Faculty Bibliography

PURPOSE: Reflux esophagitis (ReE) and eosinophilic esophagitis (EoE) are associated with the presence of eosinophils in esophageal mucosa and are considered to be important co-morbid factors for chronic cough and asthma in adults. We hypothesize that esophageal eosinophils related to ReE and EoE are present in children with refractory asthma and chronic cough and correlate with airway eosinophilia. METHODS: We performed a retrospective analysis of medical records of children who underwent "triple endoscopy" (sleep laryngoscopy, bronchoscopy with bronchoalveolar lavage (BAL) and endobronchial biopsy (EBB), and esophagogastroduodenoscopy with esophageal biopsy (EsB)) at our Aerodigestive Center for evaluation of refractory asthma and cough. Inclusion criteriawere cough for 8 weeks or more with no response to trial of antibiotics and systemic/inhaled corticosteroids (ICS), poor control of asthma symptoms, and/or airflowlimitations and air trapping despite use ICS or ICS/long-acting beta-agonist combination. Children with known cystic fibrosis, primary ciliary dyskinesia and aspiration into airway were excluded. RESULTS: Thirty-two children (22 males) met inclusion criteria. Nineteen had refractory asthma and 13 had chronic cough. There were no significant complications recorded after procedures including EBB. Eosinophils (>1%) were present in BAL of 8 (25%) children. EBB showed eosinophils in 17 (53%) children. There were a total of 19 children with eosinophils isolated from the airway (either BAL or EBB), 4 (21%) had them in BAL alone, 8 (42%) in EBB only, and 7 (37%) in both BAL and EBB. EoE was diagnosed in 6 children (19%) and ReE in 13 (41%). EsB revealed esophageal eosinophils in 47% of children. Presence of eosinophils in EsB was related to presence of eosinophils in EBB chi² (1, N = 32), p = 0.026, but not BAL (p=0.89). CONCLUSIONS: ReE and EoE with esophageal eosinophils was present in 47% of children with refractory asthma and chronic cough. There is a significant relationship between airway and esophageal eosinophils, which becomes evident only when EBB is performed for detection of airway eosinophils. Further research is required for understanding the association of airway and esophageal eosinophilia in the development and management of refractory asthma and cough

Therapies targeting inflammation reveal inconsistent results in idiopathic pulmonary fibrosis (IPF). Aerosolised interferon (IFN)-gamma has been proposed as a novel therapy. Changes in the host airway microbiome are associated with the inflammatory milieu and may be associated with disease progression. Here, we evaluate whether treatment with aerosolised IFN-gamma in IPF impacts either the lower airway microbiome or the host immune phenotype. Patients with IPF who enrolled in an aerosolised IFN-gamma trial underwent bronchoscopy at baseline and after 6 months. 16S rRNA sequencing of bronchoalveolar lavage fluid (BALF) was used to evaluate the lung microbiome. Biomarkers were measured by Luminex assay in plasma, BALF and BAL cell supernatant. The compPLS framework was used to evaluate associations between taxa and biomarkers. IFN-gamma treatment did not change alpha or beta diversity of the lung microbiome and few taxonomic changes occurred. While none of the biomarkers changed in plasma, there was an increase in IFN-gamma and a decrease in Fit-3 ligand, IFN-alpha2 and interleukin-5 in BAL cell supernatant, and a decrease in tumour necrosis factor-beta in BALF. Multiple correlations between microbial taxa common to the oral mucosa and host inflammatory biomarkers were found. These data suggest that the lung microbiome is independently associated with the host immune tone and may have a potential mechanistic role in IPF.

The use of culture-independent techniques has allowed us to appreciate that the upper and lower respiratory tract contain a diverse community of microbes in health and disease. Research has only recently explored the effects of the microbiome on the host immune response. The exposure of the human body to the bacterial environment is an important factor for immunological development; thus, the interaction between the microbiome and its host is critical to understanding the pathogenesis of disease. In this article, we discuss the mechanisms that determine the composition of the airway microbiome and its effects on the host immune response. With the use of ecological principles, we have learned how the lower airways constitute a unique niche subjected to frequent microbial migration (e.g., through aspiration) and constant immunological pressure. The discussion will focus on the possible inflammatory pathways that are up- and downregulated when the immune system is challenged by dysbiosis. Identification of potential markers and microbial targets to address the modulation of inflammation in early disease, when changes may have the most effect, will be critical for future therapies.

Despite the immune-reconstitution with antiretroviral therapy (ART), HIV-infected individuals remain highly susceptible to tuberculosis (TB) and have an enrichment of oral anaerobes in the lung. Products of bacterial anaerobic metabolism, like butyrate and other short-chain fatty acids (SCFAs), induce regulatory T cells (Tregs). We tested whether SCFAs contribute to poor TB control in a longitudinal cohort of ART-treated HIV-infected South Africans. Increase in serum SCFAs was associated with increased TB susceptibility. SCFAs inhibited IFN-gamma and IL-17A production in peripheral blood mononuclear cells from HIV-infected ART-treated individuals in response to M. tuberculosis antigen stimulation. Pulmonary SCFAs correlated with increased oral anaerobes, such as Prevotella in the lung, and with M. tuberculosis antigen-induced Tregs. Metabolites from anaerobic bacterial fermentation may, therefore, increase TB susceptibility by suppressing IFN-gamma and IL-17A production during the cellular immune response to M. tuberculosis.