There has been dramatic improvement in the early diagnosis and treatment of transplant-associated IA over the past decade [10
]. Identification of important prognostic factors could influence patient outcomes through improved prevention and treatment strategies [1
]. To date, there have been several IA outcomes studies among HSCT recipients, but few studies among SOT recipients [6
]. This analysis of the TRANSNET database, a large, prospectively collected cohort of HSCT and SOT recipients, for the first time identified important factors associated with mortality in both transplant populations. Using two different analytic methodologies to assess mortality risk, these methods provided similar, but not identical results, highlighting the complexity in analyzing outcomes in these patients.
Overall mortality at 12 weeks among HSCT patients was 57.5%, consistent with the poor outcomes described in previous studies [3
]. Independent prognostic factors included neutropenia, renal insufficiency, hepatic insufficiency, early onset IA, proven IA, and methylprednisolone use. Using a time-to-death analysis, neutropenia and early-onset IA did not predict mortality. The majority of studies to date have recognized neutropenia as an important influence on mortality, underscoring the importance of immune system recovery among HSCT patients with IA [3
]. That these data do not consistently demonstrate this association may be related to our definition of neutropenia. We did not collect detailed laboratory data as part of this study, but rather reported any episode of neutropenia, defined as an ANC<500 cells/mm3, within 30 days prior to IA diagnosis.
Renal and hepatic insufficiency were predictors of mortality among HSCT patients with IA; both have been associated with poor outcomes in previous studies [4
]. In our population, hepatic insufficiency was the strongest predictor of mortality (OR 6.2), confirming the findings of one study among HSCT patients with IA [4
], possibly explained by the complexity of drug delivery in these patients.
As demonstrated in prior experimental and observational studies, proven IA (as opposed to probable disease) is a predictor of poor outcomes [4
]. This intuitive observation- probable IA cases represent less diagnostic certainty- also suggests that proven IA may represent more advanced disease, even though this association was not affected by adjusting for disseminated IA in our final model.
Numerous studies have documented the impact of steroids on outcome in HSCT patients with IA, with receipt of high-dose (≥2 mg/kg) corticosteroids daily at the time of diagnosis being a precise predictor [2
]. We did not routinely collect daily corticosteroid doses and could not explore fully the impact of dose or duration on mortality, but among patients this reflects treatment for GVHD. GVHD did not fulfill criteria for stepwise entry into the final model, but we observed a significant interaction between GVHD and methylprednisolone.
We observed that Caucasian patients with IA had lower overall mortality when compared to other races. A clear racial predisposition to severe fungal disease has been best described among patients with coccidioidomycosis [20
]. This is a novel observation among patients with IA, and explanations for this apparent predisposition may relate to less optimal donor matching or other confounding factors.
All-cause mortality at twelve weeks was 34.4% among SOT patients with IA, and lowest among lung transplant recipients. Independent predictors of mortality included hepatic insufficiency, malnutrition and CNS disease. Prednisone use was associated with decreased risk of mortality, possibly representing more stable maintenance immunosuppression. Cox regression analysis and the logistic regression model revealed similar results, except that kidney transplantation and non-Caucasian race were poor prognostic indicators.
Several prior studies have linked CNS involvement with poor outcome [1
]. Although only 16 (7%) SOT patients had CNS IA, 13 (81%) died. Disseminated IA, defined as any extra-pulmonary disease, was also a significant predictor of death in univariate analysis, similar to what has been previously reported [1
]. Timeliness in diagnosis of IA among SOT patients remains an important issue, possibly contributing to the frequency of complicated IA in these patients. Except for routine post-transplant surveillance bronchoscopy in lung recipients, screening methods for IA are not regularly performed in SOT populations.
Antifungal management of IA remains problematic. Despite the availability of newer antifungal drugs, clinical response remains poor and few randomized, comparative treatment trials are available [10
]. Combination antifungal therapy is attractive, but there are few prospective data to support this approach [7
]. Current guidelines endorse voriconazole monotherapy as the first-line choice for primary IA [10
]. In this study, voriconazole alone was the most common approach to primary therapy, whereas primary combination therapy was used in 28% of patients. We did not demonstrate that combination therapy had an impact on survival. In comparing those who did or did not receive combination therapy, underlying characteristics were similar with few exceptions. For example, HSCT patients who received combination therapy were more likely to be malnourished (p=0.001) and older (p=0.01). These findings alone likely do not explain the lack of an observed difference among the groups; there may be confounding and unmeasured variables which more likely explain this observation.
We observed distinct differences in mortality according to the antifungal agents used. Use of an AmB formulation in HSCT or SOT patients resulted in increased risk of death at 12-weeks, despite adjustment for renal insufficiency. This confirms data from a recent trial associating initial AmB use with increased mortality [10
]. Importantly, we observed decreasing mortality during our study period, and a significant decrease in use of AmB over time. This observation has been described in several recent studies, and may be related to differences in patient selection, supportive care, and/or newer antifungal agents [1
]. Survivors were more likely to have received voriconazole, and it was used with increasing frequency throughout the study, but it was not an independent predictor of mortality.
SOT patients who received caspofungin as initial therapy had an increased risk of death. Among these patients there was an increased frequency of malnutrition (p=0.05); liver disease (p=0.008); renal insufficiency (p=0.06); and CNS disease (p=0.09), suggesting that SOT patients who received caspofungin were perceived to be more ill. Notably, caspofungin was commonly used as a combination agent with voriconazole or an AmB formulation.
Our study has several limitations, including lack of collection of extensive laboratory data [4
]. Only antifungal drug type and start date were collected, thus insights into dose, duration, and combination therapy were limited. We did not analyze attributable mortality, as a standardized definition was not employed for TRANSNET. It is notable that among four recent studies investigating predictors of IA attributable mortality, three different attributable mortality definitions were used [3
]. This underscores the difficulty of defining mortality attributable to IA and the necessity of a consensus definition [21
]. Our outcome analysis endpoint was 12-weeks after IA diagnosis. Recent reports suggest that early mortality is mostly attributable to IA, whereas later mortality is more likely related to other causes [28
]. Our database lacked some variables that may impact overall survival, including risk of underlying disease, relapsed malignancy and transplant incompatibility. Finally, we did not capture dose and duration of corticosteroid or other immunosuppressive use. Despite the limitations, this large and broadly based surveillance study provides greater credence to previous observations, and we are encouraged by the general concordance between prognostic factors described herein and those from previous studies.