Case Report Treatment of Adenovirus-Associated Haemorrhagic Cystitis with Ganciclovir

Case report Treatment of adenovirus-associated haemorrhagic cystitis with ganciclovir

FE Chen1, RHS Liang1,JYLo2, KY Yuen3, TK Chan1 and M Peiris3

1Division of Haematology, Oncology and Bone Marrow Transplantation, Department of Medicine, and 3Department of Microbiology, University of Hong Kong, Queen Mary Hospital; and 2Government Virus Unit, Department of Health, Queen Mary Hospital, Hong Kong

Summary: remission after induction chemotherapy with daunorubicin, cytarabine and etoposide. This was followed by mainte- We report a 47-year-old bone marrow transplant recipi- nance consolidation with high-dose cytarabine. The leu- ent with haemorrhagic cystitis caused by adenovirus kaemia subsequently relapsed in April 1996 but responded successfully treated with ganciclovir. This is the first to further salvage chemotherapy with MACE (mito- report on the use of ganciclovir for the successful treat- zantrone, etoposide, high-dose cytarabine, dexamethasone) ment of adenoviral infection. Shell vial culture may be and a second remission was achieved. An allogeneic related more sensitive than conventional culture in the detec- donor bone marrow transplant (BMT) was performed in tion of adenovirus in such patients. September 1996 using marrow donated by his HLA-ident- Keywords: haemorrhagic cystitis; adenovirus; ganci- ical sister. He was conditioned with busulphan (1.6 mg/kg clovir; BMT daily for 4 days), cyclophosphamide (25 mg/kg for 2 days with Mesna) and total body irradiation (2 Gy twice daily for 3 days). Graft-versus-host disease (GVHD) prophylaxis consisted of intravenous methotrexate administered on days Haemorrhagic cystitis is a relatively common complication 1, 3, 6 and 11 and cyclosporin A from day −1 onwards. following bone marrow transplantation and is often pro- The BMT proceeded uneventfully with grade II GVHD of longed and distressing for the patient. The condition is attri- the skin. He engrafted on day +12 and was discharged on buted to the effects of cyclophosphamide or to the reacti- day +36 on cyclosporin A and reducing doses of methyl- 1 vation of polyoma virus (BK) due to the immuno- prednisolone. Surveillance for CMV by PCR of peripheral compromised status of the patient. It is, however, known blood leucocytes on day +27 showed evidence of asympto- that BK virus can also be isolated in many asymptomatic matic infection and he was given pre-emptive therapy con- patients suggesting that the virus may not always be patho- sisting of ganciclovir at 5 mg/kg twice daily for 1 week genic. As there is no recognised antiviral treatment for BK followed by three times weekly doses for a further 2 weeks. virus, it is important to ensure that no other treatable aetio- On day +52 post-BMT, he was readmitted with gross logical agents are involved. We describe a patient with sev- macroscopic haematuria, severe dysuria and frequency of ere symptoms of haemorrhagic cystitis where both polyoma 20 times a day. He was commenced on hydration and virus and adenovirus were detected. The symptoms per- empirical doxycycline to cover possible chlamydial infec- sisted until the patient was treated with ganciclovir. Clinical tion but there was no improvement in his condition. Bac- improvement correlated with the clearance of adenovirus terial infection was excluded by repeated sterile cultures of from the urine suggesting that the adenovirus rather than midstream urine samples. the polyoma virus was the causative agent. The use of Viral investigations were as follows. Fresh specimens of 2–5 ganciclovir was based on studies in vitro and in animal mid-stream urine were used for shell vial culture7 and elec- 6 models demonstrating that adenoviruses are sensitive to tron microscopy. The urine specimen diluted 1:1 in virus ganciclovir. This case demonstrates that ganciclovir can transport medium was centrifuged (700 g × 45 min) on to also be effective in vivo. monolayers of human embryonic lung fibroblasts grown on coverslips, incubated for 4 days and stained for adenoviral Case report and cytomegaloviral antigen expression by indirect immunofluorescence using a mouse monoclonal antibody LCY was a 47-year-old man who presented with acute (Chemicon International, Temecula, CA, USA). Selected myeloid leukaemia in August 1995. He achieved complete specimens were also inoculated on Hep 2, Vero and human embryo lung fibroblast cell culture tubes for conventional viral culture, incubated for 21 days and observed for viral Correspondence: Dr FE Chen, Division of Haematology, Oncology and Bone Marrow Transplantation, Department of Medicine, University of cytopathic effects. Electron microscopy was carried out on Hong Kong, Queen Mary Hospital, Hong Kong the ultracentrifuged pellet obtained from 4 ml of urine after Received 14 March 1997; accepted 23 July 1997 negative staining by 3% phosphotungstic acid, pH 6–7. Adenovirus cystitis treated with ganciclovir FE Chen et al 998 Urine collected on day +54 showed evidence