Change in pulmonary pathogens three years after elexacaftor/tezacaftor/ivacaftor: an observational study in the Danish cystic fibrosis cohort

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Aug 25
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Maria Pals Bendixen ¹ ^∗, Majbritt Jeppesen ² ^∗, Oihane Irazoki ¹ ³, Camilla Bjørn Jensen ⁴, Mikala Wang ⁵, Janne Petersen ⁴ ⁶, Terese Lea Katzenstein ⁷, Tacjana Pressler ⁷ ⁸, Marianne Skov ⁸, Hanne Vebert Olesen ⁹, Søren Jensen-Fangel ², Tavs Qvist ⁷, Helle Krogh Johansen ¹ ¹⁰, the TransformCF study group ¹¹ ¹² ¹³ ¹⁴ ¹⁵

¹⁾Department of Clinical Microbiology, Rigshospitalet, Copenhagen, Denmark

²⁾Cystic fibrosis Center Aarhus, Department of Infectious Diseases, Aarhus University Hospital, Denmark

³⁾Technical University of Denmark, The Novo Nordisk Foundation – Center for Biosustainability, Kgs. Lyngby, Denmark

⁴⁾Copenhagen Phase IV Unit, Department of Clinical Pharmacology and Center for Clinical Research and Prevention, University Hospital of Copenhagen – Bispebjerg and Frederiksberg, Denmark

⁵⁾Department of Clinical Microbiology, Aarhus University Hospital, Denmark

⁶⁾Section of Biostatistics, Department of Public Health, University of Copenhagen

⁷⁾Cystic fibrosis Center Copenhagen, Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark

⁸⁾Cystic Fibrosis Center Copenhagen, Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark

⁹⁾Cystic Fibrosis Center Aarhus, Department of Paediatrics and Adolescent Medicine, Aarhus University Hospital, Denmark

¹⁰⁾Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark

¹¹⁾Cystic fibrosis Center Aarhus, Department of Infectious Diseases, Aarhus University Hospital, Denmark

¹²⁾Copenhagen Phase IV Unit, Department of Clinical Pharmacology and Center for Clinical Research and Prevention, University Hospital of Copenhagen – Bispebjerg and Frederiksberg, Denmark

¹³⁾Cystic fibrosis Center Copenhagen, Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark

¹⁴⁾Cystic Fibrosis Center Copenhagen, Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark

¹⁵⁾Cystic Fibrosis Center Aarhus, Department of Paediatrics and Adolescent Medicine, Aarhus University Hospital, Denmark

ABSTRACT

Objectives

Cystic fibrosis (CF) is a severe autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The resulting dysfunction of the CFTR chloride channel leads to dehydrated mucus, reduced mucociliary clearance, and pulmonary infections. Introduction of the CFTR modulator elexacaftor/tezacaftor/ivacaftor (ETI) has revolutionized treatment of people with CF (pwCF). ETI changes mucus composition, volume and viscosity, and improves lung function and life expectancy. Long-term ETI impact on CF pulmonary pathogens is an important clinical question. We investigated change in airway sputum sampling, change in CF pathogen prevalence, and change in infection status in pwCF before and after ETI initiation.

Methods

We conducted a national cohort study of airway pathogens from 5 years before to 3 years after ETI initiation in 282 Danish pwCF above 12 years of age. Samples comprised expectorates, nasopharyngeal aspirates, and bronchoalveolar lavages. A generalized linear mixed effects model and Wilcoxon signed-rank tests were employed in the analysis of data from the Danish CF Registry.

Results

During the 8-year study period, 19,739 airway samples were cultured. Sampling decreased from 10 to 6 samples per person per year after ETI initiation. We observed a significant reduction in the average percentage of airway cultures with growth of Pseudomonas aeruginosa, Staphylococcus aureus, Aspergillus spp., and Stenotrophomonas maltophilia in the years after ETI initiation. Despite this, 18% of the cohort had growth of P. aeruginosa in over 50% of their samples in the third year after ETI.

Conclusion

Our work underscores the positive effect of ETI on CF airway microbiology as a significant and sustained reduction of key CF airway pathogens at a population level during 3 years of follow-up. However, most pwCF remained culture positive 3 years after ETI. We emphasize the importance of continued close microbial monitoring and optimization of airway sampling procedures and microbial diagnostic methods.

Introduction

Cystic fibrosis (CF) is a severe autosomal recessive genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene [1]. The resulting CFTR protein dysfunction leads to dehydrated and sticky mucus, reduced mucociliary clearance, increased airway infection susceptibility, inflammation, and bronchiectasis 2, 3.

PwCF have recurrent sinopulmonary infection with several pathogens, the most important being Pseudomonas aeruginosa, which is associated with increased morbidity and mortality. P. aeruginosa adapts to the CF lung environment during infection, which makes eradication therapy difficult 4, 5, 6, 7. Other important pathogens, such as Staphylococcus aureus, Achromobacter spp., Burkholderia spp., and Aspergillus spp. can also be challenging to treat 8, 9, 10. P. aeruginosa pulmonary infection in pwCF has traditionally been defined by the modified Leeds criteria as chronic, if the pathogen was present in >50% of respiratory samples during the preceding 12 months, as intermittent colonization if present in 1-50% of samples, or as infection free when no growth occurred in the previous 12 months, and at least four samples were cultured [11].

