key: cord-0959628-5uoc3y4r authors: Moal, Valérie; Zandotti, Christine; Colson, Philippe title: Emerging viral diseases in kidney transplant recipients date: 2012-11-07 journal: Rev Med Virol DOI: 10.1002/rmv.1732 sha: c844a0b16e498dbf19ffdf7dcc490dcf7f137260 doc_id: 959628 cord_uid: 5uoc3y4r Viruses are the most important cause of infections and a major source of mortality in Kidney Transplant Recipients (KTRs). These patients may acquire viral infections through exogenous routes including community exposure, donor organs, and blood products or by endogenous reactivation of latent viruses. Beside major opportunistic infections due to CMV and EBV and viral hepatitis B and C, several viral diseases have recently emerged in KTRs. New medical practices or technologies, implementation of new diagnostic tools, and improved medical information have contributed to the emergence of these viral diseases in this special population. The purpose of this review is to summarize the current knowledge on emerging viral diseases and newly discovered viruses in KTRs over the last two decades. We identified viruses in the field of KT that had shown the greatest increase in numbers of citations in the NCBI PubMed database. BKV was the most cited in the literature and linked to an emerging disease that represents a great clinical concern in KTRs. HHV‐8, PVB19, WNV, JCV, H1N1 influenza virus A, HEV, and GB virus were the main other emerging viruses. Excluding HHV8, newly discovered viruses have been infrequently linked to clinical diseases in KTRs. Nonetheless, pathogenicity can emerge long after the discovery of the causative agent, as has been the case for BKV. Overall, antiviral treatments are very limited, and reducing immunosuppressive therapy remains the cornerstone of management. Copyright © 2012 John Wiley & Sons, Ltd. KT is the treatment of choice for ESRD and results in increases in the duration and quality of life for patients [1] . Worldwide, the number of KTs increases each year. In the USA, among the 571,000 patients treated for ESRD in 2009, 30% (171,000) received a renal allograft compared with 27% (93,000) in 1998 [2, 3] . In France, in 2010, the prevalence of ESRD patients treated by KT was 44.4% (29,841 patients) [4] . However, successful transplantation requires the administration of immunosuppressive therapies to prevent allograft rejection, which is inextricably linked to infection. Anti-infective regimens make immunosuppressive therapies safer, but they do not completely prevent the occurrence or increased severity of infectious diseases. Thus, infections remain an important concern and constitute the second-leading cause of mortality among KTRs behind cardiovascular complications [2, 5] . Viruses are the most important cause of infections and represent a major source of morbidity and mortality [6] [7] [8] . KTRs may acquire viral infections through exogenous routes, including community exposure, the donor organ, and blood products or by endogenous reactivation of latent viruses [6] . Virus-associated diseases may manifest as direct illness or indirect effects mediated by immunomodulation [6] , and viruses will more fully display their potential dangerousness in KTRs than in immune-competent individuals [9] . In KTRs, the most typical viral infections are those caused by Herpesviridae, hepatitis viruses, HIV, and Papillomaviridae [8, 10] . However, several emerging viral diseases have recently been highlighted in this population. The word "emerging," when applied to a viral disease, can have various meanings [11] . Emerging viral diseases are diseases that newly appear in a population or that have been recognized earlier but whose incidence or geographical range is increasing. Re-emerging viral diseases are diseases that re-appear in a same or different geographical area. Emergence can correspond to the appearance of new viruses or can rely on migrations of people, reservoir, or vectors, on new environmental conditions, new behaviors, or new medical practices. Alternatively, emergence can reflect an improved awareness by clinicians of the disease, which leads to an increase in testing and diagnosis. Finally, emergence can rely on the implementation of new diagnostic tools that reveal levels of incidence and prevalence previously underestimated. Recent decades have been very favorable for the emergence of viral agents and viral diseases. Notably, urbanization and