Recurrent Protracted Bacterial Bronchitis Research Articles

Diagnosis and management of protracted bacterial bronchitis: a survey of Chinese pediatricians.

BackgroundProtracted bacterial bronchitis (PBB) is a common cause of chronic wet cough in children. However, it is often misdiagnosed and inappropriately treated in clinical practices. This study aims to investigate the current diagnosis and management of PBB among Chinese pediatricians.MethodsAn electronic questionnaire designed to assess the diagnosis and management of PBB was sent to pediatricians in China.ResultsA total of 1,022 pediatricians completed the questionnaire. Most (68.8%) of the pediatricians diagnosed PBB in compliance with the guidelines, 44.3% and 24.5% of them followed microbiology-based and clinical-based diagnosis criteria, respectively. Only 40.4% of the pediatricians chose amoxicillin-clavulanate as the first-line antibiotic for PBB treatment, 23.7% and 23.5% of them chose third-generation cephalosporins and macrolides, respectively. The majority of pediatricians (75.4%) reported 2–4 weeks of antibiotics course, 19.3% of them prescribed a shorter course and 5% of them selected a longer course. Only 26.3% of the pediatricians performed combined investigations of chest high-resolution computed tomography scan (c-HRCT), bronchoscopy, and immunological tests for recurrences of PBB. Compared with general pediatricians (GP), pediatric pulmonologists (PP) preferred microbiology-based diagnosis criteria, prescribed more amoxicillin-clavulanate, and performed more investigations for recurrent patients (P<0.05).ConclusionsThe majority of Chinese pediatricians diagnosed PBB in compliance with guidelines. However, the reasonable antibiotics applications and the investigations for recurrent PBB need to be improved.

Azithromycin Prescribing by Respiratory Pediatricians in Australia and New Zealand for Chronic Wet Cough: A Questionnaire-Based Survey.

Aims: To determine how respiratory pediatricians across Australia and New Zealand prescribe azithromycin for children with chronic wet cough, including recurrent protracted bacterial bronchitis, chronic suppurative lung disease (CSLD) and bronchiectasis.Methods: A prospective web-based questionnaire was emailed to members of the Pediatric Special Interest Group of the Thoracic Society of Australia and New Zealand (TSANZ) between April and May 2018. It comprised eight demographic and 15 clinically focused questions.Results: Of the 73 respiratory pediatricians listed across Australia and New Zealand, 29 (40%) responded and all prescribed azithromycin for chronic wet cough. Twelve (41%) indicated that they would consider prescribing a short-course (2–4 weeks) of azithromycin for children with a chronic wet cough. Although most respondents reported prescribing long-term (>4-weeks) azithromycin for either CSLD (n = 23, 79%) or bronchiectasis (n = 24, 83%), only nine (31%) respondents would commence treatment if in the previous 12-months these children experienced three non-hospitalized exacerbations and just 12 (41%) would do so if there had been two hospitalisations for severe exacerbations during the same period in accordance with the TSANZ national guidelines. A lower threshold for prescribing azithromycin was described for Indigenous children or if co-morbidities were present. None prescribed azithromycin for >24-months. Macrolide-resistance was reported in Streptococcus pneumoniae and Staphylococcus aureus.Conclusion: Although Australian and New Zealand respiratory pediatricians in this survey prescribed azithromycin for chronic wet cough most often in children with either CSLD or bronchiectasis, many did so outside the current national guidelines. Reasons for this need exploring.

When the Cough Does Not Improve: A Review on Protracted Bacterial Bronchitis in Children.

