key: cord-0006450-y6xucacl
authors: Kinnaird, A. N.; Anstead, G. M.
title: Hemorrhagic Cystitis and Possible Neurologic Disease from BK Virus Infection in a Patient with AIDS
date: 2010-03-02
journal: Infection
DOI: 10.1007/s15010-009-9201-5
sha: e8a8e020190451eec71907356a1a1d82088bd116
doc_id: 6450
cord_uid: y6xucacl

BK virus (BKV)-associated hemorrhagic cystitis occurs in bone marrow transplant recipients but is rare among other immunosuppressed patients. We present a rare case of BKVassociated hemorrhagic cystitis in a 48-year-old man with AIDS and previously diagnosed progressive multifocal leukoencephalopathy.

BK virus (BKV) is a human polyomavirus that has been implicated as an etiology of hemorrhagic cystitis in bone marrow transplant (BMT) recipients and as a significant cause of tubulointerstitial nephritis, vasculopathy, and allograft dysfunction in renal transplant patients [1] [2] [3] [4] [5] . However, in HIV-infected patients, BKV clinical syndromes have been limited to case reports of tubulointerstitial nephritis, interstitial pneumonitis, interstitial desquamative pneumonitis, subacute meningitis, retinitis, and encephalitis [6] [7] [8] [9] [10] [11] . As for BKV-associated hemorrhagic cystitis in HIV-infected patients, there are only two other reported cases: a 41-year-old man with cytomegalovirus (CMV) antigenemia who had been treated with cyclophosphamide for a large B cell lymphoma 9 days before the onset of hemorrhagic cystitis and a 29-year-old man with HIV [12, 13] . We present a rare case of BKVassociated hemorrhagic cystitis in a 48-year-old man with AIDS and previously diagnosed progressive multifocal leukoencephalopathy.

A 48-year-old African-American man with AIDS (CDC Stage C3) was admitted for gross hematuria of one week's duration. The patient had a CD4 count of 68 cells/mm 3 (16%), with a viral load of <50 copies/mL on an antiretroviral regimen consisting of emtricitabine-tenofovir and lopinavir-ritonavir. He had been admitted several times for hematuria in the preceding 5 months. Repeat CD4 counts and HIV viral loads were not obtained during each admission. He had received an extensive evaluation for hematuria, including computed tomographic urogram, percutaneous ureteronephroscopy, intravenous pyelogram, and nephrotomography. All of these tests were unrevealing for a structural cause of the hematuria.

The patient's past medical history included HIV infection and a clinical diagnosis of progressive multifocal leukoencephalopathy (PML; a demyelinating neurodegenerative disease due to infection by the JC virus [JCV]). He was diagnosed with HIV and concurrent PML 18 months prior to admission, with a CD4 nadir of 44 cells/mm 3 (12%) and a baseline viral load of 174,000 copies/ mL. At the time of diagnosis, he was started on emtricitabinetenofovir and lopinavir-ritonavir and his HIV viral load became undetectable within 8 months. At the time of his first undetectable HIV viral load, his CD4 count had risen to 59 cells/mm 3 (11%).

The patient's presumptive diagnosis of PML was based on ataxia and cognitive and speech deficits. At the time of presentation of the neurological deficits, magnetic resonance imaging (MRI) of the brain with gadolinium contrast was performed, which showed multifocal and infratentorial foci of abnormally high T2 and FLAIR signal, not typical for PML. Furthermore, a polymerase chain reaction (PCR) assay of the cerebrospinal fluid (CSF) was negative for the presence of the JCV. Nevertheless, a brain biopsy revealed positive immunohistochemical staining with antibodies against simian virus 40 (one of the polyomaviruses). Thus, the patient was diagnosed with PML on the basis of clinical presentation and immunohistochemical staining of the brain biopsy specimen, despite the negative PCR and inconsistent MRI findings.

During the current admission to the hospital, physical examination was unremarkable except for prior cognitive deficits and suprapubic tenderness. Laboratory data were unremarkable except for a mild normocytic anemia. A Foley catheter was placed with passage of gross blood. Computed tomography (CT) of the pelvis demonstrated concentric bladder wall thickening and slight mucosal enhancement consistent with hemorrhagic cystitis (Figure 1 ) [14] . Cytological examination of the urine revealed transitional cells with enlarged, deeply staining basophilic nuclei that were suggestive of 'decoy cells.' Cultures of urine specimens were negative for bacteria, CMV, and adenovirus. PCR assays of urine samples yielded results positive for BKV and negative for JCV. The patient was started on continuous bladder irrigation and his urine cleared after 3 days. The patient was discharged and, at follow-up, has remained asymptomatic for 18 months.

Sites of BKV-associated disease, both primary and reactivated, in the non-HIV-infected population include the kidney, lung, liver, eye, and brain. In HIV-infected patients, BKV clinical syndromes have been associated with infections in the same organs and are limited to case reports of tubulointerstitial nephritis, interstitial pneumonitis, interstitial desquamative pneumonitis, subacute meningitis, retinitis, encephalitis, and the other reported cases of hemorrhagic cystitis (Table 1) [6-13, 15, 16] . A detailed discussion of these cases has been presented elsewhere [16] .

The significance of BKV detection in the cerebral tissue of HIV-infected patients is uncertain. Two different studies have detected BKV by PCR in the cerebral tissue of 3-6% of HIV-infected patients both with and without neurological symptoms [17, 18] . In another study, CSF samples from 400 immunocompromised patients with neurological symptoms were negative for BKV by PCR [10] . When it is associated with clinical disease, the virus seems to have a predilection for the ventricular and pial surfaces of the brain parenchyma [9] [10] [11] . Although BKV infections of the central nervous system are seemingly rare in HIV-infected patients, there seems to be sufficient evidence to warrant its consideration, especially in patients with concurrent central nervous system and renal or urinary tract disease.

