The role of flexible bronchoscope in the evaluation of chronic cough with and without wheeze in children

Background Chronic cough in children is a challenging symptom for clinicians. So, we aimed in this study to evalu‑ ate the diagnostic role of flexible bronchoscope in differentiating between the underlying causes of chronic wet cough and chronic cough associated with wheeze. Methods This was a prospective cross‑sectional study conducted on children referred to Tanta University Hospitals and Ain‑Shams University Hospitals between January 2021 and January 2023, presenting with a primary complaint of chronic cough lasting more than 4 weeks. The children were further classified into two groups: the first group included children with chronic wet cough not associated with wheezing (Cohort A) and the second group included children with chronic cough associated with wheezing (Cohort B). Results The study enrolled 64 children. During clinical evaluation, 25 (39.1%) children had a chronic cough with‑ out wheezing and 39 (60.9%) had a chronic wheezy cough. Bronchoscopic examination findings indicated a notable disparity between the two groups of patients with chronic cough ( p =0.006). Among Cohort A patients, the most prevalent bronchoscopic observation was purulent inflammatory secretions in 16 cases (64.0%), followed by con‑ genital airway anomalies in 3 cases (12.0%). Conversely, Cohort B patients exhibited congenital airway anomalies as the primary finding in 14 cases (35.9%), followed by purulent secretions in 7 cases (17.9%). Conclusion Flexible bronchoscopy is a valuable and safe tool for diagnosing chronic cough in children. It helped dif‑ ferentiate between the underlying causes of chronic cough in children with and without wheezing.


Background
The predominant respiratory manifestations observed in children include persistent coughing and wheezing, which have been associated with diminished quality of life, absenteeism from school, and recurrent consultations with healthcare professionals [1].The presence of chronic cough and wheezing often signifies the existence of various underlying disorders, thereby presenting a diagnostic challenge [2].
There are various definitions of chronic cough in children.The 2020 CHEST consensus statement defines chronic cough as a cough enduring for a period exceeding four weeks [3].The British Thoracic Society guidelines describe chronic cough in children lasting longer than eight weeks [4].Conversely, the European Respiratory Society guidelines characterize chronic cough as persisting for more than eight weeks in adults and more than four weeks in children [5].
A flexible bronchoscope plays a significant role in the diagnosis of chronic cough by allowing direct observation of the structure and function of the airways, as well as assessment of the mucosal lining, airway secretions, endobronchial abnormalities, and external compression of the airways [6].Furthermore, the flexible bronchoscope offers the capability to obtain bronchoalveolar lavage samples for cytological and microbiological analyses, providing an additional advantage in clinical practice [7].
The primary goal of this study was to assess the diagnostic value of flexible fiberoptic bronchoscopy for identifying the underlying causes of chronic wet cough and chronic cough accompanied by wheezing.

Study design
This was a prospective cross-sectional study conducted on pediatric patients who were referred to Tanta University Hospitals and Ain-Shams University Hospitals between January 2021 and January 2023 with a chief complaint of chronic cough lasting over four weeks.Written informed consent was obtained from the guardians of all patients.
The research ethics committee of the Faculty of Medicine, Tanta University, approved this research under number 34314/12/20.The study was conducted in accordance with the ethical standards of the institutional research committee and the 1964 Helsinki Declaration and its later amendments.
The children were further classified into two groups: the first group included children exhibiting chronic wet cough without any concurrent wheezing (Cohort A), whereas the second group comprised children with chronic cough associated with wheezing (Cohort B).
Children aged from 3 months to 18 years presenting with chronic cough of ≥4 weeks, which was persistent despite the noninvasive investigations for the diagnosis of chronic cough, were included in the study.Children were excluded from the study if they had known underlying diagnoses, such as immunodeficiency, congenital lung diseases, cystic fibrosis, or primary ciliary dyskinesia, or if they had a history of acute foreign body aspiration.
All children underwent a thorough assessment of their medical history, which included demographic information, anthropometric measurements, a local chest examination, laboratory investigations, pulmonary function test for those aged > 5 years, plain chest radiography, and, where needed, a high-resolution CT (HRCT) chest scan.

