Incidence and outcome of adenovirus disease in transplant recipients after reduced-intensity conditioning with alemtuzumab

Article Outline

• Abstract
• Introduction
• Patients and methods
  • Patients
  • Conditioning regimen
  • CMV surveillance
  • Virology
  • Definitions
  • Interventions
  • Statistical calculations
• Results
  • Incidence and pattern of adenovirus disease
  • Adenovirus-related mortality
  • Blood PCR and isolation of virus from multiple sites
  • CMV serostatus and anti-CMV therapy
  • GVHD and immunosuppressive therapy
  • Absolute lymphocyte count
  • Risk factors for progressive adenovirus disease and death
  • Nonrelapse mortality
• Discussion
• Acknowledgements
• References
• Copyright

Abstract 

Adenoviruses are emerging as a major cause of infectious complications after allogeneic transplantation. We evaluated the incidence and outcome of symptomatic adenovirus infection or adenovirus disease after alemtuzumab-based reduced-intensity conditioning in 86 consecutive patients. The overall probability of adenovirus disease was 18.4% (11/86 patients). Five patients died of progressive adenovirus disease, and this was the most important infectious cause of mortality in this cohort. The probability of nonrelapse mortality was 49% in patients with adenovirus disease compared with 25.5% in those without (P = .007). The severity of lymphocytopenia and continuation of immunosuppressive therapy were the most important risk factors for progressive adenovirus disease and death. In contrast, patients who were not receiving immunosuppressive therapy or had had it reduced or withdrawn cleared the virus. We also detected a correlation between the lack of preemptive anti-cytomegalovirus (CMV) therapy for CMV reactivation and the risk of progressive adenovirus disease (P = .05). Our findings highlight the emergence of adenovirus as an important posttransplantation pathogen even after reduced-intensity conditioning and demonstrate the effect of the severity of lymphocytopenia, anti-CMV prophylaxis, and immunosuppressive therapy on the outcome of adenovirus disease.

Keywords:  Adenovirus, Alemtuzumab, Reduced-intensity conditioning, Lymphocyte recovery

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Introduction 

Adenoviruses have been increasingly recognized as an important pathogen after stem cell transplantation; they occur in 4.9% to 20.9% of allografted patients [1], [2], [3], [4], [5], [6], [7], [8]. However, in the absence of prospective studies until recently, it has been difficult to evaluate both the actual incidence and the natural history of adenovirus infections and disease. In a recent prospective study that included both conventional and reduced-intensity transplantations, the incidences of adenovirus infection and disease were 45% and 27% in patients who received alemtuzumab (Campath-1H; Schering, West Sussex, UK) in vivo [9]. In this context, it is noteworthy that in multicenter studies from the United Kingdom of patients who received reduced intensity with exactly the same conditioning regimen as in the aforementioned prospective study, there was a high incidence of cytomegalovirus (CMV) [10] and respiratory virus infections [11]. In contrast, however, there has been no similar study of adenovirus infections that focuses exclusively on this group of patients who have received alemtuzumab-based or any other reduced-intensity conditioning protocol [12], [13], [14], [15], [16], although some groups have reported on CMV and other infectious complications [17], [18].

We therefore now report the incidence and outcome of adenovirus disease in 86 patients, all of whom received alemtuzumab-based reduced-intensity conditioning. This study includes patients from the study by Chakrabarti et al. [9] together with patients from another center, which confirms and extends their previous findings.

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Patients and methods 

Patients 

Eighty-six patients underwent reduced-intensity conditioning at 2 major collaborating centers between June 1997 and October 2001. The eligibility criteria for receiving reduced-intensity conditioning have been previously described, and the study design was approved by the local ethics committees of the participating centers [10].