Chronic cough is defined as a daily cough that persists longer than 4 weeks. Protracted bacterial bronchitis (PBB) is a common cause of chronic wet cough in preschool children with no symptoms or signs of other specific causes, and resolution usually follows a 2-week course of an appropriate oral antibiotic. The diagnosis is mainly clinical; generally, no instrumental examinations are necessary. The most common bacteria found in the bronchoalveolar lavage (BAL) of subjects with PBB include Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis. Nowadays, there is no certain evidence of the role of viruses in PBB pathogenesis even though different types of viruses have been detected in BAL from children with PBB. Airway malacia is commonly found in children with PBB; conversely, there is no correlation with any type of immunodeficiency. Amoxicillin-clavulanate acid is the most commonly used antibiotic, as first-line, prolonged therapy (longer than 2 weeks) is sometimes required to cough resolution. When the wet cough does not improve despite prolonged antibiotic treatment, an underlying disease should be considered. Moreover, there are several hypotheses of a link between PBB and bronchiectasis, as recent evidences show that recurrent PBB (>3 episodes/years) and the presence of H. influenzae infection in the lower airways seem to be significant risk factors to develop bronchiectasis. This underlines the importance of a close follow-up among children with PBB and the need to consider chest computerized tomography (CT) in patients with risk factors for bronchiectasis. In this brief review, we summarize the main clinical and pathogenetic findings of PBB, a disease that may be related to a relevant morbidity and decreased quality of life during the pediatric age.

The clinical, immunological and microbiological impact of the 10-valent pneumococcal-Protein D conjugate vaccine in children with recurrent protracted bacterial bronchitis, chronic suppurative lung disease and bronchiectasis: A multi-centre, double-blind, randomised controlled trial

ABSTRACTWe aimed to determine the efficacy of the 10-valent pneumococcal-Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) in children aged 18-months to <18-years with recurrent protracted bacterial bronchitis (rPBB), chronic suppurative lung disease (CSLD) or bronchiectasis. In a multi-centre, double-blind randomised controlled trial, children received two doses, 2-months apart of the 10vPHiD-CV or quadrivalent meningococcal-ACYW135 conjugate vaccine. Active surveillance for acute exacerbations, respiratory symptoms and antibiotic use was undertaken through to 12-months after the second vaccine dose (clinical cohort only). Serum, saliva and nasopharyngeal swabs were collected to measure immunological and microbiological effects (immunology cohort). Between December 2012 and August 2015, 62 children were enrolled onto the clinical protocol (1 excluded from clinical analyses due to unblinding), while 74 contributed to the immunology cohort (overall mean age = 6.8-years (standard deviation = 3.7), 42 (56.8%) male). The absolute risk difference comparing the 10vPHiD-CV group (n = 31 children) to the MenACYW135 group (n = 30 children) for acute exacerbations was -0.5 exacerbations/100-weeks at risk (95% confidence interval (CI) -2.0, 0.9). Compared to the MenACYW135 group, children who received the 10vPHiD-CV were less likely to have respiratory symptoms in each fortnight of surveillance (incidence density ratio (IDR) 0.82, 95%CI 0.61, 1.10) and required fewer short-course (<14-days duration) antibiotics (IDR 0.81, 95% CI 0.61, 1.09). The vaccine was immunogenic and no serious adverse events related to the vaccine were reported. In conclusion, 10vPHiD-CV might have a future role in managing children with rPBB, CSLD and bronchiectasis, but larger multicentre trials are needed to confirm or refute findings from this preliminary study.

Protracted bacterial bronchitis and primary ciliary dyskinesia in children

Protracted bacterial bronchitis (PBB) and primary ciliary dyskinesia (PCD) have the same pathogenetic change of abnormal mucociliary clearance, but the initial factors are different. The former is the secondary changes caused by infections, and the latter is caused by ciliary structure and/or dysfunction. They all have chronic wet cough, so the differential diagnosis is important.Visceral transposition, recurrent otitis media, sinusitis and pseu-domonas aeruginosa infection can help to identify PCD from PBB. But if the patients have recurrent PBB or no reaction to common antibiotic therapy, PCD is needed to be identified.Rational application of antibacterial drugs and whole course vaccine inoculation to prevent recurrent infections are important to both of the two diseases. Key words: Protracted bacterial bronchitis; Primary ciliary dyskinesia; Child