Bronchoscope
We used two sizes of flexible bronchoscopy (Fujifilm EB-530P video bronchoscope with an external diameter of 3.8 mm & a working channel of 1.2 mm) or (KARL STORZ with an external diameter of 2.8 mm &working channel of 1.2 mm) according to the patient's age under general anesthesia using laryngeal mask ventilation with spontaneous respiration.Bronchoalveolar lavage fluid (BALF) was obtained and sent for microbiological and cytological analysis.The BALF yield, macroscopic appearance, and anatomical abnormalities were recorded.
Dynamic tracheomalacia was defined as a condition of excessive tracheal collapsibility of the anterior wall, while excessive dynamic airway collapse is the excessive bulging of the posterior membranous part of the trachea with a reduction of the cross-sectional area of 50% or more during expiration with the intact cartilaginous part.Bronchomalacia was defined as excessive bronchial collapsibility [8,9].
Protracted bacterial bronchitis is defined as chronic wet cough for more than 4 weeks in preschool children with no underlying specific causes that usually resolves after a 2-week course of an appropriate oral antibiotic [10].

Statistical analysis
Data were input into the computer and analyzed using SPSS software version 20.0.The Shapiro-Wilk test was used to assess the normality of the distribution.Qualitative data are described as numbers and percentages.Quantitative data were described using the median and interquartile range (IQR) if they were abnormally distributed.Chi-square was used to compare qualitative data in both groups.The Mann-Whitney test was used to compare the two studied groups for abnormally distributed quantitative variables, and a P value of < 0.05 was used to determine statistical significance.

Demographic and clinical characteristics
A total of 64 patients were included in this study.Six patients (9.4%) within the study cohort were less than one year old, while 30 (46.9%) fell within the age range of one to five years, and 28 (43.8%) were above the age of five.Half of the participants (n = 32) were of the male gender.During clinical evaluation, 25 children (39.1%) presented with a chronic cough without wheezing, whereas 39 children (60.9%) exhibited a chronic cough accompanied by wheezing.
In terms of age, there was a significant difference between the two groups of children with chronic cough (p=0.025);children in Cohort B were younger than those in Cohort A.
Regarding the associated symptoms, Cohort A showed failure to thrive in 8.0% of individuals, shortness of breath in 24.0% of individuals, and fever in 4.0% of individuals.In contrast, Cohort B demonstrated failure to thrive in 2.6% of individuals, shortness of breath in 20.5% of individuals, and fever in 5.1% of individuals.The presence of clubbing was noted in 12.0% of Cohort A participants but was absent in Cohort B participants (Table 1).

Pulmonary function tests
Spirometry was used to perform pulmonary function tests in 27 (42.2%)patients.Among Cohort A children, nine patients (69.2%) exhibited normal findings, one patient (7.7%) displayed an obstructive pattern, and three patients (23.1%) demonstrated a restrictive pattern, which is linked to interstitial lung diseases as the underlying cause of chronic cough.In Cohort B, 12 patients (85.7%) had normal results, while two patients (14.3%) exhibited an obstructive pattern (Fig. 1).

Radiological characteristics
Chest radiographs yielded positive results in three patients within Cohort A and six patients within Cohort B. HRCT scans revealed positive results in nine patients within Cohort A, encompassing lung collapse in four patients, consolidation in one patient, ground-glass opacity in one patient, bronchiectasis in two patients, and bilateral emphysematous changes in one patient.In contrast, Cohort B exhibited positive findings on HRCT scans in 15 patients, including lung collapse in seven patients, consolidation in three patients, bilateral crazy paving opacities in one patient, and mediastinal mass and vascular ring in two patients each (Table 2).The distribution of pathogens revealed a predominance of Haemophilus influenzae (9.4%) followed by Streptococcus pneumoniae (7.8%), Stenotrophomonas (1.6%), and Acinetobacter (1.6%).Children in Cohort A had a higher rate of positive bacterial cultures (36%) than those in Cohort B (10.3%) (P=0.028)(Table 3).

