Invasive pulmonary aspergillosis (IPA) continues to be the most common invasive mold infection among lung transplant recipients.1 This fact has remained true despite advances in antifungal therapy and broader prevention strategies. Although this persistence of IPA may be simply explained by a ubiquitous organism in contact with a highly susceptible host, the challenge of making a true impact on decreasing the incidence of IPA has historically been a moving target. Concomitant advances in immunosuppressive therapies, surgical techniques, diagnostic capabilities, and therapeutic options, while welcomed, have complicated establishing an effective, uniform, and sustained approach to Aspergillus prevention after lung transplantation.2 Beyond the individual patient, environmental factors and climate change have also influenced the balance by altering the mycologic landscape.
Despite the well-established, significant impact of IPA on morbidity and mortality in the lung transplant population, there are a surprising paucity of evidence-based recommendations to guide prevention strategies.3 Although the highest threat from IPA is within the first posttransplant year, little is known about how that risk changes over time and how IPA affects long-term graft function. Likewise, as antifungal therapies evolve and we accrue more real-world experience with their use, we continue to learn not only about their effectiveness but their challenges. These uncertainties are of particular concern in the lung transplant population in which the stakes related to IPA and antifungal usage are high.
In this issue of Transplantation, Herrera et al,4 from the University of Toronto, expand on their previously published institutional experience of IPA in their lung transplant population during the first posttransplant year, by now reporting the IPA incidence between the first and fourth posttransplant years.5 Their main finding is that the incidence of IPA during this latter period was low (14/350 patients, 4%) with their institutional approach of using targeted prophylaxis and preemptive antifungal therapy during the first posttransplant year. After 1 y, antifungal therapy is provided only to those patients with proven or probable invasive aspergillosis. Voriconazole is the primary antifungal agent used for both prophylaxis and treatment at their center, although >20% of patients received an alternative antifungal agent when therapy was indicated. In contrast to their 1-y findings where in there was no difference in mortality between IPA and non-IPA groups, patients who developed IPA between years 1–4 had a significantly higher mortality rate than those without IPA (107/1000 versus 18/1000 patient-y; P < 0.0001). However, attributable mortality could not be reliably calculated and the incidence of acute and chronic rejection was not reported.
The University of Toronto experience is important to share with the broader transplant community. Although a single-center report, their lung transplant population is relatively large and the follow-up is prolonged, both of which have been limitations with previous studies. In addition, the sustained low incidence of IPA supports the longer-term success of a more targeted antifungal approach to Aspergillus prevention, which also concurrently decreased antifungal exposure by 50% compared with a universal prophylaxis strategy.5 This benefits the individual patient by simplifying their drug regimen, lessening risk for drug-drug interactions, and avoiding drug toxicity without significantly increasing their subsequent risk of IPA. It also has broader benefits of lessening patient and institutional financial burden related to direct drug cost, therapeutic drug monitoring, and assessments for drug toxicity. As antifungal stewardship interventions are increasingly implemented to preserve the antifungal armamentarium, targeted prophylaxis strategies provide even more appeal.6,7 This study supports that targeted prevention of IPA is feasible and safe, now up to 4 y post–lung transplant, and it lays the groundwork for future trial design to further define the optimal prevention strategy.
While an important contribution, the findings by Herrera et al4 do not fully reflect post–lung transplant management in many other large and small volume lung transplant centers. Institutional practices differ significantly with regards to immunosuppression management (both for induction and maintenance), antifungal use, and posttransplant surveillance. For example, the authors report that 73% of their lung transplant recipients did not receive induction immunosuppressive therapy and 76% received cyclosporine as part of a calcineurin inhibitor-based immunosuppression regimen. This is in contrast to practices in other large lung transplant centers, where induction immunosuppressive therapy and tacrolimus-based regimens are standard. Even within their study population, there was variability in patient management due to the uncontrolled study design. It is unclear what factors led to this variability in patient management and how this may have influenced their findings. Geographic differences in environmental fungal burden also likely influence infection risk. As such, a “one size fits all” approach to IPA prevention may not be achievable.
Likewise, the challenges of administering azole therapy to transplant recipients cannot be overlooked. Voriconazole specific toxicities are increasingly recognized, posing a particular risk to the lung transplant population with well-established links to hepatotoxicity, periostitis, and squamous cell carcinoma of the skin.8-10 Other patients experience difficulties with establishing and/or maintaining therapeutic serum drug concentrations, which may increase their risk for breakthrough infections. Data are even more limited on the use of posaconazole or isavuconazole for prophylaxis. Notably, Herrera et al4 used alternative antifungal agents in >20% of their patients who received antifungal therapy, suggesting they too experienced the challenges of voriconazole use in their study population, although these are not detailed. They likewise did not report a systematic approach to therapeutic drug monitoring to determine how many of their study patients achieved therapeutic voriconazole drug levels and if the levels were consistently maintained while on therapy. These issues are important practical considerations in day-to-day patient management and need to be considered when implementing a prophylactic protocol for IPA prevention.
By conducting a large retrospective cohort study and judiciously tracking aspergillosis among their lung transplant population over 4 y, Herrera et al4 demonstrate that the incidence of IPA is low using a targeted and preemptive approach to prevention. These findings move the needle by lending support to a targeted rather than a universal approach to Aspergillus prevention in the lung transplant population. This strategy has the added advantage of lower overall drug costs and fewer interactions and toxicities while promoting antifungal stewardship. Beyond moving the needle, it will be important to do additional fine tuning with future studies that account for the challenges with azole class use, the incorporation of the newer azole agents and immunosuppressants, and advances in diagnostic strategies. This will facilitate identification of the highest risk patients who will benefit most from preventive antifungal therapy.
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