Bronchiectasis is a chronic respiratory disease characterized by permanent and abnormal dilatation of the bronchi, typically associated with persistent symptoms such as cough, sputum production, and recurrent respiratory infections [1,2]. Although the pathogenesis of bronchiectasis is incompletely understood, a complex interplay between airway inflammation, chronic infection, impaired mucociliary clearance, and progressive lung damage drives both disease activity and severity [2]. Once considered an orphan and largely neglected disease, bronchiectasis has recently gained substantial consideration, as demonstrated by the national and international registries and growing awareness within scientific and clinical communities [3,4]. Despite the recent Food and Drug Administration (FDA) approval of Brensocatib, the first drug specifically developed for bronchiectasis, current management strategies recommended by international guidelines rely on off-label treatments due to limited and conflicting evidence [5–7].

In this review, we summarize current therapeutic approaches for bronchiectasis, with emphasis on emerging treatments and recent advances, including ongoing and recently completed clinical trials. Moreover, we will try to provide a critical analysis of current and emerging therapeutic strategies, highlighting their applicability to specific bronchiectasis phenotypes.

Bronchiectasis is a complex disease from a pathophysiological standpoint [8,9]. According to the “vicious vortex” model [10], a continuous interplay between airway dysfunction, altered inflammatory response, structural damage and infection drives disease pathogenesis [11]. Given this complexity, a single treatment strategy is unlikely to be effective by itself, due to variability of the predominance of the vortex components in different patients and in the same patient over time (Fig. 1). This rationale has led to diverse therapeutic strategies and efforts to tail treatment to specific bronchiectasis phenotypes and endotypes [12,13]. The marked heterogeneity of bronchiectasis has contributed to inconclusive results of several clinical trials, even those enrolling selected patient subgroup. Nonetheless, numerous studies are currently exploring novel approaches to treat bronchiectasis (Tables 1 and 2).

Fig. 1.

The complex landscape of possible new treatment strategies for bronchiectasis.

Airway clearance remains a foundational component of bronchiectasis care, given the central role of mucus viscosity, impaired mucociliary transport, and mucus plugging in perpetuating airway inflammation [14,15]. Yet real-world uptake across Europe remains suboptimal, often limited by unequal access to devices and specialized physiotherapists [47]. This mismatch between guideline recommendations and clinical practice highlights a persistent implementation gap.

Although the evidence base is modest, randomized trials support the use of oscillatory PEP devices and techniques such as ELTGOL, which have demonstrated improvements in sputum expectoration, symptoms, exercise tolerance and quality of life, and exacerbation reduction [48,49]. Given disease heterogeneity, airway clearance is most effective when individualized, integrated with patient preference, disease severity, and comorbidity profile.

Adjunctive tools are expanding the physiotherapy landscape. High-flow nasal therapy may offer benefits in mucus mobilization and exacerbation reduction, though current evidence derives mainly from small retrospective cohorts [50,51]. The AIRVO-BE (NCT04102774) and BiWaze Clear (NCT06926881) trials will clarify whether heated humidification, oscillation and combined modalities meaningfully enhance mucus clearance. These innovations exemplify the trend toward home-based, technology-supported airway management.

Mucoactive agents complement physiotherapy by improving mucus hydration and reducing viscosity. Commonly used agents (hypertonic saline, mannitol and oral mucolytics) are supported by mixed but generally favorable data, with ongoing trials evaluating their impact on mucociliary clearance and symptoms [14,15]. Ongoing studies include NCT06242795 (7% saline and mucociliary clearance), CLEAR (EudraCT 2017-000664-14) (carbocisteine and 6% saline) [52], and the BETTER trial (ACTRN12621000315819) (erdosteine in adult and pediatric patients) [53]. Overall, the emerging evidence reinforces a phenotype-based approach, where selection of airway clearance modalities and mucoactive agents is guided by patient-specific mucus characteristics, tolerance, and exacerbation profile.

Recent evidence highlights the role of CFTR-related dysfunction in patients with BE carrying either a single CF-causing mutation or CFTR polymorphisms [54,55].

The phase 4 study (NCT05743946) of Trikafta™ (elexacaftor/tezacaftor/ivacaftor) seeks to determine whether CFTR modulation can improve lung function, symptoms, and mucociliary clearance in non-CF bronchiectasis, a concept that, if validated, would substantially broaden the scope of channel-targeted therapy. Another ongoing trial (NCT06603246) is evaluating GDC-6988, an inhaled ANO1(TMEM16A) chloride channel potentiator, with the aim to enhance epithelial chloride secretion independently of CFTR in adults with muco-obstructive airway disease including bronchiectasis and COPD. These early-phase programs represent a paradigm shift toward correcting epithelial ion transport, potentially addressing mucus stasis at its biophysical root rather than solely through mechanical clearance.

Structural airway destruction represents the end-stage consequence of the bronchiectasis vicious cycle, and no current therapy reverses this injury [10]. Early-phase regenerative studies, however, offer a glimpse into a transformative future, with some first attempts to reverse structural damage potentially becoming the real game changer in bronchiectasis treatment.

Trials using autologous P63+ lung progenitor cells [56] and basal epithelial stem cells (REGEND001 trial – NCT06987214) suggest that airway epithelial repair may be feasible, with early evidence of improved gas exchange, radiologic outcomes, and quality of life. These results remain preliminary and require long-term safety validation, but they provide proof of concept that cell-based airway regeneration could interrupt disease progression beyond symptom control. Ongoing mechanistic studies (NCT06164093) will clarify engraftment durability, functional integration and optimal patient selection.

Despite these promising results, high costs, restricted worldwide availability and potential risks linked to the activation of cell proliferation pathways, put some serious concerns about this approach to bronchiectasis care, especially considering the possibility of a life-long necessity for maintenance therapy.

