Heart transplants in pediatric patients: viral infection as a loss predictor

Abstract

Future CardiologyVol. 6, No. 6 EditorialFree AccessHeart transplants in pediatric patients: viral infection as a loss predictorJeffrey A Towbin, Stephanie M Ware & John Lynn JefferiesJeffrey A Towbin† Author for correspondenceSearch for more papers by this authorEmail the corresponding author at jeffrey.towbin@cchmc.org, Stephanie M WareThe Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USASearch for more papers by this author & John Lynn JefferiesThe Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USASearch for more papers by this authorPublished Online:9 Dec 2010https://doi.org/10.2217/fca.10.105AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Keywords: heart transplantIVIGparvovirusB19transplant rejectionviral myocarditisOver the last two decades, the prevalence of heart failure has significantly increased in the developed world [1]. The major causes of heart failure include cardiomyopathies with primary systolic dysfunction and/or diastolic dysfunction, as well as some forms of congenital heart disease. In children, dilated cardiomyopathy with associated systolic dysfunction, due to known etiologies including genetic causes, metabolic causes, or acquired diseases such as viral-induced myocarditis, are the most common causes of heart failure. Although a variety of pharmacologic and mechanical/device therapies are used to overcome the progressive nature of these disorders, cardiac allograft transplantation has become the definitive therapy for end-stage heart disease in those that are unresponsive to currently accepted standard therapy. Unfortunately, the long-term survival after cardiac transplantation in children, as in adults, is limited [2,3]. Although several donor- and recipient-specific risk factors for cardiac graft loss have been identified [2,3], the underlying mechanisms responsible for graft failure in childhood are poorly understood and in the majority of cases, treatment other than retransplantation has failed to result in prolonged survival. Typically, graft loss occurs owing to rejection or transplant coronary vasculopathy [4,5]. Interestingly, cellular rejection, histologically, is reminiscent of the findings in viral-induced myocarditis, with inflammatory infiltrates, myocyte necrosis and fibrosis all being notable [6]. In the 1990s, we hypothesized that viral allograft infection is a potential risk factor for graft loss and that this etiology is potentially amenable to novel treatment approaches [7,8]. In addition, we hypothesized that understanding the relationship of viral infection of the allograft could provide an insight into the outcomes and treatments for myocarditis [9].Viral myocarditis & transplant rejectionViral myocarditis of the native heart is an established etiology for dilated cardiomyopathy [10,11]. The major causes of myocarditis in children have changed over the past several decades and we have demonstrated that this change in viral demographics appears to occur approximately every decade [12]. In the 1970s and 1980s, viral cultures and serologies were used to identify viruses, usually in the periphery and not in the heart. In these studies, enteroviruses, particularly coxsackie B viruses, were thought to be most common, but other viruses of the enteroviral class (coxsackie A and echovirus), as well as other viruses such as cytomegalovirus (CMV), Epstein–Barr virus (EBV), adenovirus, influenza viruses, and herpes simplex virus were also reported [13,14]. In the 1990s, molecular methodology, specifically PCR, was first utilized to identify the viral genome within the heart. With this approach, the viral genome within the heart muscle (obtained at biopsy, explant or autopsy) could be amplified by a million-fold or more and visualized. The use of PCR led to the identification of adenovirus as the most common virus responsible for myocarditis during that era, displacing enteroviruses (coxsackie B and A) and CMV as the most common agents [7,15–18]. In the current decade, adenovirus has been replaced by parvovirus B19 as the most common virus found in the hearts of these patients [19,20]. We previously hypothesized that viral infection of the post-transplant heart is similarly detrimental. Therefore, we also evaluated heart specimens from these patients and showed that the same viruses also cause allograft rejection and graft loss, with or without transplant coronary vasculopathy [7,8,21,22]. A similar association of viruses and rejection/graft loss has also been shown in lung and renal transplant recipients [23,24].The histologic diagnostic criteria for myocarditis, the Dallas criteria, rely heavily on the combination of inflammatory infiltrate, myocyte necrosis, edema and fibrosis [25]. Cardiac transplant rejection, as defined by the International Society of Heart and Lung Transplantation (ISHLT) [26], appears similar to the criteria for myocarditis. It is possible, therefore, that the two disorders are related, both being triggered by viral infection.Interestingly, viral infections, especially CMV, have been implicated in the pathogenesis of coronary atherosclerosis in the general population, as well as in transplant coronary artery disease in cardiac transplant patients [27–29]. Treatment with gancylclovir and anti-CMV immunoglobulin has been shown to decrease the risk of transplant coronary vasculopathy in cardiac transplant recipients with systemic CMV infection [30,31]. Intravenous immunoglobulin (IVIG) therapy for acute viral myocarditis is common in many centers, based on studies suggesting a beneficial role of IVIG in these patients [32,33]. In addition, IVIG has been utilized for its immunomodulatory effects in transplant recipients with viral infection as well as other conditions with possible ‘immune-mediated, infectious agent triggered’ etiologies [34,35]. The usual treatment for cellular rejection in children after transplantation is pulse steroids, but limited data exist regarding the short- and long-term efficacy [36–38]. In addition, many centers use steroids in the treatment of myocarditis, but limited supportive data exists [39,40]. We hypothesized that viral infection of the heart in pediatric transplant patients would result in worse outcome and that standard steroid pulse therapy would not reduce the risk of short- or long-term graft loss or demise [41]. In addition, we proposed that steroids plus IVIG would result in improved outcomes [41].Transplant allograft viral infection & outcomes in childrenThe first study that reported the use of PCR surveillance of viruses in children post-transplantation was published in 1996 by Schowengerdt et al.[7]. In this report, 40 patients who received transplants in the 1980s and early 1990s, underwent serial right ventricular endomyocardial biopsy (129 samples) for rejection surveillance, with positive results obtained in 41 samples (32%) from 21 patients (52.5%). Viral genome amplified by PCR included CMV in 16 samples, adenovirus in 14, enterovirus in six, parvovirus B19 in three, and herpes simplex virus in two children. This was also the first report of parvovirus B19 in transplant recipients. In 13 of the 21 patients that tested positive for the viral genome (62%), endomyocardial biopsy histologic scores were consistent with multifocal moderate-to-severe rejection (ISHLT scores of 3A or greater). The patient cohort was generally in the teenage years in this study.This study was followed in 1997 by a study that focused on parvovirus B19 [8]. Here, Schowengerdt et al. examined 200 transplant patients and identified six patients with viral infection by PCR. A total of four of the six transplant patients had evidence of significant rejection on the basis of endomyocardial biopsy histology. All transplant patients survived the infection. In addition, only three of 360 children with suspected myocarditis were positive for the parvovirus B19 genome and of these three patients with myocarditis, one presented with cardiac arrest leading to death, one developed dilated cardiomyopathy and the other gradually improved.In 2001, our group also studied adults with transplanted hearts [42]. We retrospectively evaluated outcomes in heart transplant recipients aged 25–66 years who had myocardial tissue tested for viral genomes. Outcomes evaluated included graft dysfunction as evidenced by decreased ejection fraction (<30%), coronary artery disease and survival. PCR analysis was performed on 28 samples from 22 transplant recipients and viral genome was amplified in six patients, including adenovirus in two, CMV in two, herpes simplex virus in one and EBV in one. In the six patients with PCR-positive samples, an adverse cardiac event occurred concomitantly. All patients in the positive group experienced graft dysfunction versus seven out of 16 patients with negative samples (p = 0.02). One patient from the positive group died due to coronary vasculopathy, one due to acute rejection and one from sudden death. The mean survival in the group with positive viral genome was 409 days versus 970 days in the patients with negative results. Transplant coronary vasculopathy was present in four patients (66%) in the positive group versus six patients out of 14 with negative results (43%). We concluded that identification of a viral genome in the myocardium of transplant recipients may be predictive of adverse clinical events, including coronary vasculopathy, graft dysfunction and death. We performed a prospective study in children at approximately the same time, in which we enrolled heart-transplant recipients aged 1 day to 18 years who were undergoing evaluation for possible rejection and coronary vasculopathy [22]. PCR analyses were performed on 553 consecutive biopsy samples from 149 transplant recipients from a collaborating institution and clinical data was blinded. Viral genomes were amplified from 48 samples (8.7%) from 34 patients (23%), with adenovirus identified in 30 samples, enterovirus in nine samples, parvovirus in five samples, CMV in two samples, herpes simplex virus in one sample, and EBV in one sample. Once the clinical data and outcomes were separated and compared with individual PCR results, it was found that in 29 of the 34 patients with positive results on PCR (85%), an adverse cardiac event occurred within 3 months after the positive biopsy, and nine of the 34 patients had graft loss due to coronary vasculopathy, chronic graft failure or acute rejection. In 39 of the 115 patients with negative results on PCR (34%), an adverse cardiac event occurred within 3 months of the negative PCR finding but graft loss did not occur in any of the patients in this group. The odds of graft loss were 6.5-times greater among those with positive results on PCR (p = 0.006). The detection of adenovirus was associated with considerably reduced graft survival (p = 0.002). The 5-year survival by Kaplan–Meier survival analysis was 96% for the PCR-negative group and 65% in the PCR-positive