The effect of CFTR modulator therapy on airway microbiology in CF

Mutational dysfunction of the CFTR protein results in multisystem disease, but the greatest morbidity is typically seen in the respiratory tract, where mucus clogs the airways, leading to inflammation and chronic infection and ultimately respiratory failure. CFTR modulator therapy targets the underlying protein defect that causes CF lung disease. The extent to which these therapies can reduce susceptibility to chronic lung infections remains to be seen.

However, by improving airway patency, reducing the need for antibiotics, and in some cases, through direct antimicrobial action, CFTR modulators are likely to lead to significant changes in the microbiology of the CF airway. These changes may contribute significantly to the clinical benefit associated with modulator therapy and may also be an important indicator of treatment efficacy and residual pathophysiology.

Our clinical experience with CFTR modulatory therapy is still in its early stages. When the underlying pathophysiology is addressed, successful CFTR-targeted therapy can restore the lower airway microbiota to levels and composition seen in healthy individuals. Thus, changes in microbiota characteristics may be a valuable indicator of the extent and nature of pathophysiological improvement and the extent of residual, irreversible airway damage.

Second, microbiological changes may be necessary, at least in part, to achieve clinical efficacy. Antibiotics or other therapies may continue to be the cornerstone of respiratory support therapy. Third, the introduction of other major CF therapies has led to changes in the microbiological characteristics of CF lung disease at the patient population level.

Potential CFTR-mediated effects of modulatory therapy on airway microbiology:

Our understanding of how CFTR regulates and protects airway physiology remains incomplete. It is therefore difficult to predict how CFTR modulators will affect airway microbiology. Effects on mucus hydration and mucociliary clearance, which are predicted to influence pathogen abundance, may be rapid and persistent. Other effects, such as pH or airway secretion chemistry, which are predicted to directly modulate pathogen behavior, may be relatively short-lived and diminish with the emergence of distinct microbial subpopulations or other adaptations.

More severe structural airway lesions, such as progressive bronchiectasis, may persist despite modulator therapy. Since bronchiectasis is itself a risk factor for chronic respiratory tract infection, the microbiota is unlikely to “normalize” in the setting of such irreversible airway damage. In addition, effective modulatory therapy is expected to reduce the need for antibiotics, reducing one of the most powerful selective pressures on the lung microbiota.

Thus, changes in airway microbiology are likely to be variable and reflect factors such as patient age, severity of disease, associated changes in treatment, and the extent and reversibility of airway damage.

For practical experience in groups of patients of different ages, with different lung lesions by bacteria, and the interaction of the corrector components with antibiotics, we suggest that you read the full version of the translated article:

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