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: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: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...

Erythroid regeneration is an important and separate element in the engraftment process in allogeneic and autologous bone marrow transplantation (alloBMT, autoBMT). Qualitative visual reticulocyte counting has proved inadequate in the evaluation of erythropoiesis after BMT but automated flow cytometry now allows the reliable quantitation of reticulocytes even to very low levels. Reticulocyte counts and highly fluorescent reticulocyte (HFR) counts (very early reticulocytes) were estimated daily in recipients of 22 autoBMT and 14 alloBMT using a Sysmex R-1000 automated reticulocyte counter. Marrow ablation caused an immediate and rapid fall in both the reticulocyte count and the HFR. Measurable numbers of reticulocytes persisted throughout the hypoplastic period, but HFR fell to zero in the majority of both the autoBMT and alloBMT. HFR rose significantly after a median time of 14 d post-autoBMT, and 12 d post-alloBMT. Attainment of 15 x 10(9)/l reticulocytes and 0.5 x 10(9)/l HFR at day 21 post-transplant was associated with ultimate engraftment in 100% cases. Inadequate engraftment was seen in the majority of patients whose responses fell below these levels. Graft-versus-host disease was associated with a transient slight reduction in reticulocyte count. Neither episodes of infection nor blood transfusions had any significant impact on trends of reticulocytes or HFR. Automated flow cytometric reticulocyte counting has been shown to provide an accessible measure of erythroid activity which may be of predictive value in the management of patients following bone marrow transplantation.

ISIS 3521 has demonstrated anti-tumour activity in patients with relapsed low-grade NHL. There may be a potential role for this agent in combination with conventional chemotherapy for advanced low-grade lymphoma, and further trials are warranted.

Summary:We prospectively examined stool specimens for enteric viruses in 75 stem cell transplant recipients (autologous 48, allogeneic 27) to determine the frequency and significance of these infections. Only six patients (8%) had a positive isolate. Five of these were allograft recipients (18%) compared to one autograft recipient (2%) (P = 0.02). Unrelated donor BMT recipients were at the highest risk for a viral isolate (OR = 10.5). Adenovirus was the commonest isolate (four patients). One patient each had an echovirus, enterovirus and small round structured virus identified. No correlation was found between the severity of gastro-intestinal symptoms and detection of a viral pathogen. There was no correlation with GVHD or CMV status. The only risk factor identified for isolation of an enterovirus was allogeneic BMT from an unrelated donor. There was a negative correlation with PBSC grafts. All the patients infected with an enteric virus had concomitant infection with other pathogens, compared to only 18% of uninfected patients (P = 0.001). The non-relapse mortality of the infected patients was 50% and only 7% in the uninfected patients (P = 0.01, OR = 12.5), although the isolated virus was the direct cause of death in one patient only. This study indicates a low rate of enteric virus isolation in recipients of PBSC grafts, both autologous and allogeneic. However, unrelated donor BMT is associated with a higher risk of enteric virus infection and an adverse outcome. Bone Marrow Transplantation (2000) 25, 277-282.

c-myc amplification is usually associated with lymphoid malignancies and Burkitt's lymphoma in particular. We present a case of AML with c-myc amplification which was associated with homogenous staining regions (hsr) and double minutes (dmin). The administration of GCSF following induction chemotherapy resulted in a marked increase in blast numbers. The GCSF was stopped and further courses of chemotherapy given, which resulted in complete remission. The patient relapsed 7 months after diagnosis and failed to go into a second remission with reinduction therapy. We conclude that c-myc amplification is a rare event in AML, but may be associated with chemotherapy resistance and a poor prognosis, are as dmins and hsr. Growth factors should be used with caution in these patients.

Summary:Pre-emptive antiviral therapy for CMV infection following allogeneic stem cell transplantation is an effective strategy for preventing CMV disease. This entails the logistic difficulty of daily intravenous therapy with ganciclovir or foscarnet to clinically asymtomatic patients. Cidofovir (CDV) is effective against CMV in vitro and has the practical advantage of weekly administration. However, there are limited data on the pre-emptive use of CDV in CMV infections. We carried out a pilot study exploring the efficacy and toxicity of CDV as primary pre-emptive therapy for CMV infections monitored by PCR-based assays. CDV was used at 5 mg/kg with probenecid and hydration, weekly for a maximum of 4 weeks, followed by fortnightly maintenance treatment. Four patients were treated with CDV and two of them responded. Both the non-responders developed CMV disease. There was no renal toxicity noted in any of the patients, but three patients had severe vomiting and one developed uveitis, which precluded maintenance treatment in the two responders. Following failure of CDV, foscarnet was effective in controlling the CMV infection in both patients, although the infection recurred in both. Thus, larger randomised studies are required before CDV can be recommended as a primary pre-emptive therapy for post-transplant CMV infections. Bone Marrow Transplantation (2001) 28, 879-881.