BK Virus infection in HSCT

Dr Chandan Krushna DasDepartment of Medical Oncology

IRCH-AIIMS

introduction

• Polyomavirus hominis 1, the BK virus:non-enveloped, encapsulated DNA Papovaviridae family

• BK virus infection early-childhood :asymptomatic or associated with fever and mild upper respiratory symptoms. Up to 90% of adults are seropositive.

• Transmission via the respiratory routeArther et al N Engl J Med. 1986 Jul 24;315(4):230-4.

BK virus infection

• BK viruria occurs in about 50% of patients after BMT, usually within 2 months of transplantation

• similar in allogeneic (range 46–53%) and autologous (range 39–54%) marrow recipients.

clinical manifestations of BK virus infection in BMT recipients

• Genitourinary tract– Hemorrhagic cystitis– Ureteral stenosis– Tubulointerstitial nephritis

• Central nervous system– Meningitis– Encephalitis– Retinitis

• Pneumonitis• Gastrointestinal infection• Disseminated infection

Pre-engraftment Post-engraftment

•Chemotherapeutic agents•Other

• Pelvic irradiation• Severe thrombocytopenia• Coagulopathy

•Infections• Polyomavirus (BK)• Cytomegalovirus• Adenovirus

•Other• Severe thrombocytopenia• Coagulopathy

Causes of hemorrhagic cystitis in BMT recipients

Cyclophosphamide, Ifosfamide Hemorrhagic cystitis

Busulfan Hemorrhagic cystitis

Thiotepa Irritation and rarely hemorrhagic cystitis

Doxorubicin Reversible hemorrhagic cystitis in 20 to 30 percent

Mitomycin Cystitis in 15 percentFludarabine Rare hemorrhagic cystitisChlorambucil Rare cases of sterile cystitis

Cabazitaxel Hemorrhagic cystitis in 17 percent; severe (grade 3 or 4) in 2 to 3 percent

Potential risk factors for BK virus-associated hemorrhagic cystitis

• Presence of pretransplant BK virus IgG antibody titer

• Type of conditioning regimen (full intensity vs reduced intensity)

• Allogeneic transplant• Type of donor (unrelated vs related)• Acute GVHD• High peak BK urine viral load or greater than 3

log increase in viral loadLeuhng et al Bone Marrow Transplant. 2002;29:509–513

Proposed steps in the pathogenesis of BK virus-associated hemorrhagic cystitis

Decoy cells in urine Sensitivity: 100%Specificity :71%

Diagnosis

• high, peaking urine viral loads (109–1010copies/ml or greater or ≥ 3 log increase from baseline

• plasma viremia > 104 copies/ml.• Biopsy of bladder epithelium and in

situ hybridization

Bone Marrow Transplant. Jan 2008; 41(1): 11–18

Treatment of hemorrhagic cystitisAntiviral agent Dose Clinical experience Proposed mechanisms of

actionFluoroquinolones Ciprofloxacin 500 mg p.o.

twice daily or 200 mg i.v.twice daily

BMT recipients had significantlylower peak urinary viral loads,likely more effective asprophylactic agent

Inhibition of helicase activityof large T antigen; modestanti-BK virus activityin vitro

Cidofovir Standard dosing regimen:5 mg/kg i.v. weekly for 2weeks, then 5 mg/kg withprobenecid every otherweekLow-dose cidofovir: 1 mg/kgi.v. weekly withoutprobenecid

≥2: 80% with clinical response;32% with resolution of viruria(qualitative PCR)clinical response 84%;virologic response 47% (at least1 log decrease in urinary viralload)

Cytosine analog that inhibitsviral DNA synthesisInhibition of DNApolymerase activity of largeT antigenModest effect on BK virusreplicationin vitro

Leflunomide Loading dose of 100 mg/dayfor 5 days; maintenance doseof 20–60 mg/day with targetblood level of 50–100 µg/ml

No hemorrhagic cystitis; treatmentof BK nephropathy in renaltransplant and refractory CMVin BMT

Interference with tyrosinekinase phosphorylation ofcellular or virally encodedproteins needed for viralreplication; modest antiviraleffect in vitro

Treatment of hemorrhagic cystitisMild hematuria1. Suprahydration2. Saline continuous bladder irrigationModerate and severe hematuria1. Alum irrigation2. Formalin instillation3. Silver nitrate instillation4. Estrogen5. Pentosan polysufate6. Phenol instillation7. Prostaglandin instillation or irrigation8. Hyperbaric oxygen9. Embolizatione. Isobutyl-2-cyanoacrylate10. Surgery

Treatment of hemorrhagic cystitis

• The fluoroquinolone antibiotics should be evaluated as a prophylactic therapy

• cidofovir and leflunomide as therapeutic agents.