key: cord-0847525-2q880b4m authors: Chang, Anne B.; Redding, Gregory J. title: 26 Bronchiectasis and Chronic Suppurative Lung Disease date: 2019-12-31 journal: Kendig's Disorders of the Respiratory Tract in Children DOI: 10.1016/b978-0-323-44887-1.00026-2 sha: 1ba4425faa445007da6fa507aca6846f571ec4b8 doc_id: 847525 cord_uid: 2q880b4m Abstract Bronchiectasis, chronic suppurative lung disease, and protracted bacterial bronchitis (PBB) are increasingly recognized conditions. Bronchiectasis is now again increasingly diagnosed, and its renewed interest has resulted in further in-depth studies in children and adults. However, diagnostic labeling of childhood bronchiectasis by radiology using adult-derived criteria has substantial limitations. Thus, pediatric-derived criteria are advocated. A paradigm presenting a spectrum related to airway bacteria, with associated degradation and inflammation products causing airway damage if untreated, entails PBB (at the mild end) to irreversible airway dilatation with cystic formation as determined by chest computed tomography (CT) scan (at the severe end of the spectrum). Increasing evidence suggest that progression of airway damage can be limited by intensive treatment, even in those predestined to have bronchiectasis (e.g., immune deficiency). Treatment is aimed at achieving a cure in those at the milder end of the spectrum to limiting further deterioration in those with severe “irreversible” radiological bronchiectasis. Anne Chang is supported by Australian National Health and Medical Research Council practitioner fellowship (1058213), Centre for Research Excellence grant (1040830) and project grants (1098443 and 1019834). Greg Redding is supported in part by Maternal Child Health Grant T72MC00007. Worldwide, there are more people with bronchiectasis unrelated to cystic fibrosis (CF) than with CF and although regarded in affluent countries as an "orphan disease," bronchiectasis remains a major contributor to chronic respiratory morbidity in affluent 1,2 and less affluent countries. 3, 4 With the increasing appreciation of bronchiectasis in adults, [5] [6] [7] the renewed interest in bronchiectasis has resulted in greater research depth, albeit [7] [8] [9] there is still proportionately little research in children. Indeed, bronchiectasis is regarded by the European Respiratory Society 10 as "one of the most neglected diseases in respiratory medicine." This chapter addresses childhood bronchiectasis, chronic suppurative lung disease (CSLD), and protracted bacterial bronchitis (PBB) unrelated to CF. Other underlying pulmonary host defense deficiencies such as ciliary dyskinesia syndromes and immunodeficiencies are covered elsewhere in this textbook. Bronchiectasis, CSLD, and PBB share common features but are different diagnostic entities with overlaps ( Fig. 26.1) . 11 Bronchiectasis is a pathologic state of the conducting airways manifested by radiographic evidence of bronchial dilation and clinically by chronic productive cough. Bronchiectasis can be focal with recurrent wet or productive cough and infectious exacerbations, or it can be diffuse, resulting in generalized airway obstruction and destruction with eventual respiratory failure. The diagnostic criteria for bronchiectasis are based on radiographic features of chest high-resolution computerized tomography (c-HRCT), although the sensitivity of adult-defined radiographic criteria has been questioned when applied to children. 12, 13 Bronchiectasis may also occur in patients with interstitial lung diseases, because traction on the airways causes secondary bronchial dilation. Traction bronchiectasis in the absence of wet or productive cough will not be considered further. CSLD describes a clinical syndrome where symptoms of chronic endobronchial suppuration exist without c-HRCT evidence of bronchiectasis. The presenting symptoms are identical to bronchiectasis, including a prolonged moist or productive cough responsive to antibiotics with or without exertional dyspnea, increased airway reactivity, and recurrent chest infections. The absence of physical signs and and poses safety concerns regarding cancer risks from radiation in children, adolescents, and young adults. 21 4. The timing of c-HRCT scans to diagnose bronchiectasis is important. Scans performed in different clinical states, such as during an acute pulmonary exacerbation, immediately following treatment, or when clinically stable, may yield different results. C-HRCT scans are ideally performed in a "non-acute state," but this state may differ from a posttreatment state. Bronchial dilatation resolved completely in 6 of 21 children with radiologically defined bronchiectasis when c-HRCT scans were repeated immediately following intensive medical therapy. 22 Thus, we recommend that HRCT scans are best performed in a nonacute state and bronchiectasis be diagnosed if symptoms of CSLD are present when HRCT findings meet the pediatric 13 rather than adult radiological criteria. PBB is a condition that is likely a prebronchiectasis state. It was first described as a diagnostic entity in 2006 with clear clinical criteria supported by laboratory studies, 23 although astute clinicians had long recognized PBB-like conditions. 11 PBB is discussed later in the chapter as a separate entity. In most affluent countries, the prevalence of childhood bronchiectasis has substantially declined since the 1940s. Field reported on 160 children with bronchiectasis over a 20-year period noting a decline in the incidence from 48 to 10 cases per 10,000 people from the 1940s to the 1960s. 24 By 1994, an English study found that only 1% of 4000 children referred to a respiratory specialty service had bronchiectasis. 25 The reduced incidence over time has been ascribed to reduced crowding, improved immunization programs, better hygiene and nutrition, and early access to medical care. However, bronchiectasis is now increasingly recognized worldwide as an important contributor to chronic respiratory morbidity in less affluent countries 4 and both indigenous 26 and nonindigenous populations in affluent countries. 27 Indeed bronchiectasis is not rare in affluent countries, 1, 5, 27 but is more common among certain groups for example, the Alaskan Yupik children in the United States, Aboriginals in Australia, and Maori and Pacific Islanders in New Zealand. 26, 28 Among these populations, the prevalence of childhood bronchiectasis is 147 to 200 per 10,000 children. 26 A Canadian study conservatively estimated that the prevalence of bronchiectasis among Inuit children living in Nunavut was 20 per 10,000. 29 The only available national incidence data on children is that from New Zealand with a rate of 3.7 per 100,000 under 15 year old children per year, 30 which is almost twice that of CF. In the Northern Territory (Australia with a high proportion of Indigenous people) the incidence in the first year of life is 12 per 10,000. 31 In adults, the estimated prevalence rate has been increasing (annual change of 8.8% from 2000 to 2007) based on a 5% sample of outpatient Medicare claims in the United States. 32 In the United Kingdom (UK), the prevalence of bronchiectasis in people aged 18 to 29 years increased from 29.3 (95% confidence interval [CI] 20.4 to 41.9) per 100,000 in 2004 to 43.4 (32. 3 to 58.4) per 100,000 in 2013. 2 These estimates far exceed the prevalence of CF. Given the need for a CT scan to diagnose bronchiectasis, prevalence or incidence data would be an underestimation. Furthermore, recognition of bronchiectasis is physician dependent and it is not surprising that many cases in children and adults are misdiagnosed as "difficult asthma" 33, 34 or chronic obstructive pulmonary disease (COPD). A proportion of adults with COPD (29% of 110) have underlying bronchiectasis. 35 Importantly, the majority of bronchiectasis in adulthood has its roots in childhood. 36, 37 One study of adults with bronchiectasis found that 80% of patients had chronic respiratory symptoms from childhood. 38 Hospitalization rates for adults with non-CF bronchiectasis in the United States have also increased in the last two decades; from 1993 to 2006, the age-adjusted rate increased significantly with an average annual percent increase of 2.4% among men and 3.0% among women. 39 German hospital statistics for 2005-2011 have also increased over that period with an annual age-adjusted rate for bronchiectasis of 9.4 hospitalizations per 100,000 population. 40 Likewise, an Australian state (Queensland) documented an increase in hospitalization from 65 to 83 per 100,000 population between 2005 and 2009. 41 Data from less affluent countries suggest that bronchiectasis is still associated with poor outcomes, for example, 22% with respiratory failure in a 6.6-year Tunisian follow-up study. 42 Mortality from pediatric bronchiectasis is rarely reported. Arguably, no child without a serious comorbidity should die from bronchiectasis. However, an England and Wales study reported 12 deaths in the 0 to 14 years age group between 2001 and 2007, 43 and 6 (7%) of 91 children 11.7, SD 2.6 years), depression and trait anxiety scores were not elevated in those with bronchiectasis, but the child-rated physical health QoL scores were significantly lower in those with bronchiectasis compared to controls. 50 The determinants of QoL were related to age, forced expiratory volume in one second (FEV 1 )/forced vital capacity (FVC) % predicted, and dyspnea severity. 50 The differences between the Australian 49 and Turkish 48,50 studies likely relate to the different QoL scales used and severity of disease. It is likely that QoL scores correlate to disease severity only in more severe disease, similar to the relationship between spirometry and radiological extent of bronchiectasis; spirometry is often normal in mild or localized disease, 52 and significant correlations between spirometry indices and radiology scores are seen only in more severe disease. 53 Nevertheless, all studies showed the negative impact of bronchiectasis on the children and/or their parents QoL and mental health. Poor sleep quality has also been reported. 54 Bronchiectasis is the result of a variety of airway insults and predisposing conditions that ultimately injure the airways and lead to recurrent or persistent airway infection and destruction. Examples of these conditions are listed in Table 26 .1. Bronchiectasis develops in some individuals when structural airway abnormalities, such as bronchomalacia, endobronchial tuberculosis, central airway compression, or retained aspirated foreign bodies impair mucus and bacterial clearance. However, there is currently no evidence of airway malacia causing bronchiectasis in human studies. Persistent airway injury and narrowing associated with bronchiolitis obliterans (BO; due to viral injury or following lung transplantation) can lead to bronchiectasis. Recurrent airway injury, such as occurs with aspiration syndromes, can also result in bronchiectasis. Selected pediatric cohorts from various settings and countries that describe the frequencies of these associated conditions are summarized in Table 26.2. Impaired upper airway defenses may also predispose to bronchiectasis based on the common association between rhinosinusitis and bronchitis/bronchiectasis. Indeed, the sinuses and Eustachian tubes have been considered a "sanctuary site" for bacterial pathogens and cytokines that may predispose to recurrent lower airway infection. Finally, there are variations in host inflammatory responses, for example, cytokine and metalloproteinase levels, and counterbalancing antiinflammatory mechanisms, for example, antioxidants and antiproteases, which may explain why some children develop bronchiectasis, while others do not despite similar exposures and living conditions. 26 It is well documented that acute lower respiratory tract infections (ALRIs) in children can lead to subsequent respiratory morbidity and lung function abnormalities. 60, 61 Classic epidemiological studies have linked acute ALRIs from adenovirus and other infections with chronic bronchitis and productive cough later in childhood. 62, 63 Recent large epidemiological studies have also shown that those with ALRIs in early childhood are at risk of lower lung function in adulthood. 64, 65 Although low lung function at birth may be the underlying died while attending a single New Zealand center between 1991 and 2006. 44 The premature mortality from bronchiectasis may carry over into young adulthood particularly in circumstances with nonoptimal management. This is depicted by a retrospective cohort study of 120 Central Australian Indigenous adults with bronchiectasis (50 diagnosed as children) hospitalized between 2000 and 2006 that reported 34% died during the period at a median age of 42.5 years. 45 In the UK, a recent study described that the crude mortality for men aged 18 to 49 years with bronchiectasis was 13.1 (95% CI 3.4 to 22.8) per 1000 population and 6.4 (0.8 to 12.0) for women compared to the general population, which are rates of 1.3 (1.3 to 1.4) and 0.8 (0.7 to 0.8), respectively. 