500646
research-article2013
AOPXXX10.1177/1060028013500646Chittick et alThe Annals of Pharmacotherapy
Case Report
BK Virus Encephalitis: Case Report, Review of the Literature, and Description of a Novel Treatment Modality
Annals of Pharmacotherapy 47(9) 1229–1233 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013500646 aop.sagepub.com
Paul Chittick, MD1, John C. Williamson, PharmD, BCPS, AAHIVE2, and Christopher A. Ohl, MD2,3
Abstract Objective: To describe a case of BK virus encephalitis with attempted direct antiviral therapy, review the reported cases of BK virus in the central nervous system, and report the novel use of intravenous cimetidine in place of oral probenecid to minimize the toxicities of intravenous cidofovir. Case Summary: A 36-year-old male with acute myelomonocytic leukemia and subsequent myelodysplastic syndrome underwent allogeneic hematopoietic stem cell transplant. His course was complicated by severe graft-versus-host disease involving his skin and gastrointestinal tract. Five weeks after transplantation, he developed fever and confusion. Magnetic resonance imaging was suggestive of limbic encephalitis and cerebrospinal fluid tested positive for BK virus. Therapy with intravenous cidofovir was thought to be indicated. Although probenecid is commonly used to minimize the toxicities of cidofovir, the patient’s severe graft-versus-host disease raised concerns about absorption of oral medications. Based on animal models and pharmacokinetic data, intravenous cimetidine was used in place of oral probenecid. Despite these therapies, the patient’s mental status did not improve. He developed progressive organ system failure, and care was ultimately withdrawn. Discussion: BK virus is increasingly described as a cause of encephalitis. The majority of reported cases have occurred in immunocompromised patients and have generally had a poor outcome. This case describes attempted antiviral therapy using cidofovir, the antiviral agent used most frequently in other syndromes due to BK virus. Intravenous cimetidine is a novel modality used to minimize ocular and renal toxicities frequently seen with cidofovir, and we believe this warrants further investigation. Conclusions: BK virus may be a cause of encephalitis in immunocompromised hosts, and cidofovir represents a possible treatment option. Intravenous cimetidine can be considered to minimize toxicities associated with cidofovir use in patients unable to tolerate or absorb oral probenecid. Keywords BK virus, encephalitis in immunocompromised hosts, cidofovir, cimetidine
The use of allogeneic hematopoietic stem cell transplant (HSCT) for hematologic malignancies has led to successful management of previously incurable diseases. However, the intense immunosuppression is associated with numerous infectious complications, including encephalitis. As diagnostic methods improve, more cases of encephalitis can be attributed to a specific cause, with recent reports describing infections with human herpesvirus 6 (HHV-6),1 Epstein–Barr virus,2 and cytomegalovirus (CMV).3 We report a case of BK virus encephalitis, review other reported cases in the English-language literature, and describe a novel treatment modality.
acute myelomonocytic leukemia 4 years earlier for which he initially received chemotherapy, resulting in remission. He subsequently developed progressive myelodysplastic syndrome and underwent HSCT on hospital day 7. His hospital course was complicated by biopsy-proven (skin biopsied hospital day 22, intestine biopsied hospital day 46) graft-versus-host disease (GVHD), including involvement of his gastrointestinal tract, causing severe diarrhea, for which he received methotrexate and high-dose
Case Report
Corresponding Author: Paul Chittick, MD, Director of Transplant Infectious Diseases, Beaumont Health System, 3601 W. 13 Mile Road, Royal Oak, MI 48073, USA. Email: [email protected]
A 36-year-old white male was admitted to our institution for a mismatched unrelated HSCT. He had been diagnosed with
1
Beaumont Health System, Royal Oak, MI, USA Wake Forest Baptist Health, Winston-Salem, NC, USA 3 Wake Forest University, Winston-Salem, NC, USA 2
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Table 1. Suggested Cidofovir and Cimetidine Dosing Protocol for BK Viral Encephalitis. Time, hours −2 −1 0 +1 +3 +7 +11
Infusion Cimetidine 600 mg intravenously infused over 1 hour 1 L normal saline infused over 1 hour Cidofovir 300 mg intravenously infused over 1 hour 1 L normal saline infused over 2 hours Cimetidine 300 mg intravenously infused over 30 minutes Cimetidine 300 mg intravenously infused over 30 minutes Start cimetidine 300 mg intravenously infused every 6 hours for 3 days
