Adenovirus infections occur in 5% to 21% of patients following stem cell transplantation (SCT), with an associated mortality of up to 50%. However, a lack of prospective studies has hampered further developments in the understanding and management of this infection in the posttransplantation setting. We prospectively studied the incidence and outcome of adenovirus infections after SCT using preemptive screening and a policy of reduction or withdrawal of immunosuppressive therapy if the virus was isolated. The incidence of adenovirus infection was 19.7% (15 of 76), and the virus was isolated exclusively in recipients of T-celldepleted grafts. Patients receiving 50 or 100 mg alemtuzumab in vivo were at the greatest risk of adenovirus infection (45% probability) regardless of donor type, and this was related to the slower lymphocyte recovery. Six (40%) of the 15 adenovirusinfected patients developed adenovirus disease. Severe lymphocytopenia (less than 300/L) at the time of first detection of adenovirus was a major risk factor for development of adenovirus disease (P ‫؍‬ .001). In addition, failure to reduce immunosuppression (P ‫؍‬ .04) and a positive result of adenovirus polymerase chain reaction (PCR) in blood at diagnosis (P ‫؍‬ .01) were both associated with fatal adenovirus disease. On the basis of this study, we recommend active surveillance for adenovirus infection in T-cell-depleted SCT and withdrawal or reduction of immunosuppressive treatment, if possible, in patients with adenovirus infection. Preemptive antiviral therapy is warranted for patients with severe lymphocytopenia or positive blood PCR, and in those in whom immunosuppressive therapy cannot be reduced. (Blood.

Herpes simplex virus (HSV) infections in 75 allogeneic stem cell transplant recipients were analyzed. Sixteen patients developed HSV disease following transplantation. The risk factors were age, sex (females), unrelated donor graft, and graft-versus-host disease (GVHD) grade >/=2. Seven patients did not respond to acyclovir, and 3 patients failed to respond to foscarnet. Isolates from 4 patients developed resistance to acyclovir/penciclovir, and 3 patients had foscarnet-resistant isolates. The remaining 3 patients failed to respond to acyclovir, despite having sensitive isolates. All the isolates were sensitive to cidofovir, for which the IC(50) values correlated inversely with those for acyclovir (P=.01). The risk factors for clinical resistance to antiviral drugs were a GVHD grade >/=2 (P=.001) and the lack of ganciclovir prophylaxis (P=.01), with a higher nonrelapse mortality in the latter group (P<.0001). Clinical as well as in vitro resistance to antiviral drugs is common in patients with severe GVHD and is associated with a poor outcome.

Summary:Adenovirus has been recognised as an important pathogen in BMT recipients, especially in patients with GVHD and those receiving T cell-depleted allografts. We report adenovirus infections from an ongoing surveillance study in four patients after a non-myeloablative transplant and their improved outcome following withdrawal of immunosuppression in two patients and donor lymphocyte infusion for relapsed disease in the others. We discuss the control of adenovirus infections following immune manipulations and the feasibility of adoptive immunotherapy for post-transplant adenovirus infections. Bone Marrow Transplantation (2000) 26, 305-307. Keywords: adenovirus; immunosuppression; donor lymphocyte infusion Adenovirus infections have been increasingly recognized as an important cause of morbidity and mortality in allogeneic stem cell transplant recipients.1-3 Most of the serious infections are reported in patients with GVHD or T celldepleted graft recipients.1-3 Despite its emergence as a lifethreatening pathogen treatment of adenovirus infections remains difficult. Anti-viral drugs have been used with variable results. 4 Immunotherapy has been used with success in other viral infections, 5 but has not yet been seriously explored in the context of adenovirus infections.We are currently carrying out a viral surveillance study, examining stool, urine and throat specimens from BMT recipients weekly for 6 months after transplantation. We report the effects of immunological interventions carried out after transplant for control of the primary disease on adenovirus infections in four patients from this surveillance study. Case reports Patient 1A 38-year-old female received an allogeneic stem cell transplant from a matched sibling donor in July 1998 for refractory AML. She was given pre-transplant conditioning with Campath 1H (anti-CD52 antibody), fludarabine, and melphalan with cyclosporin A as GVHD prophylaxis. She engrafted with full donor chimerism on day +16 post transplant. At the same time, adenovirus type 2 (Ad2) was identified from the stool sample on electron microscopy (EM) and culture. Although she was asymptomatic, 14 consecutive stool samples continued to grow adenovirus on culture. Polyomavirus (BK virus) was persistently identified in the urine by EM. Twelve weeks following the transplant she had early evidence of relapsed leukemia. Cyclosporin A was stopped. This was followed 1 week later by donor lymphocyte infusion (DLI) of 3 × 10 7 CD3 + cells/kg. Adenovirus was eradicated from the stool 4 weeks after the DLI and six subsequent stool specimens were negative for 5 weeks until she succumbed to progressive leukaemia 23 weeks after transplant without any evidence of GVHD. The polyomavirus was also cleared from the urine 6 weeks after the first DLI. Patient 2A 50-year-old female received an allogeneic stem cell transplant from a matched sibling donor in July 1998 because of refractory AML. She was given identical pretransplant conditioning and GVHD prophylaxis as patient 1. She engrafted on day +14 pos...

