Prolonged Fungal Colonization is Associated with Increased Risk of Chronic Lung Allograft Dysfunction

Abstract

<h3>Purpose</h3> Five-year mortality for lung transplant (LTx) is higher than all other solid organ transplants. The major cause of death after the first year of transplant is chronic lung allograft dysfunction (CLAD). Fungal colonization (FC) is common after LTx but its role in CLAD is ill-defined. Even less defined is the role of non-<i>Aspergillus</i> FC in CLAD, and whether prolonged FC compared to transient FC changes risk for CLAD. Our goal is to determine the frequency and epidemiology of FC in this era of antifungal prophylaxis and to elucidate the contribution of prolonged FC on CLAD. <h3>Methods</h3> We performed a single-center nested retrospective study within a prospective cohort study. The source cohort included all adults who underwent LTx between 5/2013 - 12/2017 to allow for adequate CLAD follow-up time. The primary exposure was FC, defined as ≥1 positive fungal culture obtained during surveillance bronchoscopy within the first year post-transplant. The secondary exposure was prolonged FC, defined as ≥2 positive fungal cultures. The primary outcome was development of CLAD, adjudicated by ISHLT criteria. The secondary outcome was CLAD-free survival (CFS). Analyses were performed using Kaplan-Meier survival estimates and Cox proportional hazard regression modeling. <h3>Results</h3> A total of 1,274 bronchoscopies were performed in 253 LTx recipients of which 91% (1158/1274) included fungal cultures. The median number of bronchoscopies per subject was 6 (IQR: 4-8). Twenty-five percent (313/1274) had FC: 19% (61/313) <i>Aspergillus</i> species, 21% (66/313) <i>Candida</i> species, and 69% other species. Of those with FC, 32% (80/253) had prolonged FC. Twenty-five percent (63/253) of patients developed CLAD. There was a trend towards increased risk of CLAD with any FC (HR 1.24, 95%CI: 0.98-1.57, p=0.08). Prolonged FC increased risk of CLAD (HR 1.28, 95%CI: 1.21-1.35, p<0.001), especially in those with ≥3 positive fungal cultures (HR 1.69, 95%CI: 1.34-2.13, p<0.001). CFS was shorter in those with ≥3 positive fungal cultures compared to those with 0-3 positive fungal cultures (657 days vs. 988 days, p<0.001). <h3>Conclusion</h3> FC is prevalent in LTx recipients, with nearly one third having prolonged FC. We describe the first evidence that prolonged FC increases the risk for CLAD. Further prospective studies are needed to better characterize the relationship between the duration of FC and CLAD.