General Characteristics and Epidemiology
- Family: Polyomaviridae
- Genus: Betapolyomavirus
- Human polyomavirus 1: BK virus (BKV)
- Human polyomavirus 2: JC virus (JCV)
BKV and JCV share similar characteristics:
- DNA viruses:
- Double stranded
- BKV-associated nephropathy
- Ureteral stenosis
- Hemorrhagic cystitis
- JCV: progressive multifocal leukoencephalopathy (PML)
- Much of the epidemiology of BKV and JCV in the general population is unknown:
- Source of infectious virus
- Mode of transmission
- Seroprevalence in the United States and Europe: 30%–90%
- Asymptomatic viruria is detectable in 10%–30% of healthy individuals.
- Clinical manifestations are rare.
Humans are the natural host for JCV and BKV.
- The methods of transmission are poorly understood for both BKV and JVC.
- Possible routes:
- Donor tissue
Host risk factors
The clinical disease most often arises from reactivation of the virus in immunocompromised patients:
- HIV/AIDS (PML is considered an AIDS-defining condition)
- Organ transplantation
- Hematopoietic cell transplantation (HCT)
- Hematologic malignancies
- The primary infection leads to a subclinical, lifelong persistence in host tissue.
- Once inside the cell, the virus travels to the nucleus and establishes a latent or lytic infection.
- Infection is controlled by antibodies and cytotoxic T cells.
- Failure of the immune response → reactivation
- Establishes latency (mainly in the kidneys and lymphoid tissue)
- Reactivation → replication and production of neurotropic variants
- Can cross the blood-brain barrier → lytic replication in oligodendrocytes → demyelination → PML
- Latency in kidneys
- Reactivation → ↑ replication → damage to renal tubular and uroepithelial cells and inflammatory infiltration
- Interstitial inflammation → fibrosis and tubular injury
- Most patients are asymptomatic.
- Others may have a mild respiratory illness.
- Occurs in immunosuppressed patients
- BKV-associated nephropathy (more common in renal-transplant patients):
- Acute kidney injury
- Hematuria, pyuria, and cell casts
- Can result in kidney-allograft dysfunction or loss
- Ureteral stenosis:
- Urinary tract obstruction
- Acute kidney injury
- Hemorrhagic cystitis (more common in HCT recipients):
- Lower abdominal pain
- Acute kidney injury (secondary to obstruction)
PML is a progressive (and often fatal) condition most commonly seen in patients with AIDS with a CD4 count < 200 cells/µL.
- Hemiparesis (most common finding)
- Aphasia and dysarthria
- Hemianopia or diplopia
- Gait ataxia
- Cognitive impairment
- Impaired vigilance
- Seizures (rare)
Diagnosis and Management
- Plasma-quantitative PCR for BKV DNA:
- Preferred screening test
- Perform in all renal transplant patients.
- Urine cytology for identification of infected cells
- Renal allograft biopsy:
- The gold standard for diagnosis
- Immunohistochemistry can be used to detect BKV antigens.
- Intranuclear, basophilic viral inclusions
- Variation in size of cell nuclei or hyperchromasia (indicates nuclear injury)
- Tubular injury with interstitial, inflammatory cell infiltrates
- Tubulitis (lymphocytes in the tubular basement membrane)
- CT or MRI of the brain:
- Disseminated, nonenhancing, white-matter lesions (indicates demyelination)
- Do not conform to cerebrovascular territories
- No mass effect
- Lumbar puncture with CSF analysis: PCR for JCV DNA (preferred)
- Brain biopsy:
- Considered if PCR is negative but suspicion remains high
- Abnormal astrocytes
- Enlarged oligodendroglial nuclei
- Usually, no inflammatory infiltrates
No specific therapies are available for BKV or JCV. Management is generally aimed at reducing immunosuppression.
- Reduce immunosuppressive therapy (when possible)
- Antiretroviral therapy for HIV/AIDS
- Supportive care
- CNS lymphoma: a malignancy associated with Epstein-Barr infection, which can occur in patients with AIDS with a CD4 count < 50 cells/µL. Patients may have headaches, confusion, focal neurologic deficits, seizures, and constitutional symptoms. Brain imaging, CSF studies for cytology and PCR, and brain biopsy can provide the diagnosis. Management includes antiretroviral therapy and chemotherapy.
- HIV-associated dementia: a condition in patients with AIDS with a CD4 count < 200 cells/µL. Patients present with memory loss, poor executive functioning, behavior and mood changes, and gradual loss of motor skills. MRI may show diffuse, patchy, white-matter hyperintensities. Analysis of CSF should rule out other causes, such as PML and lymphoma. Management includes antiretroviral therapy and supportive measures.
- Multiple sclerosis (MS): a chronic, inflammatory autoimmune disease leading to demyelination of the CNS. The clinical presentation may include neurological symptoms, which affect vision, motor functions, sensation, and autonomic function. Presentation varies depending on the site of the lesions. Diagnosis is made with MRI imaging of the brain and spine, as well as CSF examination. Management involves corticosteroids for acute exacerbations and disease-modifying agents to slow the progression of the disease.
- Cytomegalovirus: a ubiquitous, double-stranded DNA virus belonging to the Herpesviridae family. The initial infection is usually asymptomatic in the immunocompetent host. However, reactivation can occur in immunosuppressed patients, causing a host of manifestations such as colitis, hepatitis, pneumonitis, meningoencephalitis, and nephritis. Diagnosis can be confirmed with PCR or biopsy. Management includes antivirals and a decrease in immunosuppressive therapy.
