Polyomavirus BK Genome Comparison Shows High Genetic Diversity in Kidney Transplant Recipients Three Months after Transplantation

BK polyomavirus (BKPyV) is a human DNA virus generally divided into twelve subgroups based on the genetic diversity of Viral Protein 1 (VP1). BKPyV can cause polyomavirus-associated nephropathy (PVAN) after kidney transplantation. Detection of BKPyV DNA in blood (viremia) is a source of concern and increase in plasma viral load is associated with a higher risk of developing PVAN. In this work, we looked for possible associations of specific BKPyV genetic features with higher plasma viral load in kidney transplant patients. We analyzed BKPyV complete genome in three-month samples from kidney recipients who developed viremia during their follow-up period. BKPyV sequences were obtained by next-generation sequencing and were de novo assembled using the new BKAnaLite pipeline. Based on the data from 72 patients, we identified 24 viral groups with unique amino acid sequences: three in the VP1 subgroup IVc2, six in Ib1, ten in Ib2, one in Ia, and four in II. In none of the groups did the mean plasma viral load reach a statistically significant difference from the overall mean observed at three months after transplantation. Further investigation is needed to better understand the link between the newly described BKPyV genetic variants and pathogenicity in kidney transplant recipients.     

Late primary cytomegalovirus infection presenting with acute inflammatory demyelinating polyneuropathy in a heart transplant recipient: a case report and review of the literature

Cytomegalovirus (CMV) infection is well recognized as a cause of morbidity and mortality in heart transplant recipients. Primary CMV infection can occur early post transplant in at‐risk recipients with donor‐derived infection, or any time after transplantation in community‐acquired infection. We describe a unique case of primary CMV infection occurring 14 years after cardiac transplantation. In addition to end‐organ CMV disease, this patient developed a post‐infectious neurologic phenomenon, acute inflammatory demyelinating polyneuropathy. This entity has rarely been reported in the solid organ transplant population.     

BK virus nephropathy after allogeneic stem cell transplantation: A case report and literature review

Polyomaviruses are increasingly recognized as important human pathogens. Among those, BK virus has been identified as the main cause of polyomavirus‐associated nephropathy (PVAN), a major cause of renal allograft failure. PVAN has also been well described in the setting of non‐renal solid organ transplantation. The reports of PVAN after hematopoietic stem cell transplantation (HCT) are surprisingly very few. Here, we describe a patient with treatment‐related myelodysplastic syndrome who received an unrelated donor HCT after ablative conditioning and in vivo T cell depletion with alemtuzumab. He developed a biopsy‐proven BK nephropathy, which contributed to his renal failure. Leflunomide as well as cidofovir were given at different times, both in combination with intravenous immunoglobulin. Both treatments were effective in reducing the BK viral load, the cystitis symptoms and both stabilized but did not really improved the renal function. The patient was still dialysis‐dependent when he died from Pseudomonas sepsis 13 months after HCT. A critical review of the literature and the treatment modalities for post‐HCT PVAN are provided. Am. J. Hematol. 2009. © 2008 Wiley‐Liss, Inc.     

Absence of JC polyomavirus (JCPyV) viremia in early post‐transplant JCPyV nephropathy: A case report

JC polyomavirus (JCPyV)‐associated nephropathy (JCPyVAN) occurs in <3% of PVAN cases after renal transplantation. We report the first confirmed case to our knowledge of JCPyVAN diagnosed by kidney biopsy in the early 6 months post transplant in Thailand. In this case report, recovery of renal allograft function was not observed after reduction of immunosuppressive agents and administration of intravenous immunoglobulin and cidofovir. Despite persistent JCPyV viruria, no significant further decline in allograft function was documented at 15 months post transplant.     

Successful treatment of donor‐derived hepatitis C viral infection in three transplant recipients from a donor at increased risk for bloodborne pathogens

