key: cord-1020325-scx045c5
authors: Chang, Anne B.; Upham, John W.; Masters, I. Brent; Redding, Gregory R.; Gibson, Peter G.; Marchant, Julie M.; Grimwood, Keith
title: Protracted bacterial bronchitis: The last decade and the road ahead
date: 2015-12-04
journal: Pediatr Pulmonol
DOI: 10.1002/ppul.23351
sha: 4cccf983820c77b8b51c3c9f4ec457611de9f170
doc_id: 1020325
cord_uid: scx045c5

Cough is the single most common reason for primary care physician visits and, when chronic, a frequent indication for specialist referrals. In children, a chronic cough (>4 weeks) is associated with increased morbidity and reduced quality of life. One common cause of childhood chronic cough is protracted bacterial bronchitis (PBB), especially in children aged <6 years. PBB is characterized by a chronic wet or productive cough without signs of an alternative cause and responds to 2 weeks of appropriate antibiotics, such as amoxicillin‐clavulanate. Most children with PBB are unable to expectorate sputum. If bronchoscopy and bronchoalveolar lavage are performed, evidence of bronchitis and purulent endobronchial secretions are seen. Bronchoalveolar lavage specimens typically reveal marked neutrophil infiltration and culture large numbers of respiratory bacterial pathogens, especially Haemophilus influenzae. Although regarded as having a good prognosis, recurrences are common and if these are frequent or do not respond to antibiotic treatments of up to 4‐weeks duration, the child should be investigated for other causes of chronic wet cough, such as bronchiectasis. The contribution of airway malacia and pathobiologic mechanisms of PBB remain uncertain and, other than reduced alveolar phagocytosis, evidence of systemic, or local immune deficiency is lacking. Instead, pulmonary defenses show activated innate immunity and increased gene expression of the interleukin‐1β signalling pathway. Whether these changes in local inflammatory responses are cause or effect remains to be determined. It is likely that PBB and bronchiectasis are at the opposite ends of the same disease spectrum, so children with chronic wet cough require close monitoring. Pediatr Pulmonol. 2016;51:225–242. © 2015 Wiley Periodicals, Inc.

Cough is the single most common reason given for patients seeking treatment in primary care. 1, 2 In Australia, 7% of acute medical consultations (1.38 million/year) are for a coughing illness. 1, 3 Among these presentations are children with a chronic cough >4-weeks duration where in the previous 12 months as many as 80% are likely to have seen a doctor for their symptoms on more than five occasions. 4 Chronic cough in childhood is also associated with considerable morbidity 5 and decreased quality of life (QoL) scores, 4, 6 which normalize once the cough resolves following appropriate therapy. 7 Of the many possible etiologies, single 8 and multicenter studies 7 recruiting primarily from pediatric referral centers have found that protracted bacterial bronchitis (PBB) is the most common cause of chronic cough in childhood, exceeding by two-to-threefold other underlying diagnoses, including asthma. This article summarizes current knowledge of PBB in children, presents further preliminary data on underlying disease mechanisms, and identifies research priorities to help further close the information gap for this common, but poorly understood condition.

The term PBB was first defined a priori and was based on our clinical experience before being applied to a subgroup of children in our prospective study evaluating the etiology of chronic cough. 8 The diagnostic criteria were: (i) history of chronic wet cough; (ii) positive bronchoalveolar lavage (BAL) fluid cultures for respiratory bacterial pathogens at densities !10 4 colonyforming units (CFU)/ml of BAL fluid without serologic or polymerase chain reaction (PCR) assay evidence of infection by either Bordetella pertussis or Mycoplasma pneumoniae; and (iii) cough resolution after a 2-week course of oral antibiotics (amoxicillin-clavulanate). 8 However, undertaking flexible bronchoscopy and BAL on every young child with a chronic wet cough is impractical and many older children are also unable to expectorate sputum of sufficient quality for reliable culture. Consequently, we altered our original definition of PBB to a more pragmatic one (Table 1 ). This acknowledges the multiple causes of chronic wet cough in children. 7, 9 Diagnostic Criteria Validity While the initial PBB criteria were derived from clinical observations, each of the initial PBB criteria have now been validated. For criterion-(i), for example, chronic wet cough (>4 weeks), our urban-based study of parental recognition of wet cough showed excellent agreement with pediatric pulmonologists (kappa (k) ¼ 0.75, 95% confidence interval (CI) 0.58-0.93) and bronchoscopic findings of endobronchial secretions (area under the receiver operating curve ¼ 0.85, 95%CI 0.77-0.92). 10 Also, prospective 11, 12 and retrospective 13 studies have demonstrated that BAL cultures from children with chronic wet cough have respiratory bacterial densities (!10 4 CFU/ml) indicating lower airway infection. Further, increased amounts of secretions detected on bronchoscopy were associated with increased likelihood of infection and airway neutrophilia. 11 The original criterion-(ii) required BAL specimens to have positive respiratory bacterial cultures !10 4 CFU/ml, 8 which is a threshold often used for diagnosing lower airway infection. [14] [15] [16] The common pathogens (Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis) reported initially in PBB 8 have been reaffirmed by several other groups. 13, [17] [18] [19] Finally, a Cochrane review of two randomized controlled trial (RCTs) found that antibiotics (criterioniii) improved the odds of curing chronic wet cough in children odds ratio (OR) ¼ 7.7 (95%CI 3.1-16.7). 20 Although both RCTs were limited by small numbers (total n ¼ 140), they nevertheless provided experimental data that supported clinical observations. These results have been confirmed recently by a double-blind RCT. 21 Diagnostic Criteria Limitations Nonetheless, each criteria described above has their limitations. Recognizing wet cough is dependent upon clinical setting. The child's age, the accuracy of their 10 In our experience, older children may have an underlying productive cough despite it sounding dry when asked to cough in the clinic ("cough on request"). This may be partially related to the secretion volume relative to airway size, which has been described in animal studies where the amount of secretions alters sound characteristics. 23 While lower airway infection is often defined as bacterial growth !10 4 CFU/ml in BAL, 14, 15 the most robust cut-off remains unknown. 24 Thus, different studies employing BAL have used slightly different definitions of PBB (Tables 2-4) .

