ABSTRACT

OBJECTIVE

Non-cystic fibrosis (non-CF) bronchiectasis is a chronic lung disease, primarily characterised by neutrophilic inflammation, with Haemophilus influenzae (HI) frequently isolated from respiratory cultures. Recent adult studies have suggested a potential role for eosinophils in the frequency of pulmonary exacerbations and in lung function decline. This study aimed to evaluate the relationships among peripheral eosinophilia, lower respiratory tract pathogens, age at first pneumonia, and malnutrition in children with non-CF bronchiectasis.

MATERIAL AND METHODS

In this retrospective study, children who were diagnosed with non-CF bronchiectasis were grouped based on nutritional status, eosinophilia, age at first pneumonia, and the most frequently isolated microorganisms. Clinical outcomes were compared across groups.

RESULTS

Among 106 patients (61.3% male), malnutrition was present in 48.1% and eosinophilia in 39.6%. Primary immunodeficiency was the most common etiology (39.6%). HI and Pseudomonas aeruginosa (PA) were isolated in 61.3% and 24.5% of respiratory cultures, respectively. Patients with malnutrition had significantly lower forced expiratory volume in one second and forced vital capacity (FVC) values (P = 0.023 and P = 0.005, respectively). Eosinophilia was more prevalent in patients with PA isolation; was associated with younger ages at first pneumonia and bronchiectasis diagnoses (P = 0.009 and P = 0.017). PA isolation was associated with a higher frequency of aspiration syndromes (P < 0.001) and lower FVC values (P = 0.040). Patients who experienced their first episode of pneumonia before the age of two had more frequent exacerbations and were diagnosed with bronchiectasis at an earlier age.

CONCLUSION

Non-CF bronchiectasis in childhood may be preventable and/or non-progressive when diagnosed early. Clinical features such as malnutrition, eosinophilia, PA isolation, and early-onset pneumonia may help identify children who could benefit from closer clinical monitoring. Further pediatric studies are needed to validate these associations.

INTRODUCTION

Non-cystic fibrosis (non-CF) bronchiectasis is a chronic lung disease clinically characterized by recurrent pulmonary exacerbations accompanied by a wet or productive cough. Although bronchiectasis is typically regarded as irreversible bronchial dilation, early and effective treatment may lead to partial or complete reversal of airway damage.^{1, 2} Although chronic productive cough is the most common symptom of non-CF bronchiectasis, patients may also present with dyspnea, recurrent wheezing, persistent purulent sputum, hemoptysis, growth failure, and chest wall deformities.³ Computed tomography (CT) of the chest is the gold standard for diagnosis.⁴ Management strategies should be age-appropriate and individualized, including airway clearance techniques, mucoactive agents, pulmonary rehabilitation, and appropriate antibiotic therapy.^5-7 Given that the inflammation is typically neutrophilic, long-term macrolide therapy is often recommended.^8-12

While the incidence of pediatric non-CF bronchiectasis has decreased due to improvements in antibiotic therapy and immunization programs, it still represents a significant cause of respiratory morbidity and mortality.^{1, 5} Global incidence rates in children are heterogeneous: reported rates range from 0.2 to 2.3 per 100,000 in Europe, 13.3 per 100,000 in the United Arab Emirates, and as high as 735 per 100,000 in Australia.^{13, 14} Though data from developing countries are scarce, poor living conditions and inadequate immunization in low-income settings have been associated with increased prevalence of non-CF bronchiectasis.^{3, 6, 13, 15}

The pathophysiology of non-CF bronchiectasis is explained by a vicious cycle of infection and inflammation, in which airway infections trigger inflammatory responses that impair mucociliary clearance, leading to further airway injury and increased susceptibility to infection.¹⁶ Beyond persistent bacterial bronchitis and foreign body aspiration, other etiologies include bronchiolitis obliterans, gastroesophageal reflux disease, aspiration syndromes, primary immunodeficiencies (PID), airway hyperreactivity, primary ciliary dyskinesia (PCD), sleep-related disorders, heart failure, and rheumatologic diseases.^{6, 17} Although neutrophilic inflammation is typically predominant in bronchoalveolar lavage (BAL), some cohorts have reported eosinophilic predominance.^{5, 16, 18} Adult studies suggest that patients with eosinophilia experience more frequent exacerbations and greater declines in forced expiratory volume in one second (FEV₁).¹⁹ Among microbial pathogens, Haemophilus influenzae (HI) is the most frequently isolated organism in children with non-CF bronchiectasis.

This study examines the associations between peripheral eosinophilia, early respiratory infections, nutritional status, and airway pathogens in children with non-CF bronchiectasis, aiming to identify clinical features and potential markers relevant to disease management. Evidence regarding these associations in children is limited. Therefore, this study aims to characterise clinical features and potential markers that may help guide management in this population.

MATERIAL AND METHODS

This study was approved by the Ethics Committee of the Ankara University Faculty of Medicine in Ankara, Türkiye (approval no: 2025/235, date: 14.04.2025). Written consent was obtained from all participating children and their parents.

