Pediatr Transplantation 2014: 18: E48–E51
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12209
BK virus nephropathy complicated with meningoencephalitis after kidney transplantation Rocha A, Faria S, Costa T, Marques L, Freitas C, Mota C. BK virus nephropathy complicated with meningoencephalitis after kidney transplantation.
Ana Rocha1, Sameiro Faria1, Teresa Costa1, Laura Marques2, Cristina Freitas1 and Conceição Mota1 1
Abstract: BK disease is an opportunistic infection in organ transplant recipients and patients with other cellular immunodeficiencies. To the best of our knowledge, we report the second case of BK meningoencephalitis associated with nephropathy in a kidney transplant recipient. A 15-yr-old boy underwent a cadaveric kidney transplant without complications; however, 11 wk after the transplantation, he was admitted to the hospital for graft dysfunction and cytopenia, which were confirmed by BK nephropathy (plasma viral replication and histological evidence). Four days after his hospital admission, he developed a high-grade fever and headache. CSF analysis revealed pleocytosis with a positive PCR for BK virus. Reduction in immunosuppression and supportive care conducting cycles of immunoglobulin and cidofovir were successful in treating the patient. BK meningoencephalitis should be considered in kidney transplant recipients who present with signs and symptoms of meningoencephalitis.
Human polyomaviruses comprise a genus of DNA viruses in the Papovaviridae family, which cause clinical disease primarily in immunocompromised hosts. JC and BK viruses (JCV and BKV), which are named for the patients from whom they were isolated, are clinically significant human polyomaviruses (1). Until recently, BKV infection has only been associated with urinary tract diseases, in contrast to JCV, which exhibits neurotropism as evidenced by its ability to infect the brain in PML. This report describes a patient who developed an acute meningoencephalitis associated with BKV infection, in addition to tubulointerstitial nephropathy. Case report
A 10-yr-old boy was diagnosed with nephrotic proteinuria and renal insufficiency, without Abbreviations: ATG, antithymocyte globulin; CSF, cerebrospinal fluid; HAART, highly active antiretroviral therapy; IVIG, intravenous immunoglobulin; PCR, polymerase chain reaction; PML, progressive multifocal leukoencephalopathy.
E48
Department of Pediatric Nephrology, Centro Hospitalar do Porto, Largo Professor Abel Salazar, Porto, Portugal, 2Pediatric Infectious Diseases and Immunodeficiency Unit, Centro Hospitalar do Porto, Largo Professor Abel Salazar, Porto, Portugal Key words: polyomavirus – neurotropism – immunocompromised – tubulointerstitial nephritis – clinical case Ana Rocha, Department of Pediatric Nephrology, Centro Hospitalar do Porto, Largo Professor Abel Salazar, 4099-001 Porto, Portugal Tel.: 222 077 500 Fax: 222 053 218 E-mail: [email protected] Accepted for publication 18 November 2013
systemic symptoms or signals. A genetic evaluation showed no mutation, and a kidney biopsy was inconclusive concerning advanced fibrosis. No immunosuppressive therapy was performed. Significantly impaired renal function was subsequently noted; over the ensuing years, chronic renal failure progressed and the patient started peritoneal dialysis five yr later. At the age of 15 yr, after five months of dialysis, he received his first kidney transplant from a 12-yr-old donor without complications. The cold ischemia time was 19 h. There were two HLA-A and HLA-B mismatches and the last and peak panel reactive antibody was 0 and 10%, respectively. The donor was CMV positive, and the recipient was CMV negative. Prophylactic treatment with specific gammaglobulin and valganciclovir was initiated. Cotrimoxazole was also prescribed. Immunosuppression induction with ATG was performed. The maintenance immunosuppressive therapy included tacrolimus (adjusted to obtain a trough level of 8–10 ng/mL), mycophenolate mofetil (450 mg/m2, bid), and low doses of prednisolone. Post-operatively, his renal function was good without acute rejection.