Conditioning regimen 

Conditioning treatment consisted of alemtuzumab (Campath-1H, the immunoglobulin G1 humanized monoclonal antibody against CD52; Therapeutic Antibody Center, Oxford, UK) 20 mg/d on days −8 to −4, fludarabine 30 mg/m² days −7 to −3, and melphalan 140 mg/m² on day −2. Cyclosporine A was started from day −1 as graft-versus-host disease (GVHD) prophylaxis. Patients received unmanipulated peripheral blood stem cells from a matched family donor or unmanipulated bone marrow from an unrelated donor.

Donor lymphocyte infusion (DLI) was not a part of the protocol and was at the discretion of the treating physician. The usual indications were persistent mixed chimerism or the persistence, progression, or relapse of the disease that warranted the transplantation.

CMV surveillance 

Patients at risk of CMV infection were monitored weekly from the start of conditioning treatment to 100 days after transplantation by a qualitative polymerase chain reaction (PCR) assay and were preemptively treated with ganciclovir (GCV) 5 mg/kg twice daily as the first-line treatment or foscarnet 180 mg/kg in 3 divided doses or at half of these doses for both drugs if used in combination as second-line therapy. Two patients at 1 center received cidofovir as first-line treatment as part of a clinical trial.

Virology 

Stool, urine, and throat samples were examined as considered appropriate from patients who developed 1 or more of the following complications: fever not responding to antibacterial or antifungal therapy, diarrhea, upper respiratory illness, chest infiltrates, hepatic enzyme abnormalities, urinary symptoms, and central nervous system abnormalities. One of the centers, in addition, performed a surveillance study on stool, urine, and throat samples before transplantation and weekly to fortnightly thereafter to 180 days after transplantation in 20 patients [9].

The specimens were cultured in rhesus monkey kidney cells and, according to individual center protocol, in human embryonic lung cells or Hep2 cells and primary liver carcinoma cell lines (Alexander cells). The cell cultures were examined for cytopathic effects for 14 days. In addition, in the presence of appropriate symptoms, the stool and urine samples were also examined by electron microscopy. The tissue samples of liver, lungs, or gut obtained before or after death were examined by electron microscopy, culture, or both. The virus isolates were confirmed by direct immunofluorescence by using species-specific fluorescein-conjugated monoclonal antibodies (Dako Diagnostics, Cambridgeshire, UK). Specimens for bacteriologic and fungal investigations were concurrently processed by using standard methods of microscopy, culture, and sensitivity testing.

Peripheral blood samples were examined for presence of adenovirus DNA as previously described [9]. This was performed at 1 center as a part of a prospective study. At the other center, this was performed at the discretion of the treating physician.

Definitions 

The definitions used in this study were as described previously [9]. We defined adenovirus infection as the identification of adenovirus from a surveillance sample on culture or electron microscopy. The presence of the virus together with appropriate symptoms in the absence of any other recognizable cause was termed adenovirus disease. The isolation of adenovirus from a tissue site with or without histologic evidence of involvement was compatible with the definition of definite disease. In the absence of tissue diagnosis, the term probable adenovirus disease was used. In addition, if other pathogens that could explain the symptoms were isolated from the same site, this was termed probable adenovirus disease even in the presence of a tissue diagnosis of adenovirus.

Gut biopsy with documentation of adenovirus inclusions was considered mandatory for defining definite disease. In those who did not undergo biopsy, diarrhea was attributed to probable adenovirus disease if no other organisms were identified and the symptoms improved with clearance of the virus or progressed with definite involvement of other sites.

Upper respiratory illness was defined as the acute onset of any rhinorrhea, sinusitis, pharyngitis, or cough without clinical or radiologic evidence of lower respiratory tract involvement or hypoxia combined with the detection of adenovirus in upper respiratory secretions, in the absence of other pathogens. Lower respiratory illness was defined as clinical signs and symptoms of lower respiratory involvement with radiologic evidence of new pulmonary infiltrates with or without hypoxia associated with detection of the virus in sputum or bronchoalveolar lavage specimens. If co-pathogens were detected and a bronchoalveolar lavage specimen was not available, lower respiratory illness was defined as probable. It is worth noting that for upper respiratory infections, we did not depend on histologic detection of adenoviruses in tissue biopsy samples as evidence of adenovirus disease, because the virus could establish persistent and latent infection in the tonsils and adenoids. Respiratory samples were screened for other respiratory viruses and cultures as previously described [11].

