Chronic (>4 weeks duration) wet cough in children implies increased airway secretions and lower airway infection (1). It is associated with often unrecognized morbidity and impaired quality of life (QoL) scores (2, 3). Within Australia, the most common cause of chronic wet cough in children is protracted bacterial bronchitis (PBB), followed by bronchiectasis (4). These two entities are at the opposite ends of a spectrum of overlapping conditions characterized by chronic wet cough, airway neutrophilia, and high bacterial densities in bronchoalveolar lavage (BAL) fluid cultures (5). They also share a common risk factor of impaired airway clearance facilitating microbial colonization of the lower airways (6), while their lower airway microbiota are dominated by strains of non-typeable Haemophilus influenzae (NTHi), Streptococcus pneumoniae, and Moraxella catarrhalis (1, 7–15).

Protracted bacterial bronchitis is defined as an illness with an isolated wet cough >4 weeks duration that resolves with a prolonged 2–4 weeks of appropriate oral antibiotic treatment, usually amoxicillin–clavulanate, and where other pointers suggestive of an alternative cause of cough are absent (16). It is a relatively newly defined diagnosis, but likely represents illnesses previously termed as chronic bronchitis, persistent endobronchial infection, or pre-bronchiectasis (16, 17).

By contrast, bronchiectasis has many underlying causes and is diagnosed when there is a chronic wet cough, which has a variable response to even prolonged courses of oral antibiotics, frequent respiratory exacerbations, and radiographic demonstration of irreversible dilatation of one or more bronchi (18). These children often have other accompanying respiratory symptoms and signs too, including growth failure, exertional dyspnea, digital clubbing, chest wall deformity, hyperinflation, and adventitial sounds on chest auscultation. The most common etiologies of bronchiectasis in children include post-infectious causes following recurrent and/or severe lower respiratory infections in early life, cystic fibrosis (CF), primary ciliary dyskinesia, immunodeficiency, retained foreign body, and chronic aspiration (12, 18).

Between the diagnostic spectrum of PBB and bronchiectasis are children with chronic suppurative lung disease (CSLD) who have the clinical symptoms and signs suggestive of bronchiectasis but lack the chest high-resolution computed tomography (cHRCT) scan evidence to support a diagnosis of bronchiectasis, such as an increased broncho-arterial ratio and absence of bronchial tapering while progressing toward the lung periphery (18, 19). Some of those categorized as having CSLD live in remote Indigenous communities in Australia and Alaska where undergoing cHRCT scans is difficult logistically and may be delayed until late in adolescence. Consequently, some of the younger children with CSLD may have undiagnosed bronchiectasis. In light of this and as management is the same for both diagnostic entities (19), this review focuses upon preventing respiratory exacerbations in children with either CSLD or bronchiectasis.

While published data are currently limited, recurrent episodes of PBB can also occur. In a study of 106 children with PBB followed for 2 years (20), 43.5% had >3 episodes per year and bronchiectasis was diagnosed subsequently in 8.1% of study participants (20). H. influenzae infection in the lower airways and recurrent episodes of PBB were independently associated with a future diagnosis of bronchiectasis [odds ratio (OR) 7.60, 95% confidence interval (CI) 1.53, 37.79 and OR 11.48, 95% CI 2.33, 56.50, respectively] (20). Nevertheless, children with recurrent PBB are not included in this review as the point where they progress to CSLD or bronchiectasis is yet to be determined, especially if they respond promptly to antibiotics and do not have additional symptoms or signs of respiratory disease. While CF is an important cause of chronic wet cough and bronchiectasis, children with CF are also excluded here given differences in the type of disease and concerns that the findings of studies in this patient population should not be extrapolated to those with bronchiectasis unrelated to CF (21).

Acute pulmonary exacerbations are associated with disease severity (7), and although there are no direct data for CSLD or bronchiectasis in children, exacerbations are likely to contribute to a decline in lung function. Determinants of accelerated lung function decline in adults with bronchiectasis are frequency of hospitalized exacerbations, increased systemic inflammatory markers, and infection with Pseudomonas aeruginosa (22). Among other factors, increased mortality risk is associated with degree of lung function impairment (23). In children, studies from Australia and the United Kingdom reported that children with normal lung function at the time bronchiectasis was diagnosed maintained normal lung function 5 years later (24–26). Those children with poor lung function at diagnosis, although substantially improved, were still likely to have poor lung function 5 years afterward with the only significant predictor of pulmonary decline being the frequency of hospitalized exacerbations (25). With each hospitalized exacerbation, the forced expiratory volume in 1-s percentage (FEV₁%) predicted decreased by 1.95% adjusted for time (25). Thus, interventions that minimize exacerbation frequencies are likely to be important in the overall management of bronchiectasis (19). In addition, preventing exacerbations will potentially reduce the associated economic and social costs. In the United States, between 1993 and 2006, the median cost for adult inpatient care was US$7,827 (27). Hospitalization rates increased significantly over the study time period with an annual percentage increase of 2.4% for males and 3.0% for females (27). At a New Zealand Hospital in 2004, half of the service’s pediatric bronchiectasis patients required at least one hospital admission per year (range 1–10) for exacerbations (28). The mean length of stay was 7 days (range 1–25). Eight percent of these children had regular three to four monthly admissions for 14 days to maintain respiratory status at a mean cost in 2004 of US$5,492 (not including theater time or costs for inserting peripherally inserted central catheter vascular lines) for each hospitalization (28).

