Journal of Global Infectious DiseasesOfficial Publishing of INDUSEM and OPUS 12 Foundation, Inc. Users online:1083  
Print this pageEmail this pageSmall font sizeDefault font sizeIncrease font size     
Home About us Editors Ahead of Print Current Issue Archives Search Instructions Subscribe Advertise Login 

   Table of Contents     
Year : 2016  |  Volume : 8  |  Issue : 1  |  Page : 51-54
Progressive multifocal leukoencephalopathy in a lung transplant recipient: Isolation of John Cunningham (JC) virus from bronchoalveolar lavage

1 John and Doris Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA
2 Department of Pulmonary Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, OH, USA
3 Department of Infectious Diseases, Medicine Institute, Cleveland Clinic, Cleveland, OH, USA
4 Division of Thoracic Surgery and Interventional Pulmonology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

Click here for correspondence address and email

Date of Web Publication11-Feb-2016


Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by polyomavirus John Cunningham (JC) virus. We report the case of a 60-year-old woman who presented 16 months after right single lung transplant with worsening memory, behavioral problems, emotional lability, and progressive left upper extremity weakness. Magnetic resonance imaging revealed white matter changes suggestive of PML. JC virus infection was confirmed with polymerase chain reaction (PCR) from both the bronchoalveolar lavage (BAL) fluid and cerebrospinal fluid. To our knowledge, this is the first report of PCR isolation of JC virus from a BAL specimen. We also review the two additional cases in the literature that describe PML after lung transplantation. JC virus infection should be considered in the differential diagnosis of lung transplant recipients who develop neurological symptoms. BAL may have a role in the etiologic diagnosis of PML after lung transplantation.

Keywords: Acquired immunodeficiency syndrome, John Cunningham virus, lung transplant, progressive multifocal leukoencephalopathy

How to cite this article:
Panchabhai TS, Choudhary C, Isada C, Folch E, Mehta AC. Progressive multifocal leukoencephalopathy in a lung transplant recipient: Isolation of John Cunningham (JC) virus from bronchoalveolar lavage. J Global Infect Dis 2016;8:51-4

How to cite this URL:
Panchabhai TS, Choudhary C, Isada C, Folch E, Mehta AC. Progressive multifocal leukoencephalopathy in a lung transplant recipient: Isolation of John Cunningham (JC) virus from bronchoalveolar lavage. J Global Infect Dis [serial online] 2016 [cited 2022 Jun 28];8:51-4. Available from:

   Introduction Top

Progressive multifocal leukoencephalopathy (PML) has been reported just twice in lung transplant recipients, in men of ages 43 and 60 years, respectively. [1],[2] These patients' neurological symptoms included visual disturbances, confusion, apathy, memory loss, and mono- or hemiparesis. One patient was diagnosed after polymerase chain reaction (PCR) for polyomavirus John Cunningham (JC) virus in his cerebrospinal fluid (CSF); the other patient's PCR studies for JC virus were negative in CSF, but the definitive diagnosis was made after stereotactic brain biopsy. Here we report a case of isolation of JC virus from bronchoalveolar lavage (BAL) performed during bronchoscopy and confirmed after PCR was done on CSF. To our knowledge, this is the first report of JC virus causing PML that was diagnosed on BAL.

   Case report Top

A 60-year-old woman with severe chronic obstructive pulmonary disease (COPD) underwent right single lung transplantation. Sixteen months later, she presented with progressive weakness of the left arm of 2 months' duration, cognitive decline, memory and visual deficits, crying spells, and emotional lability. She was admitted to the hospital and was found to have appropriate levels of immunosuppression with tacrolimus (FK-506) and prednisone. Upon neurological examination, she was alert and oriented to person and place had a labile pseudobulbar affect, and was tearful. Her mini-mental status examination score had declined dramatically from 28/30 2 months before admission to 14/30 at the time of admission. Visual field testing revealed a right hemianopia. She also had left facial weakness and left upper extremity weakness, with a positive snout reflex suggestive of frontal release signs. T2-weighted, fluid-attenuated inversion recovery magnetic resonance imaging (MRI) of the brain showed circumscribed areas of hyperintensity in the dorsal right frontal lobe and right frontal operculum [Figure 1] and [Figure 2]. Lesions similar in appearance were also noted in the lateral left frontal and inferior left occipitotemporal region. Initially, these findings were thought to be side effects of the tacrolimus; she was therefore switched to rapamycin. CSF analysis revealed that her glucose, protein, and cell count were within normal limits. However, PCR for JC virus was positive, confirming the diagnosis of PML. She also underwent a bronchoscopy with BAL, which was also positive for JC virus by PCR. Her immunosuppression was switched from tacrolimus to rapamycin, and her steroid dose was lowered. When the diagnosis and prognosis were explained to the patient's family, they requested comfort measures and declined further intervention or immunosuppression. The patient received hospice care and died 3 weeks later from progressive respiratory failure. She had ceased taking her antirejection medications, a behavior that highlights the tremendous social and psychological effects of PML.
Figure 1: Axial T2-weighted magnetic resonance image shows progressive multifocal leukoencephalopathy with a large confluent hyperintense lesion in the left occipitotemporal region