2 These represent excess mortality rates of 8 to 10 times the general population. There is little data on the economic cost of bronchiectasis and none specific to children. In an United States-based casecontrol study involving 9146 children and adults (6.7% were aged <18 years), the direct medical cost increased by US$2319 per patient per year relative to the matched control from the preceding year. 46 The cost specifically for children was not described. An earlier study found that in the United States, adults with bronchiectasis averaged 2.0 (95% CI 1.7 to 2.3) additional days in hospital and that the average total annual medical-care expenditures (in 2001) were US$5681 ($4862 to $6593) higher for bronchiectasis patients than age, gender matched controls with other chronic diseases such as diabetes, COPD, and congestive heart failure. 47 In recent years, four pediatric studies in three different continents evaluated the impact of bronchiectasis on the child's and/or parents' health-related quality of life (QoL). 3, [48] [49] [50] Using the Parent Cough-Specific Quality of Life (PC-QoL) 51 and the Depression, Anxiety and Stress (DASS-21) questionnaires, a Malaysian 3 study described that children with CF had better parental mental health compared to children with non-CF CSLD. Overall, 77% of parents had abnormal DASS-21 scores (54% stressed and 51% depressed). 3 An Australian study 49 examined PC-QoL and DASS-21 scores during the stable-state and exacerbations in 69 children (median age 7 years) and their parents. In the stable state, the median PC-QoL was 6.5 (interquartile range [IQR] 5.3 to 6.9) and DASS-21 was 6 (0 to 20). Both scores were significantly worse during exacerbations (PC-QoL = 4.6 [3.8 to 5.4], P ≤ .001 and DASS = 22 [9 to 42] , P < .001). 49 DASS score showed that 38% had elevated anxiety and that 54% had abnormal depression/stress scores during the exacerbation. In the stable state, poorer QoL was significantly recorded with younger children, but QoL did not relate to the radiological extent, lung function, or underlying etiology. 49 In contrast, a Turkish study 48 described that the severity and frequency of symptoms were inversely related to the pulmonary function and the QoL scores (nonpediatric scales were used) in 42 children aged 9 to 18 years. Another Turkish study 50 involving 76 Caucasian children with bronchiectasis and 65 controls used self-reported questionnaires to evaluate the psychological status (using the Child Depression Inventory, State-Trait Anxiety Inventories for Children, and Pediatric Quality of Life Inventories). In this older cohort of children (mean age or five episodes of pneumonia and 21 times more likely if they had 6 or more pneumonias. The overall number of pneumonias rather than the site of pneumonia were associated with bronchiectasis. 67 In an Alaskan cohort, there was no association between lobe affected by first ALRI and the eventually bronchiectatic lobe, but there was an association between lobe most severely affected by ALRI and the lobes later affected by bronchiectasis. 56 Specific infectious etiologies were not described in these studies. A review on the longterm effects of pneumonia in young children 66 described a mixture of obstructive and restrictive lung deficits when followed up long term. However, the majority of studies in the review 66 were limited with case ascertainment and followup issues. Some authors have suggested that bronchiolitis is an important precursor of bronchiectasis. An Alaskan 5-year case-control follow-up of children hospitalized in infancy specifically with severe RSV infections described that they were not more likely to have been diagnosed with bronchiectasis. 68 In contrast, a study of Indigenous children hospitalized with bronchiolitis in Australia found that on CT scans performed at a median 13 months (range 3 to 23) factor of the significant association found, single severe ALRIs and multiple ALRIs in early childhood can undoubtedly lead to CSLD and bronchiectasis. 1, 66 These single ALRIs associated with bronchiectasis have been described with tuberculosis, pertussis, adenovirus, measles, and severe viral pneumonia. Although these infections do not frequently cause bronchiectasis, they remain common ALRIs in less affluent countries 4 and are still considered important antecedents to childhood bronchiectasis. In cohort studies, the most common associated cause or ascribed etiology for the bronchiectasis is past pneumonic events with lobar or diffuse alveolar infiltrates (see Table 26 .2). In the sole case-control study of childhood pneumonia and radiographically proven bronchiectasis, a strong association between hospitalized pneumonia and bronchiectasis was found. 67 Children who had been previously hospitalized due to pneumonia were 15 times more likely to develop bronchiectasis. 67 A dose effect was also shown; recurrent (>1) hospitalization for pneumonia and more severe pneumonia (episodes with longer hospital stay or oxygen requirement) increased the risk of bronchiectasis later in childhood. 67 Bronchiectasis was 3 times more likely in children with four such conditions who developed anaerobic pulmonary infections; six had poor oral hygiene. 73 In 1949, Field wrote "Irreversible bronchiectasis is not commonly seen in the better social and economic classes. Good nutrition and home conditions probably give the child a better chance of more complete recovery from lung damaging disease." 74 Poor public health conditions, including malnutrition, crowding, lack of running water, and environmental pollution, increase the risk of ALRIs and bronchitis. 75, 76 These issues are particularly important in developing countries. In affluent countries, those communities with higher prevalence of bronchiectasis are also those where poverty and low standards of housing are common. 26 In a qualitative study, community members and health care providers believed that potential contributing factors to acute and chronic lung diseases were smoke, dust, feeding practices, socioeconomic conditions, and mold. 77 Macro and selected micro malnutrition increases infection risks, as it creates an immune deficiency state and leads to the malnutrition-infection-malnutrition cycle. 78 However, data on malnutrition specifically preceding bronchiectasis are limited and inconsistent. In Central Australia, Indigenous children with bronchiectasis are 3 times more likely to have had malnutrition in early childhood prior to the diagnosis of bronchiectasis, 67 but this is not seen in Alaska or New Zealand. 26 Breast-feeding is a known protective factor against development of bronchiectasis. 67 Bronchiectasis may itself predispose to malnutrition as a result of chronic pulmonary infection, diminished appetite, and reduced caloric intake. The caloric needs and daily oxygen consumption of children with non-CF-related bronchiectasis have not been reported. One series described that children with bronchiectasis and low (<80%) baseline FEV 1 % predicted values, and those with posthospitalization, infants with persistent cough at 3 week (n = 31) after hospitalization were significantly more likely to have bronchiectasis compared to those without a cough (n = 126), OR 3.0, 95% CI 1 to 7, P = .03. 69 We surmise that bronchiectasis is not a consequence of specific viruses that produce bronchiolitis. Mechanisms by which upper respiratory infections predispose to lower airway inflammation and injury are reviewed elsewhere. 70 Bacterial pathogens colonizing the nose and mouth are shed into saliva and contaminate the lower airways. Proinflammatory cytokines from the oropharynx may also be aspirated and augment neutrophilic responses in the lower airways. Hydrolytic enzymes in infected upper airway secretions impair protective secretory molecules such as mucins in the lower airways, and thereby predispose the lower airways to infection. In vitro studies have shown that some bacteria produce factors that cause ciliary slowing, dyskinesia, and stasis, setting the stage for chronic bacterial colonization of the lower airways. 71 Whether the concentration or persistence of these pathogens in upper airways represents a significant risk factor for development or progression of bronchiectasis is unknown. In indigenous Australian children with bronchiectasis, a study relating nasopharyngeal to bronchoalveolar lavage (BAL) bacteria found a high density and diversity of respiratory bacteria along with strain concordance between upper and lower airways. 72 The study suggests a possible pathogenic role of recurrent aspiration of nasopharyngeal secretions. 72 Bronchiectasis and other forms of suppurative lung disease have been described among individuals with neurologic and neuromuscular conditions that reduce the frequency and effectiveness of cough and also increase the risk of aspirating oropharyngeal contents. Brook reported on 10 children with a Although this study was called systematic review, the review was incomplete with several studies omitted. CF, Cystic fibrosis; GERD, gastroesophageal reflux disease. of bronchiectasis in certain children. An increased or exaggerated neutrophilic response in Australian Indigenous children as a group has been described. 92 Similarly, metalloproteinases, for example, MMP-2 and 9, have been isolated from the sputum and BAL of bronchiectatic subjects, suggesting a role in airway destruction by gelatinases and collagenases. 93, 94 Whether proinflammatory cytokine and collagenase overexpression are associated with early onset disease or, particularly, progressive disease in childhood remains unknown. The histopathology of bronchiectasis was first described by Laënnec 95 in 1819. It includes alterations in subsegmental bronchial structure accompanied by neutrophilic inflammation, intraluminal secretion accumulation, and obliteration of distal airways. There are accompanying changes of peribronchial inflammation and fibrosis, distal lung collapse, bronchial and pulmonary vascular changes, and pleural adhesions. The macroscopic and microscopic features of bronchiectasis change as the disease progresses. Classical papers on bronchiectasis divided morphological types of bronchiectasis into tubular or cylindrical, early fusiform, late fusiform, fuso-saccular, and saccular types as different stages in the progression of disease. 36 The most commonly used classification is that of Reid's subtypes: cylindrical, varicose and cystic, 96 which were based on bronchographic findings. The latter findings are illustrated in Figs. 26.2 and 26.3 and they reflect progression of increasing severity. More recent HRCT scoring systems describe cylindrical and saccular changes as markers of disease severity. 97 Saccular and cystic changes tend to reflect clinically more advanced, severe, and irreversible disease. Macroscopically, the airways are tortuous and dilated, at times extending to the pleural surface. Early histologic changes include bronchial wall thickening, edema, presence of inflammatory cells, development of lymphoid nodules and follicles, and mucus gland hyperplasia. Intraluminal secretions are purulent or mucopurulent (Video 26.1). Microscopic changes include loss of ciliated epithelial cells and epithelial ulcerations. With time, chronic inflammation leads to squamous cell metaplasia and fibrotic obliteration of distal conducting immunodeficiency had significantly lower body mass index at diagnosis, and they significantly improved after appropriate therapy was instituted. 79 Also, in a double-blind randomized controlled trial on the effect of long-term azithromycin, Indigenous children randomized to the azithromycin group (c.f. placebo) had a significant improvement in weight z-score, concurrent with a reduction in exacerbations (incidence rate ratio = 0.5, 95% CI 0.35 to 0.71). 80 This suggests that effective management of children with bronchiectasis improves nutrition. Another predisposing factor to bronchiectasis is the presence of inhaled irritants, including indoor and outdoor pollutants, particularly in the presence of impaired airway clearance. The effects of environmental tobacco smoke (ETS) on children's respiratory system are well known from both in utero and ex utero exposure and include reduced airway caliber, increased lower respiratory tract infections, and middle ear disease. Reviews of ETS and its effects on the developing lung and accelerated lung decline are available elsewhere. 81 Exposure to indoor biomass combustion increases coughing illness associated with ALRIs with an exposure-response effect. 82 Exposures to other indoor pollutants (nitrogen dioxide, gas cooking) and traffic are also associated with increased cough in children in both cross-sectional and longitudinal studies. 75 There is no direct evidence of pollutants causing bronchiectasis, and the pathogenic role is likely indirect through an increased frequency of ALRIs and increased airway mucus production. In Chile, increased arsenic exposure has been associated with a variety of chronic disorders including bronchiectasis. 