BK Virus
Thea Brennan-Krohn (“BK”)
July 2010
Polyomaviruses
• Small DS DNA viruses
• Cause “poly” “omas”
• Non-human polyomaviruses:
– Murine K virus, discovered 1952 [1]
– Simian virus 40 (SV40)
• Human polyomaviruses:
– BK virus (named for the patient’s initials): isolated in 1971 from the urine of a
renal allograft recipient with ureteric obstruction [2]
– JC virus (also named for the patient’s initials): cultivated in 1971 from the
brain of a patient with progressive multifocal leukoencephalopathy in the
context of Hodgkin's disease [3]
– KI virus (“Karolinska Institutet”): identified 2007 using large-scale molecular
virus screening method to identify unrecognized human pathogens. [4]
– WU virus (“Washington University”): identified 2007 from respiratory
secretions of patients with URI symptoms. [5]
– MCV virus: found in Merkel cell carcinomas in 2008 [6]
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2.
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6.
Kilham L. Isolation in Suckling Mice of a Virus from C3H Mice Harboring Bittner Milk Agent Science 1952; 116:391
Gardner SD. New human papovavirus (B.K.) isolated from urine after renal transplantation. Lancet. 1971 Jun 19;1(7712):1253-7.
Padgett BL et al. Cultivation of papova-like virus from human brain with progressive multifocal leucoencephalopathy. Lancet. 1971 Jun 19;1(7712):1257-60
Allander T et al. Identification of a third human polyomavirus. J Virol. 2007 Apr;81(8):4130-6.
Gaynor AM et al. Identification of a novel polyomavirus from patients with acute respiratory tract infections. PLoS Pathog. 2007 May 4;3(5):e64.
Feng H et al. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science. 2008 Feb 22;319(5866):1096-100.
Naming Viruses After Patients:
A HIPAA Violation?
• “James Delany, a man about 50… had an
umbilical hernia… Eight days before
admission, in struggling to hold a pig, he felt
something give way at the tumour…”
• Plan: “give as much beef-tea and brandy-andwater as he can take, and throw up an enema
daily of strained gruel and milk.”
From Umbilical Hernia; Sloughing of Four Inches of the Small Intestines; Complete
Recovery Br Med J. 1865 July 15; 2(237): 33–35.
Epidemiology
• Seroprevalence peaks at 91% in children 5-9
• Overall seropositivity 81%. Antibody titers decrease
with age.
• Mode of transmission uncertain; may be respiratory.
• Virus can persist in kidney and urinary tract.
– BKV DNA can be found in 30 to 50% of normal kidneys and
40% of ureters, primarily in epithelial cells.
– In one study, BK viruria was present in 13.5% of normal
subjects, 33.3% with renal disease (not translplant
recipients), and 55.6% with renal disease and steroid tx. [1]
[1] Kaneko T et al. Prevalence of human polyoma virus (BK virus and JC virus) infection in patients with chronic renal disease. Clin Exp Nephrol. 2005 Jun;9(2):132-7.\
Knowles WA et al. Population-based study of antibody to the human polyomaviruses BKV and JCV and the simian polyomavirus SV40. J Med Virol. 2003
Sep;71(1):115-23.
Reploeg MD et al. BK Virus: A Clinical Review. Clin Infect Dis. 2001 Jul 15;33(2):191-202.
The Virus
• Small, nonenveloped, double-stranded DNA
icosahedral virions.
• Three structural capsid proteins and three
non-capsid regulatory proteins: large Tantigen, small t-antigen, and agnoprotein.
White MK; Khalili K. Polyomaviruses and human cancer: molecular mechanisms underlying patterns of
tumorigenesis. Virology. 2004 Jun 20;324(1):1-16.
Jiang M et al. The role of polyomaviruses in human disease. Virology. 2009 Feb 20;384(2):266-73.
Molecular Mechanisms
Attachement to a sialic acid receptor
Caveolae-mediated endocytosis
Intracellular trafficking by microtubules
Fusion with Golgi/ER
Perinuclear accumulation of virus
Dugan AS et al. Update on BK virus entry and intracellular trafficking. Transpl Infect Dis. 2006 Jun;8(2):62-7.
Clinical Manifestations
• Asymptomatic or mild URI in immunocompetant hosts
• Hemorrhagic cystitis in hematopoietic stem cell
transplant recipients
• Allograft nephropathy in renal transplant recipients
• Unusual manifestations
– Systemic vasculopathy  widespread capillary leakage,
MI, death.[1]
– Disseminated infection [2,3]
– Retinitis [4,5]
– Interstitial pneumonia [6]
– Ulcers of the colon [7]
[1] Petrogiannis-Haliotis T et al. BK-related polyomavirus vasculopathy in a renal-transplant recipient. N Engl J Med 2001; 345:1250.
[2] Rosen S et al. Tubulo-interstitial nephritis associated with polyomavirus (BK type) infection. N Engl J Med 1983; 308:1192-6.
[3] Vallbracht A et al. Disseminated BK type polyomavirus infection in an AIDS patient associated with central nervous system disease. Am J Pathol 1993;143:29-39.
[4] Bratt G et al. BK virus as the cause of meningoencephalitis, retinitis and nephritis in a patient with AIDS. AIDS 1999;13:1071-5. 12.
[5] Hedquist BG et al. Identification of BK virus in a patient with acquired immune deficiency syndrome and bilateral atypical retinitis. Ophthalmology 1999;106:129-32.
[6] Sandler ES et al. BK papova virus pneumonia following hematopoietic stem cell transplantation. Bone Marrow Transplant 1997;20:163-5
[7] Kim, GY et al. BK virus colonic ulcerations. Clin Gastroenterol Hepatol 2004; 2:175..