As for BKV-associated hemorrhagic cystitis, while it is relatively common in patients following BMT, it is rarely reported for other immunocompromised patients [2, 19] . Herein, we present the third reported case of BKV-associated hemorrhagic cystitis in an HIV-infected patient. Previous cases of BKV-associated hemorrhagic cystitis in both BMT patients as well as HIV-infected patients have relied on urine cytology and/or electron microscopy and PCR for the detection of viruria [2, 12, 13, 20, 21] . In our case, urine cytology for 'decoy cells' was suggestive of BKV infection, while PCR was positive for BKV. Positive PCR alone has been shown to be sufficient for the diagnosis of polyomaviruses, being both more sensitive and specific than cytology [22] . At the laboratory that performed our urine PCR for BKV, the limit of detection is 390 copies/mL and the PCR is specific to BKV when tested in the presence of JCV, herpes simplex virus-1, herpes simplex virus-2, varicella zoster virus, CMV, Epstein-Barr virus, and adenovirus.

It has been suggested that BKV-associated hemorrhagic cystitis in HIV-infected patients is related to immune reconstitution following the initiation of effective antiretroviral therapy [16] . In our case, the patient had his first episode of hematuria 3 months after his HIV viral load first became undetectable and at that time his CD4 count had also begun to rise. This is suggestive of an association between the onset of BKVassociated hemorrhagic cystitis and immune reconstitution. Although the patient's rise in absolute CD4 count was modest, immune reconstitution inflammatory syndrome can also occur as a result of HIV viral load reduction and the redistribution of memory CD4 lymphocytes [23] .

Interestingly, this case provides more direct evidence for the ability of BK viruria to cause hemorrhagic cystitis in an HIV-infected patient due to the lack of confounding variables present in one of the other reported cases: concomitant immunosuppression by CMV and non-Hodgkin's lymphoma and prior cyclophosphamide administration [12] .

Another question is whether or not this patient's neurologic disease may have been secondary to BKV infection. The MRI scan of the brain in this patient did not show the findings typical for PML (hyperintense T2weighted signal in the white matter adjacent to the cortex) [24] . These atypical MRI findings could not be explained by immune reconstitution because the patient had not yet been started on antiretroviral therapy at the time that his PML was diagnosed. Also, the PCR for JCV was negative; this test has a reported sensitivity of about 75% [24] . The brain biopsy specimen gave positive immunohistochemical staining with anti-SV40 antibody, but this would be cross-reactive with both JCV or BKV infection. Unfor- tunately, the patient was lost to follow-up at the time this manuscript was submitted and further CSF studies could not be performed.

Prior case reports have suggested a role for cidofovir in the treatment of BKV-associated hemorrhagic cystitis; however, the patients in these reports had mixed results [12, 20, 21] . As for other therapeutic options, currently, the most effective treatment for the other polyomavirus infection in HIV, PML, is immune reconstitution by highly active antiretroviral therapy (HAART) [25, 26] . Cidofovir does not have survival benefit in the treatment of JCV infection in AIDS patients [27] . It is unknown if HAART is effective for other polyomavirus-induced complications of HIV.

This report provides additional evidence that BK virus (BKV)-associated hemorrhagic cystitis can occur in Vallbracht et al. [9] HAART: highly active antiretroviral therapy; BKV: BK virus; PCR: polymerase chain reaction; IHC: immunohistochemistry; EM: electron microscopy; ARDS: acute respiratory distress syndrome; CSF: cerebral spinal fluid immunosuppressed patients other than transplant patients, specifically those with HIV. More investigation will be required to determine whether this condition is truly rare or simply underdiagnosed.

BK virus: a clinical review

Association of BK viruria with hemorrhagic cystitis in recipients of bone marrow transplants

Human polyoma virusassociated interstitial nephritis in the allograft kidney

Testing for polyomavirus type BK DNA in plasma to identify renal-allograft recipients with viral nephropathy

BK-related polyomavirus vasculopathy in a renal-transplant recipient

Tubulointerstitial nephritis due to a mutant polyomavirus BK virus strain, BKV(Cin), causing end-stage renal disease

BK virus renal infection in a patient with the acquired immunodeficiency syndrome

BK virus infection in AIDS

Disseminated BK type polyomavirus infection in an AIDS patient associated with central nervous system disease

BK virus as the cause of meningoencephalitis, retinitis and nephritis in a patient with AIDS

BK virus encephalitis in a patient with AIDS and lymphoma

BK virus-associated hemorrhagic cystitis in a human immunodeficiency virus-infected patient

BK virus-associated hemorrhagic cystitis in an HIV-infected man

Retroperitoneal and pelvic CT of patients with AIDS: primary and secondary involvement of the genitourinary tract

BK virus associated Meningoencephalitis in an AIDS patient treated with HAART

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

Presence of BK virus in brain tissues of four AIDS patients, detected by polymerase chain reaction (PCR)

Pathogenesis and management of polyomavirus infection in transplant recipients

Treatment of BK virus-associated hemorrhagic cystitis and simultaneous CMV reactivation with cidofovir

JF: Cidofovir treatment of human polyomavirus-associated acute haemorrhagic cystitis

Cytologic and biomolecular diagnosis of polyomavirus infection in urine specimens of HIV-positive patients

Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy

Neurological disease

Highly active antiretroviral therapy significantly improves the prognosis of patients with HIV-associated progressive multifocal leukoencephalopathy

Prolonged survival without neurological improvement in patients with AIDS-related progressive multifocal leukoencephalopathy on potent combined antiretroviral therapy

Cidofovir in combination with HAART and survival in AIDS-associated progressive multifocal leukoencephalopathy