Bronchoscopic examination findings indicated a notable disparity between the two groups of patients with chronic
Regarding the final diagnosis of the studied patients, it was revealed that in Cohort A patients, protracted bacterial bronchitis was the most common diagnosis, occurring in 56.0% of the patients, followed by congenital airway anomalies in 12.0% of the patients (Fig. 2).Conversely, in Cohort B patients, congenital airway anomalies were the prevailing diagnosis, representing 35.9% of the cases.Bronchial asthma and neglected foreign body aspiration (Fig. 3) were identified in 12.8% of the patients.The diagnosis remained unknown in 16.0% of the patients in Cohort A and 7.7% of those in Cohort B (Table 4).
Table 5 illustrates the associations between age and the radiological observations, bronchoscopic outcomes, and the final diagnosis.Concerning the radiological findings, there was no statistically significant difference observed between the two age categories.Among children below 5 years of age, the predominant finding was collapse, present in 17.6% of cases, followed by consolidation in 8.8% of cases.Conversely, in children aged 5 years and above, collapse was the most prevalent findings in 13.3% of cases, followed by bronchiectasis and vascular rings each noted in 6.7% of cases.
The bronchoscopic examination revealed that congenital airway anomalies were the most prevalent findings in children under five years of age, accounting for 38.2% of cases, while purulent secretions were observed in 26.5% of the patients.In contrast, among older children, purulent secretions emerged as the predominant bronchoscopic finding, present in 46.7% of cases, with congenital airway anomalies noted in 13.3% of the patients.
A significant difference was observed between both age groups with respect to the final diagnosis.The most frequent diagnosis in children under 5 years was congenital airway anomalies (38.2%), followed by protracted bacterial bronchitis (17.6%), and neglected foreign body aspiration (14.7%).Conversely, children aged 5 years and above exhibited protracted bacterial bronchitis as the most common diagnosis (30.0%), with congenital airway anomalies and bronchial asthma each accounting for 13.3% of the cases.Additionally, certain diagnoses such as tuberculosis, plastic bronchitis, intraluminal leiomyoma, and inflammatory myofibroblast were exclusively identified in the older age group (Table 5).

Discussion
In this study, a comparison was made between bronchoscopic observations of pediatric patients experiencing chronic cough without wheezing and those exhibiting chronic wheezy cough.This study is believed to be the first to classify patients with chronic cough into two distinct groups based on the presence or absence of wheezing, with the goal of evaluating the significance of using  In the present study, the children in Cohort B were younger than those in Cohort A. The most common diagnosis in Cohort B children was congenital airway anomalies, such as dynamic tracheobronchomalacia and bronchomalacia, which usually manifest at a younger age (mean age 2.5 years) [11].Conversely, patients in Cohort A were older, as the most common final diagnosis was protracted bacterial bronchitis, which usually occurs in older children (mean age 4.5 years) and adolescents [12].
In the current study, we observed that purulent inflammatory secretions were the most frequent finding on bronchoscopy in Cohort A children, manifesting in 16 patients (64%), followed by congenital airway anomalies in 12.0% of patients.These findings are consistent with those of Douros et al., who reported that 91 (97.8%) children exhibited evident purulent inflammation (purulent bronchitis) through bronchoscopy.Interestingly, only 25 (27.1%)patients had a history of wheeze [13].
Moreover, Marchant et al. found that out of 108 children who participated in their study, 96 (89%) had a wet cough, while 12 (11%) had a dry cough.Bronchoscopic examination revealed bronchitic changes in 57 patients and malacia disorders in 36 patients [14].
In this study, Cohort B children exhibited congenital airway abnormalities as the primary finding in 14  children (35.9%), followed by the presence of purulent secretions in 17.9% of patients.These results are consistent with the findings of Abdel-Raheem et al., who reported that congenital airway anomalies were the most common finding in 15 (25%) cases, followed by airway mucosal inflammation in 13 (21.67%)cases [15].However, Sovtic et al. found that among their studied group of persistent wheeze, the prevailing bronchoscopic abnormalities were lower airway inflammatory secretions, closely followed by primary dynamic bronchomalacia [11].This observation could be attributed to the fact that, in certain participants, bronchomalacia was further complicated by chronic bacterial infection and neutrophilic bronchoalveolar lavage fluid inflammation.
In this study, it was observed that Cohort A children had a higher occurrence of positive bacterial cultures than children in Cohort B. These findings align with those of a study conducted by Zgherea et al., which revealed that children diagnosed with purulent bronchitis had a significantly higher frequency of positive bacterial cultures than those with non-purulent bronchitis [16].
In both groups, BALF yielded non-typable Haemophilus influenzae and Streptococcus pneumoniae as the most commonly isolated pathogens in our study.These findings align with those of previous studies [13,15,17].
A flexible bronchoscope proved to be advantageous for both the identification and management of protracted bacterial bronchitis and the extraction of mucus plugs in patients belonging to Cohort A. Within Cohort B, the utilization of the bronchoscope was deemed beneficial for the detection of congenital intrinsic and extrinsic airway irregularities, intraluminal leiomyoma, and inflammatory myofibroblastic tumors, which were accountable for the wheezing observed in this group.Furthermore, the bronchoscope presented itself as a viable therapeutic choice for individuals afflicted with plastic bronchitis and pulmonary alveolar proteinosis.
Our study has a few limitations.We did not routinely check the BALF for viruses that might be responsible for the purulent appearance of the lower airway secretions.Moreover, many children had taken antibiotics prior to bronchoscopy, potentially influencing the results of BALF cellular analysis and culture.

