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BK virus colonic ulcerations
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2004;2:175–177
CASE REPORT BK Virus Colonic Ulcerations GORDON Y. KIM,* JOYCE PEJI,* GERARD NUOVO,‡ and FRED THOMAS* Departments of *Internal Medicine and Gastroenterology and ‡Pathology, The Ohio State University Medical Center, Columbus, Ohio
he papovavirus is categorized into 2 subgroups, the papilloma and the polyoma. Members of the papilloma subgroup include the human papilloma virus, whereas those of the polyoma subgroup include the BK virus (BKV), JC virus (JCV), and Simian virus 40 (SV 40). The BKV is approximately 40 nm in diameter with a nonenveloped, icosahedral virus containing doublestranded DNA. BKV is being increasingly recognized as a cause of renal allograft dysfunction and failure. Although BKV has been reported in association with cystitis,1,2 nephritis, ureteral stenosis,3–5 encephalitis,6 interstitial pneumonia,7 hepatic dysfunction,8 central nervous system neoplasm,9,10 and pancreatic islet tumors,9 to date, BKV has not been reported as a cause of gastrointestinal disease. We report a patient with cadaveric renal transplant who presented with abdominal pain and diarrhea. Colonoscopic examination showed colonic ulcers caused by BKV. To our knowledge, this is the first case reported of BKV-induced colonic ulcers in an immunocompromised host.
T
Case Report A 44-year-old woman with end-stage diabetic nephropathy and a cadaveric renal transplant 12 months before her hospitalization was admitted for abdominal pain and diarrhea for 2 months. Two months before referral, she was diagnosed with renal allograft dysfunction caused by BKV. This was confirmed by biopsy of the transplanted kidney. Her medical history was significant only for cataracts, diabetes mellitus, and hypertension. Before transplantation, she had been on peritoneal dialysis for 3 years. Renal transplantation was uneventful. After transplantation, her creatinine level improved to 1.2 mg/dL with good urine output, and immunosuppressive medications were mycophenolate 1000 mg twice a day, cyclosporine 250 mg twice a day, and prednisone 50 mg per day. Ten months after transplantation, she developed cyclosporine toxicity with a serum creatinine of 3.8 mg/dL and cyclosporine of 449 ng/mL. Cyclosporine was replaced by sirolimus 3 mg per day, and prednisone was tapered to 12.5 mg per day. A urinary tract infection was treated with ciprofloxacin. Because of deterioration of her renal function, a computed tomography (CT)– guided renal biopsy was done. Histologic
examination of this specimen showed BKV. Qualitative tests for BKV DNA PCR (Mayo Medical Laboratories, Rochester, MN) on serum and urine were positive. The renal allograft dysfunction was thought to be caused by the polyoma virus, and prednisone was discontinued. Over the next 2 months, she experienced lower abdominal cramps and diarrhea; pain was relieved with passage of semiformed, loose stool 3–5 times a day. Her abdomen was minimally tender over the right lower quadrant. Stool was positive for occult blood, and no rectal masses were palpated. White blood cell count of 11.6 ⫻ 104 cells/L, hemoglobin 11.4 g/dL, and hematocrit 33.9% were unremarkable, but serum creatinine was 6.58 mg/dL. Other viral markers for Epstein-Barr virus, herpes simplex virus, cytomegalovirus (CMV), and human immunodeficiency virus (HIV) were negative. Her serum BKV DNA PCR quantitative was greater than 200,000,000 copies/mL (Focus Technology, Cypress, CA), and BKV DNA PCR copies was greater than 8.3 log10 (Focus Technology). Abdominal/pelvic CT scan without intravenous contrast was unremarkable. Colonoscopy showed a 1-cm ulcer and a 0.5-cm ulcer at the ileocecal valve (Figure 1). The terminal ileum and the remainder of the colon appeared normal. Biopsy specimens of both ulcers showed viral inclusion bodies (Figure 2A). Immunohistochemical staining and in situ hybridization for CMV were negative. In situ hybridization for BKV11 was strongly positive (Figure 2B). Therefore, sirolimus was maintained at 3 mg per day, and mycophenolate was reduced to 500 mg twice a day. One month later, the patient’s abdominal pain and diarrhea had resolved. Unfortunately, creatinine level increased to 7.51 mg/dL, mycophenolate was discontinued, and sirolimus was reduced to 2 mg per day. A second colonoscopy 3 weeks later showed ulcer healing with minimal residual erythema. Multiple colonic biopsies failed to show BKV. At 6 weeks’ follow-up, serum BKV DNA PCR quantitative was 3600 copies/mL, BKV DNA PCR copies was 3.6 log10, and serum creatinine level had improved to 6.3 mg/dL. Abbreviations used in this paper: BKV, BK virus; CMV, cytomegalovirus; CT, computed tomography; JCV, JC virus; PCR, polymerase chain reaction; SV 40, Simian virus 40. © 2004 by the American Gastroenterological Association 1542-3565/04/$30.00 PII: 10.1053/S1542-3565(03)00316-1
176
KIM ET AL.
