Type 2 Biomarkers and Their Clinical Implications in Bronchiectasis: A Prospective Cohort Study

Our study is the first to apply three Type 2 biomarkers (BEC, total IgE, and FeNO) in an East Asian bronchiectasis cohort, revealing that 60% of patients had at least one positive marker. The impacts of these biomarkers on disease severity and outcomes varied, indicating that BEC and FeNO may represent distinct aspects of disease severity. Notably, a combination of low BEC with high FeNO suggested lower disease severity and a trend towards lower exacerbation risk. However, Pseudomonas aeruginosa colonization and high NLR (≥ 3.0) were identified as stronger exacerbation predictors. These findings imply that the clinical and pathophysiological complexity of bronchiectasis may not be sufficiently explained by the binary classification of ‘Type 2 high’ or ‘Type 2 low’ that is based solely on traditional type 2 biomarkers, as commonly applied in asthma management. This study underscores the benefits of employing multi-biomarker strategies instead of relying on single markers for a more effective risk stratification and precise treatment of bronchiectasis.

Our study on Type 2 biomarkers within an East Asian bronchiectasis cohort reveals distinct inflammation patterns when compared to asthma [10] and COPD [27]. Defining Type 2 inflammation by the presence of any positive marker, we found that 60% of our patients exhibited such inflammation, a prevalence situated between asthma (88%) [10] and COPD (42.5%) [27]. Specifically, eosinophilic bronchiectasis (BEC ≥ 300 cells/µL) was present in 15.3% of patients, lower than the 22% seen in European cohorts [6], hinting at potential regional differences due to genetic or environmental factors [6, 28, 29]. Elevated FeNO levels (≥ 25 ppb) occurred in 26.1% of patients, less than the prevalence in COPD (42.8%) [30] and asthma (51%) [10], with weakened correlation with BEC possibly resulting from the exclusion of patients with asthma [31], significant bacterial colonization [32], or the inherent heterogeneity of bronchiectasis [33]. Additionally, 36.9% had high serum IgE levels (≥ 75 kU/L), slightly below the 43.2% identified with > 60 kU/L in other studies [8]. Contrary to the findings of Ren et al. [8], our data indicate a positive correlation between IgE and BEC rather than FeNO, and a non-significant negative correlation with FeNO, highlighting the complex interplay of Type 2 biomarkers in bronchiectasis. Moreover, our analysis showed only weak and non-significant correlations between BAL eosinophils and FeNO, BEC, and serum IgE (p > 0.05), suggesting that BAL eosinophil percentages do not correlate strongly with systemic biomarkers commonly associated with inflammation and allergic responses in bronchiectasis patients. Further research is warranted to elucidate these findings.

In our study, male bronchiectasis patients who smoked with fixed airflow obstruction demonstrated elevated BEC and IgE levels, paralleling observations in COPD [34,35,36] and bronchiectasis [8, 37]. This pattern suggests a connection between these biomarkers and reduced pulmonary function. Yet, radiological severity of bronchiectasis was associated only with BEC, not total IgE, diverging from prior findings [8, 37], despite the positive BEC-IgE correlation. In contrast, higher FeNO levels (≥ 25 ppb) correlated with less radiological severity and fewer obstructive patterns, a divergence from earlier reports [7, 8, 32], but consistent with a recent Chinese bronchiectasis cohort [38], illustrating variable FeNO impacts. Furthermore, patients with high FeNO had lower blood neutrophil counts and reduced levels of airway pro-inflammatory cytokines (IL-1β, IL-6, IL-8, and TNF-α), which may explain why elevated FeNO is associated with less severe disease and a lower risk of exacerbation. Further research is warranted to clarify the relationship between elevated FeNO and bronchiectasis severity, particularly in patients without concurrent asthma.