globalization have shown dramatic expansions [12] . Concurrently, new technologies and medical practices have been implemented or their use has been increasing, as is the case for organ transplantation [5] , and the tools for scientific and medical information have grown significantly [13, 14] . Moreover, the number and performance of viral detection methods have evolved dramatically over the last decades [15] . Particularly, molecular methods have been increasingly implemented in clinical virology and have considerably impacted this field by allowing the rapid detection of viruses, including those that cannot be cultivated in the laboratory. The purpose of this review is to provide an update on emerging viral diseases and newly discovered viruses in KTRs. We first performed a search in the NCBI PubMed database by using as keywords "virus" OR "viral infection" AND "kidney transplantation", limiting the search to humans and to the last 20 years. We obtained 3444 references. We then checked these references by identifying the name of the virus or family of viruses in the title or abstract of the reference, we confirmed that the viruses occurring in most publications in the field of KT were CMV (723 references, 20% of the total number of references), HCV (656 references, 18%), EBV (478 references, 13%), HBV (280 references, 8%), HIV (168 references, 5%), and human papillomavirus (109 references, 3%) ( Figure 1 ). We focused on other viruses and the yearly evolution of the number of articles that quoted them if more than 10 papers were available over the last 20 years (Figure 2 ). The virus for which the number of citations showed the greatest increase over this period was BKV, followed by HHV-8, GB virus, PVB19, WNV, JCV, H1N1 influenza virus A, and HEV ( Figure 3) . Finally, to possibly relate emerging diseases in KTRs to newly discovered viruses, we searched the NCBI PubMed database for each virus The human polyomaviruses BK and JC have both been recognized as causative agents of polyomavirus-associated nephropathy, but BK is the major etiologic agent [16] . BKV was first isolated in 1970 from a KTR who presented with a ureteral stenosis [17] . The virus was named BKV after the initials of this patient (Table 1) . BKV was discovered well before the clinical consequences of infection could be appreciated in KTRs. In 1993, the first case of BKV interstitial nephritis was diagnosed by a renal allograft biopsy in a patient with acute renal failure [18, 19] . Infections with BKV and JCV occur early in life and are benign [20] . In blood donors, the IgG seroprevalence was 82% and 58% for BKV and JCV, respectively, whereas viruria rates were 7% and 19%. Neither BKV nor JCV was detected in plasma [21] . The distribution of latent viruses in different tissues is thought to occur during the primary viremia. The best-known site of BKV and JCV latency is the urogenital tract, and BK viral sequences can be detected in the bladder, in prostate tissues, and in kidneys (in up to 57%) procured from asymptomatic individuals [22] [23] [24] . After KT, the incidence of viruria increased to 35% for JCV and 16% for BKV, and infection by one polyomavirus was negatively associated with reactivation of the other [16] . BKV reactivation most likely occurs in the cells of the donor kidney [20] . years of BKVAN emergence, misdiagnosis of acute cellular rejection instead of viral nephritis likely resulted in unnecessary antirejection treatment that could inflate rates of allograft loss of 50%-100% recorded in earlier studies. A proactive approach to accurate and early diagnosis has decreased the incidence of BKVAN-related graft loss to less than 10% [27] . Reactivation of BKV in the ureter can manifest as a ureteric stenosis, and in the bladder, it can manifest as a hemorrhagic cystitis [30] . Renal cell carcinoma of the graft and carcinoma of the bladder are increasingly considered complications of BKV's oncogenic properties [27, 31] . Routine screening is presently the most important tool used to identify patients at increased risk for BKVAN [32] . Detection of viremia is required in KTRs with high level of urinary BKV replication (decoy cells or BKV loads > 10 7 copies/ml) because 30%-50% of them progress to BK viremia and BKVAN [20] . Screening is especially recommended during the first year of KT and whenever unexplained serum creatinine rise occurs [32]. JCV was isolated from the brain of a