corticosteroids. His white blood cell count recovered on hospital day 22 (absolute neutrophil count 1700 cells/µL), but he continued to require hospitalization because of intermittent fever, progressive hypoxia, and worsening skin and gastrointestinal tract GVHD. His initial immunosuppressive regimen consisted of tacrolimus and corticosteroids, with mycophenolate mofetil subsequently replacing tacrolimus on hospital day 32. On hospital day 40, he developed fever, hypotension, and confusion without objective focal neurologic deficits. Multiple cultures of blood, urine, and sputum were unrevealing. An electrocardiogram did not show any evidence of seizure activity. Magnetic resonance imaging of the brain demonstrated an abnormal fluid-attenuated inversion recovery signal and restricted diffusion within the right hippocampus, which was thought to be indicative of limbic or herpes encephalitis. A lumbar puncture had the following findings: white blood cell count 1 cell/mm3, total protein 14 mg/dL, and glucose 77 mg/dL. Bacterial, fungal, and acidfast bacillus cultures of cerebrospinal fluid (CSF) were negative, as were cytology, cryptococcal antigen, and viral polymerase chain reaction (PCR) studies for herpes simplex virus, JC virus, CMV, and HHV-6. On hospital day 53, the result of a CSF qualitative PCR for BK virus from the initial lumbar puncture was positive. Because of the patient’s progressive confusion and a desire to avoid more toxic antimicrobials, ciprofloxacin, and intravenous immune globulin were initiated for their purported anti-BK virus activity. The use of leflunomide was also considered but it was believed that this would be less effective for BK virus and would not result in adequate immunosuppression for his GVHD. Additionally, as leflunomide is only available orally, it would require adequate absorption from the patient’s gastrointestinal tract, which could not be certain because of the patient’s GVHD. Additional testing revealed a urine BK virus PCR greater than 39 × 106 copies/mL, the presence of decoy cells in his urine, and a negative serum BK virus
PCR. Quantitative PCR testing for BK virus in his CSF sample showed 1761 copies/mL. The patient’s confusion persisted, so intravenous cidofovir was initiated on hospital day 55. Oral probenecid is commonly used to limit the renal and ocular toxicities of cidofovir, but the patient’s severe gastrointestinal GVHD raised the concern of poor probenecid absorption. As an alternative to probenecid, intravenous cimetidine was begun, based on animal models and pharmacokinetic data, according to the dosing shown in Table 1. No additional lumbar punctures were performed as a result of the severity of his skin GVHD. Unfortunately, he developed multisystem organ failure, and care was withdrawn on hospital day 60. No improvement in mental status was noted prior to the patient’s death.
Discussion BK virus, 1 of 5 known polyomaviruses, was first isolated in 1971 from a renal transplant patient with ureteric stenosis.4 Primary infection occurs in early childhood, and it is thought that the virus establishes latent infection in uroepithelial cells, lymphocytes, and possibly other cells. Immunosuppression leads to reactivation of the virus, with 2 well-described disease associations: BK virus nephropathy in renal transplant patients and hemorrhagic cystitis in HSCT patients. Diagnosis is based on clinical findings and is supported by characteristic cytologic findings in urine, “decoy cells,” and plasma PCR assays. Encephalitis has also been described.5-18 A literature search using combinations of the search terms BK virus, encephalitis, cerebrospinal fluid, and central nervous system was performed. All relevant articles and their references were reviewed. Ultimately, we discovered 22 English-language cases of presumed BK virus central nervous system (CNS) infections, which are shown (in addition to our case) in Table 2. Most patients described have been male, with a median age of 29.5 years, and 69.5% had an underlying or comorbid illness, including 6 HSCT patients and 4 AIDS patients. Clinical manifestations have varied, although the most common symptom appears to be confusion (seen in 15 of 23 cases); 9 had concurrent renal disease also attributed to BK virus. CSF findings have been varied as well, without a characteristic pattern. All but 2 cases were diagnosed using PCR for BK virus on CSF samples, and in 7 cases, brain tissue was used to confirm the diagnosis. The prognosis for the patients in this series was poor; 8 of the 13 cases for which mortality was reported died as a direct result of the disease. Only 1 other case described attempted therapy with cidofovir, also unsuccessful, in a pediatric cardiac transplant recipient.18 None of the other cases attempted any directed antiviral therapy for BK virus. The significance of a positive BK virus PCR from CSF is admittedly unclear, both in our patient’s case and in those
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29/male
26/ female 56/male 38/ female 43/male
46/male
NR/male 48/male
6/female
36/male
Hix et al (2004)12 Friedman and Flanders (2006)13 Vidal et al (2007)14
Ferrari et al (2008)15
Behre et al (2008)16 Lopes da Silva et al (2011)17 Pereira et al (2012)18
Chittick et al (2013)
Headache, confusion
Fever
Headache, confusion, diplopia, URI, vomiting Confusion
Asymptomatic Confusion, oral ulcers, rash Confusion Headache, vomiting, diplopia Seizure
Renal transplant Confusion, lethargy Hodgkin l Confusion ymphoma/HSCT Brazil HIV/AIDS, TB Headache, confusion, ataxia, dysarthria Italy NHL Headache, diplopia, tinnitus Germany ALL/HSCT Seizure Portugal MDS/HSCT Confusion, fever, syncope US Heart transplant Confusion, lethargy, dysarthria, ataxia US AML/HSCT Confusion, fever