Airflow obstruction affects roughly one-third of bronchiectasis patients [15], yet the role of bronchodilators remains poorly defined. Current trials aim to characterize bronchodilator responsiveness across age groups (NCT05932316) and to determine whether short-acting or long-acting agents meaningfully improve exercise capacity and symptoms (NCT05183841).

These studies will provide essential functional evidence to determine whether bronchodilators should be reserved for patients with demonstrable reversibility or adopted more broadly for symptom relief.

Pulmonary rehabilitation offers consistent benefits in exercise tolerance, dyspnea and quality of life, despite small sample sizes in existing trials [57–61]. Several RCTs are evaluating rehabilitation across different settings (Table 2). Digital and home-based interventions, such as the SELF-BREATHE program (NCT06326957) reflect shifting models of care that emphasize accessibility, self-efficacy and long-term behavior change. Additional studies are exploring treatable traits and self-management strategies, such as smoking cessation (NCT05764343) and anxiety support groups (NCT06164470), underscoring a shift toward individualized, holistic care in bronchiectasis.

This broad pipeline emphasises how bronchiectasis is increasingly recognized as a highly heterogeneous condition, with differing contributions of infection, inflammation, mucus stasis, and structural airway damage across patients [62]. This variability necessitates a personalized, phenotype- and endotype-based therapeutic strategy rather than a uniform treatment approach. Aligning pathophysiological mechanisms with clinical presentation enables a more rational selection of therapies, maximizing efficacy while minimizing unnecessary interventions.

Patients characterized by predominant neutrophilic inflammation and chronic bacterial infection are most likely to benefit from combined anti-inflammatory therapy (e.g., DPP-1 inhibitors, macrolides), targeted antibiotics, and structured airway clearance techniques. These interventions aim to reduce exacerbations, suppress pathogenic burden, and modulate airway inflammation, addressing the principal drivers of disease activity.

In those with impaired mucociliary clearance and highly viscous secretions, mucoactive treatments (hypertonic saline, mannitol, oral mucolytics), alongside airway clearance and, when appropriate, high-flow nasal therapy, can improve sputum mobilization, enhance airway hydration, and mitigate mucus plugging. This highlights the value of mechanism-based therapies targeting mucus rheology beyond traditional anti-infective or anti-inflammatory approaches [63].

A molecularly defined subgroup exhibits CFTR-related dysfunction due to CFTR polymorphisms or single CF-causing mutations [64]. These patients may respond to CFTR modulators that restore epithelial ion transport, improve airway surface hydration, and facilitate mucociliary clearance, offering a precision-medicine avenue with potential disease-modifying effects in non-CF bronchiectasis [65]. For patients with advanced structural airway damage, emerging regenerative strategies including autologous lung progenitor cell or basal stem cell-based therapies aim to repair injured airways and improve lung function, although these remain experimental [66].

Overall, this phenotype-driven framework underscores that effective bronchiectasis management relies on multimodal, individualized therapy. Because many patients demonstrate overlapping phenotypes, combined strategies targeting infection, inflammation, mucus stasis, and structural impairment are often required. Linking therapeutic choices to underlying mechanisms provides a pathway to optimize clinical outcomes and support enrolment in mechanism-based clinical trials.

Despite recent advances in bronchiectasis management, significant knowledge gaps and clinical challenges remain. A key priority is the identification and validation of biomarker-defined subgroups to enable precise, endotype-driven therapy. Current trials often enroll heterogeneous populations, which limits interpretability and may obscure true treatment effects. Biomarkers that reliably predict response to anti-inflammatory, anti-infective, or regenerative therapies are essential to guide patient selection and optimize outcomes.

Standardization of outcomes represents another critical need. Clinical trials frequently employ heterogeneous endpoints, complicating cross-study comparisons and meta-analyses. Harmonized outcome measures including exacerbation definitions, patient-reported outcomes, and biomarker-based endpoints, would facilitate evidence synthesis and accelerate regulatory approval of novel therapies.

Global disparities in care remain a persistent challenge. Access to airway clearance devices, specialized physiotherapy, and novel therapeutics varies widely across regions, potentially exacerbating morbidity in underserved populations. Especially for high drug costs and limited availability for treatment as CFTR modulators and novel regenerative therapies may restrict widespread use, emphasizing the need for careful patient selection. Addressing these inequities requires integrated strategies encompassing healthcare infrastructure, education, and equitable trial design.

Finally, the complex, multifactorial nature of bronchiectasis underscores the need for combination therapies targeting multiple pathophysiologic mechanisms simultaneously. Single-modality interventions may provide limited benefit, whereas rationally designed multimodal regimens, tailored to patient phenotype, could improve disease modification and long-term outcomes. Future research should prioritize studies that evaluate such integrated approaches, incorporating both mechanistic biomarkers and patient-centered endpoints.

In summary, advancing bronchiectasis care will require a precision-medicine framework, robust outcome harmonization, equitable access to therapy, and the development of combination strategies that reflect the underlying disease heterogeneity. Addressing these unmet needs is essential to translate emerging scientific insights into meaningful clinical benefit.

The heterogeneity of bronchiectasis underscores the need for precision, phenotype- and endotype-based management rather than uniform treatment. Across airway clearance, anti-inflammatory therapy, infection control, regenerative medicine and behavioral interventions, current research is converging on individualized care pathways driven by molecular profiling, clinical traits and patient-centered outcomes. As results from ongoing phase 2 and 3 studies emerge, bronchiectasis management is poised to incorporate mechanism-based therapies that move beyond symptomatic relief toward disease modification.

The authors declare that they have no conflicts of interest.