patient suffering from Hodgkin's disease and PML in 1971 [33]. The virus was named JCV after the initials of this patient (Table 1) . JCV is the causative agent of PML in immunodeficient patients, but it has not been established if PML results from primary infection or reactivation of the latent virus. The normal brain may be a site of JCV latency, and the reactivation of the virus can lead to lytic infection of glial cells and to the onset of PML in the case of failure of immunosurveillance [34]. However, PML occurs rarely in KTRs. In a retrospective study, there were nine cases of PML identified among 32,757 adult KTRs, which corresponded to an incidence of 8.8 cases/100,000 person-years HHV-8 is the causative agent of KS, which was described in 1872 by Moritz Kaposi [44] . Kaposi described the sporadic or classic subtype. The iatrogenic subtype has subsequently been described in immunocompromised patients, particularly KTRs. HHV-8 was discovered using RDA between healthy skin and KS tumor obtained in an AIDS patient [45] ( Table 1) . Primary HHV-8 infection in immune-competent individuals is associated with mild, nonspecific symptoms of fatigue, diarrhea, rash, and lymphadenopathy [46] . Following primary infection, HHV-8 establishes latency mainly in B lymphocytes and spindle cells [46] . HHV-8 is a geographically restricted virus, and its incidence varies from low incidence (<5%) in North America to very high incidence (>50%) in Africa and the Amazon basin [46] . Contrarily to HHV-7, the pathogenic potential of HHV-8 in KTRs is clear. . In a prospective study, KS was due to HHV-8 reactivation in 87% of the cases and was due to primary infection in 13% of cases, in which seronegative KTRs received a kidney from a seropositive donor [47] . In seropositive KTRs, independent risk factors for KS were age and black skin [47] . Screening of donors and recipients for HHV-8 is recommended to assess the risk in geographic regions with high rates of infection and to monitor HHV-8 viremia after KT to determine the risk of disease in HHV-8 seropositive recipients or in those who receive a kidney from an HHV-8 seropositive donor [46] . The mean time between KT and KS onset is 20 months, with a range from a few weeks to 18 years [48] . Skin lesions are seen in >90% of all cases with KS. The lesions have a dark blue or purplish color on white skin ( Figure 4 ) and often appear pigmented on black skin. Initially macular, they are subsequently infiltrated and sometimes nodular. Most cutaneous lesions occur at the extremities. Visceral involvement is observed in 40% of the cases with KS [52]. Oral lesions consist predominantly of purple stains on the palate and are associated with visceral involvement of the gastrointestinal tract, which is typically detected as red spots during endoscopic examination of asymptomatic patients. Other visceral sites of KS are the lymph nodes and the lungs ( Figure 4 ). Regardless of the localization, the diagnosis of KS can be based on its histological features [48] . Typical lesions exhibit a network of spindle-shaped cells and large vascular spaces surrounded by an endothelial cell layer. Immunochemistry using mAb directed against HHV-8 antigens is useful for the pathological diagnosis, as is PCR to detect viral replication [46] . Other HHV-8-associated diseases include the body cavity-based PEL [53,54], MCD [55] [56] [57] , and PTLDs [55, [58] [59] [60] . These occur rarely in KTRs, and the cases reported in the literature are summarized in Table 2 . Besides, primary HHV-8 infection resulted in nonmalignant diseases with a potentially lethal acute syndrome characterized by fever, hemophagocytic syndrome, and bone marrow failure [61] . The risk factors for these less common clinical manifestations of HHV-8 infection have not been defined. HEV was discovered after an outbreak of unexplained hepatitis occurring in Soviet soldiers in Afghanistan (Table 1) . Balayan presented with hepatitis after ingestion of a pooled stool extract of patients and detected the virus in his stool by EM [62] . HEV is a leading cause of acute hepatitis in adults in developing countries, where it is hyperendemic, of genotype 1 or 2, and principally water borne [63] . In developed countries, hepatitis E was first considered imported from HEV hyperendemic geographical areas but is currently an emerging autochthonous (i.e. locally acquired) disease and a porcine zoonosis