83 The interplay between genotype, epigenetics, and environment is increasingly recognized as the key in phenotypic expression of respiratory diseases. An increased frequency of cystic fibrosis transmembrane conductance regulator (CFTR) genotypes associated with CF, presenting as heterozygotes, has been described in several case series of adults with diffuse bronchiectasis. 84 While heterozygotes for alpha-1 antitrypsin have also been described more frequently in those individuals with diffuse bronchiectasis, a causal relationship remains controversial. Older guidelines suggest optional screening for alpha-1 antitrypsin deficiency for patients with idiopathic diffuse bronchiectasis, 85 but newer guidelines described a lack of evidence and do not suggest alpha-1 antitrypsin deficiency testing for people with bronchiectasis. 86 A Turkish study (where consanguinity of parents is common) described transporter associated with antigen presentation (TAP) gene polymorphisms in their cohort of children with bronchiectasis. 87 It is interesting to note the high rate of consanguinity in several series of children with bronchiectasis from different countries. 88, 89 As with other diseases, an increasing number of gene aberrations have been associated with syndromes where bronchiectasis may occur. Examples include primary ciliary dyskinesia, autosomal dominant polycystic kidney disease (PKD1 on chromosome 16p13.3 and PKD2 on chromosome 4p21), 90 and prolidase deficiency 91 (PEPD gene). Aside from variations in specific gene frequencies, overexpression of innate pulmonary immune mechanisms, such as proinflammatory cytokine and adhesion molecule production, and receptor expression, may contribute to the development bronchiectasis is produced by local injury rather than underlying deficiencies in pulmonary host defenses. 107 The role of bacteria in the pathogenesis of chronic lung infection and bronchiectasis is reviewed elsewhere. 8, 108, 109 The majority of studies on airway inflammation have been performed in adults where, unlike children, assessment by using sputum is easy. Airway secretions are usually excessive in those with more severe bronchiectasis. The sputa from Alaskan native children with stable idiopathic bronchiectasis are less viscous (by one-third), less elastic (by one-fifth), less adhesive (by half), and more transportable (by 50%) compared to sputum from children with CF. 110 Neutrophilia is the dominant type of airway inflammation, 58 although eosinophilia has also been described in some populations 111 and when treated, airway inflammation may be absent. 58 Increased percentages of neutrophils, neutrophil elastase, myeloperoxidase, mellatoproteinases, tumor necrosis factor-α (TNF-α), interleukin (IL-8), and IL-6 have been described in lower airway secretions. 112 These generally reflect neutrophilic inflammation and are not specific to bronchiectasis. The intensity of the airway and systemic inflammation is ameliorated by treatment. 112, 113 An adult cohort involving 385 patients described a direct relationship between airway bacterial load and markers of airway inflammation (myeloperoxidase, neutrophil elastase, TNF-α, IL-8, and IL-1β) with a dose response such that higher inflammation correlated with higher bacterial loads. 112 High bacterial loads were associated with higher serum intercellular adhesion molecule-1 (ICAM-1), E-selectin, and vascular cell adhesion molecule-1 (VCAM-1), reflective of systemic inflammation. Using both short (14 days)-and long (12 months)-term antibiotic treatments, the study demonstrated a significant reduction in the airway bacterial load and inflammation (both airway and systemic) compared to those who did not receive antibiotic therapies. 112 However, there is a poor correlation between systemic and bronchial inflammatory mediators, suggesting that the inflammatory process is mostly compartmentalized to the airways. 114 There is paucity of data on BAL or sputum markers in children. A small study in children described increased median values of systemic markers (white cells, C-reactive protein [CRP], and fibrinogen) in children whose airways were colonized (n = 14) compared to those without identified bacteria in their sputum (white cell count: 8 115 While the authors concluded that systemic inflammation was absent in children with bronchiectasis compared to controls, it is highly likely that a type-1 error was present in the study. In an in-depth study, the blood of children with bronchiectasis had a significant increase in the percentage of CD8+ T cells and T and natural killer T-cells (NKT)-like subsets expressing perforin/ granzyme, interferon gamma (IFNγ), and TNFα compared with controls. 116 The proinflammatory cytotoxic T cells were more marked in Indigenous children compared to non-Indigenous children. 116 Exaggerated or persistent pulmonary inflammation present in bronchiectasis leads to increased lung destruction by many mechanisms. 8 The balance between proteases and airways and peribronchial tissue. As bronchiectasis becomes more severe, the airway walls become thin and saccular with destruction of the airway's muscular, elastic, and cartilaginous elements. 96, 98 The saccular airway walls are composed of fibrous and granulation tissue with only remnants of normal tissue. In advanced disease, mucus-filled saccular airway changes can be severe enough to appear as cystic microabscesses. Vascular changes accompany bronchial structural changes in bronchiectasis. Large bronchopulmonary anastomosis can develop, and total bronchial arterial blood flow is increased. Extensive precapillary anastomoses between the two arterial systems can serve as a shunt between the pulmonary and systemic systems, increasing cardiac work. 98 Bronchopulmonary vascular anastomoses most often occur near distal subsegmental bronchi that have undergone saccular changes. Abnormal bronchopulmonary anastomoses and enlargement of aberrant bronchial arteries are thought to be associated with the metabolic demands of hypertrophied muscle, lymphoid tissue, and peribronchial granulation tissue during the course of the organizing pneumonitis that precedes the development of bronchiectasis. 99 The presence of significant hemoptysis is likely related to these abnormalities. Additional vascular remodeling of the pulmonary arteries and arterioles occurs in association with chronic airway obstruction and alveolar hypoxia, predisposing patients to pulmonary hypertension and cor pulmonale in severe cases. The initial trigger for the bronchiectasis process is unknown, and there is little doubt that both host and pathogen factors play a role ( Fig. 26.4 ). Animal models of bronchiectasis suggest that inadequate mucus clearance and persistent infection are necessary prerequisites. 101 Mucus clearance in bronchiectasis is reduced by a combination of factors including airflow limitation, 102, 103 abnormal quantity and quality of mucus produced, 104 and factors produced by bacteria that cause ciliary slowing, dyskinesia, and mucus stasis. 71 Mucociliary clearance is enhanced by cough, exercise, and hyperventilation, 103, 105, 106 and is decreased in situations where airway caliber is diminished. 102, 103 Decreased mucociliary clearance in turn leads to increased bacterial colonization and infection, setting up a vicious cycle. This concept is schematically presented in Fig. 26 .4. Importantly, reduced mucociliary clearance is localized to the affected regions when for degradation of proteoglycans in a matrix model and that the protease secretion was stimulated by TNF-α in the presence of factors found in the sputum sol. 120 There are additional pathogenic processes associated with bronchiectasis that contribute to the persistence of airway inflammation and obstruction. Increased airway permeability has also been described with bronchiectasis when purulent sputum and significant colonization of the respiratory tract by bacterial pathogens are present. 121 Also, resolution of inflammation is normally associated with the orderly removal of apoptotic inflammatory cells, and impaired removal of apoptotic inflammatory cells has been described in children 122 and adults 123 with bronchiectasis. The pediatric study 122 also examined specifically for phagocytic activity for nontypeable Haemophilus influenzae (NTHi), whereas the adult study 123 investigated apoptosis in relation to inflammation. The adult study 123 reported that impaired apoptosis occurred in a doseresponse fashion with increasing neutrophil elastase, a marker of neutrophilic inflammation. In children with bronchiectasis, the macrophage phagocytic capacity of BAL cells to apoptotic cells (efferocytosis) and to NTHi was significantly lower than in controls (efferocytosis: 14.1%, IQR 10 to 16 vs. 18.1%, antiproteases is increasingly recognized as important to the protection of airways against hostile agents and destruction of lung tissue. Upregulation of circulating adhesion molecules (E-selectin, ICAM-1, and vascular adhesion molecule VCAM-1) have also been suggested as playing a role in the pathogenesis of bronchiectasis. 117 Collagenase activity present in the BAL of adults with moderately severe bronchiectasis originates from neutrophils and bacteria. These collagenolytic proteases are likely contributors to tissue destruction. 118 As described above, the airways of people with bronchiectasis contains collagenolytic proteinases of bacterial origin. 118 and neutrophilicassociated cytokines that, unabated, lead to increased tissue damage (e.g., metalloproteinases [MMP-2,8, and 9]). 117 MMP-9 (but not tissue inhibitors of metalloproteinase-1) measured in exhaled breath condensate of children with non-CF bronchiectasis (42.8 ± 18.1 ng/mL) were similar to those with CF (48.9 ± 26.8) and significantly higher than controls (30 ± 3.7). 119 Endobronchial biopsies in adults with bronchiectasis demonstrated an overexpression of neutrophil matrix metalloproteinases (MMPs). 117 over the affected regions. Reduced oxygen saturations and abnormal cardiac sounds associated with pulmonary hypertension are very late signs in bronchiectasis. Similar to any other serious chronic respiratory illness, children with bronchiectasis may have growth failure 52 that is associated with delayed diagnosis of bronchiectasis. The median age of diagnosis of bronchiectasis unrelated to CF in affluent countries is 4 to 5 years. 52,56 A New Zealand cohort 55 was older at 9 to 10 years old at diagnosis but also experienced more advanced disease. Idiopathic bronchiectasis is rare in infancy, but when present, it is likely to reflect congenital pulmonary malformations, such as cystic lung disease or tracheobronchomegaly, or alternatively, primary ciliary dyskinesia. Only 50% of those with ciliary dyskinesia have the Kartagener triad of situs inversus, bronchiectasis, and sinusitis. 132 Radiological risk factors for development of bronchiectasis are the presence of atelectasis 67, 133 and persistent lobar abnormalities. 134 In Alaska, children were more likely to develop bronchiectasis if chest radiographs obtained in children less than 2 years of age showed lung parenchymal densities, persistent parenchymal densities greater than 6 months duration, or repeated parenchymal densities. 134 Among Aboriginal Australian children hospitalized with lobar changes on admission chest radiographs, children with alveolar abnormalities were more likely to have bronchiectasis on follow-up. 133 In a prospective radiographic study of alveolar changes (179 lobes in 112 hospitalized children), the two most common involved lobes were the right upper lobe and left lower lobes. 133 Both lobes had similar rates of radiological clearance on follow-up (22% and 27% respectively). Children with postinfectious bronchiolitis obliterans and CSLD share some common clinical features (airway obstruction, chronic cough, recurrent ALRIs) in addition to the same etiological insult. 60, 135 In an Australian study, 6 of 19 children with postinfectious BO developed bronchiectasis. 60 A South American cohort follow-up study (mean period of 12 years, SD 3.5) described that mean FVC increased by 11%/year (95% CI 9.3 to 12.6), FEV 1 by 9%/year (95% CI 7.7 to 10.2), and FEV 1 /FVC ratio decreased by 1.9%/year (95% CI 1 to 2.8). 136 Seventy-eight percent of the 46 children in that cohort had bronchiectasis. 136 Phenotypes of childhood wheeze have been recognized and airway hyperreactivity occurs in some individuals with bronchiectasis. 135 The presence of features of asthma has been described as a bad prognostic factor in both children 24, 131 and adults 137 with bronchiectasis. The frequency of airway hyperreactivity in children with bronchiectasis varies from 26% to 74%. 52, 56 As a corollary, clinicians must recognize that wheeze and cough may not be related to asthma but to increased airway secretions and airway collapse as features of bronchiectasis. Gastroesophageal reflux disease (GERD) may coexist with any chronic respiratory illness and should be appropriately treated. However, data in adults indicate that GERD may resolve or significantly improve once the underlying respiratory disorder has been treated. 