarditis: (1) acute myocarditis with myocyte damage/necrosis and intramyocardial inflammation from active viral infection, (2) subacute/chronic myocarditis with myocyte damage from protracted viral infection and immune-mediated response, and (3) DCM from chronic myocarditis involving scarring/fibrosis of cardiac tissue.[11]

From Tables 1 and 2, 6/11 (55%) cases in our review fall within the first category (acute myocarditis), evidenced by acute systolic heart failure and histopathological evidence of myocardial inflammation and damage. These patients presented with the classic symptoms of HHV-6 primary infection: febrile illness and exanthem. Other noted symptoms within this group were tachycardia, respiratory distress, convulsions, and lymphadenopathy. Laboratory investigations revealed markers for inflammation (i.e., leukocytosis, leukocytopenia, elevated C-reactive protein) and markers for cardiac damage (i.e., elevated troponin and/or creatine kinase myocardial bound). Due to the acute, fulminant presentation of myocarditis in these cases, acute systolic heart failure typically precluded a full diagnostic workup including cardiac catheterization and EMB. Myocarditis was confirmed at autopsy.

Furthermore, our analysis shows 2/11 (18%) of the cases fell within the second category (subacute/chronic myocarditis), with involvement of mononuclear cell infiltration and a small amount of fibrosis.[12] One patient eventually recovered after left ventricular assist device (LVAD) support and antiviral treatment. Coincidentally, the patient demonstrated symptoms of exanthem subitum. In the rest, 3/11 (27%) of cases describe DCM, confirmed by echocardiograph findings of ventricular dilatation and/or histopathological evidence of endomyocardial fibrosis. This subset primarily presented with respiratory distress and arrhythmia, with no remarkable evidence of cardiac inflammation (burnt-out myocarditis) suggestive of DCM.

It is estimated that one-third of patients with viral myocarditis experience complete recovery, one-third show residual cardiac dysfunction, and one-third experience cardiac failure resulting in death or transplantation.[13] This review demonstrates that most HHV-6-associated cases of myocarditis and DCM have a severe clinical course and fall within the latter category. Seven out of 11 (64%) cases resulted in sudden death, frequently within a week of initial symptoms. This confirms a previous study conducted by Mahrholdt et al. of 31 adult patients with HHV-6-associated myocarditis.[14] Compared to patients with Coxsackie B, PVB19, and EBV infection, patients with HHV-6 more frequently presented with new-onset acute systolic heart failure and subsequently progressed toward chronic heart failure.[14]

The severe clinical course of HHV-6-associated myocarditis in our review also associated with the relatively young age of the patients. For other causative agents, such as Coxsackie B, mortality rates for pediatric myocarditis are significantly higher in infants (75%) than in older children (25%).[15] Seven out of 11 (64%) HHV-6 myocarditis patients in our review were under 2 years of age and most were suffering from a presumed primary HHV-6B infection. The immature nature of the myocardium in neonates and infants increases susceptibility to injury. In addition, cardiac catheterization poses higher risk in infants, increasing the difficulty of obtaining an EMB, and potentially delaying diagnosis and pathogen-specific antiviral treatment.[15]

Patients with HHV-6-associated myocarditis in this review demonstrated organ involvement outside of the heart. Two patients had signs of central nervous system (CNS) dysfunction, including convulsions and/or status epilepticus. Seizures are associated with HHV-6 infection as one study reports 32% of infants with status epilepticus as positive for active HHV-6 infection confirmed by plasma quantitative PCR testing.[16] Two patients also demonstrated kidney and/or liver failure. Hepatitis and end-stage renal disease have been commonly reported in transplant patients with HHV-6 reactivation.[1718] As these extracardiac findings (i.e., CNS dysfunction, liver failure, and kidney failure) are associated with HHV-6 infection, they may provide evidence to HHV-6 being etiologically involved with multiple organs in our review.

The clinical course of HHV-6-associated myocarditis may also be complicated by drug exposure. HHV-6 reactivation is commonly triggered by drug responses as seen in cases of drug-induced hypersensitivity disorder (DIHS) and drug reaction with eosinophilia and systemic symptoms (DRESS). In DIHS and DRESS, a severe cutaneous reaction erupts in response to prolonged exposure to a drug, typically an anticonvulsant or sulfonamide.[19] Myocarditis has been noted in the sequelae of adult DIHS/DRESS cases with active HHV-6 infection.[20] In seven patients whom amoxicillin-induced flare with DRESS demonstrated a direct effect of amoxicillin on HHV-6 replication in vitro.[21] DIHS/DRESS should be considered as a potential cause for HHV-6-associated myocarditis in pediatric patients, particularly those with prolonged exposure to a common culprit drug for the disease.

