Abstract
Viral infections remain a significant cause of morbidity and mortality following renal transplantation. The pediatric cohort is at high risk of developing virus-related complications due to immunological naiveté and the increased alloreactivity risk that requires maintaining a heavily immunosuppressive environment. Although cytomegalovirus is the most common opportunistic pathogen seen in transplant recipients, numerous other viruses may affect clinical outcome. Recent technological advances and novel antiviral therapy have allowed implementation of viral and immunological monitoring protocols and adoption of prophylactic or preemptive treatment approaches in high-risk groups. These strategies have led to improved viral infection management in the immunocompromised host, with significant impact on outcome. We review the major viral infections seen following kidney transplantation and discuss strategies for preventing and managing these pathogens.
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Introduction
The widespread clinical application of potent immunosuppressive regimens has significantly improved graft outcome by facilitating grafting across histoincompatibility boundaries. Long-term graft and patient survival, however, have been obtained at the expense of impaired immune surveillance, affected by the presence of other factors influencing the net state of immunosuppression, such as human leukocyte antigen (HLA) mismatching, graft damage, and concomitant infection with immunomodulating viruses [1]. Failure to activate or expand protective immunity has resulted in a significant increase in the rate of hospitalization for infectious complications over recent years [2]. Moreover, transplant recipients are experiencing serious morbidity and mortality from agents whose pathogenetic potential in immunocompetent individuals is limited [1, 3, 4].
Viral infections are potentially severe complications of transplantation, as they not only induce specific diseases, but they also favor the development of allograft damage, opportunistic infections, and acute rejection [1]. Thus, considerable effort has been made to improve posttransplant viral infection control. Establishment of a viral monitoring program has gained consideration as a useful tool in achieving this goal, as it allows the identification of preclinical or early stages of virus-related pathology, evaluation of response to treatment, and characterization of specific risk cohorts [5, 6]. Clearly, viral infections to be included in such a surveillance program must be selected. The criteria for selection are severity of virus-related pathology, availability of a suitable monitoring test, and possibility of therapeutic intervention. In addition, aspects related to local epidemiology and peculiarities of the transplant cohort, such as immunosuppressive regimen and percentage of virus-naive individuals, must be considered.
Improved management of viral infections in the immunocompromised host is partly attributable to advancements in diagnostic virology. The onset of viral replication after transplantation is dependent on exposure to a given pathogen in the absence of a protective immune response due to immunosuppression. Thus, the parameter universally selected to monitor infections is viral load. The development and implementation of sensitive, specific, and reliable diagnostic assays that allow quantification of viral load has proved to be instrumental in augmenting the clinical utility of viral monitoring [6–8]. In addition, as infection control will ultimately depend on the restoration of a protective immune response, evaluation of specific viral immunity has permitted further characterization of subgroups of patients at high risk for disease development [9, 10] and the development of therapeutic strategies based on administration of antigen-specific T cells expanded in vitro from the memory pool [10, 11]. Finally, development and application of novel antiviral therapeutic agents has also greatly contributed to the successful management of viral infections after transplantation [12, 13].
Here we review the clinical applications of viral monitoring in the setting of pediatric kidney transplantation and discuss future directions in the field of antiviral surveillance and virus-associated disease prevention and management.
Viral monitoring
The number of viral infections relevant to transplantation is constantly increasing. On the basis of prevalence, severity, availability of diagnostic tests, and therapeutic intervention, the viruses presently monitored most frequently in kidney transplant (KT) centers, other than hepatitis viruses, include cytomegalovirus (CMV), polyomavirus BK (BKV), and Epstein-Barr virus (EBV).
Cytomegalovirus
CMV is the major infectious complication in KT recipients. Transmission can occur from a seropositive organ to a seronegative recipient, causing primary infection; alternatively, reinfection/reactivation occurs in some seropositive recipients. CMV can cause a variety of end-organ diseases in KT patients, including hepatitis, gastrointestinal ulceration, pneumonitis, retinitis, or CMV syndrome with fever and leucopenia [14]. In addition to directly attributable morbidity, CMV has indirect effects [15], including an immunomodulating activity likely responsible for increased risk of opportunistic infections and EBV-related posttransplantation lymphoproliferative disease (PTLD) [16] and a role in acute and chronic allograft injury, with an increased risk of rejection [16, 17]. It has been known for many years that the serostatus of donor and recipient at the time of transplant provides prognostic information about the risk of the recipient developing CMV disease [5]. Patients at greatest risk include CMV seronegative recipients of organs from CMV seropositive donors and patients receiving antilymphocyte antibodies [18, 19]. Children are particularly vulnerable, as many are CMV seronegative at transplantation.
CMV surveillance was instituted as early as the beginning of the 1990s, when cell-culture methods for detecting CMV infection, which required 2–4 weeks, were replaced by the shell vial assay [20], which allowed identification within 16–48 h of viral replication in polymorphonuclear neutrophils (PMN) by immunofluorescence staining of immediate to early pp72 antigen, as well as the pp65-antigenemia screening assay [21, 22] that provided a semiquantitative assessment of the number of PMN stained positive for the lower-matrix protein pp65. The latter, more rapid (6 h) and specific, test prompted systematic CMV monitoring and application of preemptive treatment with effective antiviral drugs [21, 22]. Since then, quantitative polymerase chain reaction (PCR) assays for DNA determination have gradually replaced antigenemia, as they are not as operator dependent. They have equivalent efficiency for detecting viral replication and preventing disease [18, 19], but standardization across different laboratories is a problem for both tests, and, at present, each center has to validate its threshold values. Additional difficulties may arise once the patients are discharged from the transplant center and are followed elsewhere: confusion in interpreting viral load modifications, possibly due to a change in the laboratory performing the tests, could lead to inappropriate therapeutic decisions.
Without some form of preventive therapy, symptomatic CMV infection occurs in a high percentage of renal transplant recipients [18]. The two strategies commonly employed for CMV prevention are preemptive therapy and universal prophylaxis [6, 13, 19, 22]. Both approaches have advantages and disadvantages. The preemptive approach, limiting antiviral drug administration only in patients with evidence of CMV replication, allows reduction in toxicity and drug costs but is more labor and diagnostic intensive and may favor indirect effects that occur in the presence of asymptomatic infection [23, 24]. Universal prophylaxis may have the advantage of limiting indirect effects and preventing reactivation of other viruses. In the adult KT population treated prophylactically, testing for CMV viremia is generally not performed [6]. In the pediatric cohort, however, pharmacokinetics and compliance issues prompt monthly viremia screening and careful assessment of signs and symptoms of CMV disease. In the case of preemptive therapy, monitoring is recommended weekly until month +3 [6]. In the presence of viremia levels above the determined threshold cutoff, therapeutic intervention is started and continued until one or two negative tests are obtained (Fig. 1). During this phase, monitoring is performed once/twice a week. After therapy discontinuation, monitoring may be substituted by secondary antiviral prophylaxis, especially in cases of recurrent viremia.
Recently, a management question has arisen regarding the high-risk D+/R− cohort. The wide use of prophylaxis in D+/R− patients has resulted in an increased incidence of late-onset CMV disease after treatment discontinuation [13, 25]. Awareness of this occurrence is crucial for pediatric recipients, who are more likely to belong to the high-risk D+/R− cohort, in order to detect early signs of disease after prophylaxis discontinuation and provide a means to prevent disease onset. Among the possible solutions, it has been proposed to prolong prophylaxis duration from 3 to 6 months or more [26], to apply a 14-day delay in the start of prophylaxis, to allow for development of specific immunity [27], and to perform CMV monitoring beyond day + 100–200 until month +12 [28]. Regarding the latter point, a study conducted in 364 D+/R− transplant recipients receiving 100-day prophylaxis has recently shown that biweekly monitoring before day + 100 and subsequent testing at months +4, +4.5, +6, +8, and +12 was of little help in predicting disease onset [28]. However, surveillance intensification after prophylaxis discontinuation may be of help in preventing CMV disease. At present, no prospective, randomized, controlled trial has provided clear indications as to which, between preemptive or prophylactic treatment, is the optimal approach, and the choice is mostly dependent upon institution and available resources. However, prophylaxis is the preferred option in many centers for the high-risk D+/R− cohort. Finally, monitoring may be further refined by systematically evaluating viral load dynamics and constructing mathematical models that allow the prediction of viral replication evolution on the basis of the first few monitoring samples [29]. This could allow a prospective individualization of treatment that would optimize outcome.