138 There is, however, no evidence-based approach to the management of GERD associated with bronchiectasis. Caution is necessary with regard IQR 16 to 21 respectively, P < .001 and NTHi: 13.7%, IQR 11 to 16 vs. 19.0%, IQR 13 to 21 respectively, P = .004). 122 Mannose receptor expression in BAL was also found to be significantly reduced in the bronchiectasis group compared to controls (P = .019). 122 Innate defense mechanisms also play a role in the pathogenesis and upregulated response to infection in people with bronchiectasis. 8 However, there is little data specific to children. 27 In a study involving 26 children with human immunodeficiency virus (HIV)-related bronchiectasis, 124 the soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), an innate immune marker, was upregulated and more highly expressed than in children with CF. sTREM-1 also correlated with IL-8 and neutrophil elastase derived from BAL. 124 The increased expression of innate immune receptors (e.g., receptors TLR2, TLR4, and CD14) and cytokine responses (e.g., IL-8 and IL-1β) seen in adults with bronchiectasis are also found in those with neutrophilic asthma and children with PBB, 125,126 a likely forerunner of bronchiectasis. 11 This raises the possibility that some people with neutrophilic asthma have unrecognized CSLD. Indeed, many of children with PBB were previously misdiagnosed with asthma 11, 34 and in some settings has been classified as "difficult or severe asthma." There is an emerging body of evidence that impaired cellmediated immune responses and dysregulated airway inflammation are linked and could contribute to the pathobiology of CSLD. A study on systemic immunity found that children with CSLD or bronchiectasis produced significantly less IFN-γ in response to NTHi than healthy control children, whereas mitogen-induced IFN-γ production was similar in both groups. 127 The production of systemic NTHi-specific IFN-γ was significantly negatively associated with the BAL IL-6 (P = .001) and IL-1β (P = .001). 128 The presence of bacterial or viral infection and severity of bronchiectasis using modified CT Bhalla score did not influence systemic NTHi-specific IFN-γ response. 128 The clinical case definition of bronchiectasis is imprecise, but the diagnosis should be considered when children have a chronic "wet" sounding or productive cough with or without exertional dyspnea, recurrent wheezing and chest infections, hemoptysis, growth failure, clubbing, or hyperinflation. The most common symptom is persistent or recurrent wet/ productive cough with purulent or mucopurulent sputum. Sputum color reflects neutrophilic airway inflammation. 129, 130 The frequency of chest wall deformity (hyperinflation) and digital clubbing vary among case series (5% to 60%). 24, 52, 131 Digital clubbing can disappear after medical or surgical treatment in association with the disappearance of purulent sputum. 24, 131 Although hemoptysis is much less common among children than in adults with bronchiectasis, a presenting finding of hemoptysis should raise the possibility of airway bleeding due to bronchiectasis. Chest auscultation may be entirely normal or reveal coarse inspiratory crackles as this finding can also be present in other conditions (Box 26.2). Other c-HRCT signs of bronchiectasis include abnormalities in the surrounding lung may include parenchyma loss, emphysema, scars and nodular foci, 150 a linear array or cluster of cysts, dilated bronchi in the periphery of the lung, and bronchial wall thickening (Box 26.1). 154 Image quality and hence detection of bronchiectasis is dependent on the radiological technique used (tube setting, radiation dose, collimation distance, and image intervals). 155 False positive and false negative situations that may occur are listed in Box 26.2. HRCT does not differentiate the etiologies of bronchiectasis. 156 to overdiagnosis, and unnecessary treatment of GERD is given the increasing evidence of increased risk of respiratory infections in children and adults receiving proton pump inhibitors in community and hospital cohorts. 139, 140 Readers are referred to the pediatric guidelines on diagnosis and treatment of GERD. 141 Hypertrophic osteoarthropathy (clubbing, periostosis of the tubular bones, and arthritis-like signs and symptoms) may occur in children with bronchiectasis. 142 Systemic amyloidosis has also been reported as a complication or comorbidity. 143 Cardiac dysfunction, although rare, has also been reported and may not be accompanied by pulmonary hypertension. A study of 21 children with bronchiectasis showed that the ventricular systolic function was normal but some patients had changes in left ventricular diastolic function. 144 The authors also found that isovolumetric relaxation time had a significant negative correlation with the clinical severity score. Other reported comorbid conditions associated with bronchiectasis are osteopenia, 145 scoliosis, chronic suppurative ear disease, social problems, past urinary tract infections, and developmental delay. 52, 56 In adults, vitamin D deficiency has been reported to be associated with increased severity of bronchiectasis and chronic bacterial colonization of the airways. 146 However, as serum vitamin D is a negative acute phase reactant (i.e., values fall with increased inflammation), deciphering cause and effect is problematic. 147 The goals of evaluating children with suspected bronchiectasis are: (1) to confirm the diagnosis, (2) to define the distribution and severity of airway involvement, (3) to characterize extrapulmonary organ involvement associated with bronchiectasis (such as cor pulmonale), and (4) to identify familial and treatable underlying causes of bronchiectasis and contributors to its progression. Chest HRCT is the gold standard for diagnosis, 27 because plain chest radiographs are insensitive. It has been long recognized that chest x-rays can be normal in people with bronchiectasis. 148 With modern CT scanners, the images are best acquired using an MDCT scan with HRCT reconstruction which provides the best sensitivity. 27 The scan protocol must be child-appropriate to minimize radiation risk. Radiology centers inexperienced in dealing with children often utilize adult protocols that subject children to higher doses of radiation. Radiological features of bronchiectasis can also occur in association with pulmonary fibrosis, congenital lesions such as Mounier-Kuhn, and Williams-Campbell syndrome, 97 and as a result of traction in nonsuppurative lung disease. 149 The characteristic radiographic finding on HRCT in bronchiectasis is the presence of a "signet ring" where a dilated bronchus is greater than the diameter of the accompanying blood vessel in cross section (Fig. 26.5) . 97, 150 However, the cutoff (>1 to 1.5) whereby the ratio is considered abnormal should be reduced to 0.8 in children when CSLD symptoms are present. 13 While this is generally appreciated by pulmonologists, radiologists may still use the adult criteria. The presence of bronchial dilatation relative to the accompanying vessel does not always equate to the presence of bronchiectasis, investigation, and many retain the label of idiopathic or presumed postinfectious bronchiectasis (see Table 26 .2). Difficulties with ascribing an etiology to CSLD/bronchiectasis arise due to unavailability of certain tests, for example, functional tests for ciliary motility and extended immune testing, lack of a standardized approach to diagnosis, the population studied, and the CT definitions used. Identifying etiology and assessing disease severity can influence surveillance frequency, treatment intensity, and prognosis. 157, 158 Investigations for specific causes of CSLD/ bronchiectasis are recommended, even though many patients will lack an identifiable etiology. 79 Current best practices for investigating possible etiology are outlined in Table 26 .3. The diagnosis of ciliary dyskinesia 159 is addressed in another chapter (see Chapter 71) . Bronchoscopy is indicated to identify obstructive bronchiectasis, which can be intraluminal (tumors and foreign body), in the wall (tracheobronchomalacia [TBM]), or extramural from external airway compression. Bronchiectasis is a complication of inhaled foreign bodies and occurs among 25% of patients whose diagnosis of aspiration was delayed by greater than 30 days. 160 In a prospective study involving 56 children with bronchiectasis undergoing flexible bronchoscopy, there were 25 occasions in 23 children where bronchoscopic results altered empiric treatment. 111 BAL microbiology results led to antibiotic changes in five (9%) children, and an unsuspected foreign body was found in one (2%). 111 Bronchoscopic findings of major airways related to bronchiectasis have been described as five types: type I: mucosal As most patients are usually diagnosed with bronchiectasis after many years of symptoms, it may be difficult to define the etiology. Differentiating idiopathic from postinfectious bronchiectasis is particularly problematic. A common feature of many patients is impaired local or systemic host defenses to infection. 127, 157 Often, no cause is found even with extensive limitation during cardiopulmonary exercise testing does not relate to HRCT scores. 167 There are limited data on how bronchiectasis alters respiratory system resistance or reactance measured by forced oscillatory techniques (FOT). In children, indices obtained from impulse oscillometry during exacerbations were not significantly different from the stable state. 168 In the stable state, resistance at 5 Hz was poorly sensitive to lung disease. 168 In children with CF, indices from FOT are not only insensitive at baseline but also cannot detect lung progression over 12 months. 169 Another tool to assess severity of bronchiectasis is lung clearance index (LCI). The LCI reflects ventilation inhomogeneity in peripheral airways. Data in children with CF suggest that LCI changes occur early and before other physiological measurements when evaluating lung damage. 170 Among adults with stable non-CF bronchiectasis, the LCI negatively correlated with FEV 1 % predicted and was abnormal more often than FEV1. 171 However, a study involving 25 paired measurements of adults with non-CF bronchiectasis found that LCI was less sensitive than FEV 1 when evaluating improvement after treatment with intravenous antibiotics and physiotherapy for respiratory exacerbations. 170 While FEV 1 and vital capacity significantly improved, there was no significant change in LCI after intravenous antibiotics and physiotherapy. 170 The same study also undertook paired measurements in 25 adults with stable bronchiectasis and described that LCI indices were reproducible and, compared to controls, LCI was significantly higher. 170 There are no studies in children with non-CF bronchiectasis to know its sensitivity to early disease. There are at least eight radiographic scoring systems to assess severity of bronchiectasis using plain abnormality/inflammation only; type II: bronchomalacia ( Fig. 26 .6A); type III: obliterative-like ( Fig. 26 .6B); type IV: malacia/obliterative-like combination; and type V: no abnormality. 161 The frequencies of these findings among 28 children with non-CF bronchiectasis were 58%, 17%, 17%, 4%, and 2% for types I through V respectively. 161 In the 33 children with postinfectious bronchiectasis and CSLD, structural airway lesions were present in 40%. 161 A retrospective study involving 93 Greek children (0.6 to 16.4 years) described that type III (OR 5.4, 95% CI 1.9 to 15.4) and type IV (OR 8.9, 95% CI 2.5 to 15.4) bronchoscopic lesions significantly correlated to worse radiological scores, reflecting severity, and correlated with the percentage of BAL neutrophils (r = 0.23, P = .036). 162 Bronchomalacia associated with bronchiectasis can be related to chronic inflammation, 163 although it is unknown if bronchomalacia predates recurrent respiratory infections. Airway mucosal changes typical of chronic bronchitis are usually present in bronchiectatic airways at bronchoscopy. Bronchoscopic findings include atrophic mucosa, increased secretions, and airway friability. Airway flaccidity, hypertrophy of elements in wall, longitudinal corrugations, mucosal reddening, increased vascularity, dilated ducts, and displacement due to lobar collapse have also been described in the proximal conducting airways (Fig. 26.7) . 163 Pulmonary Function. In children, spirometry is insensitive in detecting early structural lung damage in children with bronchiectasis, both in CF 164 and non-CF. 52 Spirometric values may be normal, but when a spirometric abnormality is present 52, 165 ; it is usually obstructive in the earlier stages and becomes a mixed obstructive and restrictive process when bronchiectasis is more severe. Although FEV 1 correlates with chest HRCT abnormalities in some populations, it is not a sensitive measure, especially if bronchiectasis is localized. 