Reply: Antifungal Prophylaxis

From the Authors:

In our published study (1), we found a reduction in all-cause mortality in lung transplant recipients who were receiving systemic antifungal prophylaxis compared with those who were not. Although the cumulative incidence of invasive fungal disease was lower in patients who were receiving antifungal prophylaxis compared with those who were not, this difference did not reach statistical significance. Johnson and Paez cite their prior work (2) on Candida spp. respiratory tract colonization resulting in mucous plugging, respiratory failure, and death as a possible explanation for our observation. Although this is an interesting point, it is difficult to attribute the difference in mortality in our study (1) to the prevention of Candida spp. respiratory tract colonization in patients receiving antifungal prophylaxis. As has been debated in the critical care and infectious disease literature for decades, it remains unclear whether Candida spp. airway colonization is a true causality for worse outcomes or is rather a marker of illness severity. Furthermore, it is unclear whether antifungal medications are effective at respiratory tract decontamination or preventing respiratory tract colonization particularly in lung transplant recipients who have reduced blood supply at the airway anastomoses. Although Candida spp. airway colonization is relatively common in non–lung transplant critically ill patients, the incidence, impact, and natural history of Candida spp. airway colonization has not been described in the lung transplant population.

Baker and colleagues (3), in the largest study on post–lung transplant fungal epidemiology, reported the prevalence of invasive Candida infections in lung transplant recipients to be 11.4% in the setting of universal inhaled amphotericin B combined with a targeted preemptive systemic antifungal prophylactic strategy. Bloodstream, pleural space, and surgical site infections, but not respiratory tract or lung parenchymal pathology, were the dominant types of invasive Candida infection. Interestingly, about 20% of invasive Candida infections occurred while patients were receiving systemic antifungal prophylaxis. The low prevalence of respiratory system–related Candida disease and the incidence of breakthrough Candida infections while receiving systemic antifungal prophylaxis does cast doubt that Candida airway colonization could be a significant contributor to mortality in our study cohort.

Although the difference in the incidence of invasive fungal disease did not reach statistical significance in our study (1), it is still likely that the reduction in observed mortality is partly secondary to a reduction in the incidence of invasive fungal disease. Mortality is an absolute outcome. Invasive fungal disease as an outcome requires achieving the correct diagnosis and then billing the most appropriate diagnostic code. Further randomized, prospective studies are needed to fully delineate the risks and benefits of universal, systemic antifungal medications for lung transplant recipients.