Any death that occurred in a patient with probable or definite adenovirus disease was defined as adenovirus-related death if there was histologic antemortem or postmortem documentation or if death occurred within 6 weeks of the onset of symptoms with persistent isolation of adenovirus but without any other identifiable etiology. The absolute lymphocyte count (ALC) was defined as the ALC at the onset of adenovirus infection.

All patients were monitored for gastrointestinal, respiratory, and urinary symptoms. Documented infections at other sites were also noted. GVHD was graded according to standard criteria.

Interventions 

Active therapy was performed according to the existing policies of the units. Whereas 1 center offered only supportive care, the other center initiated antiviral therapy for severe adenovirus disease with intravenous ribavirin or cidofovir, as previously described [9]. In addition, an active attempt was made to wean the patients off the immunosuppression at the first detection of an adenovirus isolate at 1 center, as reported previously. Intravenous immunoglobulin was not routinely administered in the posttransplantation period.

Statistical calculations 

Univariate P values and odds ratios were calculated from 2 × 2 contingency tables by using Epi Info version 6 (Centers for Disease Control and Prevention, Atlanta, GA). Continuous variables were analyzed by using the nonparametric Mann-Whitney test. Cumulative probabilities were analyzed by the Kaplan-Meier method, and the differences between groups were compared by using log-rank χ² tests.

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Results 

The patient characteristics are shown in Table 1, Table 2. There was no difference in age, sex, or the underlying disease in terms of adenovirus disease. The time to neutrophil engraftment was also similar in the 2 groups.

Table 1. Characteristics of Nonmyeloablative Transplant Recipients with and without Adenovirus Disease

AML indicates acute myeloid leukemia; ALL, acute lymphocytic leukemia; MDS, myelodysplastic syndrome; CML, chronic myeloid leukemia; CLL, chronic lymphocytic leukaemia; HD, Hodgkin disease; NHL, non-Hodgkin disease; GCV, ganciclovir.

Table 2. Characteristics and Outcome of Patients with Adenovirus Infections

M indicates male; F female; MSD, matched sibling donor; UD, unrelated donor, UR, upper respiratory; CyA, cyclosporin A; C, continued; R, reduced; W, withdrawn; def, definite; prob, probable; ND, not done; HSV, herpes simplex virus; HZV, herpes zoster virus; Infl, influenza.

Incidence and pattern of adenovirus disease 

Eleven patients developed adenovirus disease (3 of them were reported previously [9]; Table 2). The overall probability of developing adenovirus disease was 18.4% (95% confidence interval [CI], 8.4%-28.4%). Six were categorized as probable and 5 as definite adenovirus disease (Table 1). Three patients had multiorgan involvement. Probable gut involvement was documented in 7 patients. Three patients had biopsy-proven evidence of adenovirus hepatitis, and another had probable hepatitis. Probable lower respiratory disease and definite upper respiratory disease were diagnosed in 2 patients each.

The median time to adenovirus disease was 90 days (Figure 1). All but 2 patients had the onset of disease within the first 4 months. Two patients with late-onset adenovirus disease (days 291 and 560) had evidence of adenovirus disease after the development of GVHD after DLI.

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• Figure 1. 

  Incidence of adenovirus disease after reduced-intensity transplantation.