52, 165 FEV 1 can also be normal, as in CF, in the early stages of disease even when radiological bronchiectasis was present. 164 However, when bronchiectasis is diffuse, spirometric abnormalities, although insensitive to disease activity, reflect disease severity. 164 Other pulmonary function test abnormalities described are a high residual volume, lower aerobic capacity, and lower maximal ventilation at maximal exercise. 166 Effort do not expectorate sputum even when they have substantial lower airway secretions. Hence, in young children, assessment of lower airway microbiology requires bronchoscopy to obtain BAL and lower airway samples. BAL remains the gold standard, although the criteria for defining infection remains controversial. 11, 178 Studies have generally used a threshold of bacterial growth of ≥10 4 colony forming unit (cfu)/ mL BAL to indicate infection. 11, 179 Other methods for identifying airway pathogens from children with bronchiectasis are oropharyngeal or nasopharyngeal swabs and induced sputum. In adults with bronchiectasis, sputum culture is generally reflective of lower airway organisms obtained by bronchoscopic catheter protected brushings. 180 One study on children with bronchiectasis described that the sensitivity and negative predictive value of nasopharyngeal cultures for individual respiratory bacterial pathogens, causing lower airway infection using BAL for comparison, ranged from 75% to 100%, and the specificity and positive predictive value were lower (32% to 72%). 72 Common respiratory pathogens in children with bronchiectasis are Streptococcus pneumoniae and H. influenzae nontype b. Other organisms include Moraxella catarhallis and Pseudomonas aeruginosa. In pediatric bronchiectasis, the pathogen isolation rate from sputum or BAL is 53% to 67%. 58, 109 Pseudomonas is commonly found in adults with severe bronchiectasis, but it is uncommon in children until adolescence or when bronchiectasis is severe. 58 In adults, a systematic review 181 found that persistent pseudomonas endobronchial infection was associated with increased disease severity measured radiographically, with spirometry, with death (threefold), and with more hospitalizations and poorer QoL; there are no such data in children. While nontuberculous mycobacteria and Aspergillus are commonly found in adults with bronchiectasis, they are rarely present in children with bronchiectasis. 58, 72 A number of children with bronchiectasis are persistently colonized with potential pathogenic microorganisms. 180 The largest study to report on microbiology in children with bronchiectasis was undertaken when they were clinically stable. 58 H. influenzae was identified in 32%, S. pneumoniae in 14%, M. catarrhalis in 8%, and S. aureus in 5% of BAL cultures. 58 P. aeruginosa was present in seven (6%) children of whom six had bronchiectasis involving multiple lobes, and five had other comorbidities. 58 The study also reported that respiratory viruses (principally respiratory syncytial virus and adenovirus) were present in 14 (12%) children; codetection of respiratory pathogens was found in more than half of those with positive microbiology results. 58 When the adenovirus was genotyped, almost all were type C, and the presence of adenovirus was significantly associated with bacterial coinfection with H. influenzae, M. catarrhalis, or S. pneumoniae (OR 3.27; 95% CI 1.38 to 7.75) and negatively associated with S. aureus infection (P = .03) in the BAL. 182 Studies on the microbiota (using bacterial 16S rRNA gene pyrosequencing) in children 9 and adults 183 with bronchiectasis have been reported. However, their impact on clinical management is yet to be defined. Nevertheless, one study that compared the microbiota of children and adults with bronchiectasis reported that the respiratory microbiota significantly differed from each other. 9 Pulmonary exacerbations among children with non-CF bronchiectasis are often triggered by viruses and an increased films. However, given the insensitivity of chest radiographs in detecting bronchiectasis, these scoring systems have been superseded by chest HRCT scoring systems described by Webb et al., 97 Bhalla et al., 172 and Reiff et al. 156 These chest HRCT scoring systems are based on composite scores of multiple radiological findings. Some systems utilize expiratory scans, 173 while others do not. 97 The Webb composite score 97 is a summation score of severity, extent, and features of emphysema and consolidation/atelectasis. The Bhalla score 172 comprises the sum of scores assigned to each of nine categories: severity of bronchiectasis, peribronchial thickening, extent of bronchiectasis, extent of mucus plugging, sacculations, generations of bronchi involved, number of bullae, emphysema, and collapse/consolidation. One study compared these three scoring systems in a group of 59 children with non-CF bronchiectasis. 52 The correlation between the scores ranged from 0.61 to 0.8 but none related to FEV 1 values. Magnetic resonance imaging (MRI) is an emerging technique for assessing bronchiectasis, but it is currently poorer than CT in evaluating airway diseases. 174, 175 Other Markers. A UK group developed the bronchiectasis severity index for adults 6 as a stratification tool for morbidity and mortality. The index includes features that are rare in children (e.g., FEV 1 of <30% predicted) and is thus not used in children. The world of "omics" is blooming, but there currently are no studies relevant to clinical care in bronchiectasis. In children with CF, metabolomics using mass spectrometry have described possible biomarkers of BAL neutrophilic inflammation. 176 Techniques such as expired breath analysis and breath condensate measurements described almost two decades ago have not advanced in bronchiectasis. To date, there is little research on the most sensitive and appropriate method of assessing progression of bronchiectasis in children. Clinicians rely on frequency of respiratory exacerbations and on daily clinical symptoms, which may be perceived differently by children and their parents. There is no bronchiectasis severity score for children. QoL scores that are not specific for cough have been used in children with bronchiectasis, but to date, there is no pediatric bronchiectasisspecific QoL score. The most sensitive objective assessment of early disease progression is based on HRCT changes, as these precede most pulmonary function changes. 52, 165 However, repeated HRCT scans are not recommended purely for assessment of disease progression given the known risks of radiation in young children. 177 Other assessments of disease progression include chest radiographs which are insensitive, lung function, markers of neutrophilic airway inflammation, and possibly assessments of airway proteases. One small cross-sectional study showed significant correlations between HRCT severity scores and symptoms, FEV 1 , sputum IL-8, and TNF-α levels (r values of 0.64, −0.68, 0.41 and 0.41, respectively). 53 However, there are no data relating these airway markers to imaging assessments longitudinally and disease progression. Sputum sampling is the easiest method of obtaining an endobronchial microbiologic profile, but young children often authors such as Field 74 emphasized the importance of treatment "Even with simple medical treatment, the progress of most cases can be arrested…." 74 In bronchiectasis secondary to CF and primary ciliary dyskinesia, aggressive management of infections with antimicrobials, regular use of airway clearance methods, attention to nutrition, coupled with vigilant monitoring of long-term clinical trends, and proactive care led to improved survival and preservation of lung function. 191 CF produces a specific type of progressive bronchiectasis that differs from other forms of bronchiectasis with respect to mucus rheology, airway surface abnormalities, salt content, airway microbial pathogens, and extrapulmonary organ involvement. Although blind extrapolation of management used in CF to non-CF bronchiectasis can be harmful, 192 management of children with bronchiectasis should be arguably as intensive in children with idiopathic bronchiectasis to minimize acute exacerbations, daily symptoms, and functional limitations; thus improving the prognosis. Indeed, more recent data have provided evidence that intensive treatment of children who either have bronchiectasis or who are at risk of developing severe bronchiectasis prevents poor lung function in adulthood. 79, 193 Even among children with serious underlying conditions, such as congenital immunodeficiencies and bronchiectasis, comprehensive regular care and surveillance programs have delayed decline in lung function over a period of a year. 194 The aims of regular review include optimal postnatal lung growth, prevention of premature respiratory decline, maximal QoL, and prevention of complications due to bronchiectasis. Issues that require regular monitoring are listed in Box 26.3. Ideally, a team approach with incorporation of allied health expertise (nursing, physiotherapy, nutritionist, social work) should be used, as this model has been shown to improve health outcomes for several chronic diseases. 195 Evidencebased guidelines of management of bronchiectasis in children have been published since 2002 and subsequently updated, 190 and adults have been included. 196 An umbrella Cochrane review on the interventions for bronchiectasis has been published. 197 density of known bacterial pathogens in sputum. The single prospective study in children that evaluated the point prevalence of viruses associated with exacerbations reported that respiratory viruses were detected during 37 of 77 (48%) exacerbations. 184 There is one published study that developed a standardized definition of exacerbation in children. 168 In 69 children over 900 child months, the study described validated major and minor criteria that can be used in the hospital or primary care setting. The major criteria were the presence of a wet cough and a cough severity score of ≥2 168 The minor criteria were change in sputum color, chest pain, dyspnea, hemoptysis and new chest signs on physical examination. The inclusion of investigations (investigatory criteria: elevated serum C-reactive protein, amyloid-A, or IL6) to the definition improved its specificity and positive predictive value. 168 Other infrequent features of importance are reduced exercise tolerance and energy. 185 Fever and hemoptysis are uncommon in exacerbations of bronchiectasis in the pediatric age group. 168, 185 Determinants of accelerated lung function decline in adults with bronchiectasis are frequency of hospitalized exacerbations, increased systemic inflammatory markers, and colonization with P. aeruginosa. 186 In one study of 52 children over a 3-year interval, the only significant predictor of FEV 1 decline was frequency of hospitalized exacerbations 79 ; with each exacerbation, the FEV 1 % predicted decreased by 1.95% adjusted for time. 79 It is likely that interventions that can reduce exacerbations prevent further lung dysfunction. 187 Also, exacerbations, particularly when recurrent, are one of the strongest predictors of poor QoL among adults with bronchiectasis. 188, 189 A prospective study involving 93 Indigenous children in Alaska and Australia showed that factors associated with recurrent (≥2) exacerbations included age less than 3 years, respiratory-related hospitalization in the first year of life, and pneumonia or hospitalization for exacerbations in the year preceding enrollment. 1 The study also reported that with clinical care and time exacerbations occurred less frequently. 1 Exacerbations should be treated such that at the end of treatment, there are improvements in cough character, general well-being, QoL indicators, and inflammatory markers with reduced sputum volume and purulence, decreased sputum bacterial load or pathogen clearance, and a return toward the patient's stable baseline state. 109, 190 As early as 1933, Roles and Todd emphasized the importance of early diagnosis and treatment in reducing mortality associated with bronchiectasis. 36 (adherence ≥70% reduces risk OR 0.34, 95% CI 0.14 to 0.81 compared to <70%) and baseline macrolide resistance rate. 207 The majority of the long-term studies used macrolides that have antiinflammatory and antisecretagogue effects. 208 In 18 children with CF and 15 children with idiopathic bronchiectasis, 6 months of beta-carotene supplementation reduced plasma levels of TNF-α and malondialdehyde, a marker of lipid peroxidation, 209 but did not change clinical status. In adults with bronchiectasis, nonsteroidal antiinflammatory agents have a major effect on peripheral neutrophil function, significantly reducing neutrophil chemotaxis and fibronectin degradation by resting and stimulated neutrophils, but they had no effect on bacterial colonization of the airways or superoxide anion generation by neutrophils. 