BK virus meningoencephalitis
In February 2011, 11 wk after transplantation, he was hospitalized for graft dysfunction and cytopenia. Valganciclovir, cotrimoxazole, and mycophenolate mofetil were gradually stopped. At the time of evaluation, a quantitative PCR for BKV in the plasma was performed, detecting 1 676 040 copies/mL; the results were previously negative. We reduced the calcineurin inhibitor dose and added ciprofloxacin. Four days after admission to the hospital, the patient developed a severe headache and fever. Physical examination was negative for meningeal signs and neurological deficits. Analysis of the CSF obtained showed 112 leukocytes/mm3 (72% polymorphonuclears, 45% mononuclears) and a protein level of 0.66 g/dL. A treatment regimen with intravenous ceftriaxone and vancomycin was initiated. Herpes simplex encephalitis was suspected, and acyclovir was added to the regimen. Microscopic examination of a Gram-stained specimen of CSF, and bacterial cultures were negative. After a week on this therapeutic regime, the patient’s neurological status remained unaltered, and PCR analysis of CSF revealed negative results for all human herpes viruses, JCV, and Toxoplasma gondii and positive results for polyomavirus BK. We decided to administer 500 mg/kg doses of IVIG and 0.25 mg/kg of cidofovir. The serum creatinine level increased to 2.8 mg/dL, and a kidney biopsy revealed moderate tubulointerstitial changes with mononuclear cell infiltrates and BKV inclusions. After six cycles of IVIG and cidofovir, the first two performed every two wk and the following performed every three wk, viremia became negative. Neither relapses nor sequelae occurred. At 26 months of follow-up, the patient remains asymptomatic, with normal blood pressure and stable renal function (serum creatinine, 1.2 mg/dL; estimated glomerular filtration rate, 89 mL/min/1.73 m2). The actual therapy consisted of tacrolimus (0.09 mg/kg/day) and prednisolone (5 mg/day).
Discussion
Neurological complications are frequent in renal transplant recipients and may largely contribute to morbidity and mortality. Post-transplant neurological complications may be categorized into five areas: immunosuppressive medications, stroke, peripheral neuropathies, infection, and malignancies (2). A number of complications are directly caused by the neurotoxicity of the immunosuppressive agents. Calcineurin inhibitors may cause mild symptoms, such as tremors and
paresthesia, or severe symptoms, such as disabling pain syndrome and leukoencephalopathy (3). Lymphomas are the most frequent brain tumors. They are usually associated with Epstein–Barr virus infection and are more frequent in patients who received an aggressive immunosuppressive therapy. Infection represents the most frequent neurological complication (4). In recent years, effective prophylactic strategies against a number of opportunistic pathogens and a more conservative approach toward immunosuppression have led to notable epidemiological trends in infections in transplant recipients. The most frequent types of neurological infections are acute meningitis, which is usually caused by Listeria monocytogenes, subacute and chronic meningitis caused by Cryptococcus neoformans, focal brain infection caused by Aspergillus fumigatus, Toxoplasma gondii, or Nocardia asteroides and the infection with polyomavirus type JC, the causative agent of PML, a fatal and devastating demyelinating disease of the CNS (5). Until recently, JCV was the only human polyomavirus known to have the ability to infect the CNS. However, BKV DNA has been detected in the brain tissue and CSF of both immunocompetent and immunocompromised individuals (mostly adults) with and without neurological symptoms, with a growing body of evidence demonstrating its neurotropism (6, 7). BKV and JCV DNA can be detected in bone marrow and in peripheral blood lymphocytes of the B-cell lineage. It is possible that with the entry of such infected lymphoid cells into the CNS, viral persistence in this compartment may be established. Reactivation of latent BKV or JCV could occur as a result of brain trauma, infection with another pathogen, or during immunosuppression. Thus, it is possible that the BKV DNA may be present in these patients as a result of primary or reactivated infection (6). However, BKV meningoencephalitis is a rare polyomaviral infection. Initially, it was associated with a fatal outcome among patients with AIDS because the first cases of BKV meningoencephalitis were reported post-mortem. The first report of an in vivo case of BKV-associated meningoencephalitis described a patient with AIDS who showed clinical improvement and regression of brain lesions while receiving HAART (8). Other cases have been reported on cardiac (9) and bone marrow transplantation (10). Green et al. (9) presented a case of a six-yr-old girl with an orthotopic heart transplant since the age of three. She presented with encephalopathy, with a history of slurred speech, decreased activity, and gait abnormality and subsequently E49
Rocha et al.