group. The PCR-positive group all received pulse steroid therapy for the rejection episodes. We concluded that identification of a viral genome, particularly adenovirus, in the myocardium of pediatric transplant recipients is predictive of adverse clinical events, including coronary vasculopathy and graft loss. In addition, it could be surmised that treatment with pulse steroids has limited efficacy in the mid- to long-term outcome of children with transplant rejection and that coronary vasculopathy and graft loss result from viral infection of the myocardium.More recently, we evaluated children undergoing transplantation between 2000 and 2010. Important findings were recently published in two separate papers. Breinholt et al. demonstrated the viral epidemiologic shift, with the prevalence of parvovirus B19 becoming the predominant virus of the decade that infects the heart of children [12]. From September 2002 to December 2005, 99 children (aged 3 weeks to 18 years) with heart transplants were evaluated by PCR for the presence of a viral genome, while cellular rejection was assessed by histology of specimens and transplant coronary artery disease was diagnosed by coronary angiography or histopathology concomitantly. A total of 700 biopsy specimens from these 99 patients were evaluated and the viral genome was identified in 121 specimens, with 100 (82.6%) positive for parvovirus B19, 24 for EBV, seven positive for both parvovirus B19 and EBV, three for CMV, and one for adenovirus. Unlike CMV and adenovirus in the previous studies from the 1980s and 1990s, the presence of the parvovirus B19 genome did not correlate with rejection score, nor did a higher viral copy number. Early development of advanced transplant coronary vasculopathy (p < 0.001) occurred in 20 children with persistent parvovirus B19 infection (>6 months). We concluded that parvovirus B19 is currently the predominant virus detected in pediatric heart transplant surveillance biopsy specimens, possibly representing an epidemiologic shift. Cellular rejection was not found to correlate with the presence or quantity of parvovirus B19 genome in the myocardium, but children with chronic parvovirus B19 infection have increased risk for earlier transplant coronary vasculopathy, supporting the hypothesis that parvovirus B19 negatively affects graft survival. Another study performed at approximately the same time by Moulik et al. evaluated 94 pediatric cardiac transplant patients between June 1999 and November 2004. The presence of viral genomes in serial biopsies and graft loss, advanced transplant coronary artery disease and acute rejection were compared in the PCR-positive (n = 37) and PCR-negative (n = 57) groups, using time-dependent Kaplan–Meier and Cox regression analyses [41]. Viral genomes were detected in biopsies from 37 (39%) patients and parvovirus B19, adenovirus and EBV were the most common viruses identified. The PCR-positive group (n = 37; 25% graft loss at 2.4 years) had decreased graft survival (p < 0.001) compared with the PCR-negative group (n = 57; 25% graft loss at 8.7 years) and developed advanced transplant vasculopathy prematurely (p = 0.001). The number of acute rejection episodes was similar in both groups. On multivariate analysis, the presence of viral genomes was an independent risk factor for graft loss (relative risk: 4.2; p = 0.015). As in the study from 2001, in which adenovirus was the predominant virus, this study also demonstrated a substantially better 5-year outcome of PCR-negative subjects compared with children found to be parvovirus B19 PCR-positive. We concluded that viral endomyocardial infection is an independent predictor of graft loss in pediatric cardiac transplant recipients and that this effect appears to be mediated through premature development of advanced transplant coronary artery disease.As noted, the mechanisms leading to transplant coronary disease remain unclear. Graham et al. recently studied animal models and determined that the natural killer cells play a direct role in the development of transplant coronary disease and that a natural-killer-cell-dependent pathway is triggered in the absence of T and B lymphocytes [43]. Breinholt et al. analyzed procytokine correlation in children after transplantation and in the setting of rejection [44]. The data presented demonstrated that, although proinflammatory cytokine transcripts in biopsy samples from heart transplant patients could be detected and quantified, there was no correlation between the quantity of cytokine and the degree of histopathologic rejection. For each of the cytokines, low levels of expression could be detected in the majority of the samples tested, as well as the ‘normal’ cardiac RNA used as a control. These data support the findings of Wu et al., who reported the detection of cytokines in cardiac transplant patients, both before and during rejection episodes [45]. Moreover, the same cytokines were present in the pretransplant donor heart, with the exception of IL-6 and IL-8. Baan et al. detected IL-6 and IL-10 in most pretransplant tissue samples, and the detection of IL-10 correlated with donor-specific cytotoxic hyporesponsiveness [46]. These findings demonstrate that cytokines are expressed, even in the absence of allograft rejection and therefore detection of cytokines is insufficient to describe their function in heart transplant rejection [46–48]. Breinholt et al. sought to determine whether cytokine transcript quantity would elucidate the relationship