Intravenous ganciclovir has long been the most commonly used agent for intense prophylaxis in pediatrics. The use of orally administered ganciclovir as an alternative in children has been limited by low bioavailability, necessitating large and frequent doses [30]. Valganciclovir, the valine ester of ganciclovir, has an oral bioavailability approximately tenfold greater than ganciclovir, and a recent study showed that administration to pediatric solid-organ transplant (SOT) recipients using a dosing algorithm adjusted for body size and renal function provided ganciclovir exposures similar to those established as being safe and effective in preventing CMV disease in adult transplant recipients [31]. In the case of CMV disease, it is still recommended that pediatric patients be treated with ganciclovir i.v. due to the lack of efficacy data on oral therapy in the pediatric cohort. Viral load assessment is a good predictor of response to treatment [18, 28], as decreasing CMV loads are associated with disease resolution, whereas persistently high or rising loads may indicate drug resistance. In this regard, assessing viral load by antigenemia has a major drawback compared with using DNAemia: antigenemia has a poor correlation with virus replication. This was demonstrated by showing a paradoxical rise in antigenemia and parallel decrease in DNAemia and viremia occurring at times in patients treated with ganciclovir [32].
Since the advent of extensive use of oral prophylaxis, cases of ganciclovir-resistant CMV due to mutations in the UL97 gene encoding for an enzyme involved in drug activation, or the UL54 CMV DNA polymerase gene, have increasingly been reported, particularly in the D+/R− population [33]. In case of proven ganciclovir resistance, treatment alternatives include the use of foscarnet or cidofovir, which may, however, exert significant nephrotoxicity.
Polyomavirus BK
BKV-associated nephropathy (BKVAN) is the most challenging infectious cause of renal allograft dysfunction and graft loss [34–37]. BKV transmission occurs during childhood. After primary infection, renal tubular epithelial cells and the urothelial cell layer represent sites of viral latency or replication [38]. BKVAN represents a complication linked to high-rate virus replication in the grafted kidney [8, 39–41]. The prevalence of BKVAN ranges from 1% to 10%, with approximately three quarters of cases occurring within the first year posttransplantation [34, 42]. The prevalence in pediatric recipients is similar to that observed in adults [43–49]. Renal allograft loss occurs in 10% to >80% of cases [34, 35, 42, 43], and the highest rate of graft loss is observed in cases of late diagnosis or treatment failure [35–37, 41]. To date, the therapeutic intervention of choice is reduction and/or switching of immunosuppressive drugs, because antiviral drugs – although showing some specific activity directed at the BKV life cycle in vitro – have not proven efficacious in controlled clinical trials [34, 41–43]. Analyses conducted on patients transplanted in the last 10 years indicate that treating established disease leads to poor allograft outcome [35–37].
Advances in the development of diagnostic tools and increased awareness of the importance of screening have led to treatment at earlier stages, before significant renal function deterioration has occurred. This has resulted in improved outcome [34, 35, 41–43, 50]. The diagnosis of BKVAN requires evaluation of a renal biopsy, with demonstration of polyomavirus cytopathic changes and interstitial nephritis [34, 38, 41]. Given the focal nature of the disease, and possible overlap with other pathologies that complicate the posttransplant course, early diagnosis may be difficult to obtain. It has been shown that BK viruria precedes BK viremia by a median of 4 weeks and that BK viremia precedes BKVAN by a median of 8 weeks [51]. Thus, monitoring BK viruria, generally by urine cytology or quantitative PCR for viral DNA, and monitoring BK viremia by quantitative PCR allow identification of patients at risk of developing BKVAN. BK viruria and viremia are linked, but with increasing levels of viruria, the relationship loses linearity. Moreover, kinetics of viral load in urine and plasma are not always concordant. These clinical observations are best explained by a model in which BKV replication starts in the kidney and is amplified in the urothelial compartment, with partial reflux to the allograft [39]. Urine and plasma seem to be separate replication compartments, with plasma being directly linked to graft replication. Consequently, sustained detection of BKV replication, assessed as plasma loads by quantitative PCR, is the most predictive assay for the presence of “presumptive” BKVAN [34, 38, 40, 51]. For this reason, it is recommended by current guidelines as the best assay by which to guide preemptive interventions [50, 52]. Indeed, prospective studies conducted in both adult and pediatric recipients demonstrated the feasibility of preventing BKVAN and allograft damage by treating presumptive BKVAN on the basis of plasma DNA monitoring, with reduction of immunosuppression [51, 53–55]. In the only pediatric cohort followed prospectively, immunosuppression reduction successfully induced BK viremia clearance in all 13 positive patients without BKVAN development or organ rejection [54].
Screening is essential to reach an early diagnosis and facilitate intervention for BKV replication and BKVAN. There is still debate as to which BKV screening test ought to be employed. Viruria has a high negative predictive value for BKVAN and may be usefully employed as a first-line screening test. Further advantages are that urine sampling is less invasive than blood sampling, that viruria may also be assessed by conventional cytology (decoy cells) and thus does not require molecular biology expertise, and that urine has a potentially lower PCR inhibitory activity than plasma, thus reducing the risk of false negatives for laboratories with no previous expertise. Anecdotal cases of kidney recipients with histologically proven BKVAN found negative for viremia have been reported [56] and have served as the rationale for some clinicians to drive their preemptive strategies based on viruria rather then viremia. However, the relatively low specificity of viruria as a predictive test for BKVAN prompts additional confirmation by viremia prior to a preemptive therapeutic intervention in order to avoid unnecessarily reducing immunosuppression in a large proportion of patients.
The screening methodology and schedule ought to be center specific and depend on local expertise and on the characteristics of the monitored cohort. It has been suggested to screen for BKV replication at least once every 3 months in the first year posttransplant, every 6 months up to 2 years, and annually thereafter for 5 years [52], and also in the event of an unexplained serum creatinine rise or after treatment for acute rejection [50]. Data obtained in pediatric cohorts suggest that BKV reactivation occurs earlier in children than in adults [54]. Thus, it is advisable to screen pediatric kidney recipients monthly in the first 3 months (Fig. 2). In the presence of viremia, BKV plasma load ought to be reevaluated at a 2- to 3-week interval to assess kinetics. A confirmed or rising BKV DNA load prompts intervention that may be guided by patients’ renal function. The plasma DNA level to be employed as a cutoff to start therapeutic intervention, as already mentioned for CMV, needs to be validated within the center, as BKV nucleic amplification tests (NAT) are not yet standardized. Data obtained in a prospective study indicate that the incidence of viremia is higher in pediatric patients [54], having been observed in >20% of the screened population. However, the outcome seems to be more favorable, as the prevalence of BKVAN and rate of graft loss have been reported to be similar to that observed in adults [34, 43–46, 49]. Thus, in asymptomatic children with BKV DNA load above threshold, it may be reasonable to adopt a cautious approach to intervention and consider a therapeutic reduction of immunosuppression only in the presence of persistent viremia. In the case of renal dysfunction, allograft biopsy ought to be performed and treatment administered according to biopsy findings. In detail, if concomitant rejection is ruled out, a therapeutic reduction of immunosuppression may be started. Otherwise, it is advisable to treat rejection first, and then proceed with BKVAN treatment.