None
TB
None
None
UK
None None
ALL/HSCT None
HUS
South Africa South Africa South Africa US US
Headache, fever, seizure, confusion Dizziness, deafness, retinitis, confusion Paraplegia, confusion
Headache, ataxia, incontinence, seizure
CLL, splenectomy Confusion, weakness, ataxia, coma ALL/HSCT Asymptomatic
AIDS/NHL
AIDS
UK
UK UK
France
Sweden
None
AIDS
Symptoms
CSF PCR
CSF PCR
CSF PCR CSF PCR, brain tissue PCR
Kidney
Kidney
NR Kidney, TMA
Kidney
None
CSF PCR, brain tissue PCR CSF PCR
Kidney NR
NR
NR
NR
NR
NR
NR NR
NR NR
NR
Kidney, bone marrow Kidney
Kidney, eye
None
Kidney, lung
CSF PCR Brain tissue PCR
CSF PCR
CSF PCR
CSF PCR
CSF PCR
CSF PCR
CSF PCR CSF PCR
CSF PCR CSF PCR
CSF PCR
CSF PCR, brain histopathology CSF PCR, brain tissue ISH positive CSF PCR, brain tissue PCR
CSF/brain cytopathic effects, restriction endonuclease positive for BK CSF PCR
Methods of Diagnosis
Other Organs Involved
1
NR
NR 10
NR
12
NR NR
NR
6
6
NR
NR
NR NR
NR NR
NR
121
NR
8
10
15
77
NR
NR 66
51
46
NR NR
NR
32
94
NR
NR
NR NR
NR NR
NR
106
NR
NR
NR
70
14
NR
NR 54
73
146
NR NR
NR
1904
129
NR
NR
NR NR
NR NR
NR
33
NR
644
152
58
CSF WBC CSF Count CSF Glucose Protein (Cells/µL) (mg/mL) (mg/dL)
Yes
Yes
Yes Yes
No
No
No No
NR
NR
NR
NR
NR
NR NR
NR NR
NR
Yes
Yes
Yes
No
Yes
Death
Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; CSF, cerebrospinal fluid; HSCT, hematopoietic stem cell transplant; HUS, hemolytic uremic syndrome; ISH, in situ hybridization; MDS, myelodysplastic syndrome; NHL, non-Hodgkin lymphoma; NR, not reported; PCR, polymerase chain reaction; TB, tuberculosis; TMA, thrombotic microangiopathy; URI, upper respiratory infection; WBC, white blood cell.
32/male
3/female 5/female
5/female
Behzah-Behbahani et al (2003)10
Behzad-Behbahani et al (2003)11
UK UK
49/male
Stoner et al (2002)9
16/male 13/ female 24/ female 30/male
UK
44/male
Lesprit et al (2001)8
US
26/male
Bratt et al (1999)7
Germany
34/male
Voitz et al (1996)6
Germany
27/male
Vallbracht et al (1993)5
Reference
Patient Age (Years)/ Country of Sex Origin Underlying Disease
Table 2. Review of Cases of BK Virus Isolated From the Central Nervous System.
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described in the literature, particularly given the variety of clinical presentations and the fact that it was isolated from asymptomatic patients in 2 cases, as well as those with no known medical condition. Biologic plausibility exists for BK virus to cause encephalitis, as JC virus, another polyomavirus, is a well-known cause of encephalitis and progressive multifocal leukoencephalopathy in immunocompromised patients.19 Additionally, studies from the 1990s have demonstrated that BK virus could be found by PCR in brain tissue of patients with a number of diagnoses, including multiple sclerosis and Huntington disease, as well as those without neurologic disease.20,21 This suggests that BK virus, like JC virus, may establish a latent reservoir in the CNS, with the potential to reactivate in an immunocompromised host. The case of our patient, who had detectable BK virus in both the CNS and urine but no evidence of viremia, could also support this hypothesis. Analyses of viral sequences from 2 patients with detectable BK virus in both the CNS and urine have demonstrated a unique pattern in the noncoding control region of the BK genome in CNS variants.9,22 These analyses have suggested that this variation may allow for enhanced CNS tropism or virulence, although this has not been confirmed in subsequent analyses of additional viral samples.23 There is no proven therapy for BK virus infection, although the first step in management typically consists of a reduction in immunosuppression. Several agents have been putatively used in treatment, including ciprofloxacin,24 intravenous immune globulin,25 and leflunomide.26 Cidofovir, an antiviral agent with evidence of in vitro antiBK virus activity, has been used in many small case series involving renal transplant and HSCT patients.27,28 Most notably, in a review of 57 European HSCT patients with BK virus hemorrhagic cystitis, 79% had a complete or partial response to intravenous cidofovir.29 Although there was no control group, it is noteworthy that complete response was associated with a significant reduction in mortality when compared with partial or no response. Of particular relevance in our case was the question of the usefulness of cidofovir for CNS infections. Although cidofovir is used with some success against CMV retinitis, its penetration into the eye is via an active transport system, and no known similar mechanisms exist for the CNS. According to the product labeling there is no penetration of cidofovir into the CNS.30 However, in one case report of a patient with HHV-6 encephalitis, the use of cidofovir led to a rapid reduction in CSF HHV-6 viral load.31 Unfortunately, we were unable to reassess our patient’s CSF viral load because of the overall condition of his skin and his limited survival time after initiation of therapy. Renal and ocular toxicities of cidofovir are the result of accumulation of the drug in renal proximal tubular cells and the ciliary body epithelium, respectively. Cidofovir exposure at these sites is mediated by a transport system called human organic anion transporter 1. As adjunctive treatment, probenecid inhibits this transport system, thereby preventing