Click here to view
Figure 2: Axial T2-weighted, fluid-attenuated inversion recovery magnetic resonance image shows progressive multifocal leukoencephalopathy with a high signal intensity lesion involving the white matter of the dorsal right frontal lobe and right frontal operculum, as well as lateral left frontal and inferior left occipitotemporal region with no mass effect

Click here to view

   Discussion Top

Astrom et al. [3] first described PML in 1958, and in 1971 Padgett et al. [4] cultured JC virus in fetal brain cells after inoculation with PML material. The virus takes its name from the initials of the patient from whom the material was recovered. JC virus of the polyoma group is the causative agent in almost all cases of PML. [4],[5] In some rare instances, polyomavirus simian vacuolating virus 40 (SV-40) has also been implicated as a cause of PML. [6] Furthermore, some viruses that share many antigens with SV-40 have been isolated from a few patients with PML and may represent another causative agent. [6],[7],[8],[9]

The prevalence of JC virus infection in the general population is ubiquitous, with seropositivity ranging from 50% in children to 90% in adults who have anti-JC virus antibodies. [10],[11] Currently, human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS) are the most common diseases associated with PML, and PML is one of the AIDS-defining illnesses described by the Centers for Disease Control and Prevention surveillance case definition. [11] Prior to the AIDS epidemic, several conditions (all characterized by immunosuppression) were associated with PML, including lymphoproliferative and myeloproliferative diseases, chronic infections or granulomatous diseases, organ transplantation, and corticosteroid-induced immunosuppression.

All currently known polyomaviruses such as JC virus, BK virus, and SV-40 are known to establish chronic latent infection in the human host and undergo reactivation when immunosuppression occurs. The latent infection has been described in the kidney, brain, and spleen. [12],[13] More recently, DNA sequences of these three viruses have been identified in peripheral blood B lymphocytes, [14] hematopoietic progenitor cells, and tonsillar stromal cells. This has significant implications for the latency theory of polyomaviruses. [15] In our case, the isolation of JC virus from BAL further supports the theory of reactivation of the disease when early infection occurs during childhood. [16] Whether the lungs are the site of latency for PML or are subsequently seeded by circulating B-lymphocytes carrying the virus remains unknown.

PML by JC virus has been described previously in two patients after lung transplantation; [1],[2] however, to our knowledge this is the first case of PML in a female COPD patient after lung transplantation. It is the first report of JC virus isolation from BAL fluid in a suspected case of PML. The neurological manifestations most commonly associated with PML in patients after solid organ transplantation are apathy, confusion, mono- or hemiparesis, visual symptoms, confusion, seizure activity, and frontal release signs. These symptoms are similar to those described in AIDS patients and in patients with other immunodeficiencies and are generally progressive with new or worsening neurological manifestations as the disease progresses. Computed tomography (CT) studies of patients with PML reveal hypodense, nonenhancing white matter changes. [17] MRI, which appears to be more sensitive than CT for detecting PML lesions, [18] is characterized by increased signal intensity on proton-density and T2-weighted images [Figure 1] and [Figure 2].

Neurological manifestations and white matter changes seen on neuroimaging studies of heart or lung transplant recipients mimic those caused by immunosuppression with cyclosporine or tacrolimus. [19] However, leukoencephalopathy associated with immunosuppression tends to occur earlier in the postoperative course, although late-onset neurotoxicity has also been reported. The clinical and neuroimaging findings are usually reversible after cessation or reduction of cyclosporine or tacrolimus. [19] Diagnosis can be made by brain tissue biopsy or by PCR of the CSF. [20],[21] On light microscopy, PML is characterized by white matter interspersed with foci of demyelination at different stages of evolution, which is caused by the cytopathic effects of JC virus on the oligodendrocytes. Light microscopy will also reveal nuclear enlargement, intranuclear basophilic accumulations, and loss of normal chromatin pattern. Notably, these lesions have minimal or no inflammation. [22] Whiteman et al. [23] found that in HIV-seropositive patients, PCR of the CSF for JC virus had a sensitivity of 72-93% and a specificity of 92-100%. PCR of the CSF is therefore accepted as a diagnostic test for PML when characteristic clinical and radiological evidence are also present. A positive PCR for JC virus in BAL fluid has not been previously reported, but it may be another diagnostic method for JC virus in lung transplant recipients who have neurological symptoms, helping avoid a brain biopsy. Whether the presence of JC virus reflects primary infection, reactivation after latent infection in the lung, or reactivation from another reservoir (e.g., the kidney) with seeding of the bloodstream and subsequent isolation in BAL remains to be determined.