Different immunosuppression reduction strategies have been proposed to treat presumptive BKVAN that have proved effective in clearing viremia and preventing onset of kidney damage [34, 42, 51, 53, 54]. In particular, we and others have chosen to reduce calcineurin inhibitors (CNI) as a first therapeutic step, followed by reduction/discontinuation of the antimetabolite 34, 35, 43, 54]. Other investigators propose reduction/discontinuation of the antimetabolite and only subsequently reduce CNI [34, 43, 53]. Others immediately reduce both CNI and the antimetabolite [55]. In the pediatric population, therapeutic reduction of CNI may be done slowly, starting with a 15–20% adjustment [54]. Alternatively to reduction, a switch from tacrolimus to cyclosporine A, or from CNI to a mammalian target of rapamycin (mTOR) inhibitor has also been employed [34, 43].
Epstein-Barr virus
PTLD are a recognized complication of the immunosuppression required to prevent allograft rejection and occur in 1–9% of kidney allograft recipients [57, 58]. Several factors greatly increase the risk of developing PTLD. EBV infection is critical in the pathogenesis of the majority of cases. In healthy seropositive individuals, a very tight balance exists between EBV-infected B cells and anti-EBV immunity, primarily EBV-specific, CD8-positive cytotoxic T lymphocytes (EBV-CTL) [59]. Thus, the degree of pharmacologic immunosuppression and/or HLA mismatching, and the absence of protective numbers of T cells, are major risk factors for PTLD [60]. The different combinations of these factors determine incidence variability. The highest incidence of PTLD is observed in children [61–64], as two major risk factors for PTLD development are generally peculiar prerogatives of the pediatric cohort: namely EBV-naiveté and the presence of a heavily immunosuppressive environment.
The World Health Organization (WHO) has classified PTLD into four categories: early lesions; polymorphous PTLD; monomorphic PTLD; and classical Hodgkin’s lymphoma-type PTLD [65]. Monomorphic PTLD are similar to lymphomas observed in nontransplant patients, with the vast majority being B-cell lymphomas, although T-natural killer (T/NK)-cell, or even plasma-cell disease resembling myeloma, may occur rarely; up to a third of EBV-negative cases have been observed after SOT, especially among the late-onset forms [61–67]. Most EBV-related PTLD reported in the literature are of host origin following SOT, whereas the source of EBV can be from the donor, recipient, or primary infection via natural oral transmission.
The diagnosis of EBV disease may be initially suggested by clinical history and physical examination in combination with imaging. The clinical course of PTLD after SOT is heterogeneous. Patients typically present with evidence of peripheral adenopathy, hepatosplenomegaly, and/or tonsillitis, and a history of diarrhea may be suggestive of gastrointestinal disease. In kidney recipients, there might be allograft involvement. Rarely, highly immunosuppressed patients may develop a fulminant disease with multiorgan involvement. However, clinical symptoms may be scarce, and the diagnosis of EBV-related PTLD should be considered in at-risk transplant recipients with fever lasting for more than a few days without an identified source. A tissue biopsy with histological assessment is needed for the diagnosis, although in febrile syndromes, specific tissue involvement may not be present, and in some patients, lesions may be inaccessible for biopsy.
As the onset of PTLD is preceded by a preclinical phase characterized by elevated EBV load in the peripheral blood, monitoring of EBV DNA levels in blood by PCR represents a useful tool for early diagnosis and timely treatment, although not every case of PTLD is associated with elevated EBV DNA. As with CMV and BKV, EBV quantitative assays are not standardized [7, 68–70]. In addition, as successful therapy is associated with disappearance of detectable EBV DNA, assessment of viral load is useful to monitor treatment response [7, 68–70]. Accordingly, for patients diagnosed with EBV-related PTLD and undergoing treatment, reduced EBV viral load in weekly peripheral blood monitoring is generally a sign of clinical response. However, it has been shown that disappearance of EBV DNA from peripheral blood, as seen after anti-CD20 monoclonal antibody rituximab treatment, may mask persistent disease [69]. Conversely, persistently high EBV DNA levels, particularly in the absence of clinical response, suggest the need for therapy modification. How long, or how frequently, to proceed with monitoring once the patient has responded to treatment is yet unclear.
EBV-related PTLD treatment is based on reducing the tumor burden with cytotoxic drugs [71–74] and/or B-cell-directed monoclonal antibodies [12, 69, 72] while restoring virus-specific immunity by reducing medical immunosuppression [50, 57, 60] or delivering EBV-specific CTL [11, 59, 71, 72]. In SOT recipients, reduction/withdrawal of immunosuppression remains the gold standard for first-line PTLD therapy, although there is wide variation in the reported response rate, and monoclonal PTLD are less likely to respond [75, 76]. As a side effect of this therapeutic approach, nonspecific enhancement of immunity induced by reduced immunosuppression may increase the patient’s risk of developing allograft rejection. The role of interferon (IFN)-α, immunoglobulin treatment i.v., and antiviral drugs, possibly preceded by sensitization with the short-chain fatty acid arginine butyrate, is controversial [57, 72, 77]. Cytotoxic chemotherapy based on multidrug regimens conventionally employed to treat de novo B-cell lymphomas is associated with high response rates but also with severe treatment-related toxicity and increased susceptibility to infections [73, 74]. Rituximab monotherapy has shown a good toxicity profile, but the response rate in the only phase II study conducted to date that also included pediatric patients did not exceed 44% [12]. Encouraging preliminary results in terms of stable complete remission rates have been recently described using low-dose chemotherapy regimens in children who failed reduced immune suppression [71, 78]. Gross et al. obtained a 2-year, 73% overall survival with 69% relapse-free survival in 36 pediatric SOT recipients with a cyclophosphamide/steroid regimen [78], whereas an update of a study conducted by our group of reduced-dosage chemotherapy in conjunction with rituximab and infusion of autologous EBV-CTL in pediatric kidney recipients with disseminated PTLD shows a 100% disease-free survival at a median follow-up of 5 years [unpublished update of reference 71]. However, overall outcome of PTLD in SOT recipients undergoing conventional treatment strategies is still suboptimal.
In asymptomatic transplant recipients, EBV DNA identifies patients at high risk of developing PTLD [7, 68, 70, 79], although the correlation between high viral load and PTLD onset after SOT is not as linear as that observed in hematopoietic stem-cell transplantation recipients. Patients belonging to the SOT cohort may persist with high viral loads for many months without developing PTLD. Thus, the clinical significance of the high viral load carrier status is controversial [70]. In pediatric heart transplant recipients, Bingler et al. have shown a high propensity for PTLD development in high viral load carriers (45% vs. 4% in patients with low/absent EBV load) [80], whereas lower propensity was shown in pediatric small-bowel transplant recipients (11%) [81] and pediatric liver transplant recipients (3%) [82]. Available data in kidney transplantation are limited, but our group showed, in a retrospective cohort of 200 consecutive pediatric recipients, a 20% incidence of PTLD in the 25 patients with persistent high viral loads versus 0% in those with low/absent EBV loads [83]. Generally, high viral load carriers who develop PTLD are all EBV seronegative at transplantation. It is, therefore, recommended to restrict monitoring and a possible preemptive approach in order to prevent progression to EBV disease in high-risk patients, such as high viral load carriers who are EBV seronegative at transplantation [50]. At present, data on the efficacy of preemptive antiviral drugs are lacking, whereas it has been shown that reducing immunosuppression in EBV-DNA-positive pediatric liver recipients could prevent the development of PTLD, with PTLD incidence decreasing from 16% in a historical cohort to 2% in the study group [84]. Although reducing immunosuppression could be an effective measure to induce development of specific immunity in EBV-seronegative patients experiencing primary infection, preliminary data obtained from our group indicate that pediatric kidney recipients with sustained high viral load, especially late after allografting, do not seem to benefit from reduced immunosuppression [83]. In these high viral load carriers, alternative forms of treatment are warranted.