Symptomatic treatment of CF pulmonary disease includes physiotherapy, mucolytics, bronchodilators, and antibiotics. These are all crucial in postponing bacterial acquisition and persistent infection, resulting in steadily increased life expectancy in the Danish CF cohort despite the high prevalence of the most severe CF mutation F508del 12, 13, 14.

Development of CFTR modulators (CFTRm) has brought CF treatment into a new era 14, 15, 16. The CFTRm drug combination elexacaftor/tezacaftor/ivacaftor (ETI) partly restores CFTR protein function and has led to significant clinical improvements in lung function, decline in pulmonary exacerbations, decrease in sweat chloride concentration, and improved quality of life 17, 18, 19, 20, 21. Several publications have reported CFTRm-mediated reduction in mucus volume and viscosity and a decrease in sputum abundancy of peptides, amino acids and inflammation parameters, changing the local environment in the CF airways 22, 23, 24, 25, 26, 27. Other studies showed a decreasing pathogen prevalence in airway secretion samples after ETI exposure 23, 26, 27, 28, 29, 30. Along these beneficial clinical effects arises the challenge of diagnosing and monitoring pulmonary infections in pwCF, if airway secretion sampling frequency decreases and sample volume and representativeness is reduced.

Our study objective was to investigate change in pulmonary pathogen prevalence from 5 years before, to 3 years after ETI therapy initiation in a Danish CF cohort with high airway secretion sampling frequency. The primary study outcome was change in prevalence of key CF pathogens in airway sample cultures - P. aeruginosa, S. aureus, Aspergillus spp., Stenotrophomonas maltophilia, Achromobacter spp., Burkholderia spp., Haemophilus influenza, and Moraxella catarrhalis. Secondary outcomes were change in sample frequency at cohort level, change in proportion of individuals with 0%, 1-50%, or >50% airway cultures with growth of P. aeruginosa, S. aureus, Aspergillus spp., and S. maltophilia during follow-up years, and change in percentage of samples with growth of any CF pathogen.

Section snippets

Study setting

PwCF attended the specialized CF clinics at Copenhagen University Hospital, Rigshospitalet, and Aarhus University Hospital every 4-6 weeks for clinical assessment, spirometry, microbial culture of airway secretion samples, and medication adjustment. Standard practice for many years has been to obtain a sputum sample at every visit, which in the Danish cohort has resulted in at least 10 yearly samples per individual. For pwCF unable to produce sputum, nasopharyngeal suction has been used to

Cohort demographics

A total of 295 pwCF on ETI therapy were included from the Danish CF Registry. We excluded 13 individuals due to lung transplantation (n=3), age below 12 years and compassionate use of ETI (n=5), or loss to follow up because of migration (n=5) resulting in a study cohort of 282 individuals corresponding to 95% of the Danish CF population eligible for ETI therapy (Figure S1). Study cohort characteristics at ETI initiation are presented in Table 1.

Sampling frequency

During the 8-year study period, a total of 19,739

Discussion

We investigated change in pathogen prevalence in a national cohort of pwCF with high frequency of clinic visits and airway secretion sampling 3 years after ETI initiation. We showed significant decreases in frequency of P. aeruginosa, S. aureus, Aspergillus spp. , S. maltophilia, Achromobacter spp. and Burkholderia spp. in airway secretions after initiation of ETI treatment. Our results align with recent studies, where reductions in pathogens were reported during the first years after ETI 19, 28

Conclusion

We have investigated the long-term ETI impact on pulmonary infection mediated by change in sputum viscosity and volume in an adult cohort of pwCF with irreversible structural lung disease. In conclusion, our results confirm ETI has beneficial effects on airway microbiology by significantly reducing the prevalence of several important CF pathogens. However, pathogens known to accelerate pulmonary disease persist in a substantial proportion of the cohort 3 years after ETI initiation.

Our study is....

Author contribution

Conceptualization: MPB, MJ, TQ, SJF, TP, TLK, MW, HKJ. Methodology: MPB, MJ, OI, CBJ, JP. Validation: MJ, MPB, OI, CBJ, MW, HVO. Formal analyses: MPB, MJ, OI. Investigation: MPB, MJ. Resources: HKJ, TP, CBJ, JP, SJF, HVO. Writing original draft: MJ, MPB, HKJ. Review & Editing: All authors. All authors approved the final manuscript.

Transparency declaration

HKJ was supported by a grant from CAG. - Greater Copenhagen Health - Science - Partners, 2020 and a Challenge Grant from The Nordisk Foundation, Ref.nr.: NNF19OC0056411. The research project was partly funded by The Danish Cystic Fibrosis Association and Vertex Pharmaceuticals. All funds were given to the institutions of the investigators. Authors declare no other potential conflicts of interest related to this work.