uptake of cidofovir and reducing the risk of nephrotoxicity and uveitis. Cimetidine has been shown to inhibit organic anion transporter 1 and similar transport systems.32,33 As evidenced by an animal model study,32 as well as pharmacokinetic data from a study in healthy volunteers,33 cimetidine affects the concentrations of other antivirals known to use these transport systems. De Bony and colleagues studied the effects of probenecid and cimetidine on the pharmacokinetics of orally administered valacyclovir.34 Concurrent administration of either drug resulted in a higher maximum concentration and area under the concentration–time curve for both valacyclovir and its metabolite acyclovir. This information figured prominently in our decision to use intravenous cimetidine instead of oral probenecid to limit potential toxicities of cidofovir. As illustrated in Table 1, the schedule of cimetidine relative to cidofovir administration is different from what is recommended for probenecid because of differences in the drugs’ respective pharmacokinetic parameters.30,35,36 In conclusion, although the finding of BK virus in CSF specimens is of debatable significance, it is plausible that it represents a true pathogen in certain circumstances, such as the profound immunosuppression seen in HSCT patients. Cidofovir is a reasonable choice for treatment of those with severe BK virus infection, although it did not alter our patient’s outcome. Additionally, cimetidine represents a safe and viable option for prevention of cidofovir-associated renal and ocular toxicity in patients who are unable to tolerate or absorb oral probenecid. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Seeley WW, Marty FM, Holmes TM, et al. Post-transplant acute limbic encephalitis: clinical features and relationship to HHV6. Neurology. 2007;69:156-165. 2. Kremer S, Matern JF, Bilger K, et al. EBV limbic encephalitis after allogeneic hematopoietic stem cell transplantation. J Neuroradiol. 2010;37:189-191. 3. Reddy SM, Winston DJ, Territo MC, Schiller GJ. CMV central nervous system disease in stem-cell transplant recipients: an increasing complication of drug-resistant CMV infection and protracted immunodeficiency. Bone Marrow Transplant. 2010;45:979-984. 4. Hirsch HH, Steiger J. Polyomavirus BK. Lancet Infect Dis. 2003;3:611-623. 5. Vallbracht A, Lohler J, Gossman J, et al. Disseminated BK type polyomavirus infection in an AIDS patient associated with central nervous system disease. Am J Pathol. 1993;143:29-39.
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Chittick et al 6. Voltz R, Jager G, Seelos K, Fuhry L, Hohlfeld R. BK virus encephalitis in an immunocompetent patient. Arch Neurol. 1996;53:101-103. 7. Bratt G, Hammarin AL, Grandien M, et al. BK virus as the cause of meningoencephalitis, retinitis and nephritis in a patient with AIDS. AIDS. 1999;13:1071-1075. 8. Lesprit P, Chaline-Lehmann D, Authier FJ, Ponnelle T, Gray F, Levy Y. BK virus encephalitis in a patient with AIDS and lymphoma. AIDS. 2001;15:1196-1199. 9. Stoner GL, Alappan R, Jobes DV, Ryschkewitsch CF, Landry ML. BK virus regulatory region rearrangements in brain and cerebrospinal fluid from a leukemia patient with tubulointerstitial nephritis and meningoencephalitis. Am J Kidney Dis. 2002;39:1102-1112. 10. 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. 11. Behzad-Behbahani A, Klapper PE, Vallely PJ, Cleator GM, Bonington A. BKV-DNA and JCV-DNA in CSF of patients with suspected meningitis or encephalitis. Infection. 2003;31:374-378. 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. Friedman DP, Flanders AE. MR imaging of BK virus encephalitis. AJNR Am J Neuroradiol. 2006;27:1016-1018. 14. 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. 15. Ferrari A, Luppi M, Marasca R, et al. BK virus infection and neurologic dysfunctions in a patient with lymphoma treated with rituximab. Eur J Haematol. 2008;81:244-245. 16. Behre G, Becker M, Christopeit M. BK virus encephalitis in an allogeneic hematopoietic stem cell recipient [letter]. Bone Marrow Transplant. 2008;42:499. 17. 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. 2011;13:161-167. 18. 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. 19. Tan CS, Koralnik IJ. Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol. 2010;9:425-437. 20. Elsner C, Dorries K. Evidence of human polyomavirus BK and JC infection in normal brain tissue. Virology. 1992;191:7280. 21. Vago L, Cinque P, Sala E, et al. JCV-DNA and BKV-DNA in the CNS tissue and CSF of AIDS patients and normal subjects: study of 41 cases and review of the literature. J Acquir Immune Defic Syndr Hum Retrovirol. 1996;12:139-146. 22. Jorgensen GE, Hammarin AL, Bratt G, Grandien M, Flaegstad T, Johnsen JI. Identification of a unique BK virus variant in the CNS of a patient with AIDS. J Med Virol. 2003;70:14-19.