Other viruses
Recent advances in molecular microbiology have made it possible to diagnose a growing number of community-acquired viral pathogens that may cause significant morbidity and mortality in transplant recipients [4].
Respiratory viruses
Respiratory viruses are the most common community-acquired infections in transplant recipients [85], and in these patients, they tend to have a more prolonged and complicated course, with higher rates of pneumonia and bacterial and fungal superinfection. Detecting the specific viral pathogen is crucial for diagnosis, and although conventional methods such as immunofluorescence and enzyme-linked immunosorbent assay (ELISA) are still commonly used, molecular methods – in particular, real-time PCR – have proven significantly more sensitive [86]. Among respiratory viruses, respiratory syncytial virus (RSV), influenza viruses (IV), parainfluenza viruses (PIV), and adenoviruses (AdV) cause the most serious disease in immunocompromised hosts [85, 87–89]. Complications include severe pneumonia (RSV, IV, PIV, AdV), and, in kidney recipients, pyelonephritis, hemorrhagic cystitis, and disseminated disease (AdV), although incidence is generally low and disease may be mild in this cohort. In addition, respiratory infections have been associated with acute graft rejection in pediatric SOT recipients [90].
Diagnosis of respiratory virus infection is generally made on nasopharyngeal wash or bronchoalveolar lavage fluid (BAL) specimens, or, in the case of AdV, on stools or plasma, by conventional viral culture, PCR, or direct immunofluorescence. Ribavirin has been employed in the treatment of RSV, PIV, and AdV infections [91–93], although its use is proven only in RSV-related disease, whereas neuraminidase inhibitors were effective in controlled trials in adults and children with IVs [94]. Although no randomized controlled trials of therapy for AdV infection have been published, cidofovir given i.v. has been associated with successful outcomes [84, 95]. Regarding disease prevention, palivizumab (an RSV-specific monoclonal antibody) may prevent progression of upper respiratory tract RSV infection to lower respiratory tract involvement [96], whereas vaccination of patients, family, and health care workers may prevent IV in transplanted patients [97].
Herpesvirus 6
Human herpesvirus 6 (HHV-6) is emerging as a relevant pathogen after transplantation [98]. Its role in SOT recipients is incompletely defined, but reactivation after allografting has been associated with development of myelosuppression, interstitial pneumonitis, cholestatic hepatitis, gastrointestinal manifestations, and neurological illness [4, 99]. As HHV-6 replicates in CD4+ T lymphocytes, suppression of T-cell function predisposes the patient to its development and increases severity of other opportunistic infections, including hepatitis C infection and CMV [100, 101]. Distinguishing HHV-6-active replication from latency can be challenging due to the high prevalence of infection in humans. Molecular assays are the most commonly used laboratory methods to detect HHV-6 reactivation and replication after transplantation. The use of quantitative PCR assays on serum/plasma or, better, tissue biopsy [102] specimens may be helpful in distinguishing replicating from latent HHV-6. Moreover, PCR techniques, differently from serology, are able to distinguish between subtypes A and B. Variant B most commonly causes infection posttransplant [101, 103], but HHV-6A is the variant more often associated with neurologic manifestations, which represent the severest form of HHV-6-related pathology, having a mortality rate >50% [99, 104].
Successful treatment of HHV-6 disease has been reported with either ganciclovir or foscarnet, often associated with simultaneous reduction of immunosuppression, although at present no treatment has been validated in controlled trials [104, 105]. Some strains of HHV-6B have been found resistant to ganciclovir [106], and this may explain the prevalence of HHV-6B after SOT cohorts, which often receive valganciclovir prophylaxis for CMV infection.
Monitoring virus-specific immunity
Monitoring specific immunity has gained consideration as a useful tool in managing viral infections in the immunocompromised host. In association with viral load determination, quantification of the specific immune response [107] has proved valuable in characterizing subgroups of patients at high risk of disease development [9, 108–110] and in assessing therapy response [58, 70, 75, 111]. Early demonstration that predicting virus-related diseases could benefit from combining viral load measurement with enumeration of specific T cells was obtained in EBV-seronegative liver recipients who developed PTLD posttransplant [9]. In this cohort, the inability to mount a specific immune response, measured as frequency of T cells able to produce IFN-γ in response to EBV-transformed lymphoblastoid cell lines, while experiencing a primary EBV infection, correlated with risk of developing PTLD. However, in many SOT recipients with PTLD, EBV-specific immunity is not apparently impaired, and the best immunological predictor of PTLD risk has not yet been identified.
In the setting of CMV infection, failure to control viral replication is associated with suboptimal CD4+ and CD8+ T-cell responses in terms of low numbers and impaired function. Specifically, the proportion of CMV-specific CD8+ T cells producing IFN-γ after renal transplantation has been shown to be a risk factor for the development of high-level replication and disease [109, 110], whereas high-level PD-1 expression on CD4+ and CD8+ T cells has been associated with CMV disease [112]. Similarly to observations for EBV and CMV, BK viruria and viremia development and BKV disease onset have been associated with impaired T-cell responses [10, 108, 113]. Moreover, resolution of BKV replication and disease prevention depends on recovery of BKV-specific T-cell immunity [53, 114]. Assessing BKV-specific T-cell frequency could allow identification, among patients with positive viremia, of those more likely to progress to BKVAN. Moreover, as preliminary data indicate that emergence of BKV-specific T cells coincides with reduced viral load and improved or stabilized graft function, it seems reasonable to manage therapeutic modulation of immunosuppression by complementing quantification of viral load with measurement of BKV-specific immunity [10].
Future directions
There is a need to develop assays that measure general infection risk. Technological advances facilitate accurate definition and quantization of virus-specific T-cell responses, and efforts are directed at developing high-throughput assays for measuring virus-specific cellular immunity, which may allow determination of individual risk for specific infections. The obvious choice for enumerating virus-specific T cells would rely on pulse stimulation with viral antigens and cytokine production assessment by either flow cytometry or ELISpot analysis. To date, the bottleneck in the development of such assays is the availability of standardized antigens, in particular, products that do not depend on specific HLA typing for presentation to T cells. Peptide pools derived from immunogenic proteins are the best option [54, 115], although these may not be yet available for all viral infections, and, even when available, the best combination of immunogenic proteins for each viral infection still needs validation in clinical trials.
Antiviral therapy is often limited by side effects, development of viral resistance, or weak intrinsic activity. Restoring a protective immune response by reducing immunosuppression, on the other hand, is burdened with increased risk of acute graft rejection or chronic allograft nephropathy. There is ample evidence that administering appropriately selected antigen-specific T cells can restore protective immunity and control established CMV and EBV infections [11, 116–118]. Recently, this strategy has been transferred to the setting of organ transplantation [70, 119].
Conclusions
In conclusion, implementing monitoring strategies and applying preemptive treatment has profoundly changed the course of viral infections after transplantation. Individualizing patient management through novel approaches that take into account the kinetics of viral replication will be increasingly employed in transplant patients, and, in conjunction with evaluating the immune function, may offer an optimal strategy to posttransplant infection control. Prospective studies of combined virological and immunological monitoring are warranted to assess the potential of this strategy and identify the most suitable parameters for monitoring purposes.