We report here the successful treatment of hepatitis C virus (HCV) transmitted from a nucleic acid testing (NAT)‐negative donor to three HCV‐negative recipients—two renal transplants and one liver. Both renal recipients underwent standard deceased‐donor renal transplantation with immediate graft function. The liver recipient underwent standard orthotopic liver transplantation and recovered uneventfully. The donor was a 39‐year‐old woman with a terminal serum creatinine of 0.7 mg/dL. She was high risk for bloodborne pathogens, based upon a history of sexual contact with an HCV‐infected male partner. Recipient 1 was a 45‐year‐old man with a history of end‐stage renal disease from systemic lupus erythematosus. Recipient 2 was a 62‐year‐old woman with a history of end‐stage renal disease caused by hypertension and insulin‐dependent diabetes. Recipient 3 was a 42‐year‐old man with acute liver failure from acetaminophen ingestion. All recipients became HCV polymerase chain reaction positive on post‐transplant follow‐up. Both kidney recipients were treated with ledipasvir/sofosbuvir combination therapy for 12 weeks without side effects or rejection episodes. Recipient 3 was treated with ledipasvir/sofosbuvir in combination with ribavirin for 12 weeks without side effects. All patients achieved a sustained viral response at 12 weeks and are considered cured of HCV. The kidney recipients maintained good allograft function with a serum creatinine of 1.4 mg/dL and 1.0 mg/dL, respectively. Both renal recipients maintained normal liver function post treatment and did not develop any evidence of fibrosis. The liver recipient's liver function tests returned to normal without further incident. This case report provides evidence for the successful treatment of donor‐derived HCV in transplant recipients.     

Pneumocystis jirovecii pneumonia 13 years post renal transplant following a recurrent cytomegalovirus infection

Pneumocystis jirovecii (formerly Pneumocystis carinii) pneumonia (PCP) is a rare but serious infection that usually occurs within a year after solid organ transplantation. PCP may occur after 1 year post transplantation, but the rate is reported to be very low. Studies have shown an association between cytomegalovirus (CMV) infection in solid organ transplant patients and an increased risk of opportunistic infection. This increased risk is thought to be a result of the immunomodulatory effects of the CMV infection. We present a case of PCP infection occurring 13 years after a renal transplantation. This occurred following a recurrent CMV infection while the patient was on low‐dose immunosuppressants.     

Spontaneous resolution of post‐transplant localized cytomegalovirus lymphadenitis mimicking tumor recurrence

Compromised T‐cell immunity persists for up to 1 year after autologous stem cell transplantation (ASCT), and patients treated with ASCT are more likely to develop atypical lymphoid hyperplasia that mimics tumor recurrence. Here, we present a case of cervical lymphadenitis due to cytomegalovirus (CMV) reactivation in a patient who had undergone ASCT for Burkitt lymphoma, which mimicked tumor recurrence on computed tomography and positron emission tomography‐computed tomography 6 months after ASCT. This lesion was confined to the regional lymph nodes and was not accompanied by signs of systemic involvement, such as fever, splenomegaly, an elevated C‐reactive protein level, or viremia. The localized CMV lymphadenitis resolved spontaneously without treatment after 6 months (12 months after ASCT) and the elevated CMV immunoglobulin‐M titer normalized 6 months after resolution. Our experience with this case suggests that cautious follow‐up without anti‐CMV treatment should be considered in cases of post‐ASCT localized CMV lymphadenitis without systemic involvement in patients with complete engraftment.     

Early necrotic skin lesions after a ABO‐incompatible kidney transplantation: The threat of Cunninghamella Spp.

A 49‐year‐old man underwent ABO‐incompatible kidney transplantation with a living donor. At day 33 post‐transplantation, he presented with undiagnosed epilepsy with generalized tonic‐clonic seizures. At day 44 post‐transplantation, he developed left‐sided pneumonia attributed to Aspergillus fumigatus and treatment with liposomal amphotericin B was initiated. At day 51 post‐transplantation, necrotic skin lesions appeared. DNA sequencing in a fresh cutaneous biopsy finally identified Cunninghamella Spp., a member of the order Mucorales. Unfortunately, the necrotic lesions spread, and the patient died at day 60 post‐transplantation. This case report highlights the infectious risk related to ABO‐incompatible kidney transplantation and suggests a requirement for rapid identification of every skin lesion, even in the early phases of immunosuppression.     

JC virus‐associated nephropathy in a renal transplant recipient and comparative analysis of previous cases