Although the response to 2 weeks of antibiotics is one of the criteria used to diagnose PBB, we 9 and others 18, 19 have observed that some children require a longer treatment of 4 weeks. The number needed to treat for benefit (NNT-B) by 2 weeks found in the Cochrane review 20 and the RCT 21 was 3-4 (95%CI 2-27) and it is possible that using a longer course may reduce the NNT-B (see below).

The variation in definitions is similar to pediatric asthma where varying definitions depend upon age, clinical and/or research setting, and availability of tests for airway cellularity, lung function, and airway hyper-responsiveness. Given these limitations, the definition of PBB may be refined further; particularly if a simple biomarker is identified that predicts the response to antibiotics.

To advance the field for clarity, we propose the following definition: 1. PBB-micro ¼ original definition. 8 2. PBB-clinical ¼ the modified criteria where criterion-ii (BAL component) is replaced by: "absence of other causes of wet/productive cough." 

When we first described PBB in 2006, 8 its existence as a distinct diagnostic entity was controversial. 25 However, it is becoming recognized increasingly and is now incorporated into pediatric chronic cough guidelines ( Table 2 ) and into the European pediatric respiratory training curriculum. 26 Astute clinicians alluded to PBB-like conditions previously, but did not consolidate these observations into a clinical entity supported by laboratory-based data. Various definitions used in the 1970-80s described "childhood chronic bronchitis" ranging from productive cough for 3 months/year to recurrent episodes of cough lasting >2 weeks with/without wheeze. 27 During this period, a single center review of 20 children undergoing bronchoscopy and diagnosed with chronic bronchitis found all had evidence of bronchial wall inflammation and purulent endobronchial secretions, and most improved after a course of antibiotics. 28 In the 1940s, a series of studies on childhood bronchiectasis raised the possibility of a pre-bronchiectasis state, 29 which was reversible by aggressive antibiotic treatment, while another study suggested a link between chronic bronchitis and bronchiectasis. 30 A later report described chronic bacterial bronchitis in children with tracheo-bronchomalacia, 31 and more recently others have suggested that some children with so called "difficult asthma," persistent wheeze 32 or asthma-bronchitis might have PBB (parents of children with PBB often describe wheezing illnesses). 18, 33 Indeed, a retrospective French study reported one in eight children undergoing bronchoscopy for "severe chronic asthma" had lower airway infection (defined as >10 5 CFU/ml or >10 4 CFU/ml with activated neutrophils). 34 

Several cohort studies of children with chronic cough have documented the disease burden, QoL scores, medication use and number of doctor visits for the subgroup with PBB. 4, 7 Prevalence

The true prevalence of PBB cases presenting to community clinics is unknown. Studies from specialist clinics from Australia 7,8 and Turkey 35, 36 found PBB to be among the top three diagnoses in children with chronic cough (Table 3 ). Using a standard management approach, 37 a priori definitions and validated cough outcome measures, an Australian multicenter study 7 found that 142/346 (41%) children newly referred for chronic cough had PBB, which predominated in younger children. 7 A United Kingdom (UK)-based retrospective study reported PBB was the most common diagnosis made in their clinic in children referred with difficult asthma or a chronic cough, and this disorder was increasing annually. 18 

There are limited data on the QoL of children with PBB and that of their parents. In a multi-center study, the generic health-related (PedsQL 38 ) and chronic cough-specific (PC-QoL) QoL scores of children with PBB were similar to other different diagnostic groups (asthma, bronchiectasis, those whose chronic cough resolved without treatment) presenting to pediatric pulmonologists. 39, 40 Importantly, QoL scores normalize once the cough resolves. 41 

Typically, before diagnosis, children with PBB have received multiple medications and consulted several health physicians. 4,7 A Sheffield study 18 reported that at the time of referral, 59% of 81 children with PBB were taking asthma treatments, while an Australian multicenter study found 70% of 138 children with this diagnosis had received asthma medications and 76% had seen >5 doctors previously because of persistent cough. 40 However, these findings were also similar to children with chronic cough from other causes. 40 

There are relatively few clinical studies of children with PBB (Tables 4 and 5 ). By definition, they all have a chronic wet cough. Although children with PBB are typically young (mean or median age 1.8-4.8 years, Table 4 ), PBB also occurs in older (>12 years) children. 7, 42, 43 Our first cohort of 43 children with PBB lacked systemic symptoms, including evidence of sinusitis and ear disease. 8 This was confirmed in a subsequent prospective cohort of 104 children. 33 Compared to "disease controls" undergoing bronchoscopy for non-cough-related indications (e.g., stridor or apnea), children with PBB were more likely to have attended childcare (OR ¼ 8.4, 95%CI 2.3-30.5), but their tobacco smoke exposure ($30% 8, 33 ) was similar to that of the "controls." 33 The strong association with childcare attendance raises the possibility of respiratory viruses having a role in initiating PBB, at least in some children.