Adenovirus-related mortality 

Five of 11 patients with adenovirus disease died within 6 weeks of the onset of clinical symptoms, without any definite evidence of an unrelated etiology. The overall probability of adenovirus-related death was 8.8% (95% CI, 2%-16%). The death was definitely attributable to adenovirus in 3 of them (patients 5, 7, and 11) by histologic evidence; all died of liver failure. Blood PCR was checked in 2 of them (patients 5 and 7), and both were positive approximately 2 to 3 weeks before their deaths. In the other 2 patients, the circumstantial evidence of improvement in GVHD-related symptoms before progression of adenovirus disease and death, in the absence of other pathogens, suggested adenovirus disease to be the principal contributor to the fatal outcomes. One patient (patient 4) with grade III to IV GVHD that improved on steroids and cyclosporine died of multiorgan failure after progressive respiratory involvement and diarrhea within 3 weeks of isolation of adenovirus from stool, urine, and sputum samples. Blood PCR was first positive 2 weeks before death. This patient had no other pathogen isolated from any site. Another patient (patient 10) had adenovirus isolation from stool after he developed severe GVHD after DLI. This patient was treated with steroids and antilymphocyte globulin and experienced improvement of GVHD. He presented with diarrhea and succumbed to multiorgan failure 17 days later, and there was evidence of severe hepatitis before demise. Adenovirus was the only pathogen repeatedly isolated from the stool samples until demise. The clinical course in this patient mimicked that of other patients dying from disseminated adenovirus disease. Unfortunately, a blood PCR sample was not obtained, and permission for autopsy studies could not be obtained in this patient.

All the patients who died of definite or probable adenovirus disease were receiving continued immunosuppressive therapy. Two of them (patients 4 and 11) were taking steroids and cyclosporin A for GVHD, which was continued. Two other (patients 7 and 10) received antithymocyte globulin in addition. The third patient (patient 5) was taking continued cyclosporin A because of poor graft function.

In contrast, none of patients who developed adenovirus disease and had the immunosuppressive therapy withdrawn or reduced or were not receiving immunosuppressive therapy died of adenovirus disease (patients 1, 2, 3, 8, and 9). Two of those with diarrhea had adenovirus isolated from stool samples without any co-pathogen. Another patient had biopsy-proven colitis but had Clostridium difficile toxin detected in stool samples (thus termed probable adenovirus disease) [9]. Clearance of adenovirus was associated with improvement in gut symptoms in all 3 patients. The other 2 patients had severe upper respiratory illness that improved after clearance of adenovirus from nasopharyngeal aspirates and throat samples. There was no evidence of other respiratory viruses on direct immunofluorescence and culture. Three patients (patients 2, 8, and 9) receiving steroids, cyclosporin A, or both had the immunosuppression reduced or withdrawn after isolation of the adenovirus and recovered from probable adenovirus disease. Patients 1 and 3 were not receiving any immunosuppression at the onset of adenovirus disease and had a very brief duration of symptoms.

Another patient (patient 6) who died presented with diarrhea and progressive extrapyramidal symptoms. Adenovirus was isolated from stool samples. He was on a tapering schedule of cyclosporin A and cleared the virus within 2 weeks, with improvement in diarrhea. This patient was found to have progressive lesions in the basal ganglia on repeated scans before his demise, and this was suspected to be of fungal etiology.

Blood PCR and isolation of virus from multiple sites 

PCR assay on blood was performed in 5 patients. Three patients had a positive PCR assay and succumbed to adenovirus disease within 2 to 3 weeks. Two patients with a negative PCR improved and cleared the virus.

Isolation of adenovirus from multiple sites (>1 site) did not correlate with increased mortality in this cohort (3/5 patients with compared with 2/6 patients without adenovirus-related mortality; P = .56). However, adenovirus was isolated from more than 2 sites only in patients with a fatal outcome (3/5 compared with none of the 6 patients who improved; P = .18).