G. Kantarci, Z. Eren, A. Demira?, I. Dogan, F. Çakalagaoglu, G. Yilmaz.
JC virus‐associated nephropathy in a renal transplant recipient and comparative analysis of previous cases.
Transpl Infect Dis 2011: 13: 89–92. All rights reserved Abstract: We report JC virus (JCV)‐associated nephropathy in a renal allograft recipient and summarize the clinical and laboratory data of the 8 previous cases. A 28‐year‐old male renal allograft recipient received a preemptive transplant from his father. Six months later, a kidney biopsy was performed because of deterioration of allograft function. Biopsy revealed tubulointerstitial mononuclear infiltrates with normal glomeruli; on hematoxylin and eosin staining, basophilic nuclear inclusions were seen in the nucleus of tubular cells. Urinary cytology failed to demonstrate decoy cells, but polymerase chain reaction of a urinary sample was positive for JCV 3.15 × 10¹⁰ copies/mL. Additionally, polyomavirus (SV40) immunohistochemical staining was performed and was positive in the enlarged nuclei of tubular epithelial cells in the kidney biopsy sample. After the diagnosis of polyomavirus‐associated nephropathy (PVAN) was confirmed by kidney biopsy, immunosuppressive agents were reduced. Intravenous immunoglobulin was administered 5 times at a dose of 500 mg/kg every other 3 weeks. Two months after diagnosis, the serum creatinine became stable and urinary viral load of JCV was decreased. Because viruria was still present, tacrolimus was converted to sirolimus. Four months after immunosuppressive agent conversion from tacrolimus to sirolimus, the viruria had disappeared. Review of the literature and our case demonstrates that male gender, previous acute rejection episode, low incidence of JCV viremia, PVAN pattern B histology, and reducing immunosuppression are the diagnostic touchstones for PVAN due to JCV.     

Very late‐onset cytomegalovirus disease with ganciclovir resistance >15 years following renal transplantation

Cytomegalovirus (CMV) infection is a significant cause of morbidity and mortality after solid organ transplantation. There has been a significant shift in disease epidemiology with the introduction of antiviral prophylaxis, with CMV disease occurring later and clinical presentations more atypical. We describe two cases of very late‐onset CMV disease where first disease occurred 15 and 18 years post–renal transplantation, with both cases complicated by antiviral drug resistance. We subsequently review the published cases and literature of very late‐onset CMV disease (onset > 10 years post–solid organ transplantation) as an increasingly recognized phenomenon which is emerging as an important aspect in improving long‐term patient outcomes in the current era of renal transplantation.     

Guillain–Barré syndrome associated with resistant cytomegalovirus infection after face transplantation

A 39‐year‐old male, who received a facial allograft (cytomegalovirus [CMV] donor‐seropositive, recipient‐seronegative), developed multidrug‐resistant CMV infection despite valganciclovir prophylaxis (900 mg/day) 6 months post transplantation. Lower extremity weakness with upper and lower extremity paresthesias developed progressively 11 months post transplantation, coinciding with immune control of CMV. An axonal form of Guillain–Barré syndrome was diagnosed, based on electrophysiological evidence of a generalized, non‐length‐dependent, sensorimotor axonal polyneuropathy. Treatment with intravenous immunoglobulin led to complete recovery without recurrence after 6 months.     

Cytomegalovirus maculopapular eruption in a kidney transplant patient

Abstract: Cytomegalovirus (CMV) is the most important viral agent in kidney transplantation. Clinical manifestations of CMV disease in transplantation include hepatitis, pneumonitis, pancreatitis, kidney allograft dysfunction, colitis, and meningoencephalitis. However, skin involvement is rare. We describe a severely compromised cadaveric‐kidney transplant recipient who developed renal failure, colonic ulcers, and a maculopapular rash accompanied by fever and malaise 4 months after transplantation. Only the skin biopsy was diagnostic and consistent with CMV disease. Intravenous ganciclovir administration resulted in clinical improvement of CMV‐induced skin lesions; kidney function normalized and the patient became asymptomatic after 14 days of ganciclovir therapy. Nephrologists should consider the diagnosis of CMV disease in the febrile immunosuppressed patient with skin involvement. Skin biopsy must be considered as a useful and safe procedure in patients with a rash to obtain a prompt diagnosis and efficiently treat this immunocompromised population.     

Successful treatment of monomorphic primary central nervous system post‐transplantation lymphoproliferative disorder 5 years after kidney transplantation

A 31‐year‐old man underwent living‐related kidney transplantation in 2004 as a consequence of primary focal segmental glomerulosclerosis (FSGS). Four years after the transplantation, we confirmed nephrotic syndrome caused by recurrent FSGS. We performed plasmapheresis and low‐density lipoprotein adsorption. We also combined steroid therapy with a reduction in the dose of tacrolimus and an increased dose of mycophenolate mofetil. The nephrotic syndrome improved dramatically with this combined therapeutic approach. However, 10 months after these treatments, he revisited our hospital because of altered consciousness. We detected multiple tumor masses in his brain that were ring enhanced on contrast magnetic resonance imaging. Consequently, we suspected primary central nervous system post‐transplantation lymphoproliferative disorder (CNS‐PTLD). We performed a craniotomy to biopsy the brain tumors. The biopsy specimen showed Epstein–Barr virus‐associated diffuse large B‐cell lymphoma. There is no definitive treatment for CNS‐PTLD. Therefore, we treated the primary CNS‐PTLD successfully with whole‐brain radiation and discontinuation of immunosuppression therapy.     

