Prediction of systemic fungal infection in allogeneic marrow recipients: impact of amphotericin prophylaxis in high-risk patients.

Summary:The majority of invasive aspergillosis (IA) in allogeneic stem cell transplantation (SCT) occurs during the postengraftment period. We used Cox proportional hazards regression to evaluate post-engraftment IA risk in a cohort of 217 allogeneic SCT recipients from 1991 to 1998. The aim was to quantify the effects of dose-intensity and duration of corticosteroids and other risk factors. Median duration of follow-up was 330 days. There were 19 cases of IA (overall 8.8%) with 14 post-engraftment infections. In the final model, the risk of IA was greatest within 2 weeks of high-dose corticosteroids (HR 8.5, P ¼ 0.003), with risk extending to 4 weeks with doses of 0.25-1 mg/kg/day (HR 3.1, P ¼ 0.08). Ganciclovir was associated with greatest risk (HR 13.6). Grade 3 or 4 acute GVHD (HR 5.7) and secondary neutropenia (HR ¼ 1.3) were also additive risks. In the univariate analysis, corticosteroid doses of 0.25-1.0 mg/kg/day for any duration between 2 and 10 weeks demonstrated prolonged risk for IA. Moderate doses of corticosteroids can confer an increased risk for IA for extended periods which is almost as marked as that conferred by higher doses. Knowledge of these risks may facilitate the development of targeted surveillance and prophylaxis strategies for prevention of IA.

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confidence: 99%

Risk factors for post-engraftment invasive aspergillosis in allogeneic stem cell transplantation

Thursky

Byrnes

Grigg

et al. 2004

“…6 Specific knowledge of the usual time of onset and identifiable risk factors for IA is essential to the development of more effective prevention strategies and the application of new therapeutic techniques. Previously identified risk factors include age, 3,7 unrelated donor, 3,4 transplant outside of a laminar air flow room, 5 low cell dose, 7 recipient CMV seropositivity, 7 persistent or prolonged neutropenia, 5,8 early corticosteroid use for acute graft-versus-host disease (GVHD) prophylaxis, 9 high-grade acute GVHD, 1,3,4 chronic GVHD 4,8 and graft rejection. 10 Decreased risk for IA has been ascribed to housing patients in a high-efficiency particulate air (HEPA) filtered environment.…”

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confidence: 99%

Late onset of invasive aspergillus infection in bone marrow transplant patients at a university hospital

Grow

Moreb

Roque

et al. 2002

175

144

Summary:Despite new antifungal treatment strategies, invasive aspergillosis (IA) remains a principal cause of infectious mortality after bone marrow transplantation (BMT). We reviewed the medical records of 93 allogeneic and 149 autologous transplant recipients during a 20 month period, with attention to cases of proven or probable IA. No autologous transplant recipient developed IA, whereas IA was seen in 15.1% of allogeneic recipients (including two of five patients with a prior history of IA despite prophylaxis), for an overall incidence of 5.8%. The median time to occurrence was 92 days post transplant, with no de novo cases developing prior to engraftment. Survival 100 days from diagnosis was 29%. Risk factors for the development of IA included у21 days of corticosteroid therapy of у1 mg/kg/day and post-transplant cytomegalovirus (CMV) infection. These two risk factors were statistically linked. Our data illustrate a shift toward a later occurrence of posttransplant IA, suggesting a need for close, prolonged surveillance in the outpatient environment. The contributory role of protracted corticosteroid use is also highlighted. These data have important implications in an era of alternate donor transplants and more intense immunosuppression. Established strategies implementing newer, less toxic antifungal agents as prophylaxis in high-risk patients are needed. sources and more profound immunosuppression, including T cell depletion techniques, which weaken host defenses in the post-engraftment period. The time of onset in autologous transplant recipients is typically during the preengraftment period, whereas later infections are often also seen in allogeneic recipients. 6 Specific knowledge of the usual time of onset and identifiable risk factors for IA is essential to the development of more effective prevention strategies and the application of new therapeutic techniques. Previously identified risk factors include age, 3,7 unrelated donor, 3,4 transplant outside of a laminar air flow room, 5 low cell dose, 7 recipient CMV seropositivity, 7 persistent or prolonged neutropenia, 5,8 early corticosteroid use for acute graft-versus-host disease (GVHD) prophylaxis, 9 high-grade acute GVHD, 1,3,4 chronic GVHD 4,8 and graft rejection. 10 Decreased risk for IA has been ascribed to housing patients in a high-efficiency particulate air (HEPA) filtered environment. 11 To our knowledge, no data exist comparing the risk for IA using different sources of harvested stem cells (peripheral blood vs bone marrow). Furthermore, the need exists for more data regarding the role of GVHD, as well as duration and dose of corticosteroids as predisposing factors for infection.In this study, we reviewed the current epidemiology of IA in the Bone Marrow Transplant Unit at the University of Florida with specific attention to the time of onset and survival. These findings were compared to those reported in a similar epidemiologic study done at this institution between 1981 and 1985. 11 Such a comparison can illustrate the effects of new tr...