23. Barcena-Panero A, Echevarria JE, Van Ghelue M, et al. BK polyomavirus with archetypal and rearranged non-coding control regions is present in cerebrospinal fluids from patients with neurological complications. J Gen Virol. 2012;93:17801794. 24. Leung AY, Chan MT, Yuen KY, et al. Ciprofloxacin decreased polyoma BK virus load in patients who underwent allogeneic hematopoietic stem cell transplantation. Clin Infect Dis. 2005;40:528-537. 25. Sener A, House AA, Jevnikar AM, et al. Intravenous immunoglobulin as a treatment for BK virus associated nephropathy: one-year follow-up of renal allograft recipients. Transplantation. 2006;81:117-120. 26. Wu JK, Harris MT. Use of leflunomide in the treat ment of polyomavirus BK-associated nephropathy. Ann Pharmacother. 2008;42:1679-1685. doi:10.1345/aph.1L180. 27. Ganguly N, Clough LA, Dubois LK, et al. Low-dose cidofovir in the treatment of symptomatic BK virus infection in patients undergoing allogeneic hematopoietic stem cell transplantation: a retrospective analysis of an algorithmic approach. Transpl Infect Dis. 2010;12:406-411. 28. Kuypers DR, Bammens B, Claes K, Evenepoel P, Lerut E, Vanrenterghem Y. A single-centre study of adjuvant cidofovir therapy for BK virus interstitial nephritis (BKVIN) in renal allograft recipients. J Antimicrob Chemother. 2009;63:417-419. 29. Cesaro S, Hirsch HH, Faraci M, et al. Cidofovir for BK virus– associated hemorrhagic cystitis: a retrospective study. Clin Infect Dis. 2009;49:233-240. 30. Vistide (cidofovir injection) [prescribing information]. Foster City, CA: Gilead; 2010. http://www.gilead.com/pdf/vistide. pdf. Accessed January 31, 2013. 31. Pohlmann C, Schetelig J, Reuner U, et al. Cidofovir and foscarnet for treatment of human herpesvirus 6 encephalitis in a neutropenic stem cell transplant recipient. Clin Infect Dis. 2007;44:e118-e120. 32. Burckhardt BC, Brai S, Wallis S, Krick W, Wolff NA, Burckhardt G. Transport of cimetidine by flounder and human renal organic anion transporter 1. Am J Physiol Renal Physiol. 2003;284:503-509. 33. Wang J, Nation RL, Evans AM, Cox S. Renal secretion of the antiviral nucleoside analog AM188 is inhibited by probenecid, p-aminohippuric acid, and cimetidine in the isolated perfused rat kidney. Pharm Res. 2004;21:982-988. 34. De Bony F, Tod M, Bidault R, On NT, Posner J, Rolan P. Multiple interactions of cimetidine and probenecid with valacyclovir and its metabolite acyclovir. Antimicrob Agents Chemother. 2002;46:458-463. 35. Cimetidine (cimetidine hydrochloride injection, solution) [prescribing information]. 2006. http://dailymed.nlm.nih.gov/ dailymed/drugInfo.cfm?id%20=%2047776. Accessed March 25, 2013. 36. Probenecid (probenecid tablet, film coated) [prescribing information]. June 2010. http://dailymed.nlm.nih.gov/dailymed/Lookup.cfm?setid%20=%20ae126418-5474-4fbeb83c-bde8b2b4ae6e. Accessed March 25, 2013.
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research-article2013
AOPXXX10.1177/1060028013500646Chittick et alThe Annals of Pharmacotherapy
Case Report
BK Virus Encephalitis: Case Report, Review of the Literature, and Description of a Novel Treatment Modality
Annals of Pharmacotherapy 47(9) 1229–1233 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013500646 aop.sagepub.com
Paul Chittick, MD1, John C. Williamson, PharmD, BCPS, AAHIVE2, and Christopher A. Ohl, MD2,3
Abstract Objective: To describe a case of BK virus encephalitis with attempted direct antiviral therapy, review the reported cases of BK virus in the central nervous system, and report the novel use of intravenous cimetidine in place of oral probenecid to minimize the toxicities of intravenous cidofovir. Case Summary: A 36-year-old male with acute myelomonocytic leukemia and subsequent myelodysplastic syndrome underwent allogeneic hematopoietic stem cell transplant. His course was complicated by severe graft-versus-host disease involving his skin and gastrointestinal tract. Five weeks after transplantation, he developed fever and confusion. Magnetic resonance imaging was suggestive of limbic encephalitis and cerebrospinal fluid tested positive for BK virus. Therapy with intravenous cidofovir was thought to be indicated. Although probenecid is commonly used to minimize the toxicities of cidofovir, the patient’s severe graft-versus-host disease raised concerns about absorption of oral medications. Based on animal models and pharmacokinetic data, intravenous cimetidine was used in place of oral probenecid. Despite these therapies, the patient’s mental status did not improve. He developed progressive organ system failure, and care was ultimately withdrawn. Discussion: BK virus is increasingly described as a cause of encephalitis. The majority of reported cases have occurred in immunocompromised patients and have generally had a poor outcome. This case describes attempted antiviral therapy using cidofovir, the antiviral agent used most frequently in other syndromes due to BK virus. Intravenous cimetidine is a novel modality used to minimize ocular and renal toxicities frequently seen with cidofovir, and we believe this warrants further investigation. Conclusions: BK virus may be a cause of encephalitis in immunocompromised hosts, and cidofovir represents a possible treatment option. Intravenous cimetidine can be considered to minimize toxicities associated with cidofovir use in patients unable to tolerate or absorb oral probenecid. Keywords BK virus, encephalitis in immunocompromised hosts, cidofovir, cimetidine
The use of allogeneic hematopoietic stem cell transplant (HSCT) for hematologic malignancies has led to successful management of previously incurable diseases. However, the intense immunosuppression is associated with numerous infectious complications, including encephalitis. As diagnostic methods improve, more cases of encephalitis can be attributed to a specific cause, with recent reports describing infections with human herpesvirus 6 (HHV-6),1 Epstein–Barr virus,2 and cytomegalovirus (CMV).3 We report a case of BK virus encephalitis, review other reported cases in the English-language literature, and describe a novel treatment modality.