between rejection and the detected cytokine [44]. In a semi-quantitative study, de Groot-Kruseman noted an increase in tumor necrosis factor in acutely rejecting allografts from 16 patients [49]. However, this study only showed increases in cytokines during the first 3 months postoperatively and it is difficult to determine the influence of cytokine release at the time of organ donation. In the long-term follow-up study by Breinholt et al., they failed to demonstrate a consistent trend in cytokine expression in serial biopsies with any of the studied cytokines [44]. There was a correlation between rejection score and the quantities of interferon and tumor necrosis factor mRNA; however, the strength of that correlation was small.Novel therapies for pediatric transplant patientsIn the study by Moulik et al., therapeutic comparison was made between endomyocardial biopsy PCR-positive patients treated with pulse steroids alone versus PCR-positive children treated with IVIG plus steroids [41]. In addition, all children were on standard immunosuppressive therapy including a calcineurin inhibitor (typically tacrolimus), prednisone and mycophenylate mofitil. The concept for using IVIG in PCR-positive subjects, irrespective of era, is that IVIG is manufactured from the plasma of the population in that era. Hence, since the local and national population of the country during any given era (such as 2000–2010) is exposed to the predominant virus (in other words, adenovirus in the 1990s and parvovirus B19 in the 2000s), the titers of virus in the IVIG produced at that time will be highest against the predominant virus in the population. Therefore, based on the high titers of the predominant virus, IVIG therapy will actually be viral specific. To test this hypothesis, from November 2002 to November 2004, IVIG plus steroids was administered to patients with PCR-positive biopsies (n = 20) and the outcomes were compared with IVIG-untreated (steroid treated only), PCR-positive patients (n = 17). The time to advanced transplant coronary disease after becoming PCR-positive was longer in the IVIG-treated patients (p = 0.03) with a trend towards improved graft survival (p = 0.06). Therefore, a larger trial is needed to take this from a proof of principal to a standard treatment approach, as IVIG therapy in this infected subgroup may improve survival and merits further investigation.ConclusionPediatric heart transplantation continues to be plagued by the development of graft loss due to rejection or transplant vasculopathy leading to death or retransplantation. Standard therapies for rejection, typically pulse steroids with or without advanced immunosuppression for severe cases such as increasing levels of calcineurin inhibitors (tacrolimus, cyclosporine), use of polyclonal anti-T-cell antibodies (anti-thymocyte globulin or anti-lymphocyte globulin) or monoclonal anti-T-cell antibodies (OKT3), are useful for the acute event but have not facilitated increased long-term survival for patients. Transplant coronary vasculopathy is typically the final ‘end game’ for graft function and the mechanisms causing coronary obstruction are not well understood. The studies described here suggest that viral infection of the transplanted heart may play a significant role. Furthermore, the specific type of viral infection may trigger mechanistically distinct cardiac pathology. Parvovirus B19 infections may cause a direct effect since this virus infects the endothelium and not the cardiomyocytes. Therefore, the coronary endothelium is a key target and the inflammation and fibrosis that results within the coronary artery wall leads to the risk of developing premature coronary obstruction. On the other hand, adenovirus, coxsackievirus, EBV and CMV infect the cardiomyocyte, cause necrosis and inflammation, by activating various inflammatory pathways. It is likely the combination of effects influence the development of coronary disease in this group. A critical feature of making this diagnosis and enabling prognostication and possible targeted therapies, is the use of PCR to identify viral genomes within the heart. Hence, the use of routine surveillance biopsies and, when acutely ill, diagnostic biopsies, is important for not only histology and antibody analysis, but is also essential for PCR for viral genomes. The use of PCR for all serial biopsies is important for understanding when the patient became infected, since this infection begins the march toward untoward events. Despite the different mechanisms that likely cause the ultimate unfavorable outcomes, the use of IVIG in addition to standard treatments may alter the course of the development of this downstream problem.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. 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Int.16,9–14 (2003).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByWaitlist and post-transplant outcomes for children with myocarditis listed for heart transplantation over 3 decadesThe Journal of Heart and Lung Transplantation, Vol. 42, No. 1Myocarditis—Personalized Medicine by Expanded Endomyocardial Biopsy DiagnosticsWorld Journal of Cardiovascular Diseases, Vol. 04, No. 06 Vol. 6, No. 6 Follow us on social media for the latest updates Metrics History Published online 9 December 2010 Published in print November 2010 Information© Future Medicine LtdKeywordsheart transplantIVIGparvovirusB19transplant rejectionviral myocarditisFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download