developed renal failure due to BK virus nephropathy. She received cidofovir every other week for the nephropathy without any response. An MRI of the brain was performed, which demonstrated subtle abnormal increased T2/FLAIR signal abnormality in the lower brain stem. A lumbar puncture was performed, which showed positive PCR for BKV, thus confirming BKV-related encephalomyelitis. The child’s neurological state progressively worsened and she was intubated, dying due to respiratory compromise. Lopes da Silva et al. (10) reported a case related to a 48-yr-old hematopoietic stem cell transplant female. Microbiological examination of CSF for BKV was positive. Treatment was started with meropenem, foscarnet, liposomal amphotericin B, and dexamethasone. Her neurological status continued to deteriorate, and a brain biopsy was obtained confirming the diagnosis. She subsequently developed thrombotic microangiopathy and died. There are four other published cases, two on cardiac transplant patients and two on bone marrow transplants, in which all diagnoses were by positive CSF BKV PCR and all died (11). Our clinical report is, to the best of our knowledge, the second discussion of a kidney transplant patient (12) but the first documentation on a pediatric kidney transplant recipient. The first case reported a 56-yr-old man who presented with progressive severe lethargy and confusion, which were resolved by stopping MMF and starting leflunomide. The diagnosis was performed by lumbar CSF analysis which tested positive for BKV. Individuals with CNS involvement and BKV infection usually show signs and symptoms of acute encephalitis; additionally several patients exhibit meningeal involvement. The most common symptom is headache. Other signs of neurological impairment include seizures, progressive mental deterioration, dysarthria, hallucinations, visual disturbances, and in one case paraplegia. In the pediatric group, irritability and lethargy were the preponderant manifestations (13). JCV DNA detection in CSF considerably improves the accuracy of presumptive diagnosis based only on clinical and MRI criteria. In the majority of reports thus far, which conclude that BKV is the causative agent of the neurological disorders, the primary limitation is the lack of demonstration of the virus in the brain tissue sample. However, because the majority of the cases occur in patients with AIDS and transplant recipients with multi-organ involvement and BKV infection, it is reasonable to assume that if a patient shows neurological symptoms without E50
a positive serology and PCR for other pathogens, although a positive PCR for BKV is present in the CSF and brain tissue, it strongly favors the diagnosis of BKV meningoencephalitis (13). This observation has potential importance for PML associated with BKV. In a reasonable number of patients, the JCV was not detected in the CSF or brain biopsy. This may be attributable to insensitive assay tools, sampling error, or episodes of immune restoration inflammatory syndrome that may reduce viral DNA load before the collection of CSF. It is now conceivable that several of these PML cases may be caused by BKV (14). Presently, there is no uniformly effective antiviral therapy for BKV meningoencephalitis (15). Because specific antiviral therapy does not currently exist, the cornerstone of therapy is to decrease immunosuppressive medications (16). The particular regimen is frequently center specific (17). The agents that have been associated with some anecdotal success on BKV nephropathy include quinolone antibiotics, IVIG, leflunomide, and cidofovir. Antiviral therapy should therefore be considered in those individuals with progressive disease, despite a maximal decrease in immunosuppressive therapy for a duration of several weeks to months (18). In the reported case of our patient with a disseminated infection (kidney and CNS), we opted for antiviral therapy, although the reduction in immunosuppression may not be sufficient considering the short time over which the other therapeutic options have been considered. In conclusion, our report demonstrates that BKV might be the causative agent of meningoencephalitis in kidney transplant patients and that this virus must be investigated more frequently when these patients present with neurological manifestations now that its neurotropism has been documented and elucidated. Although our patient had a life-threatening and disseminating disease, we achieved a successful outcome. We hope that this case report provides additional insight into the management of this viral infection in kidney transplant patients. References 1. WHITE MK, GORDON J, KHALILI K. The rapidly expanding family of human polyomaviruses: Recent developments in understanding their life cycle and role in human pathology. PLoS Pathog 2013: 9: e1003206. 2. PONTICELLI C, CAMPISE MR. Neurological complications in kidney transplant recipients. J Nephrol 2005: 18: 521–528. 3. KWUN WH. Tacrolimus related neurological complication after pediatric kidney transplantation. J Korean Surg Soc 2011: 81: 225–228.