- Stolt A, Sasnauskas K, Koskela P, Lehtinen M, Dillner J. (2003). Seroepidemiology of the human polyomaviruses. J Gen Virol; 84(Pt 6):1499–1504. https://pubmed.ncbi.nlm.nih.gov/12771419/
- Zanotto E, Allesina A, Barreca A, Sidoti F, Gallo E, Bottino P, Iannaccone M, Bianco G, Biancone L, Cavallo R, Costa C. (2020). Renal Allograft Biopsies with Polyomavirus BK Nephropathy: Turin Transplant Center, 2015–19. Viruses; 12(9):1047. https://www.mdpi.com/1999-4915/12/9/1047
- Tan CS, Koralnik IJ. (2010). Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol; 9(4):425–37. https://pubmed.ncbi.nlm.nih.gov/20298966/
- Iacobaeus E, Burkill S, Bahmanyar S, Hakim R, Byström C, Fored M. Olsson T, Brundin L, Montgomery S. (2018). The national incidence of PML in Sweden, 1988-2013. Neurology; 90(6):e498–e506. https://pubmed.ncbi.nlm.nih.gov/29321229/
- Tan K, Roda R, Ostrow L, McArthur J, Nath A. (2009). PML-IRIS in patients with HIV infection: clinical manifestations and treatment with steroids. Neurology; 72(17):1458–64. https://pubmed.ncbi.nlm.nih.gov/19129505/
- Kleinschmidt-DeMasters BK, Tyler KL. (2005). Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med; 353(4):369–74. https://pubmed.ncbi.nlm.nih.gov/15947079/
- Carson KR, Evens AM, Richey EA, Habermann TM, Focosi D, Seymour JF, Laubach J, Bawn SD, Gordon LI, Winter JN, Furman RR, Vose JM, Zelenetz AD, Mamtani R, Raisch DW, Dorshimer GW, Rosen ST, Muro K, Gottardi-Littell NR, Talley R., Sartor O, Green D, Major EO, Bennett CL. (2009). Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood; 113(20):4834–40. https://pubmed.ncbi.nlm.nih.gov/19264918/
- Gómez-Cibeira E, Ivanovic-Barbeito Y, Gutiérrez-Martínez E, Morales E, Abradelo M, Hilario A, Ramos A, Ruiz-Morales J, Villarejo-Galende A. (2006). Eculizumab-related progressive multifocal leukoencephalopathy. Neurology; 86(4):399–400. https://pubmed.ncbi.nlm.nih.gov/26718572/
- Harypursat V, Zhou Y, Tang S, Chen Y. (2020). JC Polyomavirus, progressive multifocal leukoencephalopathy, and immune reconstitution inflammatory syndrome: a review. AIDS Res Ther; 17(1):37. https://pubmed.ncbi.nlm.nih.gov/32631361/
- Jensen PN, Major EO. (2001). A classification scheme for human polyomavirus JCV variants based on the nucleotide sequence of the non-coding regulatory region. J Neurovirol; 7(4):280–7. https://pubmed.ncbi.nlm.nih.gov/11517403/
- Weber F, Goldmann C, Krämer M, Kaup FJ, Pickhardt M, Young P, Petry H, Weber T, Lüke W. (2001). Cellular and humoral immune response in progressive multifocal leukoencephalopathy. Ann Neurol; 49(5):636–42. https://pubmed.ncbi.nlm.nih.gov/11357954/
- Bohra C, Sokol L, Dalia S. (2017). Progressive Multifocal Leukoencephalopathy and Monoclonal Antibodies: A Review. Cancer Control. 24 (4): 1073274817729901. https://pubmed.ncbi.nlm.nih.gov/28975841/
- Kartau M, Sipilä JO, Auvinen E, Palomäki M, Verkkoniemi-Ahola A. (2019). Progressive Multifocal Leukoencephalopathy: Current Insights. Degenerative Neurological and Neuromuscular Disease. 9: 109–121. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896915/
- Greenlee, JE. (2020). Progressive multifocal leukoencephalopathy (PML). MSD Manual Professional Version. Retrieved June 18, 2021, from https://www.msdmanuals.com/professional/neurologic-disorders/brain-infections/progressive-multifocal-leukoencephalopathy-pml
- Hirsch, HH. (2019). Overview of JC polyomavirus, BK polyomavirus, and other polyovavirus infections. In Bond, S. (Ed.), UpToDate. Retrieved June 18, 2021, from https://www.uptodate.com/contents/overview-of-jc-polyomavirus-bk-polyomavirus-and-other-polyomavirus-infections
- Hirsche, HH. (2019). Virology, epidemiology, and pathogenesis of JC polyomavirus, BK polyomavirus, and other human polyomaviruses. In Bond, S. (Ed.), UpToDate. Retrieved June 18, 2021, from https://www.uptodate.com/contents/virology-epidemiology-and-pathogenesis-of-jc-polyomavirus-bk-polyomavirus-and-other-human-polyomaviruses
- Koralnik, IJ. (2020). Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis. In Dasche, JF. (Ed.), UpToDate. Retrieved June 18, 2021, from https://www.uptodate.com/contents/progressive-multifocal-leukoencephalopathy-pml-epidemiology-clinical-manifestations-and-diagnosis