of adeno- antigen expression in the cells (it does not rely on complete virus by shell vial culture and by direct electron microscopy productive virus replication) may also contribute to (Table 1). In addition, electron microscopy revealed BK increased sensitivity as well as resulting in quicker result virus in the same urine specimen. Cytomegalovirus was not (4–5 days). It is possible that adenoviral haemorrhagic cys- detected by shell vial culture. Spin cytology of the urine titis may be under-recognised by relying on conventional at this stage also revealed cells with basophilic brick-like culture methods and shell vial culture may be a more appro- intranuclear inclusions in keeping with adenovirus infec- priate diagnostic approach. The use of alternative cell lines tion. These results were available by day +67, at which such as A 549 may further improve sensitivity. time the patient was recommenced on full dose ganciclovir There are previous case reports describing the successful (5 mg/kg twice daily). The urine was still positive for aden- treatment of adenoviral haemorrhagic cystitis with ribavi- ovirus by shell vial culture 3 days after starting ganciclovir rin10,11 and vidarabine.12 Ganciclovir is often used for treat- but negative after 10 days of therapy, remaining negative ment of CMV disease in bone marrow transplant recipients. thereafter. The patient’s symptoms improved rapidly within It has also been shown to have activity against a number of 3 days of starting therapy and completely resolved after 2 adenovirus serotypes in vitro2,5 although its activity against weeks of treatment (day +79). The adenovirus could not adenovirus may be lower than that against CMV. Sensi- be isolated by conventional virus culture even from urine tivity to ganciclovir of all patient isolates could not be specimens found positive by shell vial culture. determined because it was not isolated in culture. There is only one other published report documenting the successful use of ganciclovir in adenoviral disease.13 This was in a Discussion renal transplant recipient with haemorrhagic cystitis, where improvement was concurrent with a reduction in azathio- Haemorrhagic cystitis is a common complication following prine dosage as well as ganciclovir treatment. In other com- bone marrow transplantation and chemotherapy. Some of munications its use has been proposed, but not actually these cases are due to the effects of cytotoxic drugs (eg tried.3 Ganciclovir is excreted unchanged via the urine and cyclophosphamide8) while others have been attributed to drug levels in the kidney are higher than those found in the the polyoma virus BK, adenoviruses and occasionally to blood14 whereas only 32–53% of intravenous or oral ribavi- CMV. Because these viruses are sometimes found in the rin is recoverable from the urine.15 Thus, ganciclovir may urine of immunocompromised patients without cystitis, have a pharmacokinetic advantage over oral ribavirin in the establishing a causal link between virus detection and treatment of haemorrhagic cystitis which may not necessar- pathogenicity can be difficult. In our patient we believe that ily apply to adenoviral disease in other organs. Ganciclovir adenovirus was the main cause of the cystitis because the has not previously been successfully used for adenoviral clearing of the virus by antiviral therapy was associated haemorrhagic cystitis in bone marrow transplant recipients, with prompt resolution of symptoms. Detection of BK where presumably due to the more intense immunosuppres- virus, on the other hand, did not correlate with the clinical sion, this condition is usually more intractable. course and continued to be present long after resolution of the symptoms. It is known that the adenovirus serotypes with tropism Acknowledgements for the urinary tract are usually types 11, 21, 34, 35, 37 and 9–11 other as yet unidentified types. Recombinant viruses, eg We acknowledge help from Dr KH Chan and staff at the Depart- between type 35 and serotype 7, 3 or 11 have also been ment of Microbiology, Queen Mary Hospital for technical help. described. The adenovirus serotypes associated with this patient’s cystitis could not be determined because the virus failed to grow in conventional cell culture although it was References readily detectable by shell vial culture and electron microscopy. This may reflect the increased sensitivity of the shell vial culture method. This may be due to the 1 Chan PK, Ip KW, Shiu SY et al. Association between poly- omaviruria and microscopic haematuria in bone marrow trans- additional centrifugation step used in this method. Alterna- plant recipients. J Infect 1994; 29: 139–146. tively, the fact that shell vial culture only requires viral 2 Taylor DL, Jeffries DJ, Taylor-Robinson D et al. The suscepti- bility of adenovirus infection to the anti-cytomegalovirus drug, ganciclovir (DHPG). FEMS Microbiol Lett 1988; 49: Table 1 Urine results 337–341. 3 Wreghitt TG, Gray JJ, Ward KN et al. 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