References
Fishman JA, Rubin RH (1998) Infection in organ-transplant recipients. N Engl J Med 338:1741–1751
Dharnidharka VR, Stablein DM, Harmon WE (2004) Post-transplant infections now exceed acute rejection as cause for hospitalization: a report of the NAPRTCS. Am J Transplant 4:384–389
Hirsch HH (2005) BK virus: opportunity makes a pathogen. Clin Infect Dis 41:354–360
Fischer SA (2008) Emerging viruses in transplantation: there is more to infection after transplant than CMV and EBV. Transplantation 86:1327–1339
Humar A, Michaels M (2006) American Society of Transplantation recommendations for screening, monitoring and reporting of infectious complications in immunosuppression trials in recipients of organ transplantation. Am J Transplant 6:262
Kotton CN, Kumar D, Caliendo AM, Asberg A, Chou S, Snydman DR, Allen U, Humar A, Transplantation Society International CMV Consensus Group (2010) International consensus guidelines on the management of cytomegalovirus in solid organ transplantation. Transplantation 89:779–795
Baldanti F, Gatti M, Furione M, Paolucci S, Tinelli C, Comoli P, Merli P, Locatelli F (2008) Kinetics of Epstein-Barr virus DNA load in different blood compartments of pediatric recipients of T-cell depleted HLA-haploidentical stem cell transplantation. J Clin Microbiol 46:3672–3677
Nickeleit V, Klimkait T, Binet IF Dalquen P, Del Zenero V, Thiel G, Mihatsch MJ, Hirsch HH (2000) Testing for polyomavirus type BK DNA in plasma to identify renal-allograft recipients with viral nephropathy. N Engl J Med 342:1309–1315
Smets F, Latinne D, Bazin H, Reding R, Otte JB, Buts JP, Sokal EM (2002) Ratio between Epstein-Barr viral load and anti-Epstein-Barr virus specific T-cell response as a predictive marker of posttransplant lymphoproliferative disease. Transplantation 73:1603–1610
Ginevri F, Hirsch HH, Comoli P (2008) Cellular immune responses to BK virus. Curr Opin Organ Transplant 13:569–574
Rooney CM, Smith CA, Ng CY, Loftin S, Li C, Krance RA, Brenner MK, Heslop HE (1995) Use of gene-modified virus-specific T lymphocytes to control Epstein-Barr-virus-related lymphoproliferation. Lancet 345:9–12
Choquet S, Leblond V, Herbrecht R, Socié G, Stoppa AM, Vandenberghe P, Fischer A, Morschhauser F, Salles G, Feremans W, Vilmer E, Peraldi MN, Lang P, Lebranchu Y, Oksenhendler E, Garnier JL, Lamy T, Jaccard A, Ferrant A, Offner F, Hermine O, Moreau A, Fafi-Kremer S, Morand P, Chatenoud L, Berriot-Varoqueaux N, Bergougnoux L, Milpied N (2006) Efficacy and safety of rituximab in B-cell post-transplantation lymphoproliferative disorders: results of a prospective multicenter phase 2 study. Blood 107:3053–3057
Paya C, Humar A, Dominguez E, Washburn K, Blumberg E, Alexander B, Freeman R, Heaton N, Pescovitz MD, Valganciclovir Solid Organ Transplant Study Group (2004) Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant 4:611–620
Betts RF, Freeman RB, Douglas RG Jr, Talley TE (1977) Clinical manifestations of renal allograft derived primary cytomegalovirus infection. Am J Dis Child 131:759–763
Rubin RH (1989) The indirect effects of cytomegalovirus infection on the outcome of organ transplantation. JAMA 261:3607–3609
Rubin RH (2007) The pathogenesis and clinical management of cytomegalovirus infection in the organ transplant recipient: the end of the ‘silo hypothesis’. Curr Opin Infect Dis 20:399–407
Kranz B, Vester U, Wingen AM, Nadalin S, Paul A, Broelsch CE, Hoyer PF (2008) Acute rejection episodes in pediatric renal transplant recipients with cytomegalovirus infection. Pediatr Transplant 12:474–478
Paya CV, Razonable RR (2003) Cytomegalovirus infection after organ transplantation. In:Bowden RA, Ljungman P, Paya CV, eds. Transplant Infections, 2nd Edn. Lippincott, Williams, and Wilkins, pp 298– 325
Preiksaitis JK, Brennan DC, Fishman J, Allen U (2005) Canadian society of transplantation consensus workshop on cytomegalovirus management in solid organ transplantation final report. Am J Transplant 5:218–227
Paya CV, Wold AD, Smith TF (1987) Detection of cytomegalovirus infections in specimens other than urine by the shell vial assay and conventional tube cell cultures. J Clin Microbiol 25:755–757
van den Berg AP, Klompmaker IJ, Haagsma EB, Haagsma EB, Scholten-Sampson A, Bijleveld CM, Schirm J, van der Giessen M, Slooff MJ, The TH (1991) Antigenemia in the diagnosis and monitoring of active cytomegalovirus infection after liver transplantation. J Infect Dis 164:265–270
Locatelli F, Percivalle E, Comoli P, Maccario R, Zecca M, Giorgiani G, De Stefano P, Gerna G (1994) Human cytomegalovirus (HCMV) infection in pediatric patients given allogeneic bone marrow transplantation: role of early antiviral treatment for HCMV antigenemia on patients’ outcome. Br J Haematol 88:64–71
Kalil AC, Levitsky J, Lyden E, Stoner J, Freifeld AG (2005) Metaanalysis: The efficacy of strategies to prevent organ disease by cytomegalovirus in solid organ transplant recipients. Ann Intern Med 143:870–880
Smith JM, Corey L, Bittner R, Finn LS, Healey PJ, Davis CL, McDonald RA (2010) Subclinical viremia increases risk for chronic allograft injury in pediatric renal transplantation. J Am Soc Nephrol 21:1579–1586
Khoury JA, Storch GA, Bohl DL, Schuessler RM, Torrence SM, Lockwood M, Gaudreault-Keener M, Koch MJ, Miller BW, Hardinger KL, Schnitzler MA, Brennan DC (2006) Prophylactic versus preemptive oral valganciclovir for the management of cytomegalovirus infection in adult renal transplant recipients. Am J Transplant 6:2134–2143
Humar A, Lebranchu Y, Vincenti F, Blumberg E, Punch J, Limaye A, Abramowicz D, Jardine A, Voulgari A, Ives J, Hauser I, Peeters P (2010) The efficacy and safety of 200 days valganciclovir cytomegalovirus prophylaxis in high risk kidney transplant recipients. Am J Transplant 10:1228–1237
San Juan R, Yebra M, Lumbreras C, López-Medrano F, Lizasoain M, Meneu JC, Delgado J, Andrés A, Aguado JM (2009) A new strategy of delayed long-term prophylaxis could prevent cytomegalovirus disease in (D+/R-) solid organ transplant recipients. Clin Transplant 23:666–671
Sanghavi SK, Abu-Elmagd K, Keightley MC, St George K, Lewandowski K, Boes SS, Bullotta A, Dare R, Lassak M, Husain S, Kwak EJ, Paterson DL, Rinaldo CR (2008) Relationship of cytomegalovirus load assessed by real-time PCR to pp 65 antigenemia in organ transplant recipients. J Clin Virol 42:335–342
Emery VC, Sabin CA, Cope AV, Gor D, Hassan-Walker AF, Griffiths PD (2000) Application of viral-load kinetics to identify patients who develop cytomegalovirus disease after transplantation. Lancet 355:2032–2036
Pescovitz MD, Brook B, Jindal RM, Leapman SB, Milgram MG, Filo RS (1997) Oral ganciclovir in pediatric transplant recipients: A pharmacokinetic study. Clin Transplant 11:613–617