acute myelomonocytic leukemia 4 years earlier for which he initially received chemotherapy, resulting in remission. He subsequently developed progressive myelodysplastic syndrome and underwent HSCT on hospital day 7. His hospital course was complicated by biopsy-proven (skin biopsied hospital day 22, intestine biopsied hospital day 46) graft-versus-host disease (GVHD), including involvement of his gastrointestinal tract, causing severe diarrhea, for which he received methotrexate and high-dose
Case Report
Corresponding Author: Paul Chittick, MD, Director of Transplant Infectious Diseases, Beaumont Health System, 3601 W. 13 Mile Road, Royal Oak, MI 48073, USA. Email: [email protected]
A 36-year-old white male was admitted to our institution for a mismatched unrelated HSCT. He had been diagnosed with
1
Beaumont Health System, Royal Oak, MI, USA Wake Forest Baptist Health, Winston-Salem, NC, USA 3 Wake Forest University, Winston-Salem, NC, USA 2
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Table 1. Suggested Cidofovir and Cimetidine Dosing Protocol for BK Viral Encephalitis. Time, hours −2 −1 0 +1 +3 +7 +11
Infusion Cimetidine 600 mg intravenously infused over 1 hour 1 L normal saline infused over 1 hour Cidofovir 300 mg intravenously infused over 1 hour 1 L normal saline infused over 2 hours Cimetidine 300 mg intravenously infused over 30 minutes Cimetidine 300 mg intravenously infused over 30 minutes Start cimetidine 300 mg intravenously infused every 6 hours for 3 days
corticosteroids. His white blood cell count recovered on hospital day 22 (absolute neutrophil count 1700 cells/µL), but he continued to require hospitalization because of intermittent fever, progressive hypoxia, and worsening skin and gastrointestinal tract GVHD. His initial immunosuppressive regimen consisted of tacrolimus and corticosteroids, with mycophenolate mofetil subsequently replacing tacrolimus on hospital day 32. On hospital day 40, he developed fever, hypotension, and confusion without objective focal neurologic deficits. Multiple cultures of blood, urine, and sputum were unrevealing. An electrocardiogram did not show any evidence of seizure activity. Magnetic resonance imaging of the brain demonstrated an abnormal fluid-attenuated inversion recovery signal and restricted diffusion within the right hippocampus, which was thought to be indicative of limbic or herpes encephalitis. A lumbar puncture had the following findings: white blood cell count 1 cell/mm3, total protein 14 mg/dL, and glucose 77 mg/dL. Bacterial, fungal, and acidfast bacillus cultures of cerebrospinal fluid (CSF) were negative, as were cytology, cryptococcal antigen, and viral polymerase chain reaction (PCR) studies for herpes simplex virus, JC virus, CMV, and HHV-6. On hospital day 53, the result of a CSF qualitative PCR for BK virus from the initial lumbar puncture was positive. Because of the patient’s progressive confusion and a desire to avoid more toxic antimicrobials, ciprofloxacin, and intravenous immune globulin were initiated for their purported anti-BK virus activity. The use of leflunomide was also considered but it was believed that this would be less effective for BK virus and would not result in adequate immunosuppression for his GVHD. Additionally, as leflunomide is only available orally, it would require adequate absorption from the patient’s gastrointestinal tract, which could not be certain because of the patient’s GVHD. Additional testing revealed a urine BK virus PCR greater than 39 × 106 copies/mL, the presence of decoy cells in his urine, and a negative serum BK virus
PCR. Quantitative PCR testing for BK virus in his CSF sample showed 1761 copies/mL. The patient’s confusion persisted, so intravenous cidofovir was initiated on hospital day 55. Oral probenecid is commonly used to limit the renal and ocular toxicities of cidofovir, but the patient’s severe gastrointestinal GVHD raised the concern of poor probenecid absorption. As an alternative to probenecid, intravenous cimetidine was begun, based on animal models and pharmacokinetic data, according to the dosing shown in Table 1. No additional lumbar punctures were performed as a result of the severity of his skin GVHD. Unfortunately, he developed multisystem organ failure, and care was withdrawn on hospital day 60. No improvement in mental status was noted prior to the patient’s death.