Definition and pathogenesis of protracted bacterial bronchitis in children

Protracted bacterial bronchitis (PBB) is a common cause of children with chronic wet cough.Original microbiologic-based case of PBB was defined as wet cough (>4 weeks) without signs of another cause, bacterial pathogens growing and quantitative culture ≥107 cfu/L in bronchoalveolar lavage fluid and cough resolved following a 2-week course of an appropriate oral antibiotics (usually amoxicillin-clavulanate). In recent years, clinical-based case definition of PBB, refractory PBB and recurrent PBB have been proposed to increase its clinical applicability.At present, the pathogenesis of PBB including biofilm formation, impaired airway muco-ciliary clearance, neutrophil inflammation, immune dysfunction and inappropriate use of antibiotics. Key words: Protracted bacterial bronchitis; Chronic cough; Child; Bronchoalveolar lavage fluid

Multiple inflammasomes may regulate the interleukin-1-driven inflammation in protracted bacterial bronchitis.

Protracted bacterial bronchitis (PBB) in young children is characterised by prolonged wet cough, prominent airway interleukin (IL)-1β expression and infection, often with nontypeable Haemophilus influenzae (NTHi). The mechanisms responsible for IL-1-driven inflammation in PBB are poorly understood.We hypothesised that the inflammation in PBB involves the NLRP3 and/or AIM2 inflammasome/IL-1β axis. Lung macrophages obtained from bronchoalveolar lavage (BAL), peripheral blood mononuclear cells (PBMCs), blood monocytes and monocyte-derived macrophages from patients with PBB and age-matched healthy controls were cultured in control medium or exposed to live NTHi.In healthy adult PBMCs, CD14+ monocytes contributed to 95% of total IL-1β-producing cells upon NTHi stimulation. Stimulation of PBB PBMCs with NTHi significantly increased IL-1β expression (p<0.001), but decreased NLRC4 expression (p<0.01). NTHi induced IL-1β secretion in PBMCs from both healthy controls and patients with recurrent PBB. This was inhibited by Z-YVAD-FMK (a caspase-1 selective inhibitor) and by MCC950 (a NLRP3 selective inhibitor). In PBB BAL macrophages inflammasome complexes were visualised as fluorescence specks of NLRP3 or AIM2 colocalised with cleaved caspase-1 and cleaved IL-1β. NTHi stimulation induced formation of specks of cleaved IL-1β, NLRP3 and AIM2 in PBMCs, blood monocytes and monocyte-derived macrophages.We conclude that both the NLRP3 and AIM2 inflammasomes probably drive the IL-1β-dominated inflammation in PBB.

Cytokine responses to two common respiratory pathogens in children are dependent on interleukin-1β.

Protracted bacterial bronchitis (PBB) in young children is a common cause of prolonged wet cough and may be a precursor to bronchiectasis in some children. Although PBB and bronchiectasis are both characterised by neutrophilic airway inflammation and a prominent interleukin (IL)-1β signature, the contribution of the IL-1β pathway to host defence is not clear.This study aimed to compare systemic immune responses against common pathogens in children with PBB, bronchiectasis and control children and to determine the importance of the IL-1β pathway.Non-typeable Haemophilus influenzae (NTHi) stimulation of peripheral blood mononuclear cells (PBMCs) from control subjects (n=20), those with recurrent PBB (n=20) and bronchiectasis (n=20) induced high concentrations of IL-1β, IL-6, interferon (IFN)-γ and IL-10. Blocking with an IL-1 receptor antagonist (IL-1Ra) modified the cellular response to pathogens, inhibiting cytokine synthesis by NTHi-stimulated PBMCs and rhinovirus-stimulated PBMCs (in a separate PBB cohort). Inhibition of IFN-γ production by IL-1Ra was observed across multiple cell types, including CD3+ T cells and CD56+ NK cells.Our findings highlight the extent to which IL-1β regulates the cellular immune response against two common respiratory pathogens. While blocking the IL-1β pathway has the potential to reduce inflammation, this may come at the cost of protective immunity against NTHi and rhinovirus.