BK polyomavirus encephalitis in a patient with thrombotic microangiopathy after an allogeneic hematopoietic stem cell transplant

To date, only one case of BK polyomavirus (BKPyV) encephalitis combined with transplant‐associated thrombotic microangiopathy has been reported in an hematopoietic stem cell transplantation (HCT) recipient. We report the case of an HCT recipient who developed thrombotic microangiopathy and subsequent BKPyV encephalitis. She died despite treatment with cidofovir, ciprofloxacin, and intravenous immunoglobulin without improvement in mental status. Early suspicion of BKPyV encephalitis in an HCT recipient presenting with altered mental status and hemorrhagic cystitis is important.     

Polyomavirus-associated nephropathy: update in diagnosis

The histological diagnosis of BK or JC polyomavirus allograft nephritis (PVAN) requires evaluation of a renal biopsy with demonstration of the polyomavirus cytopathic changes and confirmation with an ancillary technique such as immunohistochemistry. Three histological patterns of PVAN (A, B, and C) are identified in renal biopsies. Pattern A corresponds to the early disease, whereas patterns B and C identify intermediate and very advanced histological changes, respectively. The histological pattern found in the first biopsy correlates with graft outcome. Because PVAN affects the kidney in a random, multifocal manner, a negative biopsy does not rule out the disease. Patients with BK PVAN characteristically have high levels of BK viruria and viremia. Although the cutoff values of viral loads have not been fully determined, there is general agreement that BK viruria of >10(7)/mL and BK viremia of >10(4) are typical of patients with a biopsy showing BK PVAN. Prospective evaluation of viruria with urine cytology (decoy cells) and/or quantitative polymerase chain reaction can aid in the identification of patients at risk for developing PVAN. In addition to histological evaluation, viremia has emerged as the most specific test for the diagnosis of BK PVAN. JC PVAN is very infrequent in comparison with BK PVAN, but is also characterized by large viruria (>10(4)). On the other hand, JC viremia appears to be lower, in the order of 10(3)/mL. The inflammatory changes in PVAN need further characterization. Currently, there are no tools to differentiate acute cellular rejection from viral specific T-cell response.     

Use of the cytomegalovirus pp65 antigenemia assay for preemptive therapy in allogeneic hematopoietic stem cell transplantation: a real‐world review

Abstract: Despite advances in surveillance strategies and antivirals, cytomegalovirus (CMV) infection continues to pose problems to patients receiving hematopoietic stem cell transplants (HSCTs). The bone marrow transplant (BMT) unit at the Singapore General Hospital embraced the preemptive strategy in late 2003. Although several studies have demonstrated its usefulness, we conducted this review to document CMV‐related events at our institution. Forty‐six patients underwent CMV surveillance using the CMV pp65 antigenemia (CMV Ag) assay from January 2004 to December 2005. Twenty‐seven patients had CMV infection, and 19 remained antigenemia‐negative. No differences were found between the 2 groups for the following potential risk factors for CMV infection: age, total number of co‐morbidities, duration of neutropenia after conditioning, baseline creatinine, type of conditioning regimen (conventional vs. reduced intensity), type of transplant (matched sibling vs. others), recipient CMV status, donor CMV status, and use of total body irradiation. Two patients received alemtuzumab; both developed CMV Ag. Twelve episodes of CMV infection occurred after the 100th post‐HSCT day. Two patients developed CMV disease. One of them could be considered a failure of the preemptive strategy, as she had CMV gastritis diagnosed on the same day that she became pp65‐positive. The other developed CMV disease despite prompt institution of ganciclovir, although she had multiple post‐HSCT complications requiring enhanced immunosuppression, as well as relapsed disease. One‐year disease‐free survival was 55.5% in those with CMV infection and 52.3% in those without infection. Survival was not affected by CMV infection.     

A messenger at the door: cytomegalovirus retinitis in myeloma patients with progressive disease

Cytomegalovirus (CMV) retinitis is an uncommon manifestation of CMV disease and is a marker of severe and profound immunosuppression in human immunodeficiency virus‐positive patients. Here, we describe 2 cases of CMV retinitis in myeloma patients with progressive disease, following autologous stem cell transplantation and immunomodulatory therapy for myeloma. To our knowledge, this is the first report of CMV retinitis in this patient population. This report illustrates the need for close monitoring of relapsed and refractory myeloma patients for new presentations of opportunistic infections secondary to severe immunosuppression.     