Children with PBB typically appear well. They have normal growth and development, and lack signs of underlying chronic suppurative lung disease (CSLD), such as digital clubbing, chest wall deformity, and adventitial auscultatory chest findings, 33 although Period effect considered: temporal relationship between medication use and outcome was defined a priori. 2 Children in this RCT were from a subset of the same cohort. 7 3 Preterm birth, neuromotor-developmental delay, developmental-growth retardation, chest wall deformity, tobacco smoke exposure, clubbing, cardiac disease, any known chronic disease and/or pulmonary disease, and those unable to undertake pulmonary function tests. 36 Ã Spontaneous resolution (SR) defined as resolution of cough without therapy or, if this was tried the cough resolved more than 2 weeks after ceasing treatment.

occasionally a "rattly chest" and crackles are heard. The chest radiograph is normal or near-normal, showing only peri-bronchial changes. 9, 40, 44 When performed, both spirometry 40 and respiratory system reactance and resistance measured by the forced oscillatory technique (unpublished) are also normal. The prevalence of atopic features (eczema, systemic and airway eosinophilia, elevated IgE, or positive radioallergosorbent test) is similar to children without PBB. 33 While many parents report previous "ever wheeze" (41-81% 18,33 ), auscultation-confirmed wheeze by doctors is unusual. In the Iowa City BAL-based retrospective cohort of children with PBB, 19 17/70 (24%) children had "noisy breathing" (five also wheezed) and 27 (39%) parents reported wheezing. In the Sheffield cohort study, 18 36/81 (45%) children were referred for "difficult asthma" and 35 (43%) reported "shortness of breath," which was attributable to coughing bouts. While most children in this cohort 18 had PBB, some did not based upon our definition since 11 (13%) required more than six courses of antibiotics for recurrent chronic wet cough and 4 (5%) had radiographic-confirmed bronchiectasis.

In children, differentiation between acute bronchitis and PBB is based on the fact that acute bronchitis cough usually resolves within 2-4 weeks. 45, 46 Nevertheless, difficulties arise when recurrent and acute bronchitis episodes overlap, especially during the "respiratory virus" season. Furthermore, PBB can co-exist with other illnesses, including asthma, while recurrent episodes need to be differentiated from bronchiectasis where chronic wet cough and repeated respiratory exacerbations may not respond to oral antibiotics, physical signs of CSLD may develop and irreversible bronchial dilation and wall thickening are seen on plain radiographs or computed tomography (CT) scans of the chest. 9, 47 TREATMENT In PBB, the child's cough resolves only after a prolonged (2 weeks) course of appropriate antibiotics. 8, 21 When a typical five to seven day course of antibiotics is prescribed the cough either relapses or does not resolve completely. However, some children require up to 4 weeks of treatment. In our RCT, 21 many of the children whose cough was not cured by 2 weeks of antibiotics had underlying tracheo-bronchomalacia and needed a longer course of antibiotics before their cough disappeared. We speculate that children in this RCT 21 were also at the more severe end of the disease spectrum and more likely to require a longer antibiotic course. Hence the larger NNT-B (4, 95%CI 2-27) compared to the Cochrane review (3, 95%CI 2-5). 20 In contrast, the 2008 British Thoracic Society (BTS) cough guidelines 48 suggest all children with PBB should receive 4-6 weeks of antibiotics. This recommendation, however, was based upon expert opinion as at the time no supportive high-quality studies existed. Further studies are now needed to help identify whether those with PBB requiring a longer course of antibiotics are different (e.g., outcomes) from those responding to shorter courses.

While some children with PBB may need longer antibiotic treatment, we still advocate the shorter 2-week course initially. This reflects the principles of good antimicrobial stewardship and should also reduce drugrelated adverse events. Furthermore, a recent study showed that children with a chronic wet cough failing to resolve after 4 weeks of appropriate oral antibiotics have increased likelihood of bronchiectasis on a chest CT scan. 49 In this retrospective study, all chest multidetector CT scans performed over a 28 month period for assessment of chronic wet cough were reviewed. 49 Among the 105 children with persistent cough despite at least 4 weeks of antibiotics, 88 (83.8%) had bronchiectasis, while of the 24 children whose cough resolved after antibiotics, only six (25.0%) received this diagnosis (adjusted OR 20.9; 95%CI 5.36-81.8). 49 Chest airway clearance is now standard therapy in bronchiectasis management. 47 The BTS guidelines 48 also suggest physiotherapy for children with PBB. While this may be beneficial, the evidence to support this recommendation is limited. Furthermore, the time required for performing airway clearance techniques should not be underestimated.

Ideally, a lower airway specimen for microbiologic testing is obtained before treatment. Indeed, the BTS guidelines 48 recommend that before making a diagnosis of PBB, sputum should be cultured first and other underlying conditions excluded. However, most children with chronic wet cough are young (Tables 4 and 5 ) and unable to expectorate, even following sputum induction. Thus, obtaining reliable lower respiratory secretions requires bronchoscopy, which will be impractical in most clinical settings. Nevertheless, if a bronchoscopy is performed, purulent secretions and evidence of bronchitis ( Fig. 1) are usually present.

Consequently, from a pragmatic perspective, in children with an "isolated" chronic wet cough, who have a normal or near normal chest radiograph and are without symptoms and signs of another diagnosis (e.g., aspiration lung disease, bronchiectasis, cystic fibrosis (CF), inhaled foreign body, tuberculosis, etc.) PBB should be suspected and we recommend they receive 2 weeks of an appropriate oral antibiotic. The most widely used first line empiric antibiotic is amoxicillin-clavulanate, 21 (as commonly associated pathogens, such as H. influenzae and especially M. catarrhalis, can be amoxicillin-resistant) although depending upon local pathogen susceptibility patterns, alternatives such as an oral cephalosporin, trimethoprim-sulfamethoxazole, or macrolide may be used when immediate hypersensitivity to penicillin exists.

