Suparno Chakrabarti

Resistance to Antiviral Drugs in Herpes Simplex Virus Infections among Allogeneic Stem Cell Transplant Recipients: Risk Factors and Prognostic Significance

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.

Adenovirus infections following haematopoietic cell transplantation: is there a role for adoptive immunotherapy?

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.

Fulminant adenovirus hepatitis following unrelated bone marrow transplantation: failure of intravenous ribavirin therapy

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.

Respiratory virus infections in transplant recipients after reduced‐intensity conditioning with Campath‐1H: high incidence but low mortality

Summary. Respiratory virus infections can cause serious morbidity and mortality after conventional allogeneic stem cell transplantation. However, the incidence and outcome of these infections after reduced intensity conditioning has not been reported. Between 1997 and 2001, 35 episodes of respiratory virus infections were noted in 25 of 83 transplant recipients conditioned with fludarabine, melphalan and Campath‐1H, and 80% of them received early antiviral therapy. Parainfluenza virus (PIV) 3 was the commonest isolate (45·7%) followed by respiratory syncytial virus (37%). Patients with myeloma were more susceptible to these infections [odds ratio (OR) 4·1, P = 0·01] which were often recurrent in patients with severe acute or chronic graft‐versus‐host disease (GVHD) (OR 10·6, P = 0·03). Infection within the first 100 d (OR 5·0, P = 0·05) and PIV 3 (OR 9·2, P = 0·01) isolation were risk factors for developing lower respiratory infection. Although more than half of the episodes progressed to lower respiratory infection, the mortality was only 8%. This could have been due to early initiation of antiviral therapy, but the attenuation of pulmonary damage due to the reduced‐intensity conditioning, low incidence of GVHD and, paradoxically, the low CD4+ T‐cell subset in this setting might also have been contributory factors.

Adenovirus infections in stem cell transplant recipients: recent developments in understanding of pathogenesis, diagnosis and management.

Adenovirus is increasingly recognized as an important pathogen in stem cell transplant recipients, reflecting increased awareness about the virus, together with changes in transplant practice such as the performance of more high-risk transplants, and improvements in diagnostic methods. In retrospective studies, the reported incidence of adenovirus infections ranged between 4-20% with a similar variation in the proportion of patients developing invasive disease. In contrast, the incidence of adenovirus infection varies between 20-30% in recent prospective studies on T-cell depleted or mismatched allografts and about 30-40% of these patients develop invasive disease. These prospective studies have established a relationship between the risk of invasive adenovirus disease and a number of factors such as the extent of T-cell depletion, the intensity of immunosuppressive therapy and the kinetics of lymphocyte recovery post-transplant. Polymerase chain reaction (PCR) assays to detect adenovirus DNA in peripheral blood have shown a strong correlation between viremia and the risk of disseminated adenovirus disease. These developments have led to the possibility of a preemptive antiviral treatment strategy for asymptomatic adenovirus infections. In addition, a better understanding of the interactions between adenovirus and host immune system in the post-transplant setting might enable development of effective immunotherapeutic strategies against adenovirus infections.

T‐cell depletion with Campath‐1H ‘in the bag’ for matched related allogeneic peripheral blood stem cell transplantation is associated with reduced graft‐versus‐host disease, rapid immune constitution and improved survival

Summary. We studied the outcome of 24 peripheral blood stem cell (PBSC) graft recipients, who were T‐cell depleted (TCD) with either 20 mg (n = 14) or 10 mg (n = 10) Campath‐1H in vitro, in comparison with a retrospective cohort of 23 unmanipulated (UM) PBSC recipients. While the neutrophil engraftment was similar, the platelet engraftment occurred earlier in the TCD group (d 11 vs 14). The incidence of acute and chronic graft‐versus‐host‐disease (GVHD) was 8·7% and 4·4% in the TCD group, respectively, compared with 47·7% and 56·3% in UM group (P < 0·001). In the TCD group, 5/6 chronic myeloid leukaemia (CML) and 4/18 non‐CML patients relapsed (vs 0/6 and 3/17 in UM group, P = 0·06). All four molecular or cytogenetic relapses of CML were disease‐free survivors following donor lymphocyte infusion. There was no difference in the incidence of serious infection between the TCD and UM groups and the lymphocyte recovery at 100 d was comparable. In the TCD cohort, the lymphocyte recovery was quicker in the 10 mg Campath‐1H group. The non‐relapse mortality (19·1%vs 66·3%) and 3 year survival (73·1 vs 19·2) were improved in the TCD group (P = 0·05). Thus elimination of late mortalities related to chronic GVHD and a rapid immune reconstitution, limiting either infection or relapse related deaths, contributed to an improved outcome following T‐cell depletion with Campath‐1H ‘in the bag’.

Pre-emptive oral ribavirin therapy of paramyxovirus infections after haematopoietic stem cell transplantation: a pilot study.

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.

Respiratory virus infections in adult T cell-depleted transplant recipients: the role of cellular immunity.

BACKGROUND Little is known about the role of cellular immunity in respiratory virus infections after bone marrow transplantation. METHODS Forty allograft recipients T-cell depleted with Campath antibodies were evaluated for respiratory virus infections in an active surveillance program with early initiation of antiviral therapy. RESULTS Eighteen episodes of respiratory virus infection were detected in nine patients (22%) at a median of 95 days, with lower respiratory involvement in 44%. Fourteen episodes were treated with antiviral therapy for 7 to 46 days, with 11% mortality. Respiratory virus infections were more common in patients receiving Campath 100 mg in vivo, but delayed CD4+ recovery was the most significant risk factor. CONCLUSIONS 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.

Isolation of viruses from stools in stem cell transplant recipients: a prospective surveillance study.

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.

Will Mixed Chimerism Cure Autoimmune Diseases After A Nonmyeloablative Stem Cell Transplant

BACKGROUND Mixed chimerism after allogeneic bone marrow transplantation has been shown to cure a number of genetic disorders in both the clinical and experimental settings. Although encouraging results have been reported from animal experiments, the role of mixed chimerism in eliminating autoimmune disorders is not clear. METHODS A 50-year-old man with extensive psoriasis received an allogeneic transplant from his brother after nonmyeloablative conditioning with fludarabine, melphalan, and Campath-1H for relapsed non-Hodgkins lymphoma. The chimerism status and the immunological recovery after the transplant were serially monitored. RESULTS Twenty-one months after the transplant, the patient continues to be in complete remission from psoriasis and lymphoma with stable mixed chimerism (30% to 40% donor cells), despite significant recovery of T-cell subsets and antigen-specific response. CONCLUSIONS If mixed chimerism can be achieved safely with novel low-intensity conditioning regimens and results in sustained remission of autoimmune diseases, allogeneic transplantation may become a realistic therapy in the management of some patients with autoimmune disease.