CMV serostatus and anti-CMV therapy 

Adenovirus disease was more common in CMV low-risk patients (P = .04; Table 1). There was a trend toward a negative correlation between anti-CMV therapy and the risk of adenovirus disease (2/41 receiving GCV compared with 9/45 not receiving anti-CMV therapy; P = .07). Out of 41 patients, 39 received GCV and the other 2 received cidofovir. However, none of the 41 patients who received anti-CMV therapy developed progressive adenovirus disease, compared with 5/45 patients who did not receive preventative anti-CMV therapy (P = .05).

GVHD and immunosuppressive therapy 

GVHD occurred more frequently in patients with adenovirus disease (8/11 versus 23/75; P = .06; log-rank test). However, active GVHD that necessitated immunosuppressive therapy at the time of adenovirus disease was documented in only 5 patients (5/11 versus 23/75; P = .4; log-rank test). More patients with progressive adenovirus disease had GVHD, but this was not statistically significant (4/5 versus 1/6; P = .2; log-rank test). However, irrespective of concurrent GVHD, patients who received continued immunosuppressive therapy were more likely to develop progressive adenovirus disease and die from it (5/5 versus 0/6 patients not on continued immunosuppressive therapy; P = .01; log-rank test).

Absolute lymphocyte count 

The ALC at the onset of adenovirus disease was (mean ± SD) 237 ± 200/mm³ (Figure 2). The ALC for the patients who died was significantly lower than in those who survived (122 ± 113/mm³ versus 447 ± 393/mm³; P = .01). No threshold value for ALC was significantly associated with adenovirus-related mortality. However, there was a trend toward more adenovirus-related mortality in patients with ALC <200/mm³ (4/6 adenovirus-related deaths in patients with ALC <200/mm³ compared with 1/5 in those with a higher ALC; P = .1; log-rank test).

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• Figure 2. 

  A scatter plot showing the relationship between adenovirus-related deaths and absolute lymphocyte count (y-axis) in relation to the immunosuppressive therapy (IST; x-axis). The circles and crosses represent patients with and without adenovirus-related deaths, respectively.

Risk factors for progressive adenovirus disease and death 

The occurrence of adenovirus disease or death was not correlated with recipient age, donor type, sex, or underlying disease (Table 1). There was a trend toward more adenovirus-related mortality among patients who were not receiving anti-CMV therapy.

On univariate analysis, only continued immunosuppressive therapy and severe lymphocytopenia were significantly associated with increased mortality in patients with adenovirus disease (Figure 2). A multivariate analysis was not performed because of the small number of patients in the cohort who developed adenovirus disease.

Nonrelapse mortality 

Twenty-two patients died from nonrelapse causes. Adenovirus accounted for the most nonrelapse mortality (n = 5), followed by CMV (definite, n = 2; probable, n = 2), respiratory viruses (n = 2), Epstein-Barr virus (EBV; n = 2), and fungus (n = 2) as infectious causes. The probability of nonrelapse mortality in patients with adenovirus disease was 49.1% (95% CI, 17%-81.2%), compared with 25.5% (95% CI, 14.5%-36.5%) in patients without adenovirus disease (P = .007; Figure 3).

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• Figure 3. 

  Nonrelapse mortality among reduced-intensity transplant recipients in relation to adenovirus disease.

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Discussion 

With an improved understanding of the biology and immunology of CMV and EBV after stem cell transplantation, the preventative aspects of these infections have vastly improved, resulting in a reduction in mortality related to these viruses [19], [20]. However, deaths related to other viruses, such as adenoviruses [1], [2], [3], [4], [5], [6], [7], [8], [9], have been on the increase because effective prevention or therapeutic strategies for these pathogens have not yet been developed. Several retrospective studies on adenoviruses have suggested a role of immunosuppression in the pathogenesis of adenovirus disease [2], [3], [5], but it was not until recently that the relationship between the extent of T-cell depletion, immune recovery, immunosuppressive treatment, and the progression of adenovirus infection was conclusively demonstrated in a prospective study [9]. In the same study, adenovirus infections were shown to be increased after the use of alemtuzumab in vivo in both myeloablative and reduced-intensity transplantations.