Figure 1. Endoscopic view of a 1-cm ulcer located at the ileocecal valve.
Discussion The polyoma virus is made up of BKV, JCV, and SV 40. JCV is the etiologic agent of progressive multifocal leukoencephalopathy, first described in a patient with Hodgkin’s disease.12 In 1971 Gardner et al4 isolated BKV in the urine from a renal transplant patient. The third virus in this group, SV 40, has recently been reported in association with lymphoma.13 Primary infection with BKV usually occurs in childhood and is either a self-limited upper respiratory infection14 or is completely asymptomatic. After the primary infection, the virus might remain latent in many sites. Several sites of BKV-associated disease have been identified, i.e., the kidney, liver, lung, eye, and brain.15 Patients who are prone to BKV infection are almost exclusively immunocompromised, organ transplant recipients, or have HIV infection. Approximately 45% of renal transplant recipients have BKV reactivation.16 BKV can be isolated in urine, plasma, or tissue biopsy specimens. BKV nephropathy is associated with characteristic viral inclusion bodies, as with CMV infections. Differentiation of these 2 viral infections usually requires further testing, such as immunohistochemical analysis, in situ hybridization, or electron microscopy. Demonstration of BKV within the tissue is necessary for definitive diagnoses. In addition, the use of serum BKV DNA PCR can assist in the diagnosis. Nickeleit et al.17 demonstrated that BKV DNA PCR in serum had a sensitivity of 100%, specificity of 88%, and positive predictive value of 82% for detecting BKV nephropathy. On the other hand, identifying BKV in the urine by the presence of cells containing viral inclusion bodies known as “decoy cells” might be difficult and is associ-
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 2, No. 2
ated with clinical BKV nephropathy in only 28% of cases.18 Thus, the diagnosis of BKV infection is based on tissue analysis. On electron microscopy, the viral particles in the nucleus are round and uniform, densely packed, and sometimes aligned linearly.2,4 The most effective treatment for BKV is reduction or alteration of immunosuppressive therapy to allow better host clearance of the virus. There is risk of graft dysfunction or rejection. Cidofovir, an acyclic nucleoside analogue, has been used with some success in BKV-associated hemorrhagic cystitis in bone marrow transplant patients.19 However, cidofovir nephrotoxicity significantly limits its use in renal transplant recipients. This report strongly suggests that BKV caused our patient’s symptoms and concurrent colonic ulcers. After reducing immunosuppression, diarrhea resolved, follow-up colonoscopic biopsy specimens from the healed ulcer sites did not identify BKV, and BKV DNA PCR decreased dramatically.
Figure 2. (A) Intranuclear viral inclusions (arrow). The nuclei are enlarged and hyperchromatic. H&E stain; original magnification 1000⫻. (B) In situ hybridization; original magnification 1000⫻. The staining (brown) confirms the presence of the BK virus in the colonic mucosa via in situ hybridization.