BK virus meningoencephalitis 4. SINGH N, HUSAIN S. Infections of the central nervous system in transplant recipients. Transpl Infect Dis 2000: 2: 101–111. 5. DELBUE S, FERRARESSO M, GHIO L, et al. A review on JC virus infection in kidney transplant recipients. Clin Dev Immunol 2013: 926391. 6. BEHZAD-BEHBAHANI A, KLAPPER PE, VALLELY PJ, CLEATOR GM. BK virus DNA in CSF of immunocompetent and immunocompromised patients. Arch Dis Child 2003: 88: 174–175. 7. HIRSCH HH, STEIGER J. Polyomavirus BK. Lancet Infect Dis 2003: 3: 611–623. 8. VIDAL JE, FINK MC, CEDENO-LAURENT F, et al. BK virus associated meningoencephalitis in an AIDS patient treated with HAART. AIDS Res Ther 2007: 4: 13. 9. GREEN J, SAIGAL G, ROJAS CP, POST MJD. Rare presentation of BK encephalitis in a child: Imaging and pathological findings. Pediatr Radiol 2012: 42: 1145–1148. 10. LOPES DA SILVA R, FERREIRA I, TEIXEIRA G, et al. BK virus encephalitis with thrombotic microangiopathy in an allogeneic hematopoietic stem cell transplant recipient. Transpl Infect Dis 2010: 13: 161–167. 11. PEREIRA T, ROJAS CP, GARCIA-BUITRAGO MT, et al. A child with BK virus infection: Inadequacy of current therapeutic strategies. Pediatr Transplant 2012: 16: E269–E274.
12. HIX JK, BRAUN WE, ISADA CM. Delirium in a renal transplant recipient associated with BK virus in the cerebrospinal fluid. Transplantation 2004: 78: 1407–1408. 13. LOPES DA SILVA R. Polyoma BK virus: An emerging opportunistic infectious agent of the human central nervous system. Braz J Infect Dis 2011: 15: 276–284. 14. KNIGHT RJ, GABER LW, PATEL SJ, et al. Screening for BK viremia reduces but does not eliminate the risk of BK nephropathy: A single-center retrospective analysis. Transplantation 2013: 95: 949–954. 15. HIRSCH HH, BRENNAN DC, DRACHENBERG CB, et al. Polyomavirus-associated nephropathy in renal transplantation: Interdisciplinary analyses and recommendations. Transplantation 2013: 79: 1277. 16. DAVESON KL, ONG CW, BOWDEN S, KOINA ME, HALLAM LA. BK virus-associated progressive multifocal leukoencephalopathy. Med J Aust 2013: 198: 216–218. 17. CELIK B, SHAPIRO R, VATS A, RANDHAWA PS. Polyomavirus allograft nephropathy: Sequential assessment of histologic viral load, tubulitis, and graft function following changes in immunosuppression. Am J Transplant 2003: 3: 1378. 18. RANDHAWA P, BRENNAN DC. BK virus infection in transplant recipients: An overview and update. Am J Transplant 2006: 6: 2000.