caused by HEV genotype 3 or 4 [63] . Hepatitis E typically causes an acute and self-limiting infection in immune-competent individuals. However, fulminant hepatitis and high mortality are described, reaching 25% in cases involving pregnancy in developing countries and 70% in cases involving underlying liver disease [63] . The first case of HEV infection in a KTR was reported in 2003 in India [64] . The patient died of severe acute pancreatitis attributed to HEV infection with elevated serum alanine aminotransferase and bilirubin levels, positive anti-HEV IgM, and a surprisingly normal serum amylase level. European autochthonous acute HEV infections in KTRs were first described in Toulouse, France [65] . The incidence of HEV infections has been estimated to be 2.7 cases/100 person-years after KT in southwestern France [63] . The only independent predictive factor for HEV infection in SOTRs is the consumption of game meat [63] . In KTRs, acute hepatitis E is mostly asymptomatic [66] . Liver enzyme levels are lower, and histological lesions are less severe than those seen in immune-competent individuals [67] . Various extrahepatic manifestations have been described in KTRs in association with HEV infections, including transient cryoglobulinemia, glomerulonephritis [63] , and neurological symptoms involving both the peripheral and CNS [63] . HEV infection emerged as a clinical concern among KTRs in Europe when chronic infections associated with autochthonous genotype 3 HEV were described in 2008 [67, 68] . Chronic hepatitis E is defined as hepatitis and persistent infection documented by PCR, lasting for more than 6 months. The incidence of chronic evolution after HEV infection has been estimated to be 51% in KTRs [66] . Clinical studies suggest that the occurrence and persistence of chronic hepatitis E are related to the immunological status of patients. Indeed, this form of hepatitis E is described only in severely immunocompromised patients, especially SOTRs, HIV-infected patients, and individuals with hematological diseases [63] . In pooled SOTRs, the occurrence of chronic hepatitis E has been related to the dose of immunosuppressants [66, 69] . As in the acute form, chronic hepatitis E is often subclinical in KTRs, with mild liver abnormalities ( Figure 4 ). Twenty-seven chronic hepatitis E cases have been reported in Western Europe since 2008 [66, 68, [70] [71] [72] . Evolution to cirrhosis may occur rapidly after HEV infection [68, 73] . Three of the four reported cases of HEV-related cirrhosis have died from decompensated cirrhosis [66, 68, 71] . PVB19 was discovered in 1975 during systematic screening of hepatitis B in nine healthy blood donors, a patient with acute hepatitis, and a patient who received a renal allograft 1 week earlier, without a specific illness having been associated with PVB19 at that time (Table 1 ) [74] . Primary PVB19 infection most often occurs early in life [75] . In immune-competent individuals, PVB19 infection is generally asymptomatic but may manifest in children as a mild rash called erythema infectiosum or fifth disease and in adults as a polyarthritis [75] . The first description of hypoplastic crisis during PVB19 infection dates to 1981 in patients with sickle-cell anemia [76] . [75] . Anemia results from the viral replication in erythroid progenitors, leading to their apoptosis, and is typically refractory and severe. More rarely, leukopenia (34%) and thrombocytopenia (19.1%) were present. Renal graft dysfunction and hepatitis existed in 15.6% and 6.5% of the KTRs, respectively [75] . Collapsing glomerulopathy and thrombotic microangiopathy have been reported in renal allografts [79] . Other manifestations were seldom reported, including pneumonitis, encephalitis, [136] Unresolved Human rhinovirus C Molecular human rhinovirus screening in NPAs prospectively collected from hospitalized children with acute respiratory tract infections and negative for common respiratory viruses (co-infection with human bocavirus in 12 cases), during a myocarditis, and hemophagocytic syndrome [79] . Bone marrow examination typically reveals red cell aplasia ( Figure 4 ). Diagnosis of PVB19 infection is based on serological tests, blood/bone marrow PCR, and bone marrow examination [79] . The persistence of viral replication in the blood has been demonstrated in KTRs several months after the correction of the hematologic abnormalities [79] . Chronic