“Can’t Stop the Feeling”: Symptoms as the Key to Trial Success in Bronchiectasis?

Bronchiectasis, which is characterized by chronic, inflammatory, and irreversible airway dilatation, has a considerable disease burden, complex clinical heterogeneity, and broad etiology, and often has no identifiable cause (1, 2). Recognizable endophenotypes are emerging that may explain difficulties encountered in clinical trials (3, 4). Exacerbation frequency and associated symptoms are central to a clinician’s approach to caring for patients with bronchiectasis; however, assessing symptom burden, frequency, and variation among patients and even within an individual patient remains challenging. In a study presented in this issue of the Journal, Gao and colleagues (pp. 1499–1507) addressed this issue by examining data from 333 patients with bronchiectasis from a single center in the United Kingdom (5). The authors assessed bronchiectasis symptoms according to St. George’s Respiratory Questionnaire (SGRQ) symptom scores and the Leicester Cough Questionnaire (LCQ), using the former to classify patients as having a high, moderate, or low symptom burden. At baseline, patients with a high symptom burden exhibited more exacerbations in the preceding year, higher rates of bacterial isolation (especially Pseudomonas aeruginosa), higher body mass index, lower FEV1, and worse cough-related quality of life (lower LCQ score), suggestive of a relationship between symptom burden and more severe disease. Importantly, patients with a high symptom burden at baseline also experienced approximately twice the number of exacerbations per patient per year, a sixfold increase in hospitalizations, and shorter times to first exacerbation than patients with a low symptom burden, even after adjustment for cofounding variables such as age, sex, radiology, bacterial infection, and bronchiectasis etiology. The authors extended these findings by reporting a comparable association between symptoms and the risk of future exacerbations. Interestingly, Gao and colleagues reanalyzed results from a previously published, unsuccessful randomized clinical trial of inhaled mannitol, which failed to reduce bronchiectasis exacerbations compared with placebo (6). Although the original trial recruited patients with a history of multiple exacerbations, intriguingly, by classifying the patients’ symptom burden at study entry (using the SGRQ symptom score), the authors were able to show that highly symptomatic patients (i.e., those with high baseline symptom burdens) in the mannitol-treated group had a significant reduction in exacerbation frequency and longer times to first exacerbation (5). This critically implies that future trials of mucoactive therapies in bronchiectasis should consider baseline symptoms, which if applied here, may have resulted in a different outcome for mannitol. The study of bronchiectasis is a complex field littered with numerous but unsuccessful clinical trials despite meticulous planning, investment, and high expectations. It is hypothesized that (at least) some of these trials failed because of their inability to recruit the most appropriate “target” patient group. In agreement with this hypothesis, recent studies have further underscored the inconsistent effects of inhaled antibiotics on exacerbations and their corresponding symptoms (7, 8). One interesting consideration arising from the work of Gao and colleagues is the notion that enrichment strategies for clinical trials in bronchiectasis should emphasize the importance of a complete and thorough assessment of symptoms (including cough, dyspnea, and mucus production) rather than an overreliance on exacerbation history, which in itself has a checkered past. This is conceptually comparable to the risk assessment strategy for chronic obstructive lung disease (COPD) developed by the Global Initiative for Chronic Obstructive Lung Disease, in which exacerbations and symptoms are independently assessed to predict future risk (9). Another attractive hypothesis is that highly symptomatic bronchiectasis corresponds to a specific disease endotype, possibly characterized by a higher mucus concentration and different composition (10). Treatments that promote mucus clearance, such as physiotherapy and mannitol, would thus reduce exacerbations and their associated symptom burden in highly symptomatic patients, whereas interventions that specifically target infection (e.g., long-term macrolides) appear to be less dependent on baseline symptoms (5, 11, 12). Collectively, these observations suggest that not all bronchiectasis exacerbations are the same. Each likely has independent (and possibly co-occurring) biological mechanisms, including infection, inflammation, and mucus production, that underlie the different and heterogeneous exacerbation subtypes, each of which likely requires a specific targeted therapeutic approach. Importantly, this work does have limitations. First, the authors propose the hypothesis that “targeting daily symptoms reduces exacerbations,” which raises the “at what threshold? ” question with regard to bronchiectasis. Although the hypothesis is interesting, the authors did not assess daily symptoms but rather relied on questionnaires that assessed symptoms over months (for SGRQ) or weeks (for LCQ), both of which are subject to recall bias. Testing such a hypothesis requires the use of symptom diaries, such as the Exacerbations of Chronic Obstructive Pulmonary Disease Tool: Patient-reported Outcomes (EXACT-PRO), which was developed for COPD (13). This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http:// creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usage and reprints, please contact Diane Gern (dgern@thoracic.org).