While antibiotics are generally well tolerated, caregivers should be counseled about possible adverse events (e.g., gastrointestinal complaints, rashes, hypersensitivity) occurring. 50 When a child can expectorate, a sputum specimen should be obtained. In a minority of children, the cough will not respond to treatment and the antibiotic can be extended to a maximum of 4 weeks. However, if by this time the wet cough has not improved substantially, the child should be investigated for other causes of chronic wet cough. 9, 49 PBB can also co-exist with other conditions (e.g., asthma, tracheo-bronchomalacia) 7,18 and these conditions should be diagnosed and managed concurrently. As with all children at risk of chronic lung disease, clinicians should also counsel on preventative care including avoidance of tobacco smoke and other inhaled environmental toxicants, timely vaccinations, ensuring good nutrition, and emphasizing the importance of physical activity.

PBB often recurs at some point, particularly in the very young as recurrent respiratory infections are more common in this age group. 51 The definition of recurrence (number of episodes per year) remains uncertain, but historically either at least three or more than three lower respiratory infections per year has been used. 52, 53 Adopting the latter definition, a prospective BAL-based study was undertaken in 106 children with PBB followed for a median 25 months (IQR 24-28) after this investigation. 54 Their median age at bronchoscopy was 23 months (IQR . Compared with healthy controls (median age 27 months, children with PBB at baseline were significantly more likely to have had wet cough and to have visited their family doctor in the preceding 12 months. At the 24 month follow-up, children with PBB were more likely to be coughing compared with controls (44% vs. 12% of respective cohort, P ¼ 0.005) and to have had parent-reported wheeze in the preceding 12 months (58% vs. 16%, P ¼ 0.001). By the end of the study, 66 (62%) of those with PBB (and complete follow-up) had experienced recurrent episodes (>3 per year) and 13 (12%) had bronchiectasis diagnosed by chest CT scans. 54 The major independent risk factors for bronchiectasis were H. influenzae lower airway infection and having !2 siblings. H. influenzae infection conferred >6 times higher risk of bronchiectasis than a H. influenzae negative state (hazard ratio ¼ 6.8, 95%CI 1.5-30.8).

A UK-based retrospective study 55 described 33 children whose wet cough resolved with antibiotics ("PBB"). During the median follow-up period of 11.3 months (IQR 8.3-14.7) only eight (24%) remained cough free, while three (9%) had three or more recurrent episodes of persistent wet cough and nine were prescribed long-term antibiotics. Another retrospective study 19 reported that 43 of 70 children had recurrent symptoms (timeframe not provided). These studies suggest that physicians should warn parents about future recurrences and physicians themselves need to be aware that some children may progress to bronchiectasis.

Nevertheless, the actual rate and risk factors of PBB recurrence are likely dependent on the sampling frame and definition. Factors in those severe enough to proceed to bronchoscopy are likely different from those enrolled from the community. Additional longer term studies are warranted as recurrent PBB is associated with more intense and possibly persistent activation of interleukin (IL)-1 signalling pathways in the airways. 56 

Lower airway bacterial infection and neutrophilia are present in children with PBB. 8, 19, 57 Protracted cough implies injurious chronic airway inflammation and mucus hypersecretion, 58,59 while on-going endobronchial bacterial infection is harmful to the lungs. 60,61 Fig. 1a) . In Fig. 1a , bronchomalacia and mucus (LB10) are also present. Sometimes secretions are seen in the trachea (Fig. 1b) , but more often purulent secretions are seen in the bronchi (Fig. 1c -secretions seen at the right lower lobe bronchus).

In the first description of PBB, 8 BAL cultures grew the common respiratory bacterial pathogens, S. pneumoniae, H. influenzae, and M. catarrhalis. Subsequently, several other groups confirmed these BAL findings. 8, 18, 19, 21, 33, 55 One retrospective study also identified Staphylococcus aureus in 11/50 children with PBB, 62 but quantitative bacteriology was not performed making interpretation difficult. This latter study 62 also evaluated BAL sampling of one versus six lobes and reported sampling only one lobe in 41 children would have missed 17 potential bacterial pathogens in 15 patients. While it is generally accepted that more than one lobe should undergo BAL, additional prospective studies employing quantitative bacteriology with concomitant inflammation marker assays are needed. Data relating to current or recent antibiotic use and vaccination status should also be recorded as it is likely that antibiotics, vaccine types, and host immune response influence lower airway bacteriology in children suspected of PBB 42 and CSLD. 63, 64 H. influenzae (range 47-81%) is the most common bacteria reported in all but one 19 of the published studies describing the lower airway bacteriology in children with PBB. 8, 21, 33, 42, 55, 62 Most H. influenzae are non-typeable H. influenzae (NTHi) strains representing diverse genotypes, 42 a finding consistent with the increasing importance of NTHi in chronic pulmonary disorders in children and adults. 65, 66 In some studies, 8, 21 S. pneumoniae (24-39%) was the second most common organism detected in BAL cultures, but in others 33, 42, 55, 62 M. catarrhalis (range 19-43%) was found more commonly. However, these BAL studies are difficult to compare as samples came from different sites and numbers of lobes, some accepted all positive culture results, 55,62 while others used quantitative bacteriology to diagnose infection. 8, 19, 21, 33 S. pneumoniae serotypes were reported in one recent study involving immunized children in the UK and Greece undergoing BAL for suspected PBB. 42 Although both vaccine and non-vaccine-related serotypes were isolated from BAL cultures, vaccine serotypes were found significantly less often in children who had received pneumococcal conjugate vaccines. 42 Finally, culturing two or more bacterial pathogens was reported frequently (22-48%) in several studies, 8, 42, 55, 62 but how this influenced clinical presentation or outcomes was not commented upon.