Conclusion
Flexible bronchoscopy is a valuable and safe tool for diagnosing chronic cough in children.It helped differentiate between the underlying causes of chronic cough in children with and without wheezing.Protracted bacterial bronchitis is the most common cause of chronic wet cough, whereas airway malacia is the leading cause of chronic wheezy cough in children.

Fig. 2
Fig. 2 Bronchoscopic findings, a Whitish mass completely occluding right upper lobe bronchus, b)Thick fleshy whitish mucus plug occluding the left upper and lingual bronchi, c) Secondary Tracheomalcia due to chronic infection

Fig. 3
Fig. 3 Bronchoscopic findings of neglected foreign bodies, a) Peanut seed impacted in the right lower bronchial segments in 10 year-old child, b) Granulation tissue surrounding the neglected foreign body, c) Apple seed foreign body overlying the primary carina in 1.5 year-old child

Table 1
Characteristics of the patients with chronic cough * Statistically significant at p ≤ 0.05, Cohort A: chronic cough without wheeze, Cohort B: chronic cough with wheeze, IQR: Inter quartile range, CRP: C-reactive protein Fig.1Bar chart shows results of pulmonary function tests in twenty-seven patients who were able to perform the test cough (p=0.006).Among children in Cohort A, the most prevalent bronchoscopic observation was purulent inflammatory secretions in 16 cases (64.0%), followed by congenital airway anomalies in 3 cases (12.0%).Conversely, children in Cohort B exhibited congenital airway anomalies as the primary finding in 14 cases (35.9%), followed by purulent secretions in 7 cases (17.9%).

Table 2
Radiological findings of the patients with chronic coughStatistically significant at p ≤ 0.05, Cohort A: chronic cough without wheeze, Cohort B: chronic cough with wheeze

Table 3
Bronchoscopic findings of the patients with chronic cough * Statistically significant at p ≤ 0.05, Cohort A: chronic cough without wheeze, Cohort B: chronic cough with wheeze, IQR Inter quartile range, BAL Bronchoalveolar lavage, TLC Total leucocytic count, TB Tuberculosis

Table 4
Final diagnosis of the studied patients Statistically significant at p ≤ 0.05, Cohort A: chronic cough without wheeze, Cohort B: chronic cough with wheeze *

Table 5
Correlations between the age and the radiological findings, bronchoscopic results and the final diagnosis Statistically significant at p ≤ 0.05 *