IA, an infection previously considered to be primarily nosocomial in origin, has become a late complication after HSCT, with acquisition likely from environmental sources. Here, data suggest a seasonal pattern much like that observed for other environmentally acquired fungal infections (eg, coccidioidomycosis). Data demonstrate a high incidence of IA occurring just after seasonal periods of low precipitation and high temperatures, which coincide with high environmental spore counts in Seattle, suggesting a complex and variable nature of exposure and disease.
A previously unexplained seasonal pattern of IA incidence was noted in prior risk factor analyses that included patients in Seattle, but these trends have not been demonstrated in all studies [1
]. Recently, another study performed during a period of demolition in Germany noted that spore counts correlated with temperature and humidity, with highest counts recovered in outdoor air in the summer and autumn [22
]. However, our results demonstrate that climatic conditions affect spore counts and, potentially, rates of infection differently, because increased counts were not noted in the warm, wet weather that characterizes the summer in Houston. It is tempting to speculate that warm, dry weather allows for more avid dispersal of hydrophobic Aspergillus
conidia, as has been observed for other fungal propagules. It also seems logical that similar seasonal patterns are observed in relation to spore exposure for other disease states associated with mold exposure, such as those associated with allergy [19
Although most IA cases appear to be sporadic, outbreaks of IA infection associated with construction, particularly in the health care setting, constitute a subset of disease that has been successfully targeted with host and environmental prophylaxis. Indeed, the Healthcare Infection Control Practices Advisory Committee has recommended the use of high-efficiency particulate air filtration with appropriate pressure differentials or air exchanges and Environmental Protection Agency–registered antifungal biocides (eg, copper-8-quinolinolate) for decontaminating structural materials as environmental protective measures in the scenario of health care–associated IA infection outbreaks [31
]. Such techniques have reduced the incidence of health care–associated IA among HSCT recipients during construction activity, but it is unclear whether these strategies are independently beneficial [32
]. Our findings of a sustained elevated hazard for IA during warm periods that correlate with high ambient exposure to molds provide a compelling argument that preventive strategies need to focus on nonnosocomial sources of Aspergillus
species, especially in allogeneic HSCT recipients. For an outpatient, the most likely sources of exposure are community associated, although acquisition in outpatient health care facilities cannot be ruled out. The feasibility of nonnosocomial environmental prevention efforts is questionable, given the ubiquity of fungi in the air and/or water. One approach might be to target the host by increasing antifungal prophylaxis use during high incidence periods among HSCT recipients, especially those possessing other known independent risk factors for IA.
Comparison across periods suggests that the contribution of high hazards during the spring to summer months remained constant, whereas hazards during other months decreased in the most recent years. Overall risks for IA involve differences in hosts and preventive strategies, and these variables have changed during the 10-year period; however, these variables remain constant during the seasons, supporting a true impact of season on risks for IA.
We examined the effect of season at time of transplantation. The primary reason that we limited the analysis to the month of transplantation and risks according to transplant variables is because these risks do not change over time as do typical time-dependent factors that affect immune reconstitution. Also, analyzing the impact of environmental factors that occur >3 months after HSCT would not be feasible in patients treated in these reference centers, because patients are typically discharged to geographically diverse sites later (ie, >3 months after the procedure). Also, one can assume that climatic changes within 3-month periods are relatively small, at least when classified within typical seasons. In addition, we analyzed the effect of the current season (season at IA diagnosis), and a similar seasonal effect was found, with warm season having a high HR relative to cold season (HR, 1.97; 95% CI, 1.44–2.71; P < .001).
A direct comparison of IA incidence between transplantation centers is not valid with the use of this data set, because cases were not identified using similar methods and the incidence of reported IA can vary widely on the basis of differences in diagnostics, including use of non–culture-based assays, and differences in use of early antifungal treatment strategies. Also, the cohorts examined differed widely in underlying risks, with proportionally more autologous HSCT recipients in the MDACC, compared with the proportion in the FHCRC. Hence, differences in IA incidence or hazard should be interpreted only over seasons within and not between the transplantation centers.
This study has several limitations. With any observational study, especially a retrospective one, residual confounding is certain to be present. For example, we lack information regarding detailed risks for IA, which include multiple variables that affect immune reconstitution. There is difficulty defining or interpreting time to event in this disease, because of the uncertainties in latency period, the relative lack of sensitive diagnostic tests, and clinician-dependent differences in diagnostic aggressiveness. Further investigation is needed to explore how the finding of seasonal influence on IA may apply in other geographic settings and among different patient populations, by means of standardized diagnostic and case identification methods.
The association between environmental spore counts and IA rates in Seattle supports the notion that a substantial proportion of IA is acquired outside the hospital. Also, weather variables that affect environmental spore counts appear to differ in different geographic locales. Optimizing host and environmental prevention strategies during these high-risk periods may be an efficient means to decrease disease burden.