1 / 21

BK Virus

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 :

elroy
Download Presentation

BK Virus

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. BK Virus Thea Brennan-Krohn (“BK”) July 2010

  2. 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 uretericobstruction [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 (“KarolinskaInstitutet”): 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] • 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. PLoSPathog. 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.

  3. 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.

  4. 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.

  5. The Virus • Small, nonenveloped, double-stranded DNA icosahedralvirions. • 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.

  6. 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.

  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 polyomavirusvasculopathy 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 Pathol1993;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. ClinGastroenterolHepatol2004; 2:175..

  8. 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.

  9. 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.

  10. Diagnosis: Urine Cytology Decoy Cells http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=eurekah&part=A74503

  11. Histologic Diagnosis Viral Inclusions http://www.cap.org http://tpis1.upmc.com:81/tpis/GU/G00011a.html

  12. Diagnosis: Immunohistochemistry Staining for SV40 http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=eurekah&part=A74503

  13. Diagnosis: In Situ Hybridization http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=eurekah&part=A74503

  14. 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

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. Other Treatment Possibilities • IVIg • Ciprofloxacin

  21. The Future • Do more studies • Invent new drugs

More Related