As with the paucity of data on CSLD and bronchiectasis in children in general (29), there is a dearth of literature defining an acute exacerbation. In adults, acute exacerbations of chronic obstructive pulmonary disease (COPD) are characterized by worsening dyspnea and increasing sputum volume and/or purulence (30). In adult bronchiectasis, exacerbations have similar features to that of COPD with increased cough frequency and sputum volume or purulence and are often associated with culturing respiratory bacterial pathogens in sputum (31). In research settings, particularly studies with exacerbations as the primary outcome, the definition may also include the need for hospitalization and intravenous antibiotics (32).

Clinical trials in children are currently using (33–36) similar definitions to that used in adults, including variations in symptoms of increased cough, dyspnea, increased sputum volume or color intensity, new chest examination or radiographic findings, deterioration in FEV₁% predicted >10%, or hemoptysis. Not all definitions have, however, included the need for hospitalization or intravenous antibiotics.

In a study of 30 children with 115 exacerbations of bronchiectasis (25), increased cough frequency (88%) and change in cough character (67%) were the most frequent symptoms reported. Fever (28%), increased sputum volume (42%) and purulence (35%), and deteriorating chest auscultatory findings (58%) were also common, while changes in spirometry values compared to the stable state were not (25). Further work was undertaken from this cohort’s data (81 exacerbations included) (37) to develop a standardized definition of an exacerbation in children with bronchiectasis. Wet cough and cough severity (score ≥2) over 72 h were the best predictors of an exacerbation [receiver operating characteristic area under the curve of 0.85 (95% CI 0.79, 0.92) and 0.84 (95% CI 0.77, 0.91), respectively] (37). Sputum color, dyspnea, hemoptysis, chest signs, and chest pain were considered minor criteria and the addition of serum C-reactive protein (CRP), amyloid-A, and interleukin-6 improved the specificity and positive predictive value of the definition (37). The authors subsequently classified symptoms and laboratory measures into three sets of criteria (major, minor, and laboratory—Box 1) and then devised three options that could be used to define an exacerbation in bronchiectasis (Box 1). A limitation of the study is that there was a lack of an objective gold standard for diagnosing an exacerbation in bronchiectasis and hence the criteria were assessed against a pediatric pulmonologist’s definition that included change in symptoms and the need for additional treatment beyond the stable state. Further studies validating the definition in larger cohorts are now awaited.

The exact cause of exacerbations in young children with CSLD or bronchiectasis is not well understood, and it is unclear whether these are new infections, a resurgence of chronic infection, or a combination of both (31, 38). Part of the problem is that despite their regular use in clinical practice, upper airway secretions collected by throat or cough swabs do not reliably predict organisms within the lower airways (9), especially as the potential pathogens of interest (NTHi, S. pneumoniae, and M. catarrhalis) are also found commonly in the upper airway spaces of healthy children (39). Repeated bronchoscopies with multi-lobar BAL to collect lower airway specimens before, during, and following acute exacerbations in children too young to reliably expectorate sputum would be ideal, but impractical given their invasive nature, including the need for repeated sedation or general anesthesia. Hence the data required to confidently assign causality in research and patient care are limited.

Haemophilus influenzae, S. pneumoniae, and M. catarrhalis are frequently isolated at high densities (≥10⁴ colony-forming units/mL) from BAL specimens collected from children and adults during an acute exacerbation, but mixed infections are also common (9, 13), and few studies have searched systematically for viruses. P. aeruginosa and non-tuberculous mycobacteria are uncommon in children with bronchiectasis and, when present, raises the possibility of undiagnosed CF while also being associated with more severe underlying bronchiectasis and co-morbidities (13). A small study of 69 children with bronchiectasis that included 900 child-months of follow-up (40) identified at least one respiratory virus in nasopharyngeal aspirates in 48% of exacerbations, most commonly human rhinovirus (54% of virus-positive events). Children with virus-positive exacerbations were more likely to require hospitalization (59 vs 32.5%; p = 0.02), have fever (OR 3.1, 95% CI 1.2, 11.1), hypoxia (OR 25.5, 95% CI 2.0, 322.6), chest signs (OR 3.3, 95% CI 1.1, 10.2), and raised CRP (OR 4.7, 95% CI 1.7, 13.1), when compared with virus-negative exacerbations (40).