Discussion BK virus, 1 of 5 known polyomaviruses, was first isolated in 1971 from a renal transplant patient with ureteric stenosis.4 Primary infection occurs in early childhood, and it is thought that the virus establishes latent infection in uroepithelial cells, lymphocytes, and possibly other cells. Immunosuppression leads to reactivation of the virus, with 2 well-described disease associations: BK virus nephropathy in renal transplant patients and hemorrhagic cystitis in HSCT patients. Diagnosis is based on clinical findings and is supported by characteristic cytologic findings in urine, “decoy cells,” and plasma PCR assays. Encephalitis has also been described.5-18 A literature search using combinations of the search terms BK virus, encephalitis, cerebrospinal fluid, and central nervous system was performed. All relevant articles and their references were reviewed. Ultimately, we discovered 22 English-language cases of presumed BK virus central nervous system (CNS) infections, which are shown (in addition to our case) in Table 2. Most patients described have been male, with a median age of 29.5 years, and 69.5% had an underlying or comorbid illness, including 6 HSCT patients and 4 AIDS patients. Clinical manifestations have varied, although the most common symptom appears to be confusion (seen in 15 of 23 cases); 9 had concurrent renal disease also attributed to BK virus. CSF findings have been varied as well, without a characteristic pattern. All but 2 cases were diagnosed using PCR for BK virus on CSF samples, and in 7 cases, brain tissue was used to confirm the diagnosis. The prognosis for the patients in this series was poor; 8 of the 13 cases for which mortality was reported died as a direct result of the disease. Only 1 other case described attempted therapy with cidofovir, also unsuccessful, in a pediatric cardiac transplant recipient.18 None of the other cases attempted any directed antiviral therapy for BK virus. The significance of a positive BK virus PCR from CSF is admittedly unclear, both in our patient’s case and in those
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29/male
26/ female 56/male 38/ female 43/male
46/male
NR/male 48/male
6/female
36/male
Hix et al (2004)12 Friedman and Flanders (2006)13 Vidal et al (2007)14
Ferrari et al (2008)15
Behre et al (2008)16 Lopes da Silva et al (2011)17 Pereira et al (2012)18
Chittick et al (2013)
Headache, confusion
Fever
Headache, confusion, diplopia, URI, vomiting Confusion
Asymptomatic Confusion, oral ulcers, rash Confusion Headache, vomiting, diplopia Seizure
Renal transplant Confusion, lethargy Hodgkin l Confusion ymphoma/HSCT Brazil HIV/AIDS, TB Headache, confusion, ataxia, dysarthria Italy NHL Headache, diplopia, tinnitus Germany ALL/HSCT Seizure Portugal MDS/HSCT Confusion, fever, syncope US Heart transplant Confusion, lethargy, dysarthria, ataxia US AML/HSCT Confusion, fever
None
TB
None
None
UK
None None
ALL/HSCT None
HUS
South Africa South Africa South Africa US US
Headache, fever, seizure, confusion Dizziness, deafness, retinitis, confusion Paraplegia, confusion
Headache, ataxia, incontinence, seizure
CLL, splenectomy Confusion, weakness, ataxia, coma ALL/HSCT Asymptomatic
AIDS/NHL
AIDS
UK
UK UK
France
Sweden
None
AIDS
Symptoms
CSF PCR
CSF PCR
CSF PCR CSF PCR, brain tissue PCR
Kidney
Kidney
NR Kidney, TMA
Kidney
None
CSF PCR, brain tissue PCR CSF PCR
Kidney NR
NR
NR
NR
NR
NR
NR NR
NR NR
NR
Kidney, bone marrow Kidney
Kidney, eye
None
Kidney, lung
CSF PCR Brain tissue PCR
CSF PCR
CSF PCR
CSF PCR
CSF PCR
CSF PCR
CSF PCR CSF PCR
CSF PCR CSF PCR
CSF PCR
CSF PCR, brain histopathology CSF PCR, brain tissue ISH positive CSF PCR, brain tissue PCR
CSF/brain cytopathic effects, restriction endonuclease positive for BK CSF PCR
Methods of Diagnosis
Other Organs Involved
1
NR
NR 10
NR
12
NR NR
NR
6
6
NR
NR
NR NR
NR NR
NR
121
NR
8
10
15
77
NR
NR 66
51
46
NR NR
NR
32
94
NR
NR
NR NR
NR NR
NR
106
NR
NR
NR
70
14
NR
NR 54
73
146
NR NR
NR
1904
129
NR
NR
NR NR
NR NR
NR
33
NR
644
152
58
CSF WBC CSF Count CSF Glucose Protein (Cells/µL) (mg/mL) (mg/dL)
Yes
Yes
Yes Yes
No
No
No No
NR
NR
NR
NR
NR
NR NR
NR NR
NR
Yes
Yes
Yes
No
Yes
Death
Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; CSF, cerebrospinal fluid; HSCT, hematopoietic stem cell transplant; HUS, hemolytic uremic syndrome; ISH, in situ hybridization; MDS, myelodysplastic syndrome; NHL, non-Hodgkin lymphoma; NR, not reported; PCR, polymerase chain reaction; TB, tuberculosis; TMA, thrombotic microangiopathy; URI, upper respiratory infection; WBC, white blood cell.