Viruses Surprisingly, only one study has examined systematically for the presence of respiratory viruses in children with PBB. 33 This study reported higher rates of virus detection by PCR in the BAL fluid from 104 PBB cases than from 49 other chronic respiratory disease controls (38% vs. 9%; OR ¼ 6.3, 95%CI 2.1-19.1). The most common virus identified was adenovirus (AdV), 33 which upon genotyping belonged predominantly to AdV species C. 67 Children in the PBB AdV positive group were, however, significantly younger than those in the PBB AdV negative group (median 17 (IQR 12-22) vs. 26 (IQR 15-56) months; P ¼ 0.001) and the positive association found between AdV detection and bacterial infection disappeared after adjusting for age. 67 An extended panel for 17 viruses was undertaken in a subset of 27 children, which found rhinovirus in 11 (41%) and human bocavirus and human coronavirus in 1 (4%) each of the participants. 33 The prevalence of these other viruses was similar in the control group. 33 Other studies also report a similar prevalence of these viruses in asymptomatic children. 68 

The microbiota of the lungs of children with PBB has been examined in a single cross-sectional study. 69 Using bacterial 16S rRNA gene pyrosequencing, phylogenetic analysis and ecologic statistical tools, the core microbiota in the sputum and BAL specimens from 60 children (PBB n ¼ 12, bronchiectasis ¼ 19, CF ¼ 25, controls ¼ 4) and 68 adults (bronchiectasis ¼ 38, CF ¼n30) with chronic pulmonary disorders were compared. 69 One-way analysis of variance showed the Shannon-Weiner index (a measure of species diversity) of the lower airway microbiota in children with PBB and bronchiectasis were similar and statistically higher (i.e., richer) than in CF (Fig. 2a) . 69 However, while all three pediatric cohorts shared remarkably similar core microbiota, with H. influenzae making the greatest contribution to the observed similarity, the lung microbiota in children were significantly different from that observed in adults with CF and bronchiectasis (Fig. 2b) . 69 These findings suggest that chronic airway infections begin similarly with defective airway clearance of otherwise normal airway microbiota, but over time with antibiotic treatment and perhaps the effects of the underlying disease the microbiota in these disease groups progressively diverge from one another.

Biofilms may be another speculative reason for the chronicity and the need for longer antibiotic courses for PBB treatment. Our group first documented biofilms in the BAL fluid of children with bronchiectasis, 70 and our preliminary data show that biofilms are also present in the BAL fluid of children with PBB. None of these children had Pseudomonas aeruginosa.

A prospective study showed that children with PBB have higher and more prolonged "children's acute respiratory illness and flu" (CARIF) scores 71 with respiratory illnesses than healthy controls and children with asthma. 72 PBB is also characterized by airway neutrophilia and high densities of common respiratory pathogens in their lower airways, 8, 33 suggesting that host immunological responses play a role in its pathogenesis.

Both our initial 8 and subsequent studies 33 describing systemic immunity in children with PBB have confirmed the absence of an overt immunodeficiency. Serum levels of IgA, IgM, IgG, and IgE are normal and responses to protein (tetanus) and conjugated protein-polysaccharide (H. influenzae type b) vaccines are robust. 33 Humoral immunity, therefore, seems to be intact and no abnormalities in lymphocyte subsets have been found. 33 Innate immunity among children with PBB also appears to be activated rather than deficient. 57, 73 In one study, 57 innate immunity was assessed by examining tolllike receptors (TLRs). TLR-2 and TLR-4 are signaling 2a: Shannon-Weiner index (H 0 ), which reflects the diversity of species present, depicting that protracted bacterial bronchitis (PBB) was similar to bronchiectasis (BE), but significantly different to cystic fibrosis (CF). Species diversity is richer in the PBB and BE groups. 2b: Dendrograms of community membership similarity between the pediatric (ped) BE, PBB, and CF bacterial metacommunities and compared with adult CF and BE metacommunities. Given are whole, core, and satellite microbiota. Metacommunity profiles were compared using the Sørensen index of similarity and unweighted pair-group method using arithmetic mean (UPGMA). 69 Sørensen index varies from 0 (no similarity) to 1 (entirely similar) and accounts for the number of species present in each community and those that are shared. 69 pattern recognition receptors that play a key role in responding to invading bacteria, especially gram-positive and gram-negative bacteria, respectively. 74 Compared to controls, BAL samples from children with PBB had significantly elevated TLR-2 and TLR-4 mRNA relative expression 57 (Table 6 ). Whether the BAL of children with PBB had reduced TLR expressions levels prior to early infection is unknown. An opportunistic study of children undergoing gastroscopy for gastrointestinal symptoms, found that TLR-4 mRNA relative expression was significantly lower in children with chronic cough and BAL evidence of bacterial infection (!10 4 CFU/ml) than those without infection. 75 A second larger study evaluated pulmonary levels of three innate immunity components (human b-defensin 2 [hBD2], mannose-binding lectin [MBL] , and surfactant protein-A [SP-A]) and the cytokine production of lipopolysaccharide-stimulated BAL cells in 61 children with current PBB, 20 with previously treated PBB and 21 disease controls undergoing bronchoscopy for airway assessment of stridor. 73 Median hBD2 and MBL levels were significantly higher in the current than previous PBB group and controls (Table 6 ). SP-A levels and cytokine production of stimulated BAL cells were similar among all the groups. 73 In a preliminary study, the systemic immune responses (cytokine production) against NTHi in 20 children with PBB were similar to 20 healthy control subjects, 76 however, the caspase-1 dependent, proinflammatory pathways were activated in PBB children.