Various reports have been published regarding therapeutic regimens for PML. These include modulation of the immunosuppressive regimen to minimal blood levels; discontinuation of steroids, cytarabine, and cidofovir; and highly active antiretroviral therapy with cidofovir and cytarabine in combination with interleukin-2. However, most of the evidence for these treatments is anecdotal or based only on a few case reports. To date, the only published randomized controlled trial has shown no significant benefit to cytosine arabinoside (ARA-C). [24] An open-label study of 24 HIV patients with PML showed that cidofovir, a nucleoside analog, had minimal effect. [25] Reversing the patient's immunosuppressive state is the best treatment strategy at this time, and initiation of highly active antiretroviral therapy is critical for patients with HIV or AIDS.

We treated our patient by reducing her steroid dose and switching her prescribed immunosuppressive agent from tacrolimus to rapamycin in an effort to reach whole blood trough levels of 6-8 ng/mL. She was also treated with mirtazapine, a 5HT2A receptor antagonist with antidepressant effects that efficiently cross the blood brain barrier. Vulliemoz et al. [26] demonstrated that combined treatment of ARA-C and mirtazapine may be beneficial for HIV-negative patients with PML. We decided against using cidofovir or ARA-C in our patient, however, because their efficacy is limited and their associated side effect profiles are too severe. In summary, PML should be considered in the differential diagnosis of patients presenting with neurological symptoms after heart or lung transplantation. Presently, PML is diagnosed by a positive PCR for JC virus from the CSF or by a brain biopsy. As our case shows, isolation of JC virus from the BAL fluid may also serve as a valuable diagnostic tool. Unfortunately, the outcome of PML is invariably fatal, although in some patients it has stabilized over the course of several months with immune status improvement. PML is a rare complication of lung transplantation, but with the worldwide evolution of lung and heart-lung transplantation and increasing allograft survival, clinicians should be familiar with the clinical presentation of this entity.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Ouwens JP, Haaxma-Reiche H, Verschuuren EA, Timens W, Steenhuis LH, de Boer WJ, et al. Visual symptoms after lung transplantation: A case of progressive multifocal leukoencephalopathy. Transpl Infect Dis 2000;2: 29-32.  Back to cited text no. 1
Shitrit D, Nirit L, Shiran SI, Izbicki G, Sofer D, Eldad M, et al. Progressive multifocal leukoencephalopathy in a lung transplant recipient. J Heart Lung Transplant 2003;22:946-50.  Back to cited text no. 2
Astrom KE, Mancall EL, Richardson EP Jr. Progressive multifocal leuko-encephalopathy; a hitherto unrecognized complication of chronic lymphatic leukaemia and Hodgkin′s disease. Brain 1958;81:93-111.  Back to cited text no. 3
Padgett BL, Walker DL, ZuRhein GM, Eckroade RJ, Dessel BH. Cultivation of papova-like virus from human brain with progressive multifocal leucoencephalopathy. Lancet 1971;1:1257-60.  Back to cited text no. 4
Silverman L, Rubinstein LJ. Electron microscopic observations on a case of progressive multifocal leukoencephalopathy. Acta Neuropathol 1965;5: 215-24.  Back to cited text no. 5
Weiner LP, Herndon RM, Narayan O, Johnson RT, Shah K, Rubinstein LJ, et al. Isolation of virus related to SV40 from patients with progressive multifocal leukoencephalopathy. N Engl J Med 1972;286:385-90.  Back to cited text no. 6
Penney JB Jr, Narayan O. Studies of the antigenic relationships of the new human papovaviruses by electron microscopy agglutination. Infect Immun 1973;8:299-300.  Back to cited text no. 7
Scherneck S, Geissler E, Jänisch W, Rudolph M, Vogel F, Zimmermann W. Isolation of a SV40-like virus from a patient with progressive multifocal leukoencephalopathy. Acta Virol 1981;25:191-8.  Back to cited text no. 8
Brown P, Tsai T, Gajdusek DC. Seroepidemiology of human papovaviruses. Discovery of virgin populations and some unusual patterns of antibody prevalence among remote peoples of the world. Am J Epidemiol 1975;102:331-40.  Back to cited text no. 9
Walker DL, Padgett BL. The epidemiology of human polyomaviruses. Prog Clin Biol Res 1983;105:99-106.  Back to cited text no. 10