E51
Copyright of Pediatric Transplantation is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12209
BK virus nephropathy complicated with meningoencephalitis after kidney transplantation Rocha A, Faria S, Costa T, Marques L, Freitas C, Mota C. BK virus nephropathy complicated with meningoencephalitis after kidney transplantation.
Ana Rocha1, Sameiro Faria1, Teresa Costa1, Laura Marques2, Cristina Freitas1 and Conceição Mota1 1
Abstract: BK disease is an opportunistic infection in organ transplant recipients and patients with other cellular immunodeficiencies. To the best of our knowledge, we report the second case of BK meningoencephalitis associated with nephropathy in a kidney transplant recipient. A 15-yr-old boy underwent a cadaveric kidney transplant without complications; however, 11 wk after the transplantation, he was admitted to the hospital for graft dysfunction and cytopenia, which were confirmed by BK nephropathy (plasma viral replication and histological evidence). Four days after his hospital admission, he developed a high-grade fever and headache. CSF analysis revealed pleocytosis with a positive PCR for BK virus. Reduction in immunosuppression and supportive care conducting cycles of immunoglobulin and cidofovir were successful in treating the patient. BK meningoencephalitis should be considered in kidney transplant recipients who present with signs and symptoms of meningoencephalitis.
Human polyomaviruses comprise a genus of DNA viruses in the Papovaviridae family, which cause clinical disease primarily in immunocompromised hosts. JC and BK viruses (JCV and BKV), which are named for the patients from whom they were isolated, are clinically significant human polyomaviruses (1). Until recently, BKV infection has only been associated with urinary tract diseases, in contrast to JCV, which exhibits neurotropism as evidenced by its ability to infect the brain in PML. This report describes a patient who developed an acute meningoencephalitis associated with BKV infection, in addition to tubulointerstitial nephropathy. Case report
A 10-yr-old boy was diagnosed with nephrotic proteinuria and renal insufficiency, without Abbreviations: ATG, antithymocyte globulin; CSF, cerebrospinal fluid; HAART, highly active antiretroviral therapy; IVIG, intravenous immunoglobulin; PCR, polymerase chain reaction; PML, progressive multifocal leukoencephalopathy.
E48
Department of Pediatric Nephrology, Centro Hospitalar do Porto, Largo Professor Abel Salazar, Porto, Portugal, 2Pediatric Infectious Diseases and Immunodeficiency Unit, Centro Hospitalar do Porto, Largo Professor Abel Salazar, Porto, Portugal Key words: polyomavirus – neurotropism – immunocompromised – tubulointerstitial nephritis – clinical case Ana Rocha, Department of Pediatric Nephrology, Centro Hospitalar do Porto, Largo Professor Abel Salazar, 4099-001 Porto, Portugal Tel.: 222 077 500 Fax: 222 053 218 E-mail: [email protected] Accepted for publication 18 November 2013
systemic symptoms or signals. A genetic evaluation showed no mutation, and a kidney biopsy was inconclusive concerning advanced fibrosis. No immunosuppressive therapy was performed. Significantly impaired renal function was subsequently noted; over the ensuing years, chronic renal failure progressed and the patient started peritoneal dialysis five yr later. At the age of 15 yr, after five months of dialysis, he received his first kidney transplant from a 12-yr-old donor without complications. The cold ischemia time was 19 h. There were two HLA-A and HLA-B mismatches and the last and peak panel reactive antibody was 0 and 10%, respectively. The donor was CMV positive, and the recipient was CMV negative. Prophylactic treatment with specific gammaglobulin and valganciclovir was initiated. Cotrimoxazole was also prescribed. Immunosuppression induction with ATG was performed. The maintenance immunosuppressive therapy included tacrolimus (adjusted to obtain a trough level of 8–10 ng/mL), mycophenolate mofetil (450 mg/m2, bid), and low doses of prednisolone. Post-operatively, his renal function was good without acute rejection.