There remains significant controversy and a lack of standardized procedure in diagnosis for HHV-6-associated myocarditis. While the diagnosis of myocarditis was not in question for many of our cases, determining the subtype and etiology posed a serious challenge. Findings from EKG, chest X-ray, and echocardiography (i.e., arrhythmia, sinus tachycardia, decreased ventricular function) contribute to the evidence for myocarditis. Still, histopathological testing remains the definitive method for diagnosis of viral myocarditis, and specifically, viral myocarditis caused by HHV-6. Only 3/11 (27%) cases featured the use of biopsy to confirm the presence of HHV-6 in cardiac tissue. Other patients in this review faced a rapidly deteriorating condition in which biopsy would pose significant risk. Quantitative PCR blood tests can indicate viral load levels and provide evidence toward active viremia in acute infections. While serological testing for IgM and IgG antibodies can be used to confirm the presence of HHV-6 infection 2–4 weeks after the onset of the myocarditis, it may take up to 2 weeks to develop detectable IgM responses. Children develop primary infections from 4 months to 30 months, and they are protected for the first few months by their maternal antibodies. However, new studies reveal that fetuses and newborns are vulnerable to HHV-6 infection from mothers with inherited ciHHV-6 who can reactivate during pregnancy and pass HHV-6 virus transplacentally.[22] Two of the cases in this review fall into this category.[2324]

ACTIVE HUMAN HEREPESVIRUS-6 IINFECTION VERSUS CIHHV6

Sergi et al. describe two cases showing positive nested PCR testing of HHV-6 DNA, but negative RT-PCR testing of HHV-6 mRNA.[25] These researchers note that the HHV-6 mRNA testing was negative. However, the presence of HHV-6 DNA in plasma widely accepted as a sign of active infection, and best methods and tools for the detection of HHV-6 mRNA are still under investigation and samples collected without RNA preservative are unlikely to produce reliable results. In addition, there is evidence that HHV-6 latent infection can continue to produce inflammation in the absence of replication, with significant production of chemokines and cytokines resulting from nonlytic gene expression.[26]

Only two of the cases in our review consider ciHHV-6 in the differential diagnosis for HHV-6-associated myocarditis. ciHHV-6 status should be determined to assist with evaluation of plasma PCR DNA loads (since plasma DNA load is irrelevant in a ciHHV6 patient), but ciHHV-6 status does not help the physician determine if the HHV-6 is active.[27] In both cases of ciHHV-6 in this review, we see extremely high viral loads of 2 × 106 and 6 × 105 copies/mL, respectively. In addition, both patients presented with DCM and failed to respond to short courses (<2 weeks) of antiviral treatment. HHV-6 DNA loads of ciHHV6 patients would not be expected to demonstrate a significant response to antiviral therapy, even those with active HHV-6 infection, given the high background levels of HHV-6 DNA in these patients. In cases of unexplained LV dysfunction with high HHV-6 viral loads and absence of markers of active HHV-6 infection, ciHHV-6 should be included in the diagnostic workup.[28] According to this study, in ciHHV-6 cases, the HHV-6 may be incidental or it may be reactivated; prolonged treatment with valganciclovir resulted in significant improvement of heart failure symptoms.

POTENTIAL HUMAN HERPESVIRUS-6 SPECIFIC TREATMENT STRATEGIES

Conventional treatment of HHV-6 infection consists of the antivirals ganciclovir, cidofovir, and foscarnet. Due to the frequent acute onset of heart failure, antiviral treatment was not started in the majority of cases or was initiated the day before death. HHV-6 reactivation is more likely to occur in patients who receive prednisone or other immunosuppressant therapy.[29] As steroids can increase viral loads of HHV-6, they should be used with caution in patients with a suspected reactivation and preferably in conjunction with antiviral therapy.

Successful implantation of a LVAD was used to manage heart failure from HHV-6-associated chronic myocarditis.[12] This mechanical circulatory support can restore LV function by unloading the failing LV and allow the patient to be discharged – acting as a bridge to recovery. Implantation of an LVAD has the added benefit of obtaining the core biopsy at time of LVAD implant for histopathological and molecular study to make a specific etiological diagnosis of myocarditis.[30]

Hakacova et al. describe a case in which the antimalarial drug artesunate was used to treat HHV-6 viremia.[12] After a 2-week treatment with ganciclovir showed no improvement, the patient was started on a course of artesunate and showed an immediate decrease in HHV-6 viral load. Artesunate has shown antiherpes viral properties in vitro and in vivo, with good tolerability and a low rate of adverse side effects.[3132] While ganciclovir, cidofovir, and foscarnet target viral DNA polymerase, artesunate is thought to inhibit cellular activation pathways. This lends artesunate the ability to significantly reduce viral early protein synthesis, which cannot be accomplished with drugs targeting viral DNA polymerase.[33] Considering the tolerability, limited viral resistance, anti-inflammatory action, and good safety profile when used for malaria, artesunate should be explored as a treatment for patients who demonstrate HHV-6-associated myocarditis.[34]

CONCLUSIONS

The exact role of HHV-6 as a causal factor of inflammatory cardiomyopathy is still a matter of discussion. Nevertheless, the majority of studies suggest that HHV-6 viral persistence or presence is responsible for progression of disease in myocarditis and ultimately develops DCM. Therefore, the diagnosis of HHV-6-related inflammatory cardiomyopathy should be considered when a patient presents with an unexplained heart failure, especially a child who is within the peak period for primary infections (4–24 months) or with a rash similar to exanthem subitum. These cases should be fully evaluated with histological, immunohistochemical, serological, and molecular methods. The identification of the exact etiology for inflammatory cardiomyopathy may facilitate patient-tailored management with specific antiviral therapy. Therefore, future studies are needed to gain a better understanding of the prognostic relevance of HHV-6 viral load, replicative status, and virus coinfections as well to gain more specific insight on how to evaluate diagnostic markers such as HHV-6 viral DNA and mRNA in the pathogenesis of inflammatory cardiomyopathies. In addition, the immunogenetic background of inflammatory cardiomyopathy patients that makes them susceptible to develop heart failure on the presence of HHV-6 should be more thoroughly investigated.[40]

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Conflicts of interest

There are no conflicts of interest.