Medical records of patients under 18 years of age who were followed at our pediatric pulmonology outpatient clinic between 2015 and 2024 and who were diagnosed with bronchiectasis were retrospectively reviewed. One hundred and twenty patients under the age of 18 were diagnosed with bronchiectasis. Thirteen patients were excluded from the study because of a positive sweat test and detection of a CFTR gene mutation, resulting in a diagnosis of CF. One patient was also excluded following genetic testing that identified Hyperimmunoglobulin E syndrome (STAT 3 gene defect). Data collected included age at first pneumonia, age at diagnosis of bronchiectasis, annual frequency of pulmonary exacerbations, malnutrition, peripheral eosinophilia, extent of bronchiectasis, spirometric parameters, lower airway microbiology, and underlying etiologies of bronchiectasis.

Malnutrition was assessed using body mass index (BMI) Z-scores adjusted for age; a Z-score below -1 was considered indicative of malnutrition.²⁰ Eosinophilia was defined as a total eosinophil count (TEC) >500 cells/µL on at least two separate complete blood counts, performed at intervals of at least 4 weeks.²¹ Patients with PID associated with eosinophilia were excluded. The spirometry results included the percentages of FEV₁ and forced vital capacity (FVC) values in cooperative subjects. Respiratory pathogens identified from sputum, tracheal aspirate cultures, or BAL cultures were recorded, focusing on HI and PA. Etiological classifications of non-CF bronchiectasis were determined for all patients. Disease extent was evaluated using chest CT and categorized as localized (single lobe) or widespread (multiple lobes). Patients were grouped and compared based on nutritional status, eosinophilia presence, age at first pneumonia (<2 years vs. ≥2 years), and type of isolated microorganism. Outcomes were analyzed across groups.

To minimize potential sources of bias, we applied uniform diagnostic criteria for non-CF bronchiectasis and confirmed diagnoses by high-resolution CT. Peripheral eosinophil counts, microbiological cultures, and nutritional assessments were obtained using standardized laboratory and clinical protocols. Patients were included consecutively from our clinic to reduce selection bias; only those with complete clinical and laboratory data were analyzed. These methodological approaches aimed to enhance the reliability of our findings despite the single-center setting.

Statistical Analysis

Statistical analyses were performed using SPSS version 20.0 (IBM Corp., Armonk, NY, USA). The distribution of quantitative variables was assessed using the Shapiro-Wilk test. Categorical variables were expressed as frequencies and percentages. Descriptive statistics were presented as mean and standard deviation for normally distributed variables. Student’s t-test was used to compare continuous variables between groups, and the chi-square test was used for categorical variables. A P value of less than 0.05 was considered statistically significant.

RESULTS

A total of 106 patients diagnosed with non-CF bronchiectasis were included in the study. Demographic, clinical, and laboratory characteristics, as well as etiologies, are summarized in Table 1.

Of the patients, 61.3% were male. Chronic productive cough was reported in 89.6%, malnutrition in 48.1%, and eosinophilia in 39.6%. PID was the most frequent etiology (39.6%). HI and PA were isolated in 61.3% and 24.5% of respiratory cultures, respectively. The mean age at first pneumonia was 3.6±4.3 years, and the mean age at bronchiectasis diagnosis was 8.59±4.8 years. The average number of annual exacerbations was 5.8±2.0. Mean FEV₁ and FVC values were 73% and 75%, respectively.

When patients were compared by nutritional status, those with malnutrition had significantly lower FEV₁ and FVC values (P = 0.023 and P = 0.005, respectively) and a lower frequency of bronchial hyperreactivity (P = 0.031). No significant differences were observed in other clinical or etiological variables (Table 2).

Eosinophilia was more commonly observed in patients with PA isolation (P = 0.03), while it was significantly less common among patients with chronic productive cough, bronchial hyperreactivity, and PCD (P < 0.001, 0.004, and 0.016, respectively). Patients with eosinophilia were significantly younger at first diagnosis of pneumonia and bronchiectasis (P = 0.009 and 0.017), though no significant differences were found in annual exacerbation frequency or spirometric values (Table 3).

When patients with isolation of HI were compared with those with isolation of PA, aspiration syndromes were more frequent in those with PA (P < 0.001), and FVC values were significantly lower in this group (P = 0.040) (Table 4).

Patients who experienced their first pneumonia before age 2 were diagnosed with bronchiectasis at a younger age (P = 0.005), experienced more frequent exacerbations (P < 0.001), had a higher prevalence of PCD (P = 0.045), and had lower rates of rheumatologic disease (P = 0.041) (Table 5).

DISCUSSION

In this study of children with non-CF bronchiectasis, we found that patients with malnutrition had lower FEV₁ and FVC values; those with isolation of PA had a higher incidence of aspiration syndromes and lower FVC values; and eosinophilic patients were diagnosed at a younger age and had more frequent isolation of PA and less frequent chronic cough, PCD, and bronchial hyperreactivity, reflecting an association rather than disease severity. Furthermore, patients who experienced pneumonia before the age of two had more frequent annual exacerbations, an earlier onset of bronchiectasis, a higher prevalence of PCD, and fewer rheumatologic diagnoses.