BK virus meningoencephalitis
In February 2011, 11 wk after transplantation, he was hospitalized for graft dysfunction and cytopenia. Valganciclovir, cotrimoxazole, and mycophenolate mofetil were gradually stopped. At the time of evaluation, a quantitative PCR for BKV in the plasma was performed, detecting 1 676 040 copies/mL; the results were previously negative. We reduced the calcineurin inhibitor dose and added ciprofloxacin. Four days after admission to the hospital, the patient developed a severe headache and fever. Physical examination was negative for meningeal signs and neurological deficits. Analysis of the CSF obtained showed 112 leukocytes/mm3 (72% polymorphonuclears, 45% mononuclears) and a protein level of 0.66 g/dL. A treatment regimen with intravenous ceftriaxone and vancomycin was initiated. Herpes simplex encephalitis was suspected, and acyclovir was added to the regimen. Microscopic examination of a Gram-stained specimen of CSF, and bacterial cultures were negative. After a week on this therapeutic regime, the patient’s neurological status remained unaltered, and PCR analysis of CSF revealed negative results for all human herpes viruses, JCV, and Toxoplasma gondii and positive results for polyomavirus BK. We decided to administer 500 mg/kg doses of IVIG and 0.25 mg/kg of cidofovir. The serum creatinine level increased to 2.8 mg/dL, and a kidney biopsy revealed moderate tubulointerstitial changes with mononuclear cell infiltrates and BKV inclusions. After six cycles of IVIG and cidofovir, the first two performed every two wk and the following performed every three wk, viremia became negative. Neither relapses nor sequelae occurred. At 26 months of follow-up, the patient remains asymptomatic, with normal blood pressure and stable renal function (serum creatinine, 1.2 mg/dL; estimated glomerular filtration rate, 89 mL/min/1.73 m2). The actual therapy consisted of tacrolimus (0.09 mg/kg/day) and prednisolone (5 mg/day).
Discussion
Neurological complications are frequent in renal transplant recipients and may largely contribute to morbidity and mortality. Post-transplant neurological complications may be categorized into five areas: immunosuppressive medications, stroke, peripheral neuropathies, infection, and malignancies (2). A number of complications are directly caused by the neurotoxicity of the immunosuppressive agents. Calcineurin inhibitors may cause mild symptoms, such as tremors and
paresthesia, or severe symptoms, such as disabling pain syndrome and leukoencephalopathy (3). Lymphomas are the most frequent brain tumors. They are usually associated with Epstein–Barr virus infection and are more frequent in patients who received an aggressive immunosuppressive therapy. Infection represents the most frequent neurological complication (4). In recent years, effective prophylactic strategies against a number of opportunistic pathogens and a more conservative approach toward immunosuppression have led to notable epidemiological trends in infections in transplant recipients. The most frequent types of neurological infections are acute meningitis, which is usually caused by Listeria monocytogenes, subacute and chronic meningitis caused by Cryptococcus neoformans, focal brain infection caused by Aspergillus fumigatus, Toxoplasma gondii, or Nocardia asteroides and the infection with polyomavirus type JC, the causative agent of PML, a fatal and devastating demyelinating disease of the CNS (5). Until recently, JCV was the only human polyomavirus known to have the ability to infect the CNS. However, BKV DNA has been detected in the brain tissue and CSF of both immunocompetent and immunocompromised individuals (mostly adults) with and without neurological symptoms, with a growing body of evidence demonstrating its neurotropism (6, 7). BKV and JCV DNA can be detected in bone marrow and in peripheral blood lymphocytes of the B-cell lineage. It is possible that with the entry of such infected lymphoid cells into the CNS, viral persistence in this compartment may be established. Reactivation of latent BKV or JCV could occur as a result of brain trauma, infection with another pathogen, or during immunosuppression. Thus, it is possible that the BKV DNA may be present in these patients as a result of primary or reactivated infection (6). However, BKV meningoencephalitis is a rare polyomaviral infection. Initially, it was associated with a fatal outcome among patients with AIDS because the first cases of BKV meningoencephalitis were reported post-mortem. The first report of an in vivo case of BKV-associated meningoencephalitis described a patient with AIDS who showed clinical improvement and regression of brain lesions while receiving HAART (8). Other cases have been reported on cardiac (9) and bone marrow transplantation (10). Green et al. (9) presented a case of a six-yr-old girl with an orthotopic heart transplant since the age of three. She presented with encephalopathy, with a history of slurred speech, decreased activity, and gait abnormality and subsequently E49
Rocha et al.