February 2004
Viral infections (e.g., CMV) might be present without an obvious inflammatory process. The BKV enters latency after the primary infection, most likely in the urogenital tract. The kidney, lung, eye, liver, and brain are sites of BKV-associated disease, both primary and reactivation.15 Reactivation with viremia might be observed in an immunocompromised host. In our patient, BKV was first discovered from the renal cadaveric transplant. In this regard, Reploeg et al.15 suggest certain immunosuppressive regimens might cause BKV-induced allograft nephropathy, although there are no prospective data to support this point. The present case is the first report of colonic ulcers caused by the polyoma virus BKV. As more organ transplants are performed each year and immunosuppressive agents are used, BKV should be added to the list of differential diagnoses for colonic ulceration in an immunocompromised host. Diagnosis requires biopsy of the affected tissue and demonstration of BKV in histologic specimen via immunohistochemical analysis, electron microscopy, or in situ hybridization. Unfortunately, this case also highlights the fact that there is as yet no effective treatment for BKV in renal transplant patients.
References 1. Barouch DH, Faquin WC, Chen Y, Koralnik IJ, Robbins GK, Davis BT. BK virus-associated hemorrhagic cystitis in a human immunodeficiency virus-infected patient. Clin Infect Dis 2002;35:326 – 329. 2. Saitoh K, Sugae N, Koike N, Akiyama Y, Iwamura Y, Kimura H. Diagnosis of childhood BK virus cystitis by electron microscopy and PCR. J Clin Pathol 1993;46:773–775. 3. Coleman DV, Mackenzie EFD, Gardner SD, Poulding JM, Amer B, Russell WJI. Human polyoma-virus (BK) infection and ureteric stenosis in renal allograft recipients. J Clin Pathol 1978;31:338 – 347. 4. Gardner SD, Field AM, Coleman DV, Hulme B. New human papovavirus (B.K.) isolated from urine after renal transplantation. Lancet 1971;1:1253–1257. 5. Randhawa PS, Finkelstein S, Scantlebury V, Shapiro R, Vivas C, Jordan M, Picken MM, Demetris AJ. Human polyoma virus-associated interstitial nephritis in the allograft kidney. Transplantation 1999;67:103–109. 6. Votz R, Jager G, Seelos K, Fuhry L, Hohlfeld R. BK virus enceph-
BK VIRUS COLONIC ULCERATIONS
7.
8.
9.
10.
11.
12.
13.
14.
15. 16.
17.
18. 19.
177
alitis in an immunocompetent patient. Arch Neurol 1996;53: 101–103. Sandler ES, Aquino VM, Goss-Shohet E, Hinrichs S, Krisher K. BK papova virus pneumonia following hematopoietic stem cell transplantation. Bone Marrow Transplant 1997;20:163–165. O’Reilly RJ, Lee FK, Grossbard E, Kapoor N, Kirkpatrick D, Dinsmore R, Stutzer C, Shah KV, Nahmias AJ. Papovavirus excretion following marrow transplantation: incidence and association with hepatic dysfunction. Transplant Proc 1981;13:262–266. Corallini A, Pagnani M, Viadana P, Silini E, Mottes M, Milanesi G, Gerna G, Vettor R, Trapella G, Silvani V, Gaist G, Barbanti-Brodano G. Association of BK virus with human brain tumors and tumors of pancreatic islets. Int J Cancer 1987;39:60 – 67. Takemoto KK, Rabson AS, Mullarkey MF, Blaese RM, Garon CF, Nelson D. Isolation of papovavirus from brain tumor and