32/male
3/female 5/female
5/female
Behzah-Behbahani et al (2003)10
Behzad-Behbahani et al (2003)11
UK UK
49/male
Stoner et al (2002)9
16/male 13/ female 24/ female 30/male
UK
44/male
Lesprit et al (2001)8
US
26/male
Bratt et al (1999)7
Germany
34/male
Voitz et al (1996)6
Germany
27/male
Vallbracht et al (1993)5
Reference
Patient Age (Years)/ Country of Sex Origin Underlying Disease
Table 2. Review of Cases of BK Virus Isolated From the Central Nervous System.
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Annals of Pharmacotherapy 47(9)
described in the literature, particularly given the variety of clinical presentations and the fact that it was isolated from asymptomatic patients in 2 cases, as well as those with no known medical condition. Biologic plausibility exists for BK virus to cause encephalitis, as JC virus, another polyomavirus, is a well-known cause of encephalitis and progressive multifocal leukoencephalopathy in immunocompromised patients.19 Additionally, studies from the 1990s have demonstrated that BK virus could be found by PCR in brain tissue of patients with a number of diagnoses, including multiple sclerosis and Huntington disease, as well as those without neurologic disease.20,21 This suggests that BK virus, like JC virus, may establish a latent reservoir in the CNS, with the potential to reactivate in an immunocompromised host. The case of our patient, who had detectable BK virus in both the CNS and urine but no evidence of viremia, could also support this hypothesis. Analyses of viral sequences from 2 patients with detectable BK virus in both the CNS and urine have demonstrated a unique pattern in the noncoding control region of the BK genome in CNS variants.9,22 These analyses have suggested that this variation may allow for enhanced CNS tropism or virulence, although this has not been confirmed in subsequent analyses of additional viral samples.23 There is no proven therapy for BK virus infection, although the first step in management typically consists of a reduction in immunosuppression. Several agents have been putatively used in treatment, including ciprofloxacin,24 intravenous immune globulin,25 and leflunomide.26 Cidofovir, an antiviral agent with evidence of in vitro antiBK virus activity, has been used in many small case series involving renal transplant and HSCT patients.27,28 Most notably, in a review of 57 European HSCT patients with BK virus hemorrhagic cystitis, 79% had a complete or partial response to intravenous cidofovir.29 Although there was no control group, it is noteworthy that complete response was associated with a significant reduction in mortality when compared with partial or no response. Of particular relevance in our case was the question of the usefulness of cidofovir for CNS infections. Although cidofovir is used with some success against CMV retinitis, its penetration into the eye is via an active transport system, and no known similar mechanisms exist for the CNS. According to the product labeling there is no penetration of cidofovir into the CNS.30 However, in one case report of a patient with HHV-6 encephalitis, the use of cidofovir led to a rapid reduction in CSF HHV-6 viral load.31 Unfortunately, we were unable to reassess our patient’s CSF viral load because of the overall condition of his skin and his limited survival time after initiation of therapy. Renal and ocular toxicities of cidofovir are the result of accumulation of the drug in renal proximal tubular cells and the ciliary body epithelium, respectively. Cidofovir exposure at these sites is mediated by a transport system called human organic anion transporter 1. As adjunctive treatment, probenecid inhibits this transport system, thereby preventing
uptake of cidofovir and reducing the risk of nephrotoxicity and uveitis. Cimetidine has been shown to inhibit organic anion transporter 1 and similar transport systems.32,33 As evidenced by an animal model study,32 as well as pharmacokinetic data from a study in healthy volunteers,33 cimetidine affects the concentrations of other antivirals known to use these transport systems. De Bony and colleagues studied the effects of probenecid and cimetidine on the pharmacokinetics of orally administered valacyclovir.34 Concurrent administration of either drug resulted in a higher maximum concentration and area under the concentration–time curve for both valacyclovir and its metabolite acyclovir. This information figured prominently in our decision to use intravenous cimetidine instead of oral probenecid to limit potential toxicities of cidofovir. As illustrated in Table 1, the schedule of cimetidine relative to cidofovir administration is different from what is recommended for probenecid because of differences in the drugs’ respective pharmacokinetic parameters.30,35,36 In conclusion, although the finding of BK virus in CSF specimens is of debatable significance, it is plausible that it represents a true pathogen in certain circumstances, such as the profound immunosuppression seen in HSCT patients. Cidofovir is a reasonable choice for treatment of those with severe BK virus infection, although it did not alter our patient’s outcome. Additionally, cimetidine represents a safe and viable option for prevention of cidofovir-associated renal and ocular toxicity in patients who are unable to tolerate or absorb oral probenecid. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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