Vaudry W, Ettenger R, Jara P, Varela-Fascinetto G, Bouw MR, Ives J, Walker R, Valcyte WV16726 Study Group (2009) Valganciclovir dosing according to body surface area and renal function in pediatric solid organ transplant recipients. Am J Transplant 9:636–643
Gerna G, Sarasini A, Lilleri D, Percivalle E, Torsellini M, Baldanti F, Revello MG (2003) In vitro model for the study of the dissociation of increasing antigenemia and decreasing DNAemia and viremia during treatment of human cytomegalovirus infection with ganciclovir in transplant recipients. J Infect Dis 188:1639–1647
Limaye AP, Corey L, Koelle DM, Davis CL, Boeckh M (2000) Emergence of ganciclovir-resistant cytomegalovirus disease among recipients of solid-organ transplants. Lancet 356:645–649
Hirsch HH, Brennan DC, Drachenberg CB, Ginevri F, Gordon J, Limaye AP, Mihatsch MJ, Nickeleit V, Ramos E, Randhawa P, Shapiro R, Steiger J, Suthanthiran M, Trofe J (2005) Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation 79:1277–1286
Vasudev B, Hariharan S, Hussain SA, Zhu YR, Bresnahan BA, Cohen EP (2005) BK virus nephritis: risk factors, timing, and outcome in renal transplant recipients. Kidney Int 68:1834–1839
Ramos E, Drachenberg CB, Papadimitriou JC, Hamze O, Fink JC, Klassen DK, Drachenberg RC, Wiland A, Wali R, Cangro CB, Schweitzer E, Bartlett ST, Weir MR (2002) Clinical course of polyoma virus nephropathy in 67 renal transplant patients. J Am Soc Nephrol 13:2145–2151
Schold JD, Rehman S, Kayle LK, Magliocca J, Srinivas TR, Meier-Kriesche HU (2009) Treatment for BK virus: incidence, risk factors and outcomes for kidney transplant recipients in the United States. Transpl Int 22:626–634
Hirsch HH, Steiger J (2003) Polyomavirus BK. Lancet Infect Dis 3:611–623
Funk GA, Steiger J, Hirsch HH (2006) Rapid dynamics of polyomavirus type BK in renal transplant recipients. J Infect Dis 193:80–87
Randhawa PS, Finkelstein S, Scantlebury V, Shapiro R, Vivas C, Jordan M, Picken MM, Demetris AJ (1999) Human Polyoma virus-associated interstial nephritis in the allograft kidney. Transplantation 67:103–109
Drachenberg CB, Papadimitriou JC, Hirsch HH, Wali R, Crowder C, Nogueira J, Cangro CB, Mendley S, Mian A, Ramos E (2004) Histological patterns of polyomavirus nephropathy: Correlation with graft outcome and viral load. Am J Transplantation 4:2082–2092
Ginevri F, Hirsch HH (2008) Polyomavirus-associated nephropathy. In: Molony DA, Craig JC (eds) Evidence-Based Nephrology. John Wiley & Sons, London
Acott PD, Hirsch HH (2007) BK virus infection, replication, and diseases in pediatric kidney transplantation. Pediatr Nephrol 22:1243–1250
Dharnidharka VR, Cherikh WS, Abbott KC (2009) An OPTN analysis of national registry data on treatment of BK virus allograft nephropathy in the United States. Transplantation 87:1019–1026
Ginevri F, De Santis R, Comoli P, Pastorino N, Rossi C, Botti G, Fontana I, Nocera A, Cardillo M, Ciardi MR, Locatelli F, Maccario R, Perfumo F, Azzi A (2003) Polyomavirus BK infection in pediatric kidney-allograft recipients: a single-center analysis of incidence, risk factors, and novel therapeutic approaches. Transplantation 75:1266–1270
Haysom L, Rosenberg AR, Kainer G, Waliuzzaman ZM, Roberts J, Rawlinson WD, Mackie FE (2004) BK viral infection in an Australian pediatric renal transplant population. Pediatr Transplant 8:480–484
Herman J, Van Ranst M, Snoeck R, Beuselinck K, Lerut E, Van Damme-Lombaerts R (2004) Polyomavirus infection in pediatric renal transplant recipients: evaluation using a quantitative real-time PCR technique. Pediatr Transplant 8:485–492
Alexander RT, Langlois V, Tellier R, Robinson L, Hebert D (2006) The prevalence of BK viremia and urinary viral shedding in a pediatric renal transplant population: a single-center retrospective analysis. Pediatr Transplant 10:586–592
Smith JM, Dharnidharka VR, Talley L, Martz K, McDonald RA (2007) BK virus nephropathy in pediatric renal transplant recipients: an analysis of the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) registry. Clin J Am Soc Nephrol 2:1037–1042
KDIGO Guidelines (2009) Am J Transplant 9(Suppl 3):S44–S58
Hirsch HH, Knowles W, Dickenmann M, Passweg J, Klimkait T, Mihatsch MJ, Steiger J (2002) Prospective study of polyomavirus type BK replication and nephropathy in renal-transplant recipients. N Engl J Med 347:488–496
Hirsch HH Randhawa P, AST Infectious Diseases Community of Practice (2009) BK virus in solid organ transplant recipients. Am J Transplant 9(Suppl 4):S136–S146
Brennan DC, Agha I, Bohl DL, Schnitzler MA, Hardinger KL, Lockwood M, Torrence S, Schuessler R, Roby T, Gaudreault-Keener M, Storch GA (2005) Incidence of BK with tacrolimus versus cyclosporine and impact of preemptive immunosuppression reduction. Am J Transplant 5:582–594
Ginevri F, Azzi A, Hirsch HH, Basso S, Fontana I, Cioni M, Bodaghi S, Salotti V, Rinieri A, Botti G, Perfumo F, Locatelli F, Comoli P (2007) Prospective monitoring of polyomavirus BK replication and impact of pre-emptive intervention in pediatric kidney recipients. Am J Transplant 7:2727–2735
Saad ER, Bresnahan BA, Cohen EP, Lu N, Orentas RJ, Vasudev B, Hariharan S (2008) Successful treatment of BK viremia using reduction in immunosuppression without antiviral therapy. Transplantation 85:850–854
Vats A, Shapiro R, Singh Randhawa P, Scantlebury V, Tuzuner A, Saxena M, Moritz ML, Beattie TJ, Gonwa T, Green MD, Ellis D (2003) Quantitative viral load monitoring and cidofovir therapy for the management of BK virus associated nephropathy in children and adults. Transplantation 75:105–112
Green M (2001) Management of Epstein-Barr virus-induced post-transplant lymphoproliferative disease in recipients of solid organ transplantation. Am J Transplant 1:103–108
Opelz G, Dohler B (2003) Lymphomas after solid organ transplantation: a collaborative transplant study report. Am J Transplant 4:222–230
Merlo A, Turrini R, Dolcetti R, Martorelli D, Muraro E, Comoli P, Rosato A (2010) The interplay between EBV and the immune system: a rationale for adoptive cell therapy of EBV-related disorders. Haematologica 95:1769–1777
Dharnidharka VR, Harmon WE (2001) Management of pediatric postrenal transplantation infections. Semin Nephrol 21:521–531
Caillard S, Dharnidharka V, Agodoa L, Bohen E, Abbott K (2005) Posttransplant lymphoproliferative disorders after renal transplantation in the United States in era of modern immunosuppression. Transplantation 80:1233–1243
Dharnidharka VR, Sullivan EK, Stablein DM, Tejani AH, Harmon WE (2001) Risk factors for posttransplant lymphoproliferative disorder (PTLD) in pediatric kidney transplantation: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Transplantation 71:1065–1068
Kirk AD, Cherikh WS, Ring M, Burke G, Kaufman D, Knechtle SJ, Potdar S, Shapiro R, Dharnidharka VR, Kauffman HM (2007) Dissociation of depletional induction and posttransplant lymphoproliferative disease in kidney recipients treated with alemtuzumab. Am J Transplant 7:2619–2625