Deficient efferocytosis (impaired clearance of apoptotic cells by alveolar macrophages) 77 is another possible mechanism in PBB pathobiology. It is postulated that the apoptotic cells may undergo secondary necrosis with proinflammatory effects contributing to the perpetuation of chronic inflammation, infection and tissue damage. 78, 79 Support for this hypothesis comes from a small BALbased study showing significantly decreased ability of alveolar macrophages to phagocytose apoptotic bronchial cells and NTHi in children with bronchiectasis (n ¼ 55) and PBB (n ¼ 13) compared controls (n ¼ 13). 80 For both types of impaired phagocytosis, values in children with PBB were intermediate to those with BE and controls 80 (Table 4 ).

Neutrophil influx is an important feature of the innate immune response. We and others have described intense airway neutrophilia (median 40-44%) in children with PBB, 8, 19, 57 but whether this is a pathologically disproportionate response to infection is unknown.

There are also marked pro-inflammatory mediator responses (IL-8, matrix metalloproteinase (MMP)-9 active, IL-1b) that correlate with BAL neutrophil percentages. 56, 81 Median BAL levels of IL-8 and MMP-9 in children with PBB were 5.4-to 19.1-fold higher than in controls and in those whose cough resolved without specific treatment. 57 Levels of IL-8 and MMP-9 were also significantly correlated (r ¼ 0.61, P < 0.0001). 57 We have shown in experimental and validation cohorts that children with PBB have significantly higher BAL fluid levels of IL-1b, a-defensin, IL-1 pathway members, and CXCR2 gene and protein expression than non-PBB disease controls. 56 IL-1b levels correlated with duration and severity of cough, 56 and with elevated expression of a-defensins 1-3 in PBB cases. In those with recurrent PBB (>3 in the next 12 months), the baseline (at bronchoscopy) gene expression of the IL-1b signaling molecules pellino-1 and IL-1 receptor associated kinase (IRAK)-2 were significantly higher than those without recurrent PBB, suggesting this pathway's involvement in recurrence. 56 Other innate immune factors related to wet cough and airway neutrophilia, but not specifically studied in children with PBB include the pattern recognition receptor for advanced glycation end-products (RAGE), which plays an important, but complex role in many inflammatory responses within the lungs. 82 Soluble RAGE (sRAGE) levels within the circulation and BAL fluid were associated with age and airway inflammatory cell profiles (lower sRAGE in airway neutrophilia), highlighting a potentially important role for sRAGE in pediatric lung disease. 82 

Older studies have showed an association among airway lesions, chronic cough, 83, 84 and chronic bronchitis. 31 While some clinicians believe tracheo-bronchomalacia causes chronic cough, it is more likely that infection predisposes the individual to prolonged, inefficient airway clearance. Since the cough resolves once the underlying infection is treated, this suggests malacia has a limited causative role. 8 Nevertheless, tracheo-bronchomalacia impairs airway clearance, 85 increasing the likelihood of persistent lower airway infection and inflammation. Tracheo-bronchomalacia is also found commonly in children with PBB. 8, 19 This association may be primary (airway malacia predisposes to PBB through reduced efficiency in airway clearance) or secondary (malacia developing because of intense airway inflammation 86, 87 ). One retrospective study reported tracheo-bronchomalacia was present in 52/74 (74%) children with PBB. 19 However, a prospective study involving 104 children with PBB found that these airway abnormalities were no more common in children with PBB than in those undergoing bronchoscopy for other respiratory indications at a tertiary pediatric hospital (68% vs. 53%, respectively). 33 Nevertheless, these proportions are higher than estimates for the general population (1 in 2,100) 31 and there is little doubt that children with tracheo-bronchomalacia have a higher frequency of respiratory infections and symptoms. 88,89

In 2008, we proposed a paradigm (Fig. 3) where PBB, CSLD, and bronchiectasis shared common underlying pathobiologic mechanisms and progressed variably along an increasing spectrum of severity. 9 The current evidence suggests that this paradigm still remains clinically useful, ensuring that children with bronchiectasis are not missed. PBB overlaps with CSLD, which in turn overlaps with radiographic-confirmed bronchiectasis. 9 Children with established bronchiectasis would have had CSLD, at some stage earlier in the disease process, while those with CSLD would have had PBB previously.

The potential for injury with persistent infection and inflammation is probably more important in the growing and developing lungs of young children than in the mature lung. This is supported by animal and human studies where early lung insults are most likely to have adverse long-term effects. [90] [91] [92] As children with PBB are typically very young, 8, 9 it is plausible that recurrent PBB episodes are a risk factor for developing CSLD or bronchiectasis.