In a cross-sectional study of 245 children diagnosed with PBB or mild bronchiectasis undergoing bronchoscopy and BAL for clinical indication (median age 30 months) (41), a standard respiratory panel for viruses using polymerase chain reaction assays was performed on all specimens. Human adenovirus (HAdV) was the most common virus detected, being identified in 40 children; influenza virus was detected in 3 children, parainfluenza virus in 12, respiratory syncytial virus in 11, and human metapneumovirus in 5 children (41). HAdV detection was more common in the young age groups (p = 0.001) and was positively associated with each of the three major bacterial pathogens (41). However, this association disappeared after adjustment for age and, given both the cross-sectional nature of the study with a lack of controls, a causal association between detecting these viruses and clinical illness at the time of bronchoscopy cannot be determined.

Similarly, there are very few studies examining the risk factors for exacerbations of CSLD or bronchiectasis. A study of 93 Indigenous children from Alaska and Australia with CSLD or bronchiectasis (42) reported 74% of children experienced >2 exacerbations over a 3-year period. In this study, the factors associated with recurrent episodes were young age (<3 years), hospitalization for an acute exacerbation in the first-year of life, and pneumonia or hospitalization for an acute exacerbation in the year preceding enrollment (42). Exacerbations are also more frequent in severe bronchiectasis, and one study of 111 children reported that intensive medical intervention reduced the annual exacerbation rate by 56%; however, children still experienced a mean of 2.9 episodes per year (43).

Preventing exacerbations and reducing severity, are important goals in managing children with CSLD or bronchiectasis in order to maintain lung health and enhance their QoL (19). The cornerstone of CSLD management is a combination of airway clearance techniques and antibiotic therapy, with or without other therapies such as anti-inflammatory agents and bronchodilators (31, 38, 44). However, moderate or high-quality studies in children for either CSLD or bronchiectasis are limited (45), including those addressing broader approaches such as vaccines, health promotion, and chronic disease management strategies.

Chronic suppurative lung disease and bronchiectasis in children and adolescents are serious illnesses with significant adverse impacts on the child, their family, the health-care sector, and broader community. Despite this, there has been scant attention paid to the spectrum of disease, its management, and prevention in comparison to CF and chronic lung diseases in adults. Exacerbations of CSLD and bronchiectasis in children are important predictors of lung function decline and are associated with significant morbidity. Preventing exacerbations should, therefore, be the cornerstone of long-term disease management. However, there are only limited data on preventing acute respiratory exacerbations in children with CSLD or bronchiectasis. Hence management is currently informed largely by clinical opinion and extrapolating data from adults and/or children with CF and asthma, Unfortunately, such an approach is not without risk, where treatments highly successful in CF patients such as inhaled rhDNase, tobramycin, aztreonam, and colistin have provided disappointing results in adults with bronchiectasis (132). A standardized, validated definition of an acute exacerbation in children with CSLD and bronchiectasis is needed urgently as an outcome measure in clinical trials and to help guide clinical practice. In a similar vein, studies to determine when recurrent episodes of PBB should be classified and managed as CSLD are also required. Substantially more, and larger studies, are needed to determine the efficacy and effectiveness of both pharmacological and non-pharmacological interventions to prevent exacerbations. These studies must also include health-related QoL assessments and cost-effectiveness of the interventions. Given the burden of disease is likely to be highest in low- and middle-income countries, measures to prevent exacerbations must be translated to low socioeconomic and disadvantaged community and health-care settings that do not have access to the drugs and technology available in high-income nations.

For the clinician, the lack of robust well-designed, intervention-based RCT to guide prevention of acute exacerbations of CSLD and bronchiectasis in children and adolescents means that guidelines are more consensus than evidence-based. We follow the Thoracic Society of Australia and New Zealand (TSANZ) guidelines (19, 74) where children and adolescents are seen three times monthly and where we recommend they practice regular airway clearance techniques in consultation with a pediatric respiratory physiotherapist, encourage physical activity, monitor growth and optimize nutrition, counsel against active and passive tobacco smoke exposure, promote avoidance of other environmental inhaled toxicants, and ensure they receive their vaccinations according to the National Immunization Program, including the pneumococcal and annual seasonal influenza vaccines. At the same time, co-morbidities, such as underlying immunodeficiency or chronic aspiration, are often managed with the aid of other specialty services. Children and adolescents who are frequent exacerbators (≥3 exacerbations and/or ≥2 respiratory hospitalizations in the previous 12 months) are prescribed low-dose oral azithromycin for a trial period of 12–24 months according to the TSANZ guidelines. Selected patients are offered inhaled hypertonic saline as a mucoactive agent and/or an inhaled antibiotic, usually tobramycin, if exacerbations continue, especially if they have a chronic P. aeruginosa infection of their lower airways. These agents are trialed separately and if tolerated are continued long term. Finally, bronchodilators and inhaled corticosteroids are administered only to those with an established diagnosis of asthma and are not used routinely for other patients with CSLD or bronchiectasis.

KO devised the scope of the manuscript, performed the literature reviews, and wrote the first and final draft. KG made a substantial contribution to the content and writing of the manuscript. Both the authors approved the final version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.