Colonization With Small Conidia Aspergillus Species Is Associated With Bronchiolitis Obliterans Syndrome: A Two-Center Validation Study

Abstract

Aspergillus colonization after lung transplantation may increase the risk for bronchiolitis obliterans syndrome (BOS), a disease of small airways. We hypothesized that colonization with small conidia Aspergillus species would be associated with a greater risk of BOS, based upon an increased likelihood of deposition in small airways. We studied adult primary lung recipients from two large centers; 298 recipients at University of California, Los Angeles and 482 recipients at Duke University Medical Center. We grouped Aspergillus species by conidia diameter ≤3.5μm. We assessed the relationship of colonization with outcomes in Cox models. Pre-BOS colonization with small conidia Aspergillus species, but not large, was a risk factor for BOS (P = 0.002, HR 1.44, 95% CI 1.14–1.82), along with acute rejection, single lung, and Pseudomonas. Colonization with small conidia species also associated with risk of death (P = 0.03, HR 1.30, 95% CI 1.03–1.64). Although other virulence traits besides conidia size may be important, we have demonstrated in two large independent cohorts that colonization with small conidia Aspergillus species increases the risk of BOS and death. Prospective evaluation of strategies to prevent Aspergillus colonization of small airways is warranted, with the goal of preserving lung allograft function as long as possible.

Gene Expression Profiling of Bronchoalveolar Lavage Cells during Aspergillus Colonization of the Lung Allograft

“…This is important because we have previously reported that Aspergillus colonization is a risk factor for CLAD. 18,19 Without direct evidence until now, we have surmised that Aspergillus colonization causes subclinical injury and inflammation, which can initiate and propagate dysregulated repair mechanisms leading to CLAD. In this study, we confirm that Aspergillus colonization is dominated by differential expression of genes pertaining to defense response, response to wounding, and inflammatory response.…”

“…Given our prior work showing that Aspergillus colonization is a risk factor for CLAD, 18,19 it is interesting that BAL neutrophilia is also described as a precursor to CLAD. 36,37 However, in this study, Aspergillus colonized cases who developed CLAD did not have a greater proportion of BAL neutrophils than those who remained CLAD free.…”

“…A. niger), do not increase the risk of CLAD. 19 We have recently published on BAL cell pellet gene expression profiles associated with incipient CLAD (i.e. CLAD within 2 years of BAL sampling).…”

“…18 Furthermore, the risk of CLAD is limited to recipients colonized with small conidia Aspergillus species, such as A. fumigatus. 19 While the colonized patient may be asymptomatic, we hypothesized that Aspergillus colonization causes subclinical injury to the airway epithelium and generates immune responses that promote CLAD pathogenesis. In order to explore the mechanisms responsible, we determined the gene expression profile of bronchoalveolar lavage (BAL) cells during Aspergillus colonization of the lung allograft.…”

The Impact of Infection on Chronic Allograft Dysfunction and Allograft Survival After Solid Organ Transplantation

“…Potential mechanisms of allograft injury by CARVs in lung transplant recipients include upregulation of inflammatory cytokine production initiated by viral replication or a direct cytopathic effect on the respiratory epithelium (134). Although some authors described a trigger for acute rejection after CARV infections and a higher risk of subsequently developing BOS (133,135), data in the literature are conflicting (136)(137)(138)(139). Based on a pooled analysis including all clinical studies evaluating the role of CARVs on lung allograft outcomes, the main conclusions were that infection with CARVs was not associated with significantly higher incidence of subsequent acute rejection (odds ratio [OR] 1.35; 95% confidence interval [CI] 0.41-4.43) and that a nonsignificant higher incidence of BOS in patients with viral infection was observed (18% vs. 11.6%) (136) (Figure 2).…”