The similarities between these three conditions include chronic wet cough, AErattling breathing, or "ruttles," as well as impaired regional muco-ciliary clearance, endobronchial bacterial infection and neutrophilic airway inflammation. The core microbiota 69 and cultured classical respiratory bacterial pathogens are also similar in PBB 33 and pediatric CSLD and bronchiectasis. 16, 67 The key differences between these three entities lie in the severity of symptoms and signs, the response to 2-4 weeks of oral antibiotics, chest high-resolution CT scan findings, and consequent management. CSLD is differentiated from bronchiectasis only by lacking the radiographic signs of bronchiectasis on chest high-resolution CT scans. 9, 93 SUMMARY PBB is recognized increasingly as a common cause of chronic wet cough in children. In most PBB cases, 2 weeks of oral antibiotics are sufficient, but some will require a 4-week course. The pathobiology of PBB involves lower airway bacterial infection with intense airway neutrophilia accompanied by increased inflammatory markers involving IL-1b signaling. The pulmonary innate immune system is upregulated, but so far no systemic or local immune dysfunction has been identified, other than of decreased efferocytosis and phagocytosis of NTHi. 80 Recurrent episodes (>3 per year) occur in some, and these children have increased gene expression of the IL-1b signaling molecules pellino-1 and IRAK-2, and are more likely to have bronchiectasis diagnosed within the next 2 years. Hence, those with PBB should be monitored closely.

In addition to consolidating the preliminary data presented above, other important research questions remain to be answered in this surprisingly common, but poorly recognized pulmonary disorder. Some of these Using the pathobiologic model, protracted bacterial bronchitis (PBB), chronic suppurative lung disease (CSLD), and radiographic-confirmed bronchiectasis likely represents different ends of a spectrum with similar underlying mechanisms of airway neutrophilia, endobronchial bacterial infection, and impaired mucociliary clearance. Untreated it is likely some (but not all) children with PBB will progress to develop CSLD and some will ultimately develop bronchiectasis, initially reversible and subsequently irreversible if left to progress. There is a degree of overlap between each of the entities. 

•Determining the burden of disease (e.g., incidence, prevalence, QoL, economic cost) in the general community •Establishing modifiable risk factors •Ascertaining the long-term outcomes of children with recurrent and non-recurrent episodes •Clarifying whether children with PBB-extended have different long term outcomes Pathobiology

•Identifying the underlying developmental and pathobiologic mechanisms •Uncovering host biological susceptibility factors, including the role of airway malacia •Describing the frequency and mechanisms of virus-induced PBB episodes Management

•Detecting a biomarker that can predict response to antibiotics and risk of recurrence •Determining if longer courses of antibiotics of up to 4 weeks duration reduce recurrences •Performing multicenter intervention trials to help identify those requiring longer antibiotic courses of up to 4 weeks evaluating the role of prophylactic antibiotics in patients with frequent (>3 annually) recurrences, but still lacking disease pointers and evidence of bronchiectasis

General practice activity in Australia 1999-00 to 2008-09: 10 year data tables. General practice series no. 26. Cat. no. GEP 26

Diagnosis and management of cough executive summary: accp evidence-based clinical practice guidelines

General practice activity in Australia

What is the burden of chronic cough for families?

Persistent cough: is it asthma?

Minimally important change in a parent-proxy quality of life questionnaire for pediatric chronic cough (PC-QOL)

A multi-centre study on chronic cough in children: burden and etiologies based on a standardized management pathway

Evaluation and outcome of young children with chronic cough

State of the Art -chronic wet cough: protracted bronchitis, chronic suppurative lung disease and bronchiectasis

Cough quality in children: a comparison of subjective vs. bronchoscopic findings

A bronchoscopic scoring system for airway secretions-airway cellularity and microbiological validation

Wet cough in children: infective and inflammatory characteristics in broncho-alveolar fluid

Bronchoscopic and high resolution CT findings in children with chronic wet cough

Bronchoscopy contributes to the clinical management of Indigenous children newly doagnosed with noncystic fibrosis bronchiectasis

Microbiology of bronchoalveolar lavage fluid in children with acute nonresponding or recurrent community-acquired pneumonia: identification of nontypeable Haemophilus influenzae as a major pathogen

Lower airway microbiology and cellularity in children with newly diagnosed non-CF bronchiectasis

Bronchoscopic findings in children with chronic wet cough

Outcomes in children treated for persistent bacterial bronchitis

Protracted bacterial bronchitis in young children: association with airway malacia

Antibiotics for prolonged moist cough in children

Randomised controlled trial of amoxycillin-clavulanate in children with chronic wet cough

Accuracy of cough reporting by carers of Indigenous children

Influence of simulated mucus on cough sounds in cats

Respiratory bacterial culture from two sequential bronchoalveolar lavages of the same lobe in children with chronic cough

Pediatricians are not just small internists

ERS Handbook of Paediatric Medicine. Sheffield: European Resiratory Society

Chronic bronchitis in childhood: what is it?

Characteristics of children with endoscopically proved chronic bronchitis

Bronchiectasis in childhood; III. Prophylaxis, treatment and progress with a follow-up study of 202 cases of established bronchiectasis

Prospects for prevention of chronic bronchitis and bronchiectasis; rational management of bronchopulmonary infections by penicillin aerosol therapy

Tracheomalacia and bronchomalacia in children: incidence and patient characteristics

In young children, persistent wheezing is associated with bronchial bacterial infection: a retrospective analysis

Prospective characterisation of protracted bacterial bronchitis in children

Bacterial flora of the lower respiratory tract in children with bronchial asthma

Evaluation of chronic cough in children

The assessment and management of chronic cough in children according to the British Thoracic Society guidelines: descriptive, prospective, clinical trial

Can a management pathway for chronic cough in children improve clinical outcomes: protocol for a multicentre evaluation

The PedsQL 4.0 as a pediatric population health measure: feasibility, reliability, and validity