The findings elucidate the nuanced relationship between type 2 biomarkers and exacerbation risk in bronchiectasis. Elevated BEC (≥ 300 cells/µL) correlates with higher E-FACED scores and a tendency for more frequent exacerbations, whereas FeNO levels ≥ 25 ppb are linked to a lower risk. Notably, a combination of low BEC and high FeNO significantly reduced modified Reiff scores and exacerbation rates, suggesting that BEC and FeNO reflect distinct aspects of disease severity, as seen in a retrospective Chinese cohort [38], akin to findings in a prior COPD study [30]. Building on these observations, we infer that in eosinophilic COPD, particularly in cases of severe COPD and emphysema, reduced FeNO levels often result from severe peripheral airway narrowing or obliteration, or the development of emphysema [30, 39, 40]. Similar phenomena may be observed in bronchiectasis, where severe ciliary damage and excess mucus can sequester liberated FeNO in the lung peripheries, rendering it inaccessible for proximal airway measurement [41, 42]. This pattern suggests a shared pathophysiological mechanism in these conditions, where structural changes in the lungs can significantly impact FeNO levels.

However, the relationship between exacerbation risk and other biomarkers such as serum IgE levels is less straightforward. Notably, serum IgE levels did not show a strong correlation with exacerbation risk, challenging the predictability based on Type 2 biomarkers alone. Our research highlights BEC and FeNO as composite biomarkers for enhancing risk stratification in eosinophilic bronchiectasis, a treatable trait that predisposes patients to exacerbation risks [43, 44]. The potential benefits of therapies such as inhaled corticosteroids (ICS) [44,45,46] and anti-IL-5/anti-IL-5 receptor biologics [47] in mitigating exacerbations emphasize their importance for personalized treatment, pending further evaluation.

Despite 86.9% of our cohort showing pathogen colonization detected by BAL samples, no significant differences in microbiome profiles, including Klebsiella pneumoniae and Pseudomonas aeruginosa, were observed across Type 2 biomarker levels, consistent with prior studies [7, 8]. However, contrasts with European cohorts [6, 17] might stem from our use of conventional culture methods instead of next-generation sequencing (NGS) analysis [6, 17] and different inflammatory cluster classifications [17]. Our findings align with existing literature that identifies Pseudomonas aeruginosa colonization [2, 3], airflow limitation [2, 48, 49], increased airway neutrophilic inflammation, NLR [2, 3, 38, 50], and high BSI scores [2, 25] as significant predictors of exacerbations. Multivariable analysis identified Pseudomonas aeruginosa colonization and high NLR (≥ 3.0) as independent predictors of exacerbations. The interplay of low BEC and high FeNO hinted at reduced exacerbation risks, albeit without statistical significance. Our data indicate that while traditional risk factors like Pseudomonas colonization and high NLR are confirmed predictors of exacerbations, Type 2 biomarker combinations could enhance patient stratification, supporting a multi-biomarker approach in developing personalized bronchiectasis treatment plans [6,7,8, 17, 33].

The strength of this study lies in its comprehensive integration of three Type 2 biomarkers, systemic and local inflammatory markers, and microbiological data within a well-defined bronchiectasis cohort, with exclusion criteria applied to patients with clinical asthma and ABPA. However, it encounters several limitations. Firstly, the lack of research on T2-high endotypes and the establishment of thresholds for type 2 biomarkers in bronchiectasis underscores the need for consensus on diagnostic benchmarks. Secondly, its cross-sectional design precludes the observation of longitudinal changes in Type 2 biomarkers. Thirdly, the relatively small sample size in specific subgroups, especially those with low BEC and high FeNO, as well as in the eosinophilic bronchiectasis subgroup, limits our ability to fully evaluate their impact on exacerbation risks. This limitation underscores the need for further studies to confirm these preliminary findings and to enhance our understanding of their clinical implications. Fourthly, the absence of control groups constrains comparative analyses. Fifthly, reliance on conventional culture methods rather than NGS restricts the scope of our microbiome analysis. Sixthly, sample collection during stable disease states necessitates follow-up studies to monitor biomarker changes during exacerbations. Lastly, conducting this study within a Taiwanese East Asian population highlights the necessity for further validation across diverse geographical and ethnic contexts.

In conclusion, our investigation offers groundbreaking perspectives on Type 2 biomarkers within an East Asian bronchiectasis cohort, demonstrating the differential roles of BEC, FeNO, and serum IgE in influencing exacerbation risk. These findings highlight the multifaceted nature of bronchiectasis, advocating for holistic patient assessments that combine biomarker insights with airway microbiology and clinical indices. Our study reinforces the utility of multi-biomarker strategies, as opposed to single-marker methods, for nuanced risk stratification and individualized bronchiectasis treatment.

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