infection can manifest as chronic anemia or relapses of anemia [78, 84, 85] . The relapses of anemia are more frequent after primary infection [84] . Recurrences of PVB19 infections occur in 34% of the KTRs [75] . A new strain of influenza A H1N1 was first recognized in 2009 and resulted in a worldwide pandemic (Table 1 ) [86] . This pandemic H1N1 has been characterized as a reassortant virus with genes from swine, avian, and human influenza viruses [87] . Severe disease has been noted in children, pregnant women, and people with comorbid disorders including chronic lung or heart disease, diabetes, and obesity [88] . In SOTRs, pandemic H1N1 resulted in a spectrum of illness ranging from mild and selflimiting to severe disease. The largest study reported data on 237 SOTRs from North America; of which, the majority (37%) was KTRs [89] . The most common presenting symptoms were cough, fever, myalgias, rhinorrhoea, sore throat, and headache. Lung imaging showed pneumonia in 32% of patients. H1N1 was diagnosed by PCR on nasopharyngeal swabs ( Figure 4 ). The incidence of hospitalization was 71%, and the rate of admission to the intensive care unit was 16%. Of these patients, 21 needed mechanical ventilation. Two adults and one child received extracorporeal membrane oxygenation. The type of transplant in these patients was not specified, but it did not seem to affect the outcomes. Ten adults died (7%). The overall mortality rate was 4%. Different studies showed that morbidity and mortality observed in KTRs and non-immunocompromised patients infected with pandemic H1N1 were similar [90] . WNV is an example of a previously known pathogen whose emergence is related to epidemiological factors that favored its spread. The appearance of WNV in New York in 1999 and the panzootic that followed have drawn attention to this virus, which was isolated for the first time in 1937 in a woman suffering from fever in the province of West Nile in Uganda (Table 1 ) [91] . Whereas WNV fever may be a real emerging disease in the Americas with a peak of activity in 2003 that affected 9862 persons, including 2866 cases of neuroinvasive disease and 264 deaths [92] , in the Old World, less than 200 human deaths have been recorded over the past decade [93] . Birds are the primary reservoir of WNV (Figure 4) , and mosquitoes are the vectors, acquiring the infection by feeding on a viremic bird and transmitting it to humans from bites. In immune-competent individuals, 80% of the infections are asymptomatic, whereas 20% have a self-limited febrile illness that may be accompanied by a maculopapular rash [94] . The estimated rate of neurological involvement is less than 1% [94, 95] . KTRs may acquire WNV by three primary mechanisms: from an infected organ donor, an infected blood product, and community-acquired exposure. To date, WNV infections after KTs and blood product transfusions have been reported in six KTRs [96] [97] [98] [99] (Table 3 ). The majority of reports of WNV infections in KTRs describe infections acquired by mosquito exposure occurring from 2 months to 8 years post-transplant [94, 95, [100] [101] [102] [103] . The incubation period seems to be longer among SOTRs than among the general population. A study conducted in >800 SOTRs after an epidemic of WNV in Canada found that seroprevalence was low (0.25%) and the risk of neurological disease was 40%, much higher than for the general population [104] . SOTRs had a 40 times greater risk of symptomatic infection than normal hosts [94] . New viruses were discovered after 1990 in two different settings: in well-characterized human diseases, for example during outbreaks (Table 4) , or Prevalence of WU and KI polyomaviruses was established in plasma (3.6%), urine (14%), and upper respiratory tract specimens (10%) in KTRs. All the patients with a positive respiratory specimen had acute upper respiratory tract infection, but none of these samples were tested for any acute respiratory virus [142] Prevalence of WU and KI polyomaviruses was determined in immunocompromized patients. KI polyomavirus was detected in 16 of the 200 patients by RT-PCR. One of them was a 72-year-old KTR that presented with an acute upper respiratory tract infection and was co-infected with human rhinovirus. The sample positive for the viruses was a NPA [143] due to systematic screening of samples (Table 5 ). In the latter case, the viruses were found from human samples