We further attempted to investigate the outcome of symptomatic adenovirus infections after alemtuzumab-based reduced-intensity conditioning regimens in a larger cohort that included patients from the previously mentioned prospective study [9]. The median time for the onset of adenovirus disease was 90 days, which was similar to the pattern previously described in adult transplant recipients [2], [9]. Only 2 patients had adenovirus disease beyond 4 months after transplantation that were related to intensive immunosuppressive therapy for severe GVHD after DLI.

There is a lack of uniformity in defining adenovirus disease in the published studies. We have followed the definitions used in a previous publication by investigators from our group [9]. However, the criteria for defining probable and definite adenovirus diseases need to be revisited since the documentation of the significance of detection of adenovirus DNA in blood by PCR-based assays. It is often difficult to be absolutely certain of the exact contribution of adenovirus to mortality, even after postmortem examination, particularly in the presence of GVHD or other infections. In the absence of histologic evidence, we have considered deaths to be probably related to adenovirus only if they occurred within 6 weeks of the onset of adenovirus disease in the absence of other definite etiologic agents and persistent isolation of other viruses. For the sake of uniformity in future trials, the definitions of adenovirus disease and death need to be agreed on in a consensus meeting.

This study extends previous observations of the role of lymphocyte recovery and immunosuppressive therapy on the outcome of adenovirus infections [9]. The most important observation was that the patients receiving continued immunosuppression were at the highest risk of a fatal outcome. Reduction of immunosuppression resulted in clinical improvement and clearance of the virus. Steroid use was the strongest risk factor for CMV disease and death [19], and the same seems to be true for the outcome of adenovirus disease as well. This strongly suggests that similar to CMV and EBV, the containment of adenovirus in the posttransplantation setting is dependent on the reconstitution of adenovirus-specific immunity, the kinetics of which are determined by the speed of immune reconstitution and the use of immunosuppressive therapy. Although almost all the patients with adenovirus disease had an ALC <300/mm³, it may not be prudent to assume that there is such a critical value of ALC. Instead, this simply reflects the severity of lymphocytopenia, and this might vary in different clinical situations. In a recent report on pediatric transplant recipients [20], a similar outcome of adenovirus infections in relation to the severity of lymphocytopenia was documented; an ALC <200/mm³ correlated with mortality. We also found that the risk of adenovirus-related mortality tended to be higher in patients with ALC <200/mm³. However, more important than the ALC at a single time point is the failure of the lymphocyte counts to improve during the course of adenovirus infection.

It might be hypothesized on the basis of the findings from this study and others [9], [20] that, in patients with previous exposure to adenovirus, after allogeneic transplantation adenovirus might reactivate from lymphoepithelial tissues of the gut or upper respiratory tract, with no or localized symptoms. The further outcome of adenovirus infection would depend on the ability of the host immune system to contain the viral replication. If the patient is not severely lymphocytopenic and is not receiving continued immunosuppression, adenovirus infection is likely to remain localized and improve, such as in patients 1, 2, 3, 6, 8, and 9. Those who are severely lymphocytopenic and are receiving continued immunosuppression are likely to have disseminated disease, which is usually preceded by a period of asymptomatic viremia. Persistent lymphopenia is most commonly due to continued intensive immunosuppressive therapy, which hampers the lymphocyte recovery. The withdrawal or reduction of the immunosuppressive therapy might not be easily achievable in the presence of GVHD but should be consciously attempted if adenovirus is isolated. The use of high-dose antithymocyte globulin results in severe lymphopenia that is not immediately reversible and could contribute to a high incidence of mortality from adenovirus even in the late posttransplantation period. Patients receiving high doses of steroids or other immunosuppressive therapies are candidates for intensive surveillance for adenovirus and should receive preemptive therapy as discussed below. Ultimately we need to investigate the kinetics of adenovirus-specific T-cell reconstitution in relation to the progression of adenovirus infection and develop adoptive immunotherapy for patients at risk of adenovirus disease.