Protracted Bacterial Bronchitis in Children: Natural History and Risk Factors for Bronchiectasis

Protracted bacterial bronchitis (PBB) and bronchiectasis are distinct diagnostic entities that share common clinical and laboratory features. It is postulated, but remains unproved, that PBB precedes a diagnosis of bronchiectasis in a subgroup of children. In a cohort of children with PBB, our objectives were to (1) determine the medium-term risk of bronchiectasis and (2) identify risk factors for bronchiectasis and recurrent episodes of PBB. One hundred sixty-one children with PBB and 25 control subjects were prospectively recruited to this cohort study. A subset of 106 children was followed for 2 years. Flexible bronchoscopy, BAL, and basic immune function tests were performed. Chest CT was undertaken if clinical features were suggestive of bronchiectasis. Of 161 children with PBB (66%boys), 13 were diagnosed with bronchiectasis over the study period (8.1%). Almost one-half with PBB (43.5%) had recurrent episodes (> 3/y). Major risk factors for bronchiectasis included lower airway infection with Haemophilus influenzae (recovered in BAL fluid) (P= .013) and recurrent episodes of PBB (P= .003). H influenzae infection conferred a more than seven times higher risk of bronchiectasis (hazard ratio, 7.55; 95%CI, 1.66-34.28; P= .009) compared with no H influenzae infection. The majority of isolates (82%) were nontypeable H influenzae. No risk factors for recurrent PBB were identified. PBB is associated with a future diagnosis of bronchiectasis in a subgroup of children. Lower airway infection with H influenzae and recurrent PBB are significant predictors. Clinicians should be cognizant of the relationship between PBB and bronchiectasis, and appropriate follow-up measures should be taken in those with risk factors.

Is Alveolar Macrophage Phagocytic Dysfunction in Children With Protracted Bacterial Bronchitis a Forerunner to Bronchiectasis?

Children with recurrent protracted bacterial bronchitis (PBB) and bronchiectasis share common features, and PBB is likely a forerunner to bronchiectasis. Both diseases are associated with neutrophilic inflammation and frequent isolation of potentially pathogenic microorganisms, including nontypeable Haemophilus influenzae (NTHi), from the lower airway. Defective alveolar macrophage phagocytosis of apoptotic bronchial epithelial cells (efferocytosis), as found in other chronic lung diseases, may also contribute to tissue damage and neutrophil persistence. Thus, in children with bronchiectasis or PBB and in control subjects, we quantified the phagocytosis of airway apoptotic cells and NTHi by alveolar macrophages and related the phagocytic capacity to clinical and airway inflammation. Children with bronchiectasis (n = 55) or PBB (n = 13) and control subjects (n = 13) were recruited. Alveolar macrophage phagocytosis, efferocytosis, and expression of phagocytic scavenger receptors were assessed by flow cytometry. Bronchoalveolar lavage fluid interleukin (IL) 1β was measured by enzyme-linked immunosorbent assay. For children with PBB or bronchiectasis, macrophage phagocytic capacity was significantly lower than for control subjects (P = .003 and P < .001 for efferocytosis and P = .041 and P = .004 for phagocytosis of NTHi; PBB and bronchiectasis, respectively); median phagocytosis of NTHi for the groups was as follows: bronchiectasis, 13.7% (interquartile range [IQR], 11%-16%); PBB, 16% (IQR, 11%-16%); control subjects, 19.0% (IQR, 13%-21%); and median efferocytosis for the groups was as follows: bronchiectasis, 14.1% (IQR, 10%-16%); PBB, 16.2% (IQR, 14%-17%); control subjects, 18.1% (IQR, 16%-21%). Mannose receptor expression was significantly reduced in the bronchiectasis group (P = .019), and IL-1β increased in both bronchiectasis and PBB groups vs control subjects. A reduced alveolar macrophage phagocytic host response to apoptotic cells or NTHi may contribute to neutrophilic inflammation and NTHi colonization in both PBB and bronchiectasis. Whether this mechanism also contributes to the progression of PBB to bronchiectasis remains unknown.