Polyomavirus Allograft Nephropathy
• Prevalence among RT recipients ~10%.
• Higher risk with greater immunosuppression.
• ATG for rejection (but not for induction) with
ProGraf/CellCept/steroid therapy associated
with virus replication.
Hirsch HH, Knowles W, Dickenmann M, et al. Prospective study of polyomavirus type BK replication and
nephropathy in renal-transplant recipients. N Engl J Med 2002; 347: 488.
Diagnosis
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Serum or urine PCR
Urine cytology
Biopsy
Electron microscopy of biopsy or urine
Screening by urine cytology or PCR
recommended
– Every three months for first 2 years post transplant
– With graft dysfunction
– With all biopsies
Hirsch HH. Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and
recommendations. Transplantation 2005 May 27;79(10):1277-86.
Diagnosis: Urine Cytology
Decoy Cells
http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=eurekah&part=A74503
Histologic Diagnosis
Viral Inclusions
http://www.cap.org
http://tpis1.upmc.com:81/tpis/GU/G00011a.html
Diagnosis: Immunohistochemistry
Staining for SV40
http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=eurekah&part=A74503
Diagnosis: In Situ Hybridization
http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=eurekah&part=A74503
Diagnosis: Electron Microscopy
A) Free viral particles (~45 nm
diameter) shed in the urine.
B) Polyoma Allograft Nephropathy:
3D, cast-like polyomavirus
aggregates (‘Haufen’) in urine are
diagnostic of intra-renal disease.
http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=eurekah&part=A74503
Classification
• PVAN A (Early)
– Viral cytopathic changes: minimal to mild
– Inflammatory infiltrates, tubular atrophy, fibrosis:
insignificant
• PVAN B (Florid)
– Viral cytopathic changes: mild to severe
– Inflammatory infiltrates: moderate to severe
– Tubular atrophy, fibrosis: mild
• PVAN C (Advanced Sclerosing)
– Viral cytopathic changes: variable
– Inflammatory infiltrates: variable
– Tubular atrophy, fibrosis: moderate to severe
Hirsch HH et al. Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary
analyses and recommendations. Transplantation. 2005 May 27;79(10):1277-86.
Prognosis
• PVAN A (Early): 13% graft loss
• PVAN B (Florid)
– B1 (<25% of biopsy core affected): 40% graft loss
– B2 (25-50% of biopsy core affected): 56% graft loss
– B3 (>50% of biopsy core affected): 78% graft loss
• PVAN C (Advanced Sclerosing): 100% graft loss
(3/3 cases)
Drachenberg CB et al. Histological patterns of polyomavirus nephropathy: correlation with graft
outcome and viral load. Am J Transplant. 2004 Dec;4(12):2082-92.
Treatment: Adjustment of Immunosuppression
• Reduction of immunosuppression
– Tacrolimus trough <6 ng/mL
– MMF <1 gm/day
– Cyclosporine A trough 100-150 ng/mL
– Discontinuation of tacrolimus or MMF
• Change in immunosuppression
– Tacrolimus  cyclosporine A or sirolimus
– MMF  azathioprine, sirolimus or leflunomide
Hirsch HH et al. Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary
analyses and recommendations. Transplantation. 2005 May 27;79(10):1277-86.
Treatment: Cidofovir
• Cytosine-phosphate analog, originally used for
CMV retinitis in patients with AIDS
• Shown to have in vitro activity against BK virus
• Concentrates in tubular epithelial cells and urine
• A few studies have shown improvement in
patients treated with cidofovir, but no RCTs.[1-3]
– In one study patients treated with cidofovir had no
decline in BKV and had decreased renal function
compared to those not treated.[4]
• 0.25– 0.33 mg/kg IV q2–3 weeks (10–20% of the
CMV dose) without probenicid.[5]
[1] Vats A, Shapiro R, Singh RP, et al. Quantitative viral load monitoring and cidofovir therapy for the management of BK virus-associated nephropathy in children
and adults. Transplantation 2003; 75: 105.
[2] Kadambi PV, Josephson MA, Williams J, et al. Treatment of refractory BK virus-associated nephropathy with cidofovir. Am J Transplant 2003; 3: 186.
[3] Vats A, Shapiro R, Randhawa PS, et al. BK Virus associated nephropathy and cidofovir: long term experience. Am J Transplantation 2003; 3: 190 (Abstract #148).
[4]Pallet N. Cidofovir may be deleterious in BK virus-associated nephropathy. Transplantation. 2010 Jun 27;89(12):1542-4.
[5] Hirsch HH et al. Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation. 2005 May
27;79(10):1277-86.
Treatment: Leflunomide
• A disease-modifying anti-rheumatic drug
• In one study, 12/13 patients treated by
exchanging leflunomide for MMF and lowering
the trough level of the calcineurin-inhibitor
cleared the virus.[1]
• In another study 5/12 pts treated by exchanging
leflunomide for MMF and decreasing
immunosuppresion cleared the virus.[2]
[1] Teschner S et al. Leflunomide therapy for polyomavirus-induced allograft nephropathy: efficient BK
virus elimination without increased risk of rejection. Transplant Proc. 2009 Jul-Aug;41(6):2533-8.
[2] Faguer S. Leflunomide treatment for polyomavirus BK-associated nephropathy after kidney
transplantation. Transpl Int. 2007 Nov;20(11):962-9. Epub 2007 Jul 30.
Johnston O et al. Treatment of polyomavirus infection in kidney transplant recipients: a systematic
review. Transplantation. 2010 May 15;89(9):1057-70.
Other Treatment Possibilities
• IVIg
• Ciprofloxacin
The Future
• Do more studies
• Invent new drugs