210 There are no studies on oral nonsteroidal antiinflammatory drugs (NSAIDs), but a Cochrane review on inhaled NSAIDs found a single trial in CSLD. 211 In adults with bronchiectasis, Tamaoki et al. reported a significant reduction in sputum production over 14 days in the treatment group (4 days of inhaled indomethacin) compared to placebo and significant improvement in a dyspnea score. 212 There was no significant difference between groups in lung function or blood indices. Emerging drugs in development have been recently reviewed. 213 Mucoactive agents enhance mucus clearance from the respiratory tract in conditions where mucus clearance is impaired. 104 Mucolytics reduce mucus crosslinking and viscosity by disruption of polymer networks in the secretions through severing disulfide bonds, depolymerizing mucopolysaccharides, liquefying proteins, and degrading DNA filaments and actin. 104 In adults, high doses of bromhexine (not available in some countries) used with antibiotics eased difficulty in expectoration and reduced sputum production. 197 Recombinant deoxyribonuclease (rhDNAse) is efficacious in CF but is contraindicated in non-CF bronchiectasis. In a double-blind, RCT, multicenter study for 24-weeks in 349 adults with bronchiectasis, those given rhDNAse had higher exacerbation and hospitalization rates and more rapid pulmonary decline (decrease in FEV 1 3.6% in rhDNase group; 1.6% in placebo group). 192 Inhaled osmotic agents, such as 7% hypertonic saline and mannitol, improve airway clearance and lung function and reduce exacerbation frequency in people with CF but studies in adults with non-CF bronchiectasis show a benefit only in time to first exacerbation and QoL and not in exacerbation rates. 214 There are no studies in children and clinically selected children can be commenced on hypertonic saline. When used, pretreatment with a short-acting bronchodilator is recommended to avoid bronchospasm, which occurs in up to 30% of patients. Antisecretagogues reduce airway mucus production and secretion. These agents include anticholinergic agents, macrolide antibiotics, and bromhexine. Fourteen-member-ring macrolides are antibiotics with antiinflammatory activities and their use is discussed in the antimicrobials section. There are no RCTs on anticholinergics in the treatment of acute or stable bronchiectasis. Some anticholinergic agents such as atropine and glycopyrrolate slow mucociliary transport and predispose to further mucus stasis. An Antimicrobial treatment is a key intervention in the management of patients with bronchiectasis. 109 In stable adult patients, there was a direct relationship between bacterial load and the risk of both subsequent and severe exacerbations (ORs of 1.2, 95% CI 1.1 to 1.3 and 1.1, 95% CI 1.0 to 1.2; respectively). 112 However, there are few published randomized controlled treatment trials on childhood bronchiectasis and none that focus on acute exacerbations. 198 Brief antimicrobial interventions significantly improve the inflammatory profile in the airways, 199,200 and blood, 199,200 sputum production, cough frequency, and QoL measures. 200, 201 Use of antimicrobials for bronchiectasis was recently summarized. 109 In general, the type of antimicrobial should target known pathogens and the route dependent on the severity of the illness and response to previous treatments. 109, 190 Ideally, a sputum culture should be obtained prior to initiating antibiotics. Oral antibiotics are usually prescribed initially, but more severe episodes, or failure to improve with oral agents, require intravenous antibiotics combined with more intensive airway clearance techniques. Although robust evidence is lacking, a course of antibiotics for 14 days has been recommended by respiratory specialists. 112, 190 Comprehensive care programs for bronchiectasis have used both intermittent antibiotics to treat exacerbations and chronic or maintenance antibiotic treatment strategies. The use of maintenance antimicrobials may be suitable in selected situations where frequent exacerbations are likely to occur. Old studies in adults demonstrated that regular use of macrolides and trimethoprim reduced pulmonary inflammation, infective exacerbations and improved lung function. 202, 203 A pediatric randomized controlled trial (RCT) involving 25 children (12 weeks of roxithromycin 4 mg/kg twice a day or placebo) also described a significant improvement in sputum markers and of airway responsiveness in the roxithromycin group, but improvements in FEV 1 were not observed in either group. 204 More recent studies in adults and children have confirmed these findings. 205 However, many questions remain, such as when should maintenance antibiotics be started and in whom, what is the optimal duration (studies suggest effects are evident only after 3 months), whether macrolides are the best choice of maintenance treatment, and which macrolides to use. Other questions are the optimal type and dosing regimen (daily-to-weekly) and whether associated increases in S. aureus and other macrolideresistant bacteria are harmful at individual or community levels. 206 The latest Cochrane review (children and adults included) consisted of 18 studies whereby the meta-analysis showed that in patients with at least one exacerbation, the use of maintenance antibiotics (for >4 weeks) significantly reduced exacerbations compared to placebo or usual care with a reduction of 275 exacerbations per 1000. 205 Hospitalization was also reduced (50 fewer hospitalizations per 1000 people treated). 205 There was a threefold higher likelihood of antibiotic resistance in the group using maintenance antibiotics. 205 However, in the sole RCT that reported on use of antibiotics for conditions other than respiratory exacerbations, those in the antibiotic arm required 50% less other antibiotics (Incidence Rate Ratio = 0.5, 95% CI 0.31 to 0.81). 80 The factors affecting the risk of development of resistance to long-term macrolide therapy are adherence In utero tobacco smoke exposure alters respiratory control and pulmonary development and physiology. 81, 220 Tobacco smoke also skews the early immune function, 81 but its role in permanently altering local and systemic pulmonary immunity is unknown. Exposure to ETS increases susceptibility to respiratory infections, causes adverse respiratory health outcomes, and increases coughing illnesses. 81 Cessation of parental smoking reduces children's cough. 221 Behavioral counseling and motivational interviewing for smoking mothers reduces young children's ETS exposure in both reported and objective measures of ETS. 222 Indoor wood smoke also increases acute respiratory infections, demonstrating an exposure-response effect. 223 Thus efforts to reduce smoke and biomass exposure including in utero exposure and children's exposure in the home must be maximized. There is low to moderate quality evidence that repairing houses decreases respiratory tract infections. 224 Vaccination as per national schedules is recommended. Many of the diseases described as causing bronchiectasis (e.g., pertussis and measles) are now controlled in developed countries. Vaccinations for prevention of influenza are recommended despite the lack of evidence specific for bronchiectasis. 225, 226 While there is no specific evidence for influenza vaccine in those with CSLD/bronchiectasis, 225 indirect evidence suggests that annual influenza vaccinations reduce morbidity, mortality, and health care cost in "at risk" groups. 227 For pneumococcal vaccination, limited evidence supports the use of the 23-valent pneumococcal vaccine in reducing acute infective exacerbations. 226 23-valent pneumococcal vaccine is recommended for high-risk children, including those with bronchiectasis. 228, 229 Current evidence support revaccination, although the frequency of revaccination is controversial. 228 A recent study found that vaccination with the pneumococcal 10-serotype with H. influenzae protein D conjugate vaccine was associated with improvements in NTHi-specific cell-mediated and humoral immune responses in children with CSLD. 230 While this is promising, further confirmatory data are required. Surgery is considered most often when bronchiectasis is focal and medical therapy has failed. Surgery is very rarely undertaken now in affluent countries but is still a common intervention in less affluent countries. 231 Perioperative mortality for lobectomy and pneumonectomy has fallen dramatically. In a retrospective series of 109 children (mean age 7.6 years, range 1 to 15.5), 36% had minor postoperative complications (transient atelectasis in 26%, air leak 6%) and one child died within the 30-day postoperative period. Of the 83 children with an average follow-up period of 667 days, 76% showed improvement of clinical symptoms. This is similar to several reviews of surgical therapy for bronchiectasis; the compiled group of adult and pediatric patients experienced 1% mortality (6/597) and an operative complication rate of 8.5% (51/597). 232, 233 Complications included empyema, bronchopulmonary fistula, hypotension, and bleeding, but surgical treatment of bronchiectasis was more effective in patients with localized disease. 233 Appearance of new uncontrolled trial of tiotroprium in adults with hypersecretory states, including bronchiectasis that was resistant to macrolides, reduced daily symptoms and improved QoL with short-term use, 215 but it is not currently recommended in children. Although it is lacking a robust evidence-base, 216 airway clearance techniques (encompassing various types of chest physiotherapy) are recommended in children and adults. 190, 196 Available studies suggest that airway clearance techniques are beneficial with improved QoL and exercise capacity and reduced cough and sputum volumes. 216 Thus daily chest physiotherapy is recommended in a form that maximizes potential benefit and minimizes burden of care. In the past, postural drainage was standard therapy for children with CSLD/bronchiectasis. However, this treatment may increase gastroesophageal reflux and possible aspiration. 217 Given the availability of multiple techniques for airway clearance and the lack of clear superiority of any one technique, specific choices should be individualized and pediatric-specific physiotherapist expertise sought. In addition, children with bronchiectasis should be encouraged to participate in exercise activities. Asthma in children with bronchiectasis should be treated on its own merits. Inhaled corticosteroids (ICS), at best, have a modest benefit in those with severe CSLD/bronchiectasis and those with P. aeruginosa. 218 The Cochrane review (six studies in adults, no pediatric studies) found that in the short term (ICS for <6 months duration), adults on very high doses of ICS (2 g per day of budesonide equivalent) had significantly improved FEV 1 , FVC, QoL, and sputum volume but no improvement in peak flow, exacerbations, cough, or wheeze when compared to adults in the control arm (no ICS). When only placebo-controlled studies were included in the review, there were no significant differences between groups in any of the outcomes examined (spirometry, clinical outcomes of exacerbation or sputum volume). A single study on medium-term (>6 months) outcomes showed no significant effect of inhaled steroids on any of the outcomes. 218 There is no published RCT on the use of ICS for children with CSLD/bronchiectasis. 218 One study reported that 12-week withdrawal of ICS resulted in a significant increase in bronchial hyperreactivity and decrease in neutrophil apoptosis but no change in the children's clinical parameters or sputum inflammatory markers. 219 This suggests that ICS have little role in the management of CSLD/bronchiectasis in children when asthma does not coexist. Short-and long-acting β-2 agonists also have an indeterminate role in the management of bronchiectasis, 197 and their use must be individualized. Although the presence of asthma is associated with advanced bronchiectasis and a worse prognosis, treatment of asthma to alter long-term outcomes has not been studied. It may be that the asthmatic features associated with diffuse bronchiectasis reflect the disease itself rather than a concurrent condition. Whether published guidelines for asthma care pertain to patients with wheeze and airway hyperactivity is unclear. Increased cough in children with bronchiectasis should be initially treated as an exacerbation of bronchiectasis. Given the heterogeneity of etiological factors and host responses, regional severity, and distribution of bronchiectasis, it is not surprising that the prognosis is varied, ranging from mild respiratory morbidity to death from airway obstruction, pulmonary infection, and respiratory failure with hypercapnia. There are cases where bronchiectasis resolves radiographically with treatment. 