Mediators of Neutrophil Function in Children With Protracted Bacterial Bronchitis

Protracted bacterial bronchitis (PBB) is a common and treatable cause of chronic wet cough in children in which the mechanisms are not understood. This study investigates the IL-1 pathway and a neutrophil gene expression signature in PBB. BAL was collected from children in an experimental cohort (n = 21, PBB; n = 33, control subjects), and a second validation cohort (n = 36, PBB; n = 11, control subjects). IL-1β, IL-1 receptor antagonist (IL-1RA), and α-defensins 1-3 were assayed by enzyme-linked immunosorbent assay, western blot, and quantitative real-time polymerase chain reaction, together with selected IL-1 pathway members and neutrophil-related molecules. In the experimental cohort, children with symptomatic PBB had significantly higher levels of IL-1β and α-defensin gene and protein expression. Expression of the neutrophil chemokine receptor C-X-C motif receptor 2 was also higher in PBB. IL-1RA protein was higher, however, the IL-1RA:IL-1β ratio was lower in children with PBB than control subjects. In the validation cohort, protein and gene expression of IL-1β and α-defensins 1-3 were confirmed higher, as was gene expression of IL-1 pathway members and C-X-C motif receptor 2. IL-1β and α-defensin 1-3 levels lowered when PBB was treated and resolved. In children with recurrent PBB, gene expression of the IL-1β signaling molecules pellino-1 and IL-1 receptor-associated kinase 2 was significantly higher. IL-1β protein levels correlated with BAL neutrophilia and the duration and severity of cough symptoms. IL-1β and α-defensin 1-3 levels were highly correlated. PBB is characterized by increased IL-1β pathway activation. IL-1β and related mediators were associated with BAL neutrophils, cough symptoms, and disease recurrence, providing insight into PBB pathogenesis.

Does a 10-valent pneumococcal-Haemophilus influenzae protein D conjugate vaccine prevent respiratory exacerbations in children with recurrent protracted bacterial bronchitis, chronic suppurative lung disease and bronchiectasis: protocol for a randomised controlled trial.

BackgroundRecurrent protracted bacterial bronchitis (PBB), chronic suppurative lung disease (CSLD) and bronchiectasis are characterised by a chronic wet cough and are important causes of childhood respiratory morbidity globally. Haemophilus influenzae and Streptococcus pneumoniae are the most commonly associated pathogens. As respiratory exacerbations impair quality of life and may be associated with disease progression, we will determine if the novel 10-valent pneumococcal-Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) reduces exacerbations in these children.MethodsA multi-centre, parallel group, double-blind, randomised controlled trial in tertiary paediatric centres from three Australian cities is planned. Two hundred six children aged 18 months to 14 years with recurrent PBB, CSLD or bronchiectasis will be randomised to receive either two doses of PHiD-CV or control meningococcal (ACYW135) conjugate vaccine 2 months apart and followed for 12 months after the second vaccine dose. Randomisation will be stratified by site, age (<6 years and ≥6 years) and aetiology (recurrent PBB or CSLD/bronchiectasis). Clinical histories, respiratory status (including spirometry in children aged ≥6 years), nasopharyngeal and saliva swabs, and serum will be collected at baseline and at 2, 3, 8 and 14 months post-enrolment. Local and systemic reactions will be recorded on daily diaries for 7 and 30 days, respectively, following each vaccine dose and serious adverse events monitored throughout the trial. Fortnightly, parental contact will help record respiratory exacerbations. The primary outcome is the incidence of respiratory exacerbations in the 12 months following the second vaccine dose. Secondary outcomes include: nasopharyngeal carriage of H. influenzae and S. pneumoniae vaccine and vaccine- related serotypes; systemic and mucosal immune responses to H. influenzae proteins and S. pneumoniae vaccine and vaccine-related serotypes; impact upon lung function in children aged ≥6 years; and vaccine safety.DiscussionAs H. influenzae is the most common bacterial pathogen associated with these chronic respiratory diseases in children, a novel pneumococcal conjugate vaccine that also impacts upon H. influenzae and helps prevent respiratory exacerbations would assist clinical management with potential short- and long-term health benefits. Our study will be the first to assess vaccine efficacy targeting H. influenzae in children with recurrent PBB, CSLD and bronchiectasis.Trial registrationAustralia and New Zealand Clinical Trials Registry (ANZCTR) number: ACTRN12612000034831.