urine of a patient with Wiskott-Aldrich Syndrome. J Natl Cancer Inst 1974; 53:1205–1207. Nuovo GJ, Baylin SLB, Bolinsky S, Herman JG, Plaia T. In situ detection of the hypermethylation-induced inactivation of the p16 gene as an early event in oncogenesis. Proc Natl Acad Sci U S A 1999;96:12754 –12759. Padgett BL, ZuRhein GM, Walker DL, Eckroade RJ. Cultivation of papova-like virus from human brain with progressive multifocal leukoencephalopathy. Lancet 1971;1:1257–1260. Vilchez RA, Madden CR, Kozinetz CA, Halvorson J, White ZS, Jorgensen JL, Finch CJ. Association between simian virus 40 and non-Hodgkin’s lymphoma. Lancet 2002;359:817– 823. Goudsmit H, Wertheim–van Dillen PW, VanStrien A, Van der Noordaa J. The role of BK virus in acute respiratory tract disease and the presence of BKV DNA in tonsils. J Med Virol 1982;10: 91–99. Reploeg MD, Storch GA, Clifford DB. BK virus: a clinical review. Clin Infect Dis 2001;33:191–202. Gardner SD, MacKenzie EF, Smith C, Porter AA. Prospective study the human polyomaviruses BK and JC and cytomegalovirus in renal transplant recipients. J Clin Pathol 1984;37:578 –586. Nickeleit V, Klimkait T, Binet IF, Dalquen P, Del Zenero V, Thiel G, Mihatsch J, Hirsch HH. Testing for polyomavirus type BK DNA in plasma to identify renal-allograft recipients with viral nephropathy. N Engl J Med 2000;342:1309 –1315. Randhawa PS, Demetris A. Nephropathy due to polyoma virus type BK. N Engl J Med 2000;342:1361–1363. Held TK, Biel SS, Nitsche A, Kurth A, Chen S, Gelderblom HR, Siegert W. Treatment of BK virus-associated hemorrhagic cystitis and simultaneous CMV reactivation with cidofovir. Bone Marrow Transplant 2000;26:347–350.
Address requests for reprints to: Gordon Y. Kim, D.O., The Ohio State University Medical Center, Department of Gastroenterology, 410 West 10th Avenue, Doan Hall N 214, Columbus, Ohio 43210. e-mail: [email protected]; fax: (614) 293-8518.
CASE REPORT BK Virus Colonic Ulcerations GORDON Y. KIM,* JOYCE PEJI,* GERARD NUOVO,‡ and FRED THOMAS* Departments of *Internal Medicine and Gastroenterology and ‡Pathology, The Ohio State University Medical Center, Columbus, Ohio
he papovavirus is categorized into 2 subgroups, the papilloma and the polyoma. Members of the papilloma subgroup include the human papilloma virus, whereas those of the polyoma subgroup include the BK virus (BKV), JC virus (JCV), and Simian virus 40 (SV 40). The BKV is approximately 40 nm in diameter with a nonenveloped, icosahedral virus containing doublestranded DNA. BKV is being increasingly recognized as a cause of renal allograft dysfunction and failure. Although BKV has been reported in association with cystitis,1,2 nephritis, ureteral stenosis,3–5 encephalitis,6 interstitial pneumonia,7 hepatic dysfunction,8 central nervous system neoplasm,9,10 and pancreatic islet tumors,9 to date, BKV has not been reported as a cause of gastrointestinal disease. We report a patient with cadaveric renal transplant who presented with abdominal pain and diarrhea. Colonoscopic examination showed colonic ulcers caused by BKV. To our knowledge, this is the first case reported of BKV-induced colonic ulcers in an immunocompromised host.