Summary:Infections with the paramyxoviruses, respiratory syncytial virus (RSV) and parainfluenza virus (PIV) can result in serious morbidity and mortality after haemopoietic stem cell transplant (HSCT). Once pneumonia develops, the outcome of these infections is often poor despite anti-viral therapy. Aerosolised ribavirin has been evaluated as pre-emptive therapy for post-transplant RSV infections with some success. Due to the financial and logistic burden involved with the use of aerosolised ribavirin, we explored the efficacy and toxicity of oral ribavirin for pre-emptive therapy of post-transplant RSV and PIV infections in a dose escalating schedule (15-60 mg/kg/day). Five episodes each of RSV and PIV were treated in seven patients. Five patients were receiving treatment for GVHD and two acquired the infection in the pre-engraftment period. All the episodes of RSV infection improved with oral ribavirin with dose escalation to 30-45 mg/kg in three of them. On the other hand, only two of the five PIV infections improved with oral ribavirin. Of the three non-responders, two infections were acquired in the pre-engraftment period with one death from PIV pneumonia. Reversible anaemia was the only side-effect noted in patients treated for over 2 weeks. Thus, the use of oral ribavirin was well tolerated in the post-transplant period with no untoward toxicities. There was a trend towards better response in RSV infections, which needs to be further explored in controlled studies. Bone Marrow Transplantation (2001) 28, 759-763.

Summary:Fulminant hepatic failure due to adenovirus infection is a rare complication following stem cell transplantation. We report this complication in an unrelated bone marrow transplant recipient 30 weeks post-transplant. Treatment with intravenous ribavirin was started within 36 h of admission, but he succumbed to unusually fulminant hepatic failure. Adenovirus type 2 was isolated from stool surveillance samples and from post-mortem liver samples. Adenovirus DNA was detected by PCR in blood and sputum samples at admission and was identified in post-mortem liver tissue by electron microscopy. Implications of the failure of ribavirin therapy are discussed. Keywords: adenovirus; bone marrow transplantation; liver failure; ribavirin Adenovirus infections have been increasingly reported in marrow transplant recipients over the past few years. [1][2][3] This is probably attributable to the increase in intensity of immunosuppression and the use of T cell depletion in unrelated donor transplants. Although effective treatment strategies have evolved for cytomegalovirus infection in stem cell transplant recipients, little progress has been made in the treatment of adenovirus infection. Ribavirin, a broad spectrum antiviral agent has often been used in adenovirus disease in stem cell transplant recipients with variable results. [4][5][6][7] We report an uncommon presentation of adenovirus infection in an unrelated bone marrow transplant recipient with failure of ribavirin therapy and briefly discuss its implications. Case reportA 44-year-old male with chronic myeloid leukaemia in chronic phase underwent bone marrow transplantation from an unrelated HLA-matched donor in August 1997. He received cyclophosphamide (120 mg/kg) and total body Correspondence: Dr DW Milligan, Clinical Haematology, Birmingham Heartlands Hospital, Birmingham, B9 5SS, UK Received 4 November 1998; accepted 17 January 1999 irradiation (1440 cGy) as the conditioning regimen, together with Campath-1G antibody (10 mg/day) from day −5 to day +4. GVHD prophylaxis was cyclosporin A and short course methotrexate. The patient also received prophylactic aciclovir, fluconazole and ciprofloxacin. He had evidence of neutrophil engraftment by day +19. Grade 2-3 acute GVHD of the skin developed and was treated with intravenous methylprednisolone (5 mg/kg) followed by oral prednisolone (100 mg/day). At his discharge on day +28 he was on tapering doses of prednisolone. During this period he had stomatitis related to herpes simplex virus which responded to valaciclovir and also an episode of respiratory illness of unproven aetiology. After initial good engraftment, there was a fall in neutrophil and platelet counts. This was associated with normal marrow cellularity. The pancytopenia was thought to be autoimmune or related to GVHD. This was treated with prednisolone, intravenous immunoglobulin, azathioprine and G-CSF with little success. Parvovirus B19 and human herpesvirus-6 infections were excluded. Recurrent herpes simplex stomatitis unresponsive to valaciclovir...

Parainfluenza virus (PIV) infection can be a problem among hematopoetic stem cell transplant recipients. 125 patients were prospectively evaluated for respiratory viral infections. We describe 5 patients with PIV 3 infection and their response to early treatment with ribavirin.

Respiratory virus infections are common and often recurrent in patients with severe CD4+ T lymphopenia. However, the mortality was low, which may have been due to early institution of antiviral treatment or reduced inflammatory damage to the lungs due to severe lymphopenia.

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