developed renal failure due to BK virus nephropathy. She received cidofovir every other week for the nephropathy without any response. An MRI of the brain was performed, which demonstrated subtle abnormal increased T2/FLAIR signal abnormality in the lower brain stem. A lumbar puncture was performed, which showed positive PCR for BKV, thus confirming BKV-related encephalomyelitis. The child’s neurological state progressively worsened and she was intubated, dying due to respiratory compromise. Lopes da Silva et al. (10) reported a case related to a 48-yr-old hematopoietic stem cell transplant female. Microbiological examination of CSF for BKV was positive. Treatment was started with meropenem, foscarnet, liposomal amphotericin B, and dexamethasone. Her neurological status continued to deteriorate, and a brain biopsy was obtained confirming the diagnosis. She subsequently developed thrombotic microangiopathy and died. There are four other published cases, two on cardiac transplant patients and two on bone marrow transplants, in which all diagnoses were by positive CSF BKV PCR and all died (11). Our clinical report is, to the best of our knowledge, the second discussion of a kidney transplant patient (12) but the first documentation on a pediatric kidney transplant recipient. The first case reported a 56-yr-old man who presented with progressive severe lethargy and confusion, which were resolved by stopping MMF and starting leflunomide. The diagnosis was performed by lumbar CSF analysis which tested positive for BKV. Individuals with CNS involvement and BKV infection usually show signs and symptoms of acute encephalitis; additionally several patients exhibit meningeal involvement. The most common symptom is headache. Other signs of neurological impairment include seizures, progressive mental deterioration, dysarthria, hallucinations, visual disturbances, and in one case paraplegia. In the pediatric group, irritability and lethargy were the preponderant manifestations (13). JCV DNA detection in CSF considerably improves the accuracy of presumptive diagnosis based only on clinical and MRI criteria. In the majority of reports thus far, which conclude that BKV is the causative agent of the neurological disorders, the primary limitation is the lack of demonstration of the virus in the brain tissue sample. However, because the majority of the cases occur in patients with AIDS and transplant recipients with multi-organ involvement and BKV infection, it is reasonable to assume that if a patient shows neurological symptoms without E50
a positive serology and PCR for other pathogens, although a positive PCR for BKV is present in the CSF and brain tissue, it strongly favors the diagnosis of BKV meningoencephalitis (13). This observation has potential importance for PML associated with BKV. In a reasonable number of patients, the JCV was not detected in the CSF or brain biopsy. This may be attributable to insensitive assay tools, sampling error, or episodes of immune restoration inflammatory syndrome that may reduce viral DNA load before the collection of CSF. It is now conceivable that several of these PML cases may be caused by BKV (14). Presently, there is no uniformly effective antiviral therapy for BKV meningoencephalitis (15). Because specific antiviral therapy does not currently exist, the cornerstone of therapy is to decrease immunosuppressive medications (16). The particular regimen is frequently center specific (17). The agents that have been associated with some anecdotal success on BKV nephropathy include quinolone antibiotics, IVIG, leflunomide, and cidofovir. Antiviral therapy should therefore be considered in those individuals with progressive disease, despite a maximal decrease in immunosuppressive therapy for a duration of several weeks to months (18). In the reported case of our patient with a disseminated infection (kidney and CNS), we opted for antiviral therapy, although the reduction in immunosuppression may not be sufficient considering the short time over which the other therapeutic options have been considered. In conclusion, our report demonstrates that BKV might be the causative agent of meningoencephalitis in kidney transplant patients and that this virus must be investigated more frequently when these patients present with neurological manifestations now that its neurotropism has been documented and elucidated. Although our patient had a life-threatening and disseminating disease, we achieved a successful outcome. We hope that this case report provides additional insight into the management of this viral infection in kidney transplant patients. References 1. WHITE MK, GORDON J, KHALILI K. The rapidly expanding family of human polyomaviruses: Recent developments in understanding their life cycle and role in human pathology. PLoS Pathog 2013: 9: e1003206. 2. PONTICELLI C, CAMPISE MR. Neurological complications in kidney transplant recipients. J Nephrol 2005: 18: 521–528. 3. KWUN WH. Tacrolimus related neurological complication after pediatric kidney transplantation. J Korean Surg Soc 2011: 81: 225–228.