collected during authenticated infectious syndromes or from laboratories but without clinical data. The clinical significance of newly discovered viruses without accompanying clinical data is often unknown. In contrast, new viruses that have been discovered in human outbreaks are clearly pathogens, and 66% are zoonotic (Table 4) . Among viruses discovered after 1990, HHV-8 is the only virus to clearly cause an emerging disease in KTRs. Very few new respiratory viruses have been studied in KTRs ( Figure 5 ), and we have summarized these studies in Table 6 . However, community exposure of KTRs to respiratory viruses is important. The consequences of respiratory viral infections include higher rates of viral pneumonia in KTRs than in immune-competent individuals and increased risk of superinfection with bacterial and fungal pathogens [8] . Nevertheless, identification of viruses in respiratory infections in KTRs is difficult. In a prospective study of respiratory viral infections, detection of a respiratory virus was positive only in 17 of the 68 (25%) cases [105] . Large No specific antiviral drug [75, 79] . Reduce immunosuppressive therapy [75, 79] . Iv Ig infusions are given [75, 79] . The clinical response is a reticulocytosis and correction of the anemia. Erythrocyte transfusion could be required [79] . No specific antiviral drug. Reduce or discontinue immunosuppressive therapy. Treatment is mainly supportive [94, 102] prospective controlled studies in KTRs with comprehensive viral testing are needed to establish the epidemiology and to determine whether newly discovered respiratory viruses cause respiratory diseases in this population. Finally, several reports have been published on GB virus C and TTV in KTRs, peaking in 1997 and 2003, respectively, and then decreasing. Despite the fact that GB virus C and TTV were first found in serum samples of patients with unexplained hepatitis [106] [107] [108] , most papers have dismissed significant roles for these viruses as etiologic agents of diseases in immune-competent individuals [106, [108] [109] [110] and in KTRs [111] [112] [113] [114] [115] (Supplementary Table) . TREATMENT Except for H1N1 flu and hepatitis E, there is no available antiviral intervention. Reduced immunosuppressive therapy and supportive treatment are the main recommendations for the treatment of emerging viral diseases that are presented here. [144] . The H1N1-adjuvanted vaccine was of limited efficacy with a seroconversion rate around only 50% but was safe in KTRs [145] . During an influenza pandemic [144] Tables 7 and 8 . This review summarized the current knowledge on viruses that had shown the greatest increase over the last two decades in the field of KT according to the number of citations. The viral diseases that were discussed result from endogenous reactivation or from community exposure. They were most often the first and only described in immunosuppressed populations, and their clinical expression has become apparent several years after the discovery of the virus. Apart from HHV8, the viruses that have been discovered over the last two decades are infrequently involved in clinical diseases in KTRs. Nonetheless, in favorable circumstances, the pathogenicity of a newly discovered virus can fully express itself long after its discovery. Virology remains a very fast-moving field because of the implementation of new technologies. These technologies are helpful in detecting new or old pathogens in undiagnosed infections [116] and are also influential in conducting technology-based research [117] . Viruses are suspected to be the most abundant inhabitants of our biosphere and to number approximately 3 Â 10 12 in the human body [118] . Metagenomics now allows us to characterize the virome in clinical samples, which has revealed the presence of expected and unexpected viruses and a large number of viral coinfections [119] . The increased use of these tools in special populations, such as KTRs, that are particularly concerned with infectious diseases might lead to breakthroughs in the knowledge of the biology and clinical impact of viruses. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases Annual Data Report, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases Transplantation 50 years later-progress, challenges, and promises Viral infection in the renal transplant recipient Viral infection after renal transplantation: surveillance and management Risks and epidemiology of infections after renal transplantation Emerging viruses in transplantation Emerging viral infections in transplant recipients Emerging infections: a perpetual challenge urbanization and globalization: the unholy trinity of the 21(st) century ProMED-mail: an early warning system for emerging diseases PubMed and beyond: a survey of web tools for searching biomedical literature Prospects for the future using genomics and proteomics in clinical microbiology Inhibitory interactions between BK and JC virus among kidney transplant recipients New human papovavirus (B.K.) isolated from urine after renal transplantation BK virus infection in a kidney allograft diagnosed by needle biopsy Human polyoma virus infection of renal allografts: histopathologic diagnosis, clinical significance, and literature review BK virus in solid organ transplant recipients Human herpesvirus 8 and Epstein-Barr virus-related monotypic large B-cell lymphoproliferative disorder coexisting with mixed variant of Castleman's disease in a lymph node of a renal transplant recipient Castleman's disease in a renal allograft recipient Case report: fatal pulmonary Kaposi's sarcoma and Castleman's disease in a renal transplant recipient Post renal transplantation human herpesvirus 8-associated lymphoproliferative disorder and Kaposi's sarcoma Posttransplantation plasmacytic proliferations related to Kaposi's sarcoma-associated herpesvirus Epstein-Barr virus-and human herpesvirus 8-associated primary cutaneous plasmablastic lymphoma in the setting of renal transplantation Severe pancytopenia and hemophagocytosis after HHV-8 primary infection in a renal transplant patient successfully treated with foscarnet Evidence for a virus in non-A, non-B hepatitis transmitted via the fecaloral route Acute pancreatitis following kidney transplantation -role of viral infections Acute hepatitis and renal function impairment related to infection by hepatitis E virus in a renal allograft recipient Factors associated with chronic hepatitis in patients with hepatitis E virus infection who have received solid organ transplants Hepatitis E virus and chronic hepatitis in organ-transplant recipients Chronic hepatitis E with cirrhosis in a kidneytransplant recipient Influence of immunosuppressive therapy on the natural history of genotype 3 hepatitis-E virus infection after organ transplantation Hepatitis E virus as an emerging cause of chronic liver disease in organ transplant recipients Hepatitis E virus infection among solid organ transplant recipients, the Netherlands Hepatitis E virus-related cirrhosis in kidney-and kidney-pancreas-transplant recipients Parvovirus-like particles in human sera Parvovirus B19 infection after transplantation: a review of 98 cases Parvovirus infections and hypoplastic crisis in sickle-cell anaemia Slow clearance of human parvovirus B19 viremia following acute infection Long-term remission of recurrent parvovirus-B associated anemia in a renal transplant recipient induced by treatment with immunoglobulin and positive seroconversion Parvovirus B19 in kidney transplant patients Clinical implications of quantitative real timepolymerase chain reaction of parvovirus B19 in kidney transplant recipients -a prospective study B19 virus infection in renal transplant recipients Incidence and clinical significance of human parvovirus B19 infection in kidney transplant recipients Relapsing severe anaemia due to primary parvovirus B19 infection after renal transplantation: a case report and review of the literature Recurrent anemia in kidney transplant recipients with parvovirus B19 infection Emergence and pandemic potential of swine-origin H1N1 influenza virus Severe 2009 H1N1 influenza in pregnant and postpartum women in California Outcomes from pandemic influenza A H1N1 infection in recipients of solid-organ transplants: a multicentre cohort study Morbimortality of pandemic influenza A H1N1 infection in kidney transplant recipients requiring hospitalization: a comparative analysis with nonimmunocompromised patients A neurotropic virus isolated from the blood of a native of Uganda West Nile Virus Activity in the United States West Nile virus in Europe: understanding the present to gauge the future Community-acquired West Nile virus infection in solid-organ transplant recipients West Nile virus encephalitis Transmission of West Nile virus from an organ donor to four transplant