Impact of low‐level BK polyomavirus viremia on intermediate‐term renal allograft function

Background

BK polyomavirus (BKPyV)‐associated nephropathy (PyVAN) is a significant cause of premature renal transplant failure. High‐level BKPyV viremia is predictive for PyVAN; however, low‐level BKPyV viremia does not necessarily exclude the presence of PyVAN. As data are limited regarding whether or not low‐level BKPyV viremia has an effect on intermediate‐term graft outcome, this study analyzes the impact of low‐level BKPyV viremia on intermediate‐term graft function and outcome compared with high‐level viremia and non‐viremic patients.

Methods

All renal transplant patients received follow‐up examinations at the Department of Nephrology, University Hospital Essen. Patients were screened for BKPyV viremia and stratified into three groups according to their maximum BKPyV load in serum (low‐level viremia, high‐level viremia, and no viremia).

Results

In 142 of 213 (67%) patients, BKPyV was never detected in serum; 42 of 213 (20%) patients were found positive for low‐level viremia (≤10⁴ copies/mL); and 29 of 213 (13%) patients showed high‐level viremia (>10⁴ copies/mL). No significant differences regarding transplant function and graft failure were observed between patients without BKPyV viremia (delta estimated glomerular filtration rate [eGFR] +0.1 mL/min [month 1 vs last visit at month 44]) and patients with low‐level BKPyV viremia (delta eGFR ?1.7 mL/min). In patients with high‐level viremia, transplant function was significantly restricted (delta eGFR ?6.5 mL/min) compared with low‐level viremia until the last visit at 44 ± 9.7 months after transplantation. Although the graft function and graft loss were worse in the high‐level viremia group compared with no viremia (eGFR 37 vs 45 mL/min), the difference was not significant.

Conclusions

High‐level viremia was associated with impaired graft function. In contrast, low‐level BKPyV viremia had no significant impact on intermediate‐term graft function.     

Tetramer monitoring to assess risk factors for recurrent cytomegalovirus reactivation and reconstitution of antiviral immunity post allogeneic hematopoietic stem cell transplantation

S. Borchers, S. Luther, U. Lips, N. Hahn, J. Kontsendorn, M. Stadler, S. Buchholz, H. Diedrich, M. Eder, U. Koehl, A. Ganser, E. Mischak‐ Weissinger. Tetramer monitoring to assess risk factors for recurrent cytomegalovirus reactivation and reconstitution of antiviral immunity post allogeneic hematopoietic stem cell transplantation.
Transpl Infect Dis 2011: 13: 222–236. All rights reserved Background. Reactivation of cytomegalovirus (CMV) is a major cause of morbidity after allogeneic hematopoietic stem cell transplantation (HSCT). In healthy individuals, virus‐specific T cells (CMV‐CTL) control the reactivation of latent CMV. The monitoring of virus‐epitope‐binding CD8⁺ T cells using major histocompatibility complex‐I‐peptide complexes (tetramers) has recently been established, allowing assessment of the reconstitution of CMV‐CTL post HSCT. Patients and methods. In order to study immune reconstitution and reactivation control through CMV‐CTL, we regularly monitored all patients undergoing allogeneic HSCT in our department for 2 years, who matched at least 1 of 6 commercially available tetramers for common human leukocyte antigen (HLA) types. To verify risk factors for CMV reactivations in our cohorts, clinical characteristics of all patients transplanted within the last 10 years were included in statistical analyses determining the relative risk for single and recurrent CMV reactivations. Results. As expected, CMV serostatus, HLA match, and donor source significantly influenced the risk of recurrent CMV reactivation. Applying CMV‐CTL tetramer monitoring for 2 years allowed the monitoring of 114 (85%) of 134 patients, by testing a set of tetramers representing 6 epitopes from 3 different CMV proteins. The presence of CMV‐CTL before day +50 and their expansion post reactivation seem to protect against recurrent CMV reactivations. The mean number of CMV‐CTL by day +100 was >5‐fold higher in the recipient CMV‐positive/donor‐positive (R+/D+) group (91/μL) compared with the R+/D? (13/μL) and the R?/D+(2/μL) group. Seventy‐nine percent of patients from the R+/D+ setting recovered >10 CMV‐CTL per μL by day +100, while almost 50% of the other groups failed to mount a CMV‐specific response by that time (R+/D?: 58%; R?/D+: 43%). Conclusion. Tetramer monitoring can help to predict (recurrent) CMV reactivation and is a useful approach to monitor individual patients with increased risk for recurrent reactivation post HSCT; thus, it could help to identify patients in need of adoptive transfer of CMV‐CTL or to optimize the use of antiviral drugs.