Centers for Disease Control and Prevention. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Morb Mortal Wkly Rep 1992;41:1-20.  Back to cited text no. 11
Butel JS, Lednicky JA. Cell and molecular biology of simian virus 40: Implications for human infections and disease. J Natl Cancer Inst 1999;91:119-34.  Back to cited text no. 12
Lednicky JA, Arrington AS, Stewart AR, Dai XM, Wong C, Jafar S, et al. Natural isolates of simian virus 40 from immunocompromised monkeys display extensive genetic heterogeneity: New implications for polyomavirus disease. J Virol 1998;72:3980-90.  Back to cited text no. 13
Azzi A, De Santis R, Ciappi S, Leoncini F, Sterrantino G, Marino N, et al. Human polyomaviruses DNA detection in peripheral blood leukocytes from immunocompetent and immunocompromised individuals. J Neurovirol 1996;2:411-6.  Back to cited text no. 14
Monaco MC, Atwood WJ, Gravell M, Tornatore CS, Major EO. JC virus infection of hematopoietic progenitor cells, primary B lymphocytes, and tonsillar stromal cells: Implications for viral latency. J Virol 1996;70:7004-12.  Back to cited text no. 15
Padgett BL, Walker DL. Prevalence of antibodies in human sera against JC virus, an isolate from a case of progressive multifocal leukoencephalopathy. J Infect Dis 1973;127:467-70.  Back to cited text no. 16
Krupp LB, Lipton RB, Swerdlow ML, Leeds NE, Llena J. Progressive multifocal leukoencephalopathy: Clinical and radiographic features. Ann Neurol 1985;17:344-9.  Back to cited text no. 17
Ciricillo SF, Rosenblum ML. Use of CT and MR imaging to distinguish intracranial lesions and to define the need for biopsy in AIDS patients. J Neurosurg 1990;73:720-4.  Back to cited text no. 18
Mark AS, Atlas SW. Progressive multifocal leukoencephalopathy in patients with AIDS: Appearance on MR images. Radiology 1989;173:517-20.  Back to cited text no. 19
Antinori A, Ammassari A, De Luca A, Cingolani A, Murri R, Scoppettuolo G, et al. Diagnosis of AIDS-related focal brain lesions: A decision-making analysis based on clinical and neuroradiologic characteristics combined with polymerase chain reaction assays in CSF. Neurology 1997;48:687-94.  Back to cited text no. 20
Richardson EP Jr. Progressive multifocal leukoencephalopathy. N Engl J Med 1961;265:815-23.  Back to cited text no. 21
Kwak EJ, Vilchez RA, Randhawa P, Shapiro R, Butel JS, Kusne S. Pathogenesis and management of polyomavirus infection in transplant recipients. Clin Infect Dis 2002;35:1081-7.  Back to cited text no. 22
Whiteman ML, Post MJ, Berger JR, Tate LG, Bell MD, Limonte LP. Progressive multifocal leukoencephalopathy in 47 HIV-seropositive patients: Neuroimaging with clinical and pathologic correlation. Radiology 1993;187:233-40.  Back to cited text no. 23
Hall CD, Dafni U, Simpson D, Clifford D, Wetherill PE, Cohen B, et al. Failure of cytarabine in progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. AIDS Clinical Trials Group 243 Team. N Engl J Med 1998;338:1345-51.  Back to cited text no. 24
Marra CM, Rajicic N, Barker DE, Cohen BA, Clifford D, Donovan Post MJ, et al. A pilot study of cidofovir for progressive multifocal leukoencephalopathy in AIDS. AIDS 2002;16:1791-7.  Back to cited text no. 25
Vulliemoz S, Lurati-Ruiz F, Borruat FX, Delavelle J, Koralnik IJ, Kuntzer T, et al. Favourable outcome of progressive multifocal leucoencephalopathy in two patients with dermatomyositis. J Neurol Neurosurg Psychiatry 2006;77:1079-82.  Back to cited text no. 26

Correspondence Address:
Atul C Mehta
Department of Pulmonary Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, OH
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0974-777X.176150

Rights and Permissions


  [Figure 1], [Figure 2]

This article has been cited by
1 Progressive multifocal leukoencephalopathy in a lung transplant recipient presenting with memory impairment: Case report and literature review
Thomas Crowhurst, Barbara Koszyca, Mark Holmes, Chien-Li Holmes-Liew
Transplant Infectious Disease. 2020; 22(3)
[Pubmed] | [DOI]


    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Email Alert *
    Add to My List *
* Registration required (free)  

   Case report
    Article Figures

 Article Access Statistics
    PDF Downloaded56    
    Comments [Add]    
    Cited by others 1    

Recommend this journal

Sitemap | What's New | Feedback | Copyright and Disclaimer | Privacy Notice | Contact Us
2008 Journal of Global Infectious Diseases | Published by Wolters Kluwer - Medknow
Online since 10th December, 2008