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]1. Kilham L.  Isolation in Suckling Mice of a Virus from C3H Mice Harboring Bittner Milk Agent Science 1952; 116:3912. Gardner SD. New human papovavirus (B.K.) isolated from urine after renal transplantation. Lancet. 1971 Jun 19;1(7712):1253-7.3. Padgett BL et al. Cultivation of papova-like virus from human brain with progressive multifocal leucoencephalopathy. Lancet. 1971 Jun 19;1(7712):1257-604. Allander T et al. Identification of a third human polyomavirus. J Virol. 2007 Apr;81(8):4130-6.5. Gaynor AM et al. Identification of a novel polyomavirus from patients with acute respiratory tract infections. PLoS Pathog. 2007 May 4;3(5):e64.6. 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-and-water 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 T-antigen, 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

• 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 Inclusionshttp://www.cap.orghttp://tpis1.upmc.com:81/tpis/GU/G00011a.html

Diagnosis: Immunohistochemistry

http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=eurekah&part=A74503

Staining for SV40

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