Development of a parent-proxy quality-of-life chronic cough-specific questionnaire: clinical impact vs psychometric evaluations

Children with chronic cough: when is watchful waiting appropriate? Development of likelihood ratios for assessing children with chronic cough

A cough algorithm for chronic cough in children: a multicentre, randomized controlled study

Bacterial bronchitis caused by Streptococcus pneumoniae and nontypable Haemophilus influenzae in children: the impact of vaccination

The evaluation of children with prolonged cough accompanied by American College of Chest Physicians guidelines

Utility of signs and symptoms of chronic cough in predicting specific cause in children

The Thoracic Society of Australia and New Zealand. Position statement. Cough in children: definitions and clinical evaluation

Duration of symptoms of respiratory tract infections in children: systematic review

Chronic suppurative lung disease and bronchiectasis in children and adults in Australia and New Zealand Thoracic Society of Australia and New Zealand guidelines

Thoracic Society Guidelines Recommendations for the assessment and management of cough in children

Does failed chronic wet cough response to antibiotics predict bronchiectasis

Efficacy, safety and tolerability of 3 Dayazithromycin versus 10 Dayco-amoxiclav in the treatment of children with acute lower respiratory tract infections

A community-based study of respiratory episodes in Melbourne

OM-85 BV, an immunostimulant in pediatric recurrent respiratory tract infections: a systematic review

Poverty, global health and infectious disease: lessons from Haiti and Rwanda

Protracted Bacterial Bronchitis (PBB) in children: natural history and risk for bronchiectasis

Outcomes in children with protracted bacterial bronchitis confirmed by bronchoscopy

Mediators of neutrophil function in children with protracted bacterial bronchitis

Prospective assessment of protracted bacterial bronchitis: airway inflammation and innate immune activation

Toll-like receptor (TLR)-based networks regulate neutrophilic inflammation in respiratory disease

Reducing the toll of inflammatory lung disease

Role of bacteria in the pathogenesis and progression of acute and chronic lung infection

Inflammation: a two edged sword. The model of bronchiectasis

Bacterial distribution in the lungs of children with protracted bacterial bronchitis

Improving immunity to Haemophilus influenzae in children with chronic suppurative lung disease

Respiratory bacterial pathogens in the nasopharynx and lower airways of Australian Indigenous children with bronchiectasis

Non-typeable Haemophilus influenzae, an under-recognised pathogen

Children with chronic suppurative lung disease have a reduced capacity to synthesize interferon-gamma in vitro in response to non-typeable Haemophilus influenzae

Adenovirus species C is associated with chronic suppurative lung diseases in children

Detecting respiratory viruses in asymptomatic children

Three clinically distinct chronic pediatric airway infections share a common core microbiota

Identification of biofilm in bronchoalveolar lavage from children with bronchiectasis without Pseudomonas aeruginosa infection

Canadian Acute Respiratory Illness and Flu Scale (CARIFS): development of a valid measure for childhood respiratory infections

Asthma and protracted bronchitis: who fares better during an acute respiratory infection?

Pulmonary innate immunity in children with protracted bacterial bronchitis

Toll-like receptors: sentinels of host defence against bacterial infection

Impaired toll-like receptor 4 and substance P gene expression is linked to airway bacterial colonisation in children

Immnue responses to non typebale Haemophilus influenzae in protracted bacterial bronchitis

Alveolar macrophages from subjects with chronic obstructive pulmonary disease are deficient in their ability to phagocytose apoptotic airway epithelial cells

Burying the dead: the impact of failed apoptotic cell removal (efferocytosis) on chronic inflammatory lung disease

Increased airway epithelial and T-cell apoptosis in COPD remains despite smoking cessation

Is alveolar macrophage phagocytc dysfunction in children with protracted bacterial bronchitis a forerunner to bronchiectasis?

Chronic bronchitis before age 50 years predicts incident airflow limitation and mortality risk

Soluble receptor for advanced glycation end products in the lungs of children

Localised tracheomalacia or bronchomalacia in children with intractable cough

Persistent cough in childrenoveruse of medications

Primary bronchomalacia in infants and children

Bronchoscopic findings in children with non-cystic fibrosis chronic suppurative lung disease

Acquired tracheomalacia: etiology and differential diagnosis

Quantified tracheobronchomalacia disorders and their clinical profiles in children

Longitudinal quantification of growth and changes in primary tracheobronchomalacia sites in children

Childhood respiratory illness and lung function at ages 14 and 50 years

Lung parenchyma at maturity is influenced by postnatal growth but not by moderate preterm birth in sheep

Postnatal growth rate, but not mild preterm birth, influences airway structure in adult sheep challenged with house dust mite

Management of bronchiectasis and chronic suppurative lung disease (CSLD) in Indigenous children and adults from rural and remote Australian communities

Guidelines for evaluating chronic cough in pediatrics: ACCP Evidence-Based Clinical Practice Guidelines

State of the Art: cough, cough receptors, and asthma in children

CICADA: Cough in Children and Adults: Diagnosis and Assessment. Australian Cough Guidelines summary statement

The Japanese Respiratory Society guidelines for management of cough

Prolonged cough in children: a summary of the Belgian primary care clinical guideline

Guideline for diagnosis and treatment of chronic cough in Chinese children

Use of management pathways or algorithms in children with chronic cough: systematic reviews

Subjective scoring of cough in children: parent-completed vs child-completed diary cards vs an objective method

None of the authors have any fiscal conflict of interest and none received an honorarium or other form of payment to produce the manuscript.

epidemiology, pathobiologic, and management research goals are listed in Table 7 .