22 However, these children remain at risk of developing bronchiectasis and should be monitored regularly for reemergence of symptoms and obstructive lung disease. More often, bronchiectasis persists on HRCT but becomes less severe clinically with fewer infectious exacerbations and less cough evident later in childhood. In a series of 46 children with HRCT-documented bronchiectasis, a third improved, a third remained symptomatic but stable, and a third worsened while receiving medical therapy 56 Both Field 131 and Landau et al. 238 reported reductions in exacerbations during the second and third decade of life despite persistence of bronchiectasis radiographically. What happens in the following decades is inferred from case series of adults with bronchiectasis, many of whom had onset of respiratory problems, if not bronchiectasis in childhood. However, these series do not depict the era of minimal symptoms that occur at adolescence and anecdotally reappear at age 35 to 40 years old. There are three published studies (all retrospective) on longitudinal FEV 1 changes in children with non-CF bronchiectasis studied over variable intervals with varying results. 79, 239, 240 A British study (n = 59 over 2 years, n = 31 over 4 years) found that lung function improves with intensive treatment but does not necessary normalize. 239 Likewise, an Australian study (n = 52 over 3 years, n = 25 over 5 years) 79 found that lung function and anthropometric parameters remain stable over a 3-to 5-year follow-up period once appropriate therapy is instituted, and those with low function at diagnosis (FEV 1 % predicted <80%) improved with time. 79 In contrast, a New Zealand (NZ) study of 44 children over 4.5 years found that FEV 1 declined at 1.9% per annum. 240 The explanations for this contrast are speculative but likely include the different age groups, children from different ethnicities, and health care differences. Also, the NZ cohort had more extensive radiological disease with 89% bilateral disease (median of four diseased lobes, 95% with multilobar involvement). The Brisbane study found that the only significant predictor of FEV 1 decline (over 3 years) was frequency of exacerbations requiring hospitalization 79 The other two cohorts 239,240 did not examine for determinants of lung function decline. Published data also suggest that delayed diagnosis is associated with poorer outcomes. 27, 79 A large study of adults newly diagnosed with bronchiectasis showed that the decline in FEV 1 correlates with the duration of chronic wet cough, 37 the most common symptom of bronchiectasis. 241 For each additional year of productive cough, FEV 1 % predicted declined by 0.51% in nonsmokers. 37 Adults with bronchiectasis who were symptomatic from childhood have much poorer lung function and worse chest CT scan scores than those with adult-onset symptoms. 37 In the Brisbane longitudinal study, children diagnosed earlier and hence managed earlier were significantly younger and had better long-term spirometry and growth parameters. 79 FEV 1 % predicted decreased by bronchiectasis following surgical management has been described. 52, 234 Indications for surgical intervention are controversial, and data from the 1940 to 1950's cannot be applied given the major advances in antibiotics, airway clearance techniques, and nutrition supplementation, and socioeconomic standards among underserved populations. Our suggested indications for surgical intervention are outlined in Box 26.4. Although lung transplantation has been reported widely for patients with CF, this option has only been used for adults with end-stage non-CF bronchiectasis, 235 and outcomes following lung transplantation in children without CF have not been reported. Finally, health cannot be isolated from social, economic, environmental, and educational issues. Health and health behaviors are closely linked to socioeconomic factors, 236, 237 and increased poverty, with its associated consequences such as poor housing and poor water supply, is an independent risk factor for increased respiratory infections and associated mortality. 237 To effectively reduce the morbidity and mortality from CSLD and bronchiectasis in children, a multifaceted approach encompassing good clinical care and public health concerns bears consideration. Although it is beyond the scope of this article to address this important issue, future work must focus on the public health issues predisposing to childhood bronchiectasis if the disparity between developed and developing countries is to be reduced. Delivery of chronic disease programs requires comprehensive and highly skilled culturally competent primary health care. Education of primary health providers should ideally focus on identifying children for appropriate referral and high quality local management. Initial assessment requires specialist expertise, and specialist evaluation is recommended to confirm diagnosis, investigate etiology, assess baseline severity, and develop a management plan. Similar to other chronic illnesses, individualized and multidisciplinary case management operating within an interprofessional framework is optimal. Similarly, deterioration should prompt early referral for specialist care. In addition, those with moderate or severe disease are best managed by a multidisciplinary team approach. with chronic cough, with the prevalence ranging from 6% to 42%. 11 In the first description of PBB, 23 BAL cultures grew the common respiratory bacterial pathogens, S. pneumoniae, H. influenza, and M. catarrhalis (Fig. 26.8) . Subsequent studies confirmed this finding, although one retrospective study also identified S. aureus (11 of 50 children), 254 255 which upon genotyping, belonged predominantly to AdV species C. 182 The presence and role of biofilms in the BAL of children with PBB have not been studied, but their presence has been speculated. 11 The microbiota of the lungs of children with PBB has been examined in a single cross-sectional study. 9 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. The lung microbiota in children were significantly different from those observed in adults with CF and bronchiectasis, suggesting that chronic airway infections begin similarly with 1.64% points for each year increase in age at diagnosis, but this was statistically nonsignificant. 79 When bronchiectasis worsens, it may become increasingly saccular within a local lung region (see Figs. 26.2 and 26.3). Alternatively, bronchiectasis can extend to additional airways, either due to endobronchial spread of infection or evolution of disease at multiple airway sites. The frequency with which bronchiectasis extends to new lung regions varies with different series, from 2% to 35%. 242,243 Local progression of disease rather than extension to new areas is likely more common. The most severe cases of bronchiectasis have diffuse airway involvement and are accompanied by airflow limitation, with or without concomitant airway hyperreactivity. The diagnosis of asthma in the context of an underlying lung disease may be difficult. Wheeze and asthma symptoms are common in people with CSLD/bronchiectasis, although reported prevalence varies from 11% to 46%. 57, 244 While some studies describe asthma as a cause of bronchiectasis, it is more likely that wheezing illness is a secondary or coexistent condition or that asthma was initially misdiagnosed. Asthmalike symptoms in adults with bronchiectasis may be associated with an accelerated decline in lung function. 137 King reported that increased use of bronchodilators led to a trend of a greater FEV 1 decline over time in adults. 245 The NZ cohort found that while the presence of asthma was associated with lower FEV 1 at diagnosis, asthmatics had a slower rate of decline over the 5-year follow-up. 240 Unfavorable prognostic factors for patients with bronchiectasis include presence of asthma, bilateral lung involvement, 131,246 saccular bronchiectasis, 246 frequency of exacerbations, and presence of P. aeruginosa in the airways. 181 The advent of better antibiotics, inhaled antibiotics, longterm oxygen therapy, and improved nutrition has improved prognosis. Cor pulmonale and right heart failure are now uncommon complications of advanced bronchiectasis in children. In one series, echocardiography in 50 children with bronchiectasis found only one child with pulmonary hypertension. 52 In addition, chronic lung infection and inflammation are independent risk factors for developing cardiovascular disease in adults. 247 Prior to a diagnosis of PBB, most children with a chronic wet cough received multiple medications and consulted several health physicians. 34, 248 An Australian multicenter study found 70% of 138 children with PBB had received asthma medications, and 76% had seen greater than five doctors previously because of persistent cough. 249 However, these findings were also similar to children with a chronic cough from other causes. 249 QoL scores of children with PBB were similar to children with cough due to asthma or bronchiectasis presenting to pediatric pulmonologists. 249, 250 Importantly, QoL scores normalized once the cough resolved. 251 While the prevalence of PBB cases in the community clinics is unknown, studies from specialist clinics (pediatrics and/or pediatric pulmonology) from Australia 23, 34 and Turkey 252, 253 found PBB to be among the top three diagnoses in children bronchoscopy for other respiratory indications at a tertiary pediatric hospital (68% vs. 53%, respectively). 255 However, it has been shown in a prospective study that, children with TBM (c.f. controls) have a higher frequency of respiratory infections and symptoms. 260, 261 Children with PBB have a chronic wet cough but otherwise typically appear well with an absence of recurrent nasal or ear disease. They have normal growth and development, and lack signs of underlying CSLD. The prevalence of atopic features (eczema, systemic and airway eosinophilia, elevated IgE, or positive radioallergosorbent test) is similar to children without PBB. 255 While many parents report previous "ever wheeze" (41% to 81%), 255,262 wheeze on auscultation confirmed by doctors is unusual. Occasionally, a "rattly chest" can be palpated and crackles are heard. The chest radiograph is normal or near-normal, showing only peribronchial changes. 12, 249, 263 When performed, both spirometry 249 and respiratory system reactance and resistance measured by FOT are normal. 11 When PBB was first described in 2006, 23 its existence as a distinct diagnostic entity was controversial. However, it is becoming recognized increasingly and is now incorporated into all national pediatric chronic cough guidelines. 11 It is also forms part of the European pediatric respiratory training curriculum. 264 PBB was first defined a priori and was based on clinical experience before being applied to a subgroup of children in a prospective study evaluating the etiology of chronic cough. 23 The diagnostic criteria were (1) history of chronic wet cough, (2) positive BAL cultures for respiratory bacterial pathogens at densities ≥10 4 cfu/mL without serologic or PCR assay evidence of infection by either Bordatella pertussis or Mycoplasma pneumoniae, and (3) cough resolution after a 2-week course of oral antibiotics (amoxicillinclavulanate). 23 The consideration of feasibility in day-to-day clinical practice and further research has resulted in definitions (Box 26.5) based on recurrence and clinical setting. 11 Each criteria has been validated. 11 However, uncertainties remain and include (1) diagnosis can only be determined after a trial of therapy, (2) lack of research data on an optimal length of antibiotics, and (3) uncertainty of the diagnostic threshold for determining lower airway infection. 11 Differentiation between acute bronchitis and PBB is because acute bronchitis cough usually resolves within 2 to 4 weeks. Difficulties arise when recurrent and acute bronchitis episodes overlap, especially during the "respiratory virus" season. 11 Furthermore, PBB can coexist with other illnesses, including asthma, and recurrent episodes need to be differentiated from defective airway clearance of otherwise normal airway microbiota. Over time with antibiotic treatment and perhaps the effects of the underlying disease, the microbiota in these disease groups progressively diverge. 11, 182 Immunity and Inflammation. Studies on immunity in children with PBB 11 reported the following features: (1) absence of an overt systemic immunodeficiency (normal serum IgA, IgM, IgG, and IgE levels), (2) robust responses to protein (tetanus) and conjugated protein-polysaccharide (H. influenzae type b) vaccines, 255 and (3) 122 BAL from children with PBB typically shows intense airway neutrophilia (median 40% to 44%).Whether this is a pathologically disproportionate response to infection is unknown. 11 There are also marked proinflammatory mediator responses (increased IL-8, MMP-9, and IL-1β) that correlate with BAL neutrophil percentages. 256, 257 Median BAL levels of IL-8 and MMP-9 in children with PBB were 5-to 19-fold higher than controls and children whose cough resolved without treatment. 256 Children with PBB had significantly higher BAL fluid levels of IL-1β, α-defensin, IL-1 pathway members and CXCR2 gene and protein expression than non-PBB disease controls. 