T
Case Report A 44-year-old woman with end-stage diabetic nephropathy and a cadaveric renal transplant 12 months before her hospitalization was admitted for abdominal pain and diarrhea for 2 months. Two months before referral, she was diagnosed with renal allograft dysfunction caused by BKV. This was confirmed by biopsy of the transplanted kidney. Her medical history was significant only for cataracts, diabetes mellitus, and hypertension. Before transplantation, she had been on peritoneal dialysis for 3 years. Renal transplantation was uneventful. After transplantation, her creatinine level improved to 1.2 mg/dL with good urine output, and immunosuppressive medications were mycophenolate 1000 mg twice a day, cyclosporine 250 mg twice a day, and prednisone 50 mg per day. Ten months after transplantation, she developed cyclosporine toxicity with a serum creatinine of 3.8 mg/dL and cyclosporine of 449 ng/mL. Cyclosporine was replaced by sirolimus 3 mg per day, and prednisone was tapered to 12.5 mg per day. A urinary tract infection was treated with ciprofloxacin. Because of deterioration of her renal function, a computed tomography (CT)– guided renal biopsy was done. Histologic
examination of this specimen showed BKV. Qualitative tests for BKV DNA PCR (Mayo Medical Laboratories, Rochester, MN) on serum and urine were positive. The renal allograft dysfunction was thought to be caused by the polyoma virus, and prednisone was discontinued. Over the next 2 months, she experienced lower abdominal cramps and diarrhea; pain was relieved with passage of semiformed, loose stool 3–5 times a day. Her abdomen was minimally tender over the right lower quadrant. Stool was positive for occult blood, and no rectal masses were palpated. White blood cell count of 11.6 ⫻ 104 cells/L, hemoglobin 11.4 g/dL, and hematocrit 33.9% were unremarkable, but serum creatinine was 6.58 mg/dL. Other viral markers for Epstein-Barr virus, herpes simplex virus, cytomegalovirus (CMV), and human immunodeficiency virus (HIV) were negative. Her serum BKV DNA PCR quantitative was greater than 200,000,000 copies/mL (Focus Technology, Cypress, CA), and BKV DNA PCR copies was greater than 8.3 log10 (Focus Technology). Abdominal/pelvic CT scan without intravenous contrast was unremarkable. Colonoscopy showed a 1-cm ulcer and a 0.5-cm ulcer at the ileocecal valve (Figure 1). The terminal ileum and the remainder of the colon appeared normal. Biopsy specimens of both ulcers showed viral inclusion bodies (Figure 2A). Immunohistochemical staining and in situ hybridization for CMV were negative. In situ hybridization for BKV11 was strongly positive (Figure 2B). Therefore, sirolimus was maintained at 3 mg per day, and mycophenolate was reduced to 500 mg twice a day. One month later, the patient’s abdominal pain and diarrhea had resolved. Unfortunately, creatinine level increased to 7.51 mg/dL, mycophenolate was discontinued, and sirolimus was reduced to 2 mg per day. A second colonoscopy 3 weeks later showed ulcer healing with minimal residual erythema. Multiple colonic biopsies failed to show BKV. At 6 weeks’ follow-up, serum BKV DNA PCR quantitative was 3600 copies/mL, BKV DNA PCR copies was 3.6 log10, and serum creatinine level had improved to 6.3 mg/dL. Abbreviations used in this paper: BKV, BK virus; CMV, cytomegalovirus; CT, computed tomography; JCV, JC virus; PCR, polymerase chain reaction; SV 40, Simian virus 40. © 2004 by the American Gastroenterological Association 1542-3565/04/$30.00 PII: 10.1053/S1542-3565(03)00316-1
176
KIM ET AL.
Figure 1. Endoscopic view of a 1-cm ulcer located at the ileocecal valve.