McDonald RA, Smith JM, Ho M, Lindblad R, Ikle D, Grimm P, Wyatt R, Arar M, Liereman D, Bridges N, Harmon W, CCTPT Study Group (2008) Incidence of PTLD in pediatric renal transplant recipients receiving basiliximab, calcineurin inhibitor, sirolimus and steroids. Am J Transplant 8:984–989
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (2008) WHO classification of tumours of haematopoietic and lymphoid tissues, 4th edn. IARC Press, Lyon, France
Cohen JI (2000) Epstein-Barr virus infection. N Engl J Med 343:481–492
Nalesnik M, Jaffe R, Starzl TE, Demetris AJ, Porter K, Burnham JA, Makowka L, Ho M, Locker J (1988) The pathology of posttransplant lymphoproliferative disorders occurring in the setting of cyclosporin A-prednisone immunosuppression. Am J Pathol 133:173–192
Baldanti F, Grossi P, Furione M, Simoncini L, Sarasini A, Comoli P, Maccario R, Fiocchi R, Gerna G (2000) High levels of Epstein-Barr virus DNA in blood of solid-organ transplant recipients and their value in predicting posttransplant lymphoproliferative disorders. J Clin Microbiol 38:613–619
Yang J, Tao Q, Flinn IW, Murray PG, Post LE, Ma H, Piantadosi S, Caligiuri MA, Ambinder RF (2000) Characterization of Epstein-Barr virus-infected B cells in patients with posttransplantation lymphoproliferative disease: disappearance after rituximab therapy does not predict clinical response. Blood 96:4055–4063
Rowe DT, Webber S, Schauer EM, Reyes J, Green M (2001) Epstein-Barr virus load monitoring: its role in the prevention and management of post-transplant lymphoproliferative disease. Transpl Infect Dis 3:79–87
Comoli P, Maccario R, Locatelli F, Valente U, Basso S, Garaventa A, Tomà P, Botti G, Melioli G, Baldanti F, Nocera A, Perfumo F, Ginevri F (2005) Treatment of EBV-related post-renal transplant lymphoproliferative disease with a tailored regimen including EBV-specific T cells. Am J Transplant 5:1415–1422
Comoli P, Rooney CM (2006) Treatment of Epstein-Barr virus infections. In: Jenson HB, Tselis A (eds) Epstein-Barr virus. Taylor & Francis, New York, pp 351–372
Swinnen LJ, Mullen GM, Carr TJ, Costanzo MR, Fisher RI (1995) Aggressive treatment for postcardiac transplant lymphoproliferation. Blood 86:3333–3340
Muti G, Cantoni S, Oreste P, Klersy C, Gini G, Rossi V, D'Avanzo G, Comoli P, Baldanti F, Montillo M, Nosari A, Morra E (2002) Post-transplant lymphoproliferative disorders: improved outcome after clinico-pathologically tailored treatment. Haematologica 87:67–77
Starzl TE, Porter KA, Iwatsuki JT, Rosenthal BW, Shaw RW Jr, Atchison MA, Nalesnik M Ho, Griffith BP, Hakala TR, Hardesty RL, Jaffe R, Bahnson HT (1984) Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporin-steroid therapy. Lancet 1:583
Porcu P, Eisenbeis CF, Pelletier RP, Davies EA, Baiocchi RA, Roychowdhury S, Vourganti S, Nuovo GJ, Marsh WL, Ferketich AK, Henry ML, Ferguson RM, Caligiuri MA (2002) Successful treatment of posttransplant lymphoproliferative disorder (PTLD) following renal allografting is associated with sustained CD8+ T-cell restoration. Blood 100:2341–2348
Perrine SP, Hermine O, Small T, Suarez F, O'Reilly R, Boulad F, Fingeroth J, Askin M, Levy A, Mentzer SJ, Di Nicola M, Gianni AM, Klein C, Horwitz S, Faller DV (2007) A phase 1/2 trial of arginine butyrate and ganciclovir in patients with Epstein-Barr virus-associated lymphoid malignancies. Blood 109:2571–2578
Gross TG, Bucuvalas JC, Park JR, Greiner TC, Hinrich SH, Kaufman SS, Langnas AN, McDonald RA, Ryckman FC, Shaw BW, Sudan DL, Lynch JC (2005) Low-dose chemotherapy for Epstein-Barr virus-positive post-transplantation lymphoproliferative disease in children after solid organ transplantation. J Clin Oncol 23:6481–6488
Savoie A, Perpete C, Carpentier L, Joncas J, Alfieri C (1994) Direct correlation between the load of Epstein-Barr virus-infected lymphocytes in the peripheral blood of pediatric transplant patients and risk of lymphoproliferative disease. Blood 83:2715–2722
Bingler MA, Feingold B, Miller SA, Quivers E, Michaels MG, Green M, Wadowsky RM, Rowe DT, Webber SA (2008) Chronic high Epstein-Barr viral load state and risk for late-onset posttransplant lymphoproliferative disease/lymphoma in children. Am J Transplant 8:442–5
Lau AH, Soltys K, Sindhi RK, Bond G, Mazareigos G, Green M (2010) Chronic high Epstein-Barr viral load carriage in pediatric small bowel transplant recipients. Pediatr Transplant 14:549–553
Green M, Soltys K, Rowe DT, Webber SA, Mazareigos G (2009) Chronic high Epstein-Barr viral load carriage in pediatric liver transplant recipients. Pediatr Transplant 13:319–323
Ginevri F, Di Marco E, Parodi A, Gurrado A, Cirillo C, Botti G, Fontana I, Valente U, Locatelli F, Comoli P (2008) EBV viral load monitoring and reduction of immunosuppression do not successfully prevent PTLD after pediatric kidney transplantation. Am J Transplant 8(s2):477
Lee TC, Savoldo B, Rooney CM, Heslop HE, Gee AP, Caldwell Y, Barshes NR, Scott JD, Bristow LJ, O'Mahony CA, Goss JA (2005) Quantitative EBV viral loads and immunosuppression alterations can decrease PTLD incidence in pediatric liver transplant recipients. Am J Transplant 5:2222–2228
Kim Y, Boeckh M, Eglund JA (2007) Community respiratory virus infections in immunocompromised patients: hematopoietic stem cell and solid organ transplant recipients, and individuals with human immunodeficiency virus infection. Semin Respir Crit Care Med 28:222–242
Kuypers J, Wright N, Ferrenberg J, Huang ML, Cent A, Corey L, Morrow R (2006) Comparison of real-time PCR assays with fluorescent-antibody assays for diagnosis of respiratory virus infections in children. J Clin Microbiol 44:2382–2388
Blanchard SS, Gerrek M, Siegel C, Czinn SJ (2006) Significant morbidity associated with RSV infection in immunosuppressed children following liver transplantation: case report and discussion regarding need of routine prophylaxis. Pediatr Transplant 10:826–829
Apalsch AM, Green M, Ledesma-Medina J, Nour B, Wald ER (1995) Parainfluenza and influenza virus infections in pediatric organ transplant recipients. Clin Infect Dis 20:394–399
Ardehall H, Volmar K, Roberts C, Huang ML, Cent A, Corey L, Morrow R (2000) Fatal disseminated adenoviral infection in a renal transplant patient. Transplantation 71:998
Shirali GS, Ni J, Chinnock RE, Johnston JK, Rosenthal GL, Bowles NE, Towbin JA (2001) Association of viral genome with graft loss in children after cardiac transplantation. N Engl J Med 344:1498–1503
Pelaez A, Lyon GM, Force SD, Ramirez AM, Neujahr DC, Foster M, Naik PM, Gal AA, Mitchell PO, Lawrence EC (2009) Efficacy of oral ribavirin in lung transplant patients with respiratory syncytial virus lower respiratory tract infection. J Heart Lung Transplant 28:67–71