Study Limitations

There are also some limitations to our study. Since our centre is a tertiary care facility, our patients completed their treatment without being admitted to us during each pulmonary exacerbation. The number of pulmonary exacerbations per patient was reported as a mean value based on parents’ reports obtained during routine follow-up visits. In addition, patients who had their first pneumonia before the age of 2 years were less cooperative during spirometry at follow-up because they were younger. This may be the reason why there was no significant difference in FEV₁ and FVC values. We are aware that the results of our study involving 106 children with non-CF bronchiectasis cannot be generalised because of the uneven distribution of participants among groups; however, we believe that the similarity of conditions such as eosinophilia, malnutrition, and PA isolation between our cohort and previous adult studies is a strength of the study.

In our cohort, the majority of patients (89.6%) presented with a chronic productive cough. The mean age at first pneumonia was 3.66 years, and the mean age at bronchiectasis diagnosis was 8.59 years. Nearly half of the patients (48.1%) were malnourished. Previous studies in low- to middle-income countries report similarly high rates of productive cough (53–96%).^22-25 A Thai study involving 35 children with non-CF bronchiectasis reported a mean age at diagnosis of 36 months.²⁶ An Italian study involving 105 children reported that the mean age at first pneumonia was 1.3 years, and the mean age at diagnosis of bronchiectasis was 7 years.²⁷ The longer interval between initial pneumonia and diagnosis, observed in developed countries, may be attributed to better healthcare access and lower rates of malnutrition.

While CF is the most common cause of bronchiectasis in high-income countries, epidemiological data for non-CF bronchiectasis remain unclear. Although reported causes are influenced by local diagnostic capabilities, PID, aspiration syndromes, post-infectious conditions, PCD, and congenital malformations are the most common causes worldwide.⁶ Among pediatric populations in low- and middle-income countries, non-CF bronchiectasis is more common due to insufficient immunization coverage and higher rates of malnutrition. Although it is often classified as idiopathic due to limited diagnostic facilities, in our study the most common cause of non-CF bronchiectasis was PID (39.6%), a rate similar to that reported in studies from developed countries (10-34%).¹³

Consistent with the literature, HI (61.3%) was the most frequently isolated pathogen in our study, followed by PA (24.5%).^{2, 25} PA was more frequently identified in children with aspiration syndromes than in those with HI, and it was associated with significantly lower FVC. While this has been linked to higher morbidity in adults, pediatric data are lacking.^{2, 25, 28}

Li et al.²⁹ reported a positive correlation of low BMI and low serum albumin/prealbumin levels with bronchiectasis severity on chest CT in adults. Similar pediatric studies are lacking. Similar to Li et al.²⁹, we also found that patients with malnutrition had lower FEV₁ and FVC values, indicating a greater reduction in lung capacity. Because children often have difficulty performing spirometry, further studies are needed to evaluate the relationship between lung capacity and malnutrition in patients with non-CF bronchiectasis.

Although neutrophilic inflammation predominates in non-CF bronchiectasis, some cohorts have shown eosinophilic involvement.^{30, 31} Previous studies suggest that PA may suppress Th1 responses via exotoxins and promote type 2 inflammation through elastase B and other virulence factors.³² Guan et al.³³ defined eosinophilic bronchiectasis in adults as peripheral TEC >300 cells/µL (excluding eosinophilic syndromes), and found that eosinophilic patients more frequently had PA isolation and experienced higher morbidity and mortality. Consistent with previous studies in adults, eosinophilic children in our cohort showed a higher frequency of PA isolation; however, lung function parameters did not differ significantly between the groups. These findings may be associated with a different clinical profile, though conclusions regarding disease severity cannot be drawn from this study. Whether targeted anti-inflammatory approaches could be beneficial in selected pediatric patients requires validation in future controlled studies.

Among patients whose first episode of pneumonia occurred before age two, we observed higher exacerbation rates, earlier diagnosis of bronchiectasis, and higher frequency of PCD. These findings align with a study by Santamaria et al.²⁷ in Italy, which reported that early-onset pneumonia in children with non-CF bronchiectasis was often associated with underlying conditions, such as PCD, PID, and aspiration syndromes.

CONCLUSION

In our study of children with non-CF bronchiectasis, we demonstrated that malnutrition and PA isolation were associated with reduced lung capacity; eosinophilic patients had higher rates of poor-prognosis PA isolation; and age at first pneumonia was associated with earlier bronchiectasis diagnosis and higher annual exacerbation frequency. Non-CF bronchiectasis in childhood may be preventable or nonprogressive when diagnosed early, as suggested by previous studies. Greater attention to clinical features such as malnutrition, eosinophilia, PA isolation, and early-onset pneumonia may help identify children who could benefit from closer follow-up. Nevertheless, further research is needed in the pediatric population to better understand and manage this disease.