Discussion The polyoma virus is made up of BKV, JCV, and SV 40. JCV is the etiologic agent of progressive multifocal leukoencephalopathy, first described in a patient with Hodgkin’s disease.12 In 1971 Gardner et al4 isolated BKV in the urine from a renal transplant patient. The third virus in this group, SV 40, has recently been reported in association with lymphoma.13 Primary infection with BKV usually occurs in childhood and is either a self-limited upper respiratory infection14 or is completely asymptomatic. After the primary infection, the virus might remain latent in many sites. Several sites of BKV-associated disease have been identified, i.e., the kidney, liver, lung, eye, and brain.15 Patients who are prone to BKV infection are almost exclusively immunocompromised, organ transplant recipients, or have HIV infection. Approximately 45% of renal transplant recipients have BKV reactivation.16 BKV can be isolated in urine, plasma, or tissue biopsy specimens. BKV nephropathy is associated with characteristic viral inclusion bodies, as with CMV infections. Differentiation of these 2 viral infections usually requires further testing, such as immunohistochemical analysis, in situ hybridization, or electron microscopy. Demonstration of BKV within the tissue is necessary for definitive diagnoses. In addition, the use of serum BKV DNA PCR can assist in the diagnosis. Nickeleit et al.17 demonstrated that BKV DNA PCR in serum had a sensitivity of 100%, specificity of 88%, and positive predictive value of 82% for detecting BKV nephropathy. On the other hand, identifying BKV in the urine by the presence of cells containing viral inclusion bodies known as “decoy cells” might be difficult and is associ-
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 2, No. 2
ated with clinical BKV nephropathy in only 28% of cases.18 Thus, the diagnosis of BKV infection is based on tissue analysis. On electron microscopy, the viral particles in the nucleus are round and uniform, densely packed, and sometimes aligned linearly.2,4 The most effective treatment for BKV is reduction or alteration of immunosuppressive therapy to allow better host clearance of the virus. There is risk of graft dysfunction or rejection. Cidofovir, an acyclic nucleoside analogue, has been used with some success in BKV-associated hemorrhagic cystitis in bone marrow transplant patients.19 However, cidofovir nephrotoxicity significantly limits its use in renal transplant recipients. This report strongly suggests that BKV caused our patient’s symptoms and concurrent colonic ulcers. After reducing immunosuppression, diarrhea resolved, follow-up colonoscopic biopsy specimens from the healed ulcer sites did not identify BKV, and BKV DNA PCR decreased dramatically.
Figure 2. (A) Intranuclear viral inclusions (arrow). The nuclei are enlarged and hyperchromatic. H&E stain; original magnification 1000⫻. (B) In situ hybridization; original magnification 1000⫻. The staining (brown) confirms the presence of the BK virus in the colonic mucosa via in situ hybridization.
February 2004
Viral infections (e.g., CMV) might be present without an obvious inflammatory process. The BKV enters latency after the primary infection, most likely in the urogenital tract. The kidney, lung, eye, liver, and brain are sites of BKV-associated disease, both primary and reactivation.15 Reactivation with viremia might be observed in an immunocompromised host. In our patient, BKV was first discovered from the renal cadaveric transplant. In this regard, Reploeg et al.15 suggest certain immunosuppressive regimens might cause BKV-induced allograft nephropathy, although there are no prospective data to support this point. The present case is the first report of colonic ulcers caused by the polyoma virus BKV. As more organ transplants are performed each year and immunosuppressive agents are used, BKV should be added to the list of differential diagnoses for colonic ulceration in an immunocompromised host. Diagnosis requires biopsy of the affected tissue and demonstration of BKV in histologic specimen via immunohistochemical analysis, electron microscopy, or in situ hybridization. Unfortunately, this case also highlights the fact that there is as yet no effective treatment for BKV in renal transplant patients.
References 1. Barouch DH, Faquin WC, Chen Y, Koralnik IJ, Robbins GK, Davis BT. BK virus-associated hemorrhagic cystitis in a human immunodeficiency virus-infected patient. Clin Infect Dis 2002;35:326 – 329. 2. Saitoh K, Sugae N, Koike N, Akiyama Y, Iwamura Y, Kimura H. Diagnosis of childhood BK virus cystitis by electron microscopy and PCR. J Clin Pathol 1993;46:773–775. 3. Coleman DV, Mackenzie EFD, Gardner SD, Poulding JM, Amer B, Russell WJI. Human polyoma-virus (BK) infection and ureteric stenosis in renal allograft recipients. J Clin Pathol 1978;31:338 – 347. 4. Gardner SD, Field AM, Coleman DV, Hulme B. New human papovavirus (B.K.) isolated from urine after renal transplantation. Lancet 1971;1:1253–1257. 5. Randhawa PS, Finkelstein S, Scantlebury V, Shapiro R, Vivas C, Jordan M, Picken MM, Demetris AJ. Human polyoma virus-associated interstitial nephritis in the allograft kidney. Transplantation 1999;67:103–109. 6. Votz R, Jager G, Seelos K, Fuhry L, Hohlfeld R. BK virus enceph-
BK VIRUS COLONIC ULCERATIONS
7.
