Evaluation of Bronchoalveolar Lavage Fluid Cytokines as Biomarkers for Invasive Pulmonary Aspergillosis in At-Risk Patients

Abstract

Background: Invasive pulmonary aspergillosis (IPA) is an infection that primarily affects immunocompromised hosts, including hematological patients and stem-cell transplant recipients. The diagnosis of IPA remains challenging, making desirable the availability of new specific biomarkers. High-throughput methods now allow us to interrogate the immune system for multiple markers of inflammation with enhanced resolution.Methods: To determine whether a signature of alveolar cytokines could be associated with the development of IPA and used as a diagnostic biomarker, we performed a nested case-control study involving 113 patients at-risk.Results: Among the 32 analytes tested, IL-1β, IL-6, IL-8, IL-17A, IL-23, and TNFα were significantly increased among patients with IPA, defining two clusters able to accurately differentiate cases of infection from controls. Genetic variants previously reported to confer increased risk of IPA compromised the production of specific cytokines and impaired their discriminatory potential toward infection. Collectively, our data indicated that IL-8 was the best performing cytokine, with alveolar levels ≥904 pg/mL predicting IPA with elevated sensitivity (90%), specificity (73%), and negative predictive value (88%).Conclusions: These findings highlight the existence of a specific profile of alveolar cytokines, with IL-8 being the dominant discriminator, which might be useful in supporting current diagnostic approaches for IPA.

Cytokine profile in lung transplant recipients with Aspergillus spp colonization

“…The pro‐inflammatory profile of the Suspected IPA group and the IPA group is in concordance with the study of Gonçalves et al that examined a heterogeneous group of immunocompromised patients including solid organ transplants with IPA. They found significantly higher levels of IL‐1b, IL‐6, IL‐8, IL‐17A, IL‐23, and TNF‐alpha in BAL compared to controls without IPA . Differences in the specific cytokines pro‐inflammatory between our cohort and theirs can be explained by the fact that our samples were collected at the time of Aspergillus isolation when the patients did not meet criteria for probable or proven IPA.…”

“…Cytokine profiles have been classically studied in serum rather than BAL samples, and there is a lack of studies of cytokines in BAL 29 Differences in the specific cytokines pro-inflammatory between our cohort and theirs can be explained by the fact that our samples were collected at the time of Aspergillus isolation when the patients did not meet criteria for probable or proven IPA.…”

Immune Parameters for Diagnosis and Treatment Monitoring in Invasive Mold Infection

“…These studies also found increased production of IL-6 by A549 pulmonary epithelial cells and primary epithelial cells [37], and this is thought to play an important role in T-cell recruitment. Other studies have shown that in vitro opsonization of A. fumigatus conidia with H-ficolin, L-ficolin [38], and M-ficolin play essential roles in pathogen recognition and complement activation through the lectin pathway and potentiate IL-8 secretion by A549 lung epithelial cells [39,40].…”

Host Genetic Signatures of Susceptibility to Fungal Disease

“…The alveolar concentrations of PTX3 are known be determined at the genetic level (Cunha et al 2014), and, as such, one could expect a further improvement to the diagnostic performance of PTX3 by knowing in advance the genotypic profile of the patient. In addition, PTX3 deficiency was also shown to influence the levels of alveolar cytokines in hematological patients suffering from IPA and to impact their ability in discriminating infection (Gonçalves et al 2017). More important, reinstating the normal levels of PTX3 in vitro with the recombinant protein was sufficient to restore the efficacy of the antifungal effector functions of neutrophils (Cunha et al 2014).…”