Antiviral therapy in the treatment of progressive antiviral disease has been dismal [21], [22]. In this context, our observation of the inverse correlation between prolonged preemptive GCV use for CMV reactivation and progressive adenovirus disease is of interest. Although this might be only a chance observation given the small number of patients, prolonged anti-CMV therapy might have a suppressive effect on adenovirus replication, and this has been suggested by a recent retrospective study as well [23]. A protective effect of GCV prophylaxis on severe resistant herpes simplex virus infections has also been reported [24]. However, the effect of GCV on adenoviruses in vitro is only moderate, and these findings resemble the reduction of CMV deaths with the use of high-dose acyclovir despite its having a weak anti-CMV effect [25]. These findings, in addition, further highlight the fact that patients not at risk of CMV disease might still be at risk of severe complications related to adenoviruses or other viruses if the graft is T-cell depleted or if GVHD supervenes.

Similar to CMV, a preemptive strategy to initiate antiviral therapy at the onset of adenovirus infection, when the patient is still asymptomatic, needs to be developed. Viremia, as diagnosed by the presence of adenovirus DNA in peripheral blood, has been the most important predictor of disseminated disease and adverse outcome [9], [20], [26]. This has been documented to a limited extent in our study as well. Although a PCR assay on whole-blood samples might guide such treatment, as suggested by 2 prospective studies [9], [26], continued immunosuppressive therapy and poor lymphocyte recovery could be additional indications for initiation of treatment [9]. Our data suggest that although most adenovirus infections are likely to occur in the first 150 days after transplantation, patients who receive intensive immunosuppression at any stage, even ≥18 months, after transplantation are at an increased risk of severe adenovirus infection, as evidenced in patients 4 and 10. Surveillance and preemptive strategies should thus be tailored according to the clinical situation beyond 150 days after transplantation. The choice of antiviral agents is limited to ribavirin and cidofovir. The efficacy of either of these agents has not been conclusively proven, although both drugs are effective in vitro [22]. Whether such an approach would be effective and, if so, which antiviral agent should be preferred can be answered only through multicenter randomized trials.

In this cohort of patients, the incidence of adenovirus disease was higher than that of CMV disease and accounted for the highest mortality amongst the nonrelapse causes. This highlights the emerging role of this virus and the urgency to improve the understanding of its biology and prevent this fatal complication. We previously reported a high incidence of both CMV and respiratory viruses after reduced-intensity conditioning with alemtuzumab [10], [11]. In keeping with these findings, adenovirus disease was documented in nearly one fifth of the patients. Alemtuzumab, when used at a high dose in vivo, has already been shown to impair immune reconstitution, and this was the main predisposing factor for adenovirus disease. However, when GVHD supervenes in an already fragile immune system and the patients are exposed to heavy immunosuppressive therapy, adenovirus infections can rapidly progress to disseminated disease and death. In view of these findings, the role of adenoviruses in other reduced-intensity conditioning protocols that are associated with a high incidence of severe GVHD requiring immunosuppressive therapy needs to be studied prospectively.

In conclusion, adenovirus accounted for most of the infection-related deaths after alemtuzumab-based reduced-intensity transplantation. Lack of anti-CMV prophylaxis, severe lymphocytopenia, and continued immunosuppressive therapy were associated with a progression of adenovirus infection and fatal outcome. Routine surveillance and preemptive therapy may prevent mortality associated with adenovirus. Finally, a better understanding of adenovirus-specific immunity in the posttransplantation setting would enable the development of novel immunotherapeutic strategies.

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Acknowledgements 

We thank the staff of the Therapeutic Antibody Centre, University of Oxford, for their contributions to the production of Campath-1H antibody. Their work was supported by the United Kingdom Medical Research Council, Leukosite Inc., and the E.P. Abraham’s Trust.

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