8.
9.
10.
11.
12.
13.
14.
15. 16.
17.
18. 19.
177
alitis in an immunocompetent patient. Arch Neurol 1996;53: 101–103. Sandler ES, Aquino VM, Goss-Shohet E, Hinrichs S, Krisher K. BK papova virus pneumonia following hematopoietic stem cell transplantation. Bone Marrow Transplant 1997;20:163–165. O’Reilly RJ, Lee FK, Grossbard E, Kapoor N, Kirkpatrick D, Dinsmore R, Stutzer C, Shah KV, Nahmias AJ. Papovavirus excretion following marrow transplantation: incidence and association with hepatic dysfunction. Transplant Proc 1981;13:262–266. Corallini A, Pagnani M, Viadana P, Silini E, Mottes M, Milanesi G, Gerna G, Vettor R, Trapella G, Silvani V, Gaist G, Barbanti-Brodano G. Association of BK virus with human brain tumors and tumors of pancreatic islets. Int J Cancer 1987;39:60 – 67. Takemoto KK, Rabson AS, Mullarkey MF, Blaese RM, Garon CF, Nelson D. Isolation of papovavirus from brain tumor and urine of a patient with Wiskott-Aldrich Syndrome. J Natl Cancer Inst 1974; 53:1205–1207. Nuovo GJ, Baylin SLB, Bolinsky S, Herman JG, Plaia T. In situ detection of the hypermethylation-induced inactivation of the p16 gene as an early event in oncogenesis. Proc Natl Acad Sci U S A 1999;96:12754 –12759. Padgett BL, ZuRhein GM, Walker DL, Eckroade RJ. Cultivation of papova-like virus from human brain with progressive multifocal leukoencephalopathy. Lancet 1971;1:1257–1260. Vilchez RA, Madden CR, Kozinetz CA, Halvorson J, White ZS, Jorgensen JL, Finch CJ. Association between simian virus 40 and non-Hodgkin’s lymphoma. Lancet 2002;359:817– 823. Goudsmit H, Wertheim–van Dillen PW, VanStrien A, Van der Noordaa J. The role of BK virus in acute respiratory tract disease and the presence of BKV DNA in tonsils. J Med Virol 1982;10: 91–99. Reploeg MD, Storch GA, Clifford DB. BK virus: a clinical review. Clin Infect Dis 2001;33:191–202. Gardner SD, MacKenzie EF, Smith C, Porter AA. Prospective study the human polyomaviruses BK and JC and cytomegalovirus in renal transplant recipients. J Clin Pathol 1984;37:578 –586. Nickeleit V, Klimkait T, Binet IF, Dalquen P, Del Zenero V, Thiel G, Mihatsch J, Hirsch HH. Testing for polyomavirus type BK DNA in plasma to identify renal-allograft recipients with viral nephropathy. N Engl J Med 2000;342:1309 –1315. Randhawa PS, Demetris A. Nephropathy due to polyoma virus type BK. N Engl J Med 2000;342:1361–1363. Held TK, Biel SS, Nitsche A, Kurth A, Chen S, Gelderblom HR, Siegert W. Treatment of BK virus-associated hemorrhagic cystitis and simultaneous CMV reactivation with cidofovir. Bone Marrow Transplant 2000;26:347–350.
Address requests for reprints to: Gordon Y. Kim, D.O., The Ohio State University Medical Center, Department of Gastroenterology, 410 West 10th Avenue, Doan Hall N 214, Columbus, Ohio 43210. e-mail: [email protected]; fax: (614) 293-8518.