Thea BrennanKrohn BK July 2010 Polyomaviruses Small DS DNA viruses Cause poly omas Nonhuman polyomaviruses Murine K virus discovered 1952 1 Simian virus 40 SV40 ID: 597923
Download Presentation The PPT/PDF document "BK Virus" is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
Slide1
BK Virus
Thea Brennan-Krohn (“BK”)
July 2010Slide2
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]
Kilham
L.
Isolation in Suckling Mice of a Virus from C
3
H 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.Slide3
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.Slide4
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.Slide5
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. Slide6
Molecular Mechanisms
Attachement
to a
sialic acid receptorCaveolae-mediated endocytosisIntracellular trafficking by microtubulesFusion with Golgi/ERPerinuclear accumulation of virusDugan AS et al. Update on BK virus entry and intracellular trafficking. Transpl Infect Dis. 2006 Jun;8(2):62-7.Slide7
Clinical Manifestations
Asymptomatic or mild URI in
immunocompetant
hostsHemorrhagic cystitis in hematopoietic stem cell transplant recipientsAllograft nephropathy in renal transplant recipientsUnusual manifestationsSystemic 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..Slide8
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.Slide9
Diagnosis
Serum or urine PCR
Urine cytology
BiopsyElectron microscopy of biopsy or urineScreening by urine cytology or PCR recommendedEvery three months for first 2 years post transplantWith graft dysfunctionWith all biopsiesHirsch HH. Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation 2005 May 27;79(10):1277-86.Slide10
Diagnosis: Urine Cytology
Decoy Cells
http://
www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=eurekah&part=A74503Slide11
Histologic
Diagnosis
Viral Inclusions
http://www.cap.orghttp://tpis1.upmc.com:81/tpis/GU/G00011a.htmlSlide12
Diagnosis: Immunohistochemistry
http://
www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book
=eurekah&part=A74503Staining for SV40Slide13
Diagnosis: In Situ Hybridization
http://
www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book
=eurekah&part=A74503Slide14
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=A74503Slide15
Classification
PVAN A (Early)
Viral
cytopathic changes: minimal to mildInflammatory infiltrates, tubular atrophy, fibrosis: insignificantPVAN B (Florid)Viral cytopathic changes: mild to severe Inflammatory infiltrates: moderate to severeTubular atrophy, fibrosis: mildPVAN C (Advanced Sclerosing)Viral cytopathic changes: variableInflammatory infiltrates: variableTubular atrophy, fibrosis: moderate to severeHirsch HH et al. Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation. 2005 May 27;79(10):1277-86.Slide16
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 lossB3 (>50% of biopsy core affected): 78% graft lossPVAN 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.Slide17
Treatment: Adjustment of
Immunosuppression
Reduction of
immunosuppressionTacrolimus trough <6 ng/mLMMF <1 gm/dayCyclosporine A trough 100-150 ng/mLDiscontinuation of tacrolimus or MMFChange in immunosuppressionTacrolimus cyclosporine A or sirolimusMMF azathioprine, sirolimus or leflunomideHirsch HH et al. Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation. 2005 May 27;79(10):1277-86.Slide18
Treatment:
Cidofovir
Cytosine-phosphate analog, originally used for CMV retinitis in patients with AIDS
Shown to have in vitro activity against BK virusConcentrates in tubular epithelial cells and urineA 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.Slide19
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.Slide20
Other Treatment Possibilities
IVIg
CiprofloxacinSlide21
The Future
Do more studies
Invent new drugs