(464) Impact of Elexacaftor/Tezacaftor/Ivacaftor on the Sinonasal Microbiome

Thursday, November 3, 2022

12:00 PM – 12:40 PM ET

Presenting Author(s)

Anna Zemke, MD, PhD (she/her/hers)

Assistant Proffessor
University of Pittsburgh
Pittsburgh, Pennsylvania, United States

Co-Author(s)

AS

Amanda Stapleton

Assistant Professor
Children's Hospital Pittsburgh, United States
Adam Kimple

Assistant Professor
University of North Carolina
Chapel Hill, North Carolina, United States
Jennifer L. Goralski, MD

Assistant Professor
The University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States
YH

Yasmin Hilliam

United States
SA

Shaffer Amber

PhD/Research Coordinator
Children's Hospital of Pittsburgh, United States
JP

Joseph Pilewski, MD

Professor
University of Pittsburgh
Pittsburgh, Puerto Rico, United States
BS

Brent Senior

Professor of Otolaryngology/Neurosurgery Vice Chairman for Clinical Affairs
University of North Carolina, United States
SL

Stella Lee

United States
VC

Vaughn Cooper, PhD

Professor
University of Pittsburgh, United States

Background: Chronic rhinosinusitis (CRS) is a common manifestation of cystic fibrosis and may contribute to the development of lower respiratory infections. The sinonasal microbiome in CF can have very low diversity and is often dominated by a single pathogenic taxon. Elexacaftor/tezacaftor/ivacaftor leads to a rapid improvement in the symptoms of CRS, but the impact of ETI on the sinonasal microbiome is unknown. This study tests the hypothesis that ETI returns the sinonasal microbiome towards the non-CF state. We also examined the baseline cohort to determine the relationship between demographic variables and the microbiome.

Methods: We conducted a pre-post study of individuals newly started on elexacaftor/tezacaftor /ivacaftor. Participants age 12 and older were enrolled at Univ. Pittsburgh or Univ. of North Carolina. Participants had an endoscopically guided swab collected from their right middle meatus prior to starting therapy, and after a median of 9 months of treatment. The clinical cohort is described in [1]. 29 individuals had adequate sequencing samples at baseline, and 23 paired samples were available for analysis. 16S amplicon sequencing was done, followed by analysis with the QIIME2 pipeline. Alpha and beta diversity metrics were calculated with QIIME2. Subsequent analysis was done in R with the packages vegan and ggplot2.

Results: Our cohort was younger (32% individuals age 12-21) than those previously studied, and was overall less symptomatic than cohorts recruited from tertiary care rhinology clinics, with 25% of the cohort having no prior sinus surgeries, and several individuals reporting minimal sinonasal symptoms. Staphylococcus was by far the dominant taxa, and only 10% of the cohort had a microbiome dominated by Pseudomonas. At baseline, a history of sinus surgery was associated with lower alpha diversity and richness. Allergic rhinitis affected community structure, as measured by the Bray-Curtis Index, and may be associated with a Staphylococcus dominated community. Treatment did not affect alpha or beta diversity measurements. However, we did see a reduction in the number of communities dominated by a single, Gram-negative pathogen shown in (Figure 1).

Conclusions: In a cohort of individuals who started elexacaftor/tezacaftor/ivacaftor therapy, a history of prior sinus surgeries was associated with a less diverse sinonasal microbiome. Treatment did not lead to increased alpha diversity in these profoundly non-diverse microbial communities. However, we may see a decrease in microbiomes dominated by Gram-negative organisms not found at high abundance in the non-CF healthy sinonasal microbiome.

Acknowledgements: This work was supported by Cystic Fibrosis Foundation Grants: ZEMKE19A0 and ZEMKE16Q0 and RDP BOMB19

References: < ![1] Stapleton AL, et al. Elexacaftor-Tezacaftor-Ivacaftor improves sinonasal outcomes in cystic fibrosis. J Cyst Fibros. 2022 Online Ahead of Print doi: 10.1016/j.jcf.2022.03.002