To the Editor:

Pulmonary exacerbations remain the most important cause of morbidity, loss of lung function, and reduced quality of life in patients with cystic fibrosis (CF), and are characterised by chronic bacterial airway infection and persistent neutrophilic inflammation [1]. Historically, treatments for CF have predominantly concentrated on combating infections, and anti-inflammatory therapy has been neglected. Chronic neutrophil-dominant airway inflammation is a major contributor to the permanent loss of lung function and progression of disease [2]. Corticosteroids are potent and widely used anti-inflammatory agents in acute exacerbations of other chronic respiratory diseases [3, 4]; however, to date, data on the efficacy of corticosteroids from randomised controlled trials (RCTs) involving CF patients have been limited to clinically stable children and vary in dosing and duration of treatment. Definitive evidence for oral corticosteroid treatment in CF patients with pulmonary exacerbations is still lacking, and whether the therapy was associated with superior clinical outcomes is unclear.

We read the study conducted by Waters et al. [5] with great interest, as it explained important clinical questions that had been rarely reached until now. This was the first landmark research to evaluate the efficacy of oral prednisone for CF pulmonary exacerbation through a randomised, double-blind, placebo-controlled trial. The study provided new insights into the management of pulmonary exacerbations in patients who did not respond adequately to antibiotic therapy alone. By focusing on patients who failed to regain 90% of their baseline lung function after 7 days of intravenous antibiotic treatment, the authors effectively screened out a subset of patients with more severe and persistent inflammation. This strategy allowed for a clearer evaluation of the potential benefits of adding oral prednisone to the treatment. Although the study did not demonstrate a statistically significant clinical benefit of prednisone adjuvant therapy, the exploration of this hypothesis remains valuable. It highlighted the complexity of CF management and the urgent need for personalised treatment, especially for patients who do not respond to standard antibiotic therapies. Furthermore, the comprehensive data collection and analysis sets a high standard for future clinical trials in this field.

Despite the excellence of this study, we would like to provide a few recommendations for future research. First, we have some minor concerns regarding the participants of this study. Several previous RCTs exploring the use of oral corticosteroids in people with CF presenting with pulmonary exacerbations have not shown a benefit in lung function [1, 6]. In these studies, data on baseline eosinophilic level and serum IgE were not available for the entire cohort; CF had a predominantly neutrophilic inflammatory profile, while eosinophilic inflammation had also been documented in both the airways and the systemic circulation of these patients [7]. Patients with eosinophilic phenotype, if anything, were more likely to benefit from oral corticosteroid therapy than other patients with CF and pulmonary exacerbations. However, to date, no study has addressed the benefit of oral corticosteroids for pulmonary exacerbations in CF patients with eosinophilic phenotype (blood eosinophil count ≥300 cells·µL−1). The study conducted by Waters et al. [5] showed the data on eosinophilic level at different time points for all the non-responders, but the inclusion criteria of the study did not specify the eosinophil level of participants. As discussed, there is a question of whether oral corticosteroids might be more beneficial in CF patients with pulmonary exacerbations of eosinophilic phenotype. Nevertheless, these clinical variables potentially identify a subset of CF patients that would benefit from adjunctive corticosteroid therapy and urgently should be considered as randomisation criteria in future prospective RCTs.

Additionally, previous studies have shown that oral corticosteroids at a prednisolone equivalent dose of 1–2 mg·kg−1 alternate days appeared to slow the progression of CF, but the benefit needed to be weighed against the occurrence of adverse events [8]. More importantly, experts had called for an analysis of the benefits of low-dose alternate-day corticosteroids for people with CF and stressed that the role of short-term oral corticosteroids use should be more fully evaluated [8, 9]. In this study, the dosage of prednisone used – 1 mg·kg−1 twice daily (up to a maximum of 60 mg·day−1) – was relatively high and could pose risks of immunosuppression and associated complications. Therefore, relevant RCTs exploring the efficacy of low-dose alternate day corticosteroid therapy or alternative anti-inflammatory agents for cystic fibrosis pulmonary exacerbation are urgently needed in the near future.

Briefly, the study provided new insights into treatment strategies for CF pulmonary exacerbations. Targeting inflammation, a key component of disease progression, opens up new pathways for CF-related studies. Relevant RCTs are urgently needed to identify a subset of CF patients that would benefit more from adjunctive corticosteroid therapy, as well as the optimal dosage of it. These are critical to developing more effective and individualised treatments for CF, ultimately improving the prognosis of the disease.