“…Risk factors for later onset IMI include T-cell depletion, graft-versus-host disease (GVHD), use of highdose corticosteroids, CMV disease and neutropenia. 2,3,5,6 Risk factors for IMI and its incidence appear similar after nonmyeloablative conditioning. 7 Corticosteroids contribute to the risk of IMI independently of GVHD due to complex immunobiological dysregulatory effects; 8 both the duration and dose of corticosteroids are important.…”

Section: Gvhdmentioning

confidence: 99%

A pilot study of targeted itraconazole prophylaxis in patients with graft-versus-host disease at high risk of invasive mould infections following allogeneic stem cell transplantation

Grigg

Brown

Roberts

et al. 2004

Summary:Patients with severe graft-versus-host disease (GVHD) requiring intensive immunosuppression are at high risk of invasive mould infections (IMI). Prophylaxis with an active, oral antifungal agents with reliable absorption in this context is desirable. A total of 44 patients at high risk of post-engraftment IMI received itraconazole solution 2.5 mg/kg b.d. as prophylaxis. Two of the first nine patients, in whom bioavailability was compromised due to significant vomiting and/or diarrhoea, died of probable or proven invasive aspergillus. None of the subsequent 35 patients, some of whom had severe gut GVHD and who received liposomal amphotericin B prophylaxis until itraconazole was reliably tolerated and absorbed, developed IMI. The overall incidence of IMI was substantially lower than in historical controls. Itraconazole was generally well tolerated, with five patients (11%) ceasing the drug due to intolerance or disturbed liver function. Targeted prophylaxis with oral or parenteral antifungal agents in high-risk allograft recipients appears to be effective in reducing the incidence of IMI. GVHDInvasive mould infections (IMI), particularly with aspergillus species, occur in up to 11% of patients after allogeneic BMT and may be increasing in incidence due to more invasive transplantation procedures in higher risk patients. 1 Characteristically, there is a bimodal pattern of IMI: an early peak during the initial period of neutropenia after conditioning and a late peak around 2-5 months post transplant, 2-4 the latter now comprising the majority of infections. Risk factors for later onset IMI include T-cell depletion, graft-versus-host disease (GVHD), use of highdose corticosteroids, CMV disease and neutropenia. 2,3,5,6 Risk factors for IMI and its incidence appear similar after nonmyeloablative conditioning. 7 Corticosteroids contribute to the risk of IMI independently of GVHD due to complex immunobiological dysregulatory effects; 8 both the duration and dose of corticosteroids are important. 2,9,10 In our institution, the overall incidence of IMI in allograft recipients from 1991 to 1998 was 8%, 11 rising to 20% in those with grades III-IV acute GVHD. 12 An analysis of risk factors for post-engraftment IMI identified prolonged (42 weeks) use of 40.25 mg/kg/day of prednisolone or equivalent corticosteroid as a major risk factor. 12 In order to reduce this incidence, in 1998, our unit examined available prophylactic fungal strategies. Various amphotericin B-based approaches such as low-dose IV 6,13 or inhaled 14 amphotericin B or liposomal amphotericin B 15 had been examined as prophylaxis with either negative or inconclusive results. Important problems with these strategies included the high cost of liposomal amphotericin B, the impracticality of prolonged parenteral delivery in the outpatient setting and renal toxicity.Key features of an ideal strategy included availability of an oral preparation with reliable and good bioavailability, activity against aspergillus and sufficient tolerability to enable admini...