Chávez-Bueno S, Mejías A, Merryman RA, Ahmad N, Jafri HS, Ramilo O (2007) Intravenous palivizumab and ribavirin combination for respiratory syncytial virus disease in high-risk pediatric patients. Pediatr Infect Dis J 26:1089–1093
McCurdy LH, Milstone A, Dummer S (2003) Clinical features and outcomes of paramyxoviral infection in lung transplant recipients treated with ribavirin. J Heart Lung Transplant 22:745–753
Whitley RJ, Hayden FG, Reisinger KS, Young N, Dutkowski R, Ipe D, Mills RG, Ward P (2001) Oral oseltamivir treatment of influenza in children. Pediatr Infect Dis J 20:127–133
Carter BA, Karpen SJ, Quiros-Tejeira RE, Chang IF, Clark BS, Demmler GJ, Heslop HE, Scott JD, Seu P, Goss JA (2002) Intravenous cidofovir therapy for disseminated adenovirus in a pediatric liver transplant recipient. Transplantation 74:1050–1052
Thomas NJ, Hollenbeck CS, Ceneviva GD, Geskey JM, Young MJ (2007) Palivizumab prophylaxis to prevent respiratory syncytial virus mortality after pediatric bone marrow transplantation: A decision analysis model. J Pediatr Hematol/Oncol 29:227–232
Scharpé J, Evenepoel P, Maes B, Bammens B, Claes K, Osterhaus AD, Vanrenterghem Y, Peetermans WE (2008) Influenza vaccination is efficacious and safe in renal transplant recipients. Am J Transplant 8:332–337
Clark DA, Griffiths PD (2003) Human herpesvirus 6: relevance of infection in the immunocompromised host. Br J Haematol 120:384–395
Abdel Massih RC, Razonable RR (2009) Human herpesvirus 6 infections after liver transplantation. World J Gastroenterol 15:2561–2569
Mendez JC, Dockrell DH, Espy MJ, Smith TF, Wilson JA, Harmsen WS, Ilstrup D, Paya CV (2001) Human beta-herpesvirus interactions in solid organ transplant recipients. J Infect Dis 183:179–184
Razonable RR, Brown RA, Humar A, Covington E, Alecock E, Paya CV (2005) Herpesvirus infections in solid organ transplant patients at high risk of primary cytomegalovirus disease. J Infect Dis 192:1331–1339
Gupta M, Diaz-Mitoma F, Feber J, Shaw L, Forget C, Filler G (2003) Tissue HHV6 and 7 determination in pediatric solid organ recipients: a pilot study. Pediatr Transplant 7:458–463
Singh N, Carrigan DR (1996) Human Herpesvirus-6 in transplantation: An emerging pathogen. Ann Intern Med 124:1065–1071
Nash PJ, Avery RK, Tang WH, Starling RC, Taege AJ, Yamani MH (2004) Encephalitis owing to human herpesvirus-6 after cardiac transplant. Am J Transplant 4:1200–1203
Montejo M, Ramon Fernandez J, Testillano M, Valdivieso A, Aguirrebengoa K, Varas C, Olaizola A, De Urbina JO (2002) Encephalitis caused by human herpesvirus-6 in a liver transplant recipient. Eur Neurol 48:234–235
Takahashi K, Suzuki M, Iwata Y, Shigeta S, Yamanishi K, De Clercq E (1997) Selective activity of various nucleoside and nucleotide analogues against human herpesvirus 6 and 7. Antivir Chem Chemother 8:24–31
Yang J, Lemas VM, Flinn IW, Krone C, Ambinder RF (2000) Application of the ELISPOT assay to the characterization of CD8+ responses to Epstein-Barr virus antigens. Blood 95:241–248
Comoli P, Azzi A, Maccario R, Basso S, Botti G, Basile G, Fontana I, Labirio M, Cometa A, Poli F, Perfumo F, Locatelli F, Ginevri F (2004) Polyomavirus BK-specific immunity after kidney transplantation. Transplantation 78:1229–1232
Mattes FM, Vargas A, Kopycinski J, Hainsworth EG, Sweny P, Nebbia G, Bazeos A, Lowdell M, Klenerman P, Phillips RE, Griffiths PD, Emery VC (2008) Functional Impairment of Cytomegalovirus Specific CD8 T Cells Predicts High-Level Replication After Renal Transplantation. Am J Transplant 8:990–999
Kumar D, Chernenko S, Moussa G, Cobos I, Manuel O, Preiksaitis J, Venkataraman S, Humar A (2009) Cell-mediated immunity to predict cytomegalovirus disease in high-risk solid organ transplant recipients. Am J Transplant 9:1214–1222
Savoldo B, Rooney CM, Quiros-Tejeira RE, Caldwell Y, Wagner HJ, Lee T, Finegold MJ, Dotti G, Heslop HE, Goss JA (2005) Cellular immunity to Epstein-Barr virus in liver transplant recipients treated with rituximab for post-transplant lymphoproliferative disease. Am J Transplant 5:566–572
Sester U, Presser D, Dirks J, Gartner BC, Kohler H, Sester M (2008) PD-1 expression and IL-2 loss of cytomegalovirus- specific T cells correlates with viremia and reversible functional anergy. Am J Transplant 8:1486–1497
Binggeli S, Egli A, Schaub S, Binet I, Mayr M, Steiger J, Hirsch HH (2007) Polyomavirus BK-specific cellular immune response to VP1 and Large T-antigen in kidney transplant recipients. Am J Transplant 7:1131–1139
Prosser SE, Orentas RJ, Jurgens L, Cohen EP, Hariharan S (2008) Recovery of BK virus Large-T-antigen-specific cellular immune response correlates with resolution of BK virus nephropathy. Transplantation 85:185–192
Bunde T, Kirchner A, Hoffmeister B, Habedank D, Hetzer R, Cherepnev G, Proesch S, Reinke P, Volk HD, Lehmkuhl H, Kern F (2005) Protection from cytomegalovirus after transplantation is correlated with immediate early 1-specific CD8 T cells. J Exp Med 201:1031–1036
Heslop HE, Slobod KS, Pule MA, Hale GA, Rousseau A, Smith CA, Bollard CM, Liu H, Wu MF, Rochester RJ, Amrolia PJ, Hurwitz JL, Brenner MK, Rooney CM (2010) Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients. Blood 115:925–935
Walter EA, Greenberg PD, Gilbert MJ, Finch RJ, Watanabe KS, Thomas ED, Riddell SR (1995) Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med 333:1038–1044
Feuchtinger T, Opherk K, Bethge WA, Topp MS, Schuster FR, Weissinger EM, Mohty M, Or R, Maschan M, Schumm M, Hamprecht K, Handgretinger R, Lang P, Einsele H (2010) Adoptive transfer of pp 65-specific T cells for the treatment of chemorefractory cytomegalovirus disease or reactivation after haploidentical and matched unrelated stem cell transplantation. Blood 116:4360–4367
Comoli P, Locatelli F, Ginevri F, Maccario R (2002) Cellular immunotherapy for viral infections in solid organ transplant recipients. Curr Opin Organ Transplant 7:314–319
Acknowledgments
This study was partly supported by grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC) to PC; Ministero della Salute: Progetti Ricerca Oncologica [grant numbers RFPS-2006-4-341763 to PC; RFPS-2006-Regione Umbria to PC], and Progetti Ricerca Finalizzata; grant from Agenzia Italiana del Farmaco to FG; Fondazione IRCCS Istituto Gaslini, Progetti di Ricerca Corrente to FG; and Fondazione Malattie Renali del Bambino, Genova, to FG. We thank Laurene Kelly for manuscript editing.
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Comoli, P., Ginevri, F. Monitoring and managing viral infections in pediatric renal transplant recipients. Pediatr Nephrol 27, 705–717 (2012). https://doi.org/10.1007/s00467-011-1812-2
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DOI: https://doi.org/10.1007/s00467-011-1812-2