recipients West Nile virus infections in organ transplant recipients-New York and Pennsylvania Transmission of West Nile virus through blood transfusion in the United States in 2002 West Nile virus encephalitis in a kidney transplant recipient Natural and nosocomial infection in a patient with West Nile encephalitis and extrapyramidal movement disorders West Nile virus encephalitis in organ transplant recipients: another high-risk group for meningoencephalitis and death West Nile virus-associated encephalitis in recipients of renal and pancreas transplants: case series and literature review Seroprevalence of West Nile virus infection in solid organ transplant recipients A seroprevalence study of West Nile virus infection in solid organ transplant recipients Clinical implications of respiratory virus infections in solid organ transplant recipients: a prospective study The GB viruses: a review and proposed classification of GBV-A, GBV-C (HGV), and GBV-D in genus Pegivirus within the family Flaviviridae A novel DNA virus (TTV) associated with elevated transaminase levels in posttransfusion hepatitis of unknown etiology Torque teno virus (TTV): current status The incidence of transfusion-associated hepatitis G virus infection and its relation to liver disease Global distribution of transfusion-transmitted virus GB virus C/hepatitis G virus infection in dialysis patients and kidney transplant recipients in Central Brazil High prevalence, low pathogenicity of hepatitis G virus in kidney transplant recipients High prevalence of hepatitis G virus (HGV) infection in renal transplantation GB virus C/hepatitis G virus and TT virus infections among high risk renal transplant recipients in India Prevalence of transfusion transmitted virus infection and its effect on renal graft survival in renal transplant recipients A new arenavirus in a cluster of fatal transplantassociated diseases Technology-driven research will dominate hypothesis-driven research: the future of microbiology Metagenomics and future perspectives in virus discovery Characterization of the viral microbiome in patients with severe lower respiratory tract infections, using metagenomic sequencing New arenavirus isolated in Brazil A morbillivirus that caused fatal disease in horses and humans Human influenza A H5N1 virus related to a highly pathogenic avian influenza virus Fatal encephalitis due to Nipah virus among pig-farmers in Malaysia A novel coronavirus associated with severe acute respiratory syndrome Identification of a novel coronavirus in patients with severe acute respiratory syndrome Coronavirus as a possible cause of severe acute respiratory syndrome A newly discovered human pneumovirus isolated from young children with respiratory tract disease Characterization and complete genome sequence of a novel coronavirus, coronavirus HKU1, from patients with pneumonia A previously undescribed coronavirus associated with respiratory disease in humans Identification of a new human coronavirus Discovery of a new human T-cell lymphotropic virus (HTLV-3) in Central Africa Emergence of unique primate T-lymphotropic viruses among central African bushmeat hunters Cloning of a human parvovirus by molecular screening of respiratory tract samples Identification of a third human polyomavirus Identification of a novel polyomavirus from patients with acute respiratory tract infections Clinical features and complete genome characterization of a distinct human rhinovirus (HRV) genetic cluster, probably representing a previously undetected HRV species, HRV-C, associated with acute respiratory illness in children Clonal integration of a polyomavirus in human Merkel cell carcinoma Acute respiratory infection in a renal transplant recipient Prevalence and clinical symptoms of human metapneumovirus infection in hospitalized patients Clinical disease in children associated with newly described coronavirus subtypes Prevalence of WU and KI polyomaviruses in plasma, urine, and respiratory samples from renal transplant patients Polyomaviruses KI and WU in immunocompromised patients with respiratory disease Guidance on novel influenza A/H1N1 in solid organ transplant recipients Influenza A/H1N1 vaccine in patients treated by kidney transplant or dialysis: a cohort study The authors have no competing interest. We are grateful to Laurence Camoin, Rémi Charrel, Laurent Daniel, Stéphane Garcia, and Philippe Souteyrand for providing images.