BK virus meningoencephalitis 4. SINGH N, HUSAIN S. Infections of the central nervous system in transplant recipients. Transpl Infect Dis 2000: 2: 101–111. 5. DELBUE S, FERRARESSO M, GHIO L, et al. A review on JC virus infection in kidney transplant recipients. Clin Dev Immunol 2013: 926391. 6. BEHZAD-BEHBAHANI A, KLAPPER PE, VALLELY PJ, CLEATOR GM. BK virus DNA in CSF of immunocompetent and immunocompromised patients. Arch Dis Child 2003: 88: 174–175. 7. HIRSCH HH, STEIGER J. Polyomavirus BK. Lancet Infect Dis 2003: 3: 611–623. 8. VIDAL JE, FINK MC, CEDENO-LAURENT F, et al. BK virus associated meningoencephalitis in an AIDS patient treated with HAART. AIDS Res Ther 2007: 4: 13. 9. GREEN J, SAIGAL G, ROJAS CP, POST MJD. Rare presentation of BK encephalitis in a child: Imaging and pathological findings. Pediatr Radiol 2012: 42: 1145–1148. 10. LOPES DA SILVA R, FERREIRA I, TEIXEIRA G, et al. BK virus encephalitis with thrombotic microangiopathy in an allogeneic hematopoietic stem cell transplant recipient. Transpl Infect Dis 2010: 13: 161–167. 11. PEREIRA T, ROJAS CP, GARCIA-BUITRAGO MT, et al. A child with BK virus infection: Inadequacy of current therapeutic strategies. Pediatr Transplant 2012: 16: E269–E274.
12. HIX JK, BRAUN WE, ISADA CM. Delirium in a renal transplant recipient associated with BK virus in the cerebrospinal fluid. Transplantation 2004: 78: 1407–1408. 13. LOPES DA SILVA R. Polyoma BK virus: An emerging opportunistic infectious agent of the human central nervous system. Braz J Infect Dis 2011: 15: 276–284. 14. KNIGHT RJ, GABER LW, PATEL SJ, et al. Screening for BK viremia reduces but does not eliminate the risk of BK nephropathy: A single-center retrospective analysis. Transplantation 2013: 95: 949–954. 15. HIRSCH HH, BRENNAN DC, DRACHENBERG CB, et al. Polyomavirus-associated nephropathy in renal transplantation: Interdisciplinary analyses and recommendations. Transplantation 2013: 79: 1277. 16. DAVESON KL, ONG CW, BOWDEN S, KOINA ME, HALLAM LA. BK virus-associated progressive multifocal leukoencephalopathy. Med J Aust 2013: 198: 216–218. 17. CELIK B, SHAPIRO R, VATS A, RANDHAWA PS. Polyomavirus allograft nephropathy: Sequential assessment of histologic viral load, tubulitis, and graft function following changes in immunosuppression. Am J Transplant 2003: 3: 1378. 18. RANDHAWA P, BRENNAN DC. BK virus infection in transplant recipients: An overview and update. Am J Transplant 2006: 6: 2000.
E51
Copyright of Pediatric Transplantation is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