257 IL-1β levels correlated with duration and severity of cough, 257 and with elevated expression of α-defensins 1 to 3 in PBB cases. In those with recurrent PBB (>3 in the next 12 months), gene expression of the IL-1β signaling molecules pellino-1 and IL-1 receptor associated kinase (IRAK)-2 (in BAL at initial bronchoscopy) were significantly higher than those without recurrent PBB, suggesting this pathway's involvement in recurrence. 257 Thus, "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." 257 Large Airway Lesions. While some clinicians believe TBM causes chronic ineffective cough, it is as likely that the airway malacia predisposes individuals to prolonged, inefficient airway clearance and hence increases risk of infection. Since the cough resolves once the underlying infection is treated, this suggests malacia has a limited causative role. 23 Nevertheless, TBM is found commonly in children with PBB. 23, 258 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 and infection). 161, 259 One retrospective study reported TBM was present in 52/74 (74%) children with PBB. 258 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 received this diagnosis (adjusted OR 20.9; 95% CI 5.4 to 81.8). 268 There are many causes of chronic wet cough in children, and further investigation to elucidate the cause is necessary when the child does not respond to antibiotics and/or has other clinical features, for example, coughing with feeds. 11, 179 These are addressed elsewhere in this textbook. Bronchitis is a component of many airway diseases. In the literal translation of the word, bronchitis refers to inflammation of the bronchus or bronchi. However, bronchitis has different major overlapping constructs based on duration (acute, subacute, chronic), inflammation type (neutrophilic, eosinophilic, lymphocytic, neurogenic), phenotype, or clinical syndromes (e.g., acute bronchitis, larygnotracheobronchitis, PBB, aspiration bronchitis). A diagnostic entity may have varying types of airway inflammation (Table 26 .4). For example, acute viral bronchitis is associated with both lymphocytic and neutrophilic inflammation. Although the types of airway inflammation do not distinguish etiology of the bronchitis in children, it provides support for the diagnosis. Cough usually occurs when bronchitis is present. Chronic (>4 weeks) wet cough in children signifies the persistence of increased airway secretion production or decreased airway clearance in the large airways. 283 The greater the amount of secretions seen at bronchoscopy, the higher the likelihood of bacterial infection and intense neutrophilia in the airways. 284 Clinicians need to be cognizant that recognition of wet cough is dependent on the clinical setting, and it is also likely age dependent. It is easier to detect a wet cough in young children, while older children may have a productive cough but may have a dry cough when asked to cough. Parents and clinicians have varying ability to recognize cough quality. In Australia, Brisbane-based parents were more accurate in determining the type of cough (compared to pulmonologists [kappa = 0.75, 95% CI 0.58 Elevated IL-8, neutrophil elastase, TNF-α, IL-1β Cystic fibrosis 270 Elevated IL-8, neutrophil elastase, proteases Protracted bacterial bronchitis 11, 257 Elevated IL-8, MMP-9, IL-1β and related mediators that reflect IL-1β pathway activation Chronic lung disease of prematurity 271 Proinflammatory cytokines and chemokines Severe bronchiolitis 272, 273 Myeloperoxidase, CD11b RSV proteins and mRNA transcripts in severe RSV bronchiolitis Bronchiolitis obliterans 274 Elevated IL-6, IL-8, TNF-α, IL-1β Aspiration lung disease 275 Index of lipid-laden macrophages (nonspecific marker), amylase, pepsin (still needs validation) Eosinophilic Atopic asthma 276 Elevated nitric oxide in steroid naive Helminth infections 111 e.g., toxocara and strongyloides Allergic bronchopulmonary aspergillosis 277 Neutrophilic inflammation may also be present with elevated IL-8 and MMP-9 Hypersensitivity, eosinophilic pneumonia 278 Lymphocytic Acute viral infection 269 Soluble intercellular adhesion molecule-1 Bronchiolitis obliterans 279, 274 CD8+T lymphocytes Autoimmune disease* 280 Neurogenic Post RSV infection 281 substance P, nerve growth factor Cough with gastroesophageal reflux 282 Calcitonin G-related peptide a Specific cough pointers [265] [266] [267] are: chest pain, history suggestive of inhaled foreign body, dyspnea, exertional dyspnea, hemoptysis, failure to thrive, feeding difficulties (including choking/vomiting), cardiac or neurodevelopmental abnormalities, recurrent sinopulmonary infections, immunodeficiency, epidemiological risk factors for exposure to tuberculosis, signs of respiratory distress, digital clubbing, chest wall deformity, auscultatory crackles, chest radiographic changes (other than perihilar changes), lung function abnormalities. bronchiectasis when chronic wet cough does not respond to greater than 4 weeks of oral antibiotics. 268 Among 105 children with persistent cough despite at least 4 weeks of antibiotics, 88 (83.8%) had bronchiectasis; of the 24 children whose cough resolved after antibiotics, only six (25.0%) with controls (44% vs. 12% of respective cohort, P = .005) and to have had parent-reported wheeze in the preceding 12 months (58% vs. 16%, P = .001). By the end of the study, 66 (62%) of those with PBB had experienced recurrent episodes (>3 per year) and 13 (12%) had bronchiectasis diagnosed by chest CT scans. 288 The major independent risk factors for bronchiectasis were H. influenzae (mainly NTHi) lower airway infection and having ≥2 siblings. H. influenzae infection conferred greater than six times higher risk of bronchiectasis than a H. influenzae negative state (hazard ratio = 6.8, 95% CI 1.5 to 30.8). 288 There is high-quality evidence that in children with greater than 4 weeks' duration of wet or productive cough, the use of appropriate antibiotics improves cough resolution. 179 In PBB, the child's cough resolves only after a 2-week course of appropriate antibiotics, in contrast to shorter durations of treatment. 23, 286 Meta-analyses of three RCTs that used 10 to 14 days of antibiotics for chronic wet cough found that the number needed to treat (for benefit by end of study) was 3 (95% CI 2.0 to 4.3) Although the British Thoracic Society (BTS) cough guidelines 287 suggest all children with PBB should receive 4 to 6 weeks of antibiotics, there is no prospectively derived evidence for this. While some children with PBB may need longer antibiotic treatment, we advocate the shorter 2-week course initially. 11 The rate and risk factors of PBB recurrence are likely dependent on the sampling frame and definition. Factors in those severe enough to need to bronchoscopy and BAL sampling are probably different from those enrolled from the community. The sole prospective study to date was undertaken in 106 children with PBB followed for a median of 25 months (IQR 24 to 28). 288 Their median age at bronchoscopy was 23 months (IQR 14 to 53). 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effect on neutrophil function and lung secretion Inhaled non-steroid antiinflammatories for children and adults with bronchiectasis Effect of indomethacin on bronchorrhea in patients with chronic bronchitis, diffuse panbronchiolitis, or bronchiectasis Emerging drugs for bronchiectasis: an update Inhaled mannitol for non-cystic fibrosis bronchiectasis: a randomised, controlled trial Tiotropium ameliorates symptoms in patients with chronic airway mucus hypersecretion which is resistant to macrolide therapy Airway clearance techniques for bronchiectasis Lung structure abnormalities, but normal lung function in pediatric bronchiectasis Reduced exercise capacity in non-cystic fibrosis bronchiectasis HRCT lung abnormalities are not a surrogate for exercise limitation in bronchiectasis Defining pulmonary exacerbation in children with non-cystic fibrosis bronchiectasis Impact of lung disease on respiratory impedance in young children with cystic fibrosis The reproducibility and responsiveness of the lung clearance index in bronchiectasis Lung clearance index is a repeatable and sensitive indicator of radiological changes in bronchiectasis Cystic fibrosis: scoring system with thin-section CT Airflow obstruction in bronchiectasis: correlation between computed tomography features and pulmonary function tests Assessment of CF lung disease using motion corrected PROPELLER MRI: a comparison with CT Ultra-short echo-time pulmonary MRI: evaluation and reproducibility in COPD subjects with and without bronchiectasis Metabolomic evaluation of neutrophilic airway inflammation in cystic fibrosis Cancer risk in 680,000 people exposed to computed tomography scans in childhood or adolescence: data linkage study of 11 million Australians Respiratory bacterial culture from two sequential bronchoalveolar lavages of the same lobe in children with chronic cough Children with chronic wet or productive cough-treatment and investigations: a systematic review Bacterial colonisation in patients with bronchiectasis: microbiological pattern and risk factors A Comprehensive analysis of the impact of Pseudomonas aeruginosa colonization on prognosis in adult bronchiectasis Adenovirus species C is associated with chronic suppurative lung diseases in children Clinical measures of disease in adult non-CF bronchiectasis correlate with airway microbiota composition Respiratory viruses in exacerbations of non-cystic fibrosis bronchiectasis in children Exacerbations in non cystic fibrosis bronchiectasis: clinical features and investigations Factors associated with lung function decline in adult patients with stable non-cystic fibrosis bronchiectasis Non-cystic fibrosis bronchiectasis exacerbations Quality-of-life determinants in patients with clinically stable bronchiectasis Quality of life and inflammation in exacerbations of bronchiectasis Bronchiectasis and chronic suppurative lung disease (CSLD) in children and adults in Australia 242. Wilson JF, Decker AM. The surgical management of childhood bronchiectasis Bronchiectasis in childhood Bronchiectasis: the consequence of late diagnosis in chronic respiratory symptoms Outcome in adult bronchiectasis Bronchiectais: A study of prognosis based on follow-up of 400 patients Symptoms of chronic bronchitis and the risk of coronary disease What is the burden of chronic cough for families? Children with chronic cough: when is watchful waiting appropriate? Development of likelihood ratios for assessing children with chronic cough Development of a parentproxy quality-of-life chronic cough-specific questionnaire: clinical impact vs psychometric evaluations A cough algorithm for chronic cough in children: a multicentre, randomized controlled study The assessment and management of chronic cough in children according to the British Thoracic Society guidelines: descriptive, prospective, clinical trial Bacterial distribution in the lungs of children with protracted bacterial bronchitis Prospective characterisation of protracted bacterial bronchitis in children Prospective assessment of protracted bacterial bronchitis: airway inflammation and innate immune activation Mediators of neutrophil function in children with protracted bacterial bronchitis Protracted bacterial bronchitis in young children: association with airway malacia 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 Outcomes in children treated for persistent bacterial bronchitis Utility of signs and symptoms of chronic cough in predicting specific cause in children ERS Handbook of Paediatric Medicine The Thoracic Society of Australia and New Zealand. Position statement. Cough in children: definitions and clinical evaluation Guidelines for evaluating chronic cough in pediatrics: ACCP Evidence-Based Clinical Practice Guidelines State of the Art: cough, cough receptors, and asthma in children Does failed chronic wet cough response to antibiotics predict bronchiectasis? Bronchoalveolar lavage fluid cellularity and soluble intercellular adhesion molecule-1 in children with colds Postural drainage in cystic fibrosis: is there a link with gastro-oesophageal reflux? Inhaled steroids for bronchiectasis Withdrawal of inhaled steroids in children with non-cystic fibrosis bronchiectasis Secondhand tobacco smoke exposure differentially alters nucleus tractus solitarius neurons at two different ages in developing non-human primates Effect of counselling mothers on their children's exposure to environmental tobacco smoke: randomised controlled trial Family and carer smoking control programmes for reducing children's exposure to environmental tobacco smoke Indoor air pollution from biomass combustion and acute respiratory infections in Kenya: an exposure-response study Remediating buildings damaged by dampness and mould for preventing or reducing respiratory tract symptoms, infections and asthma Influenza vaccine for children and adults with bronchiectasis Pneumococcal vaccines for children and adults with bronchiectasis Influenza: the virus and prophylaxis with inactivated influenza vaccine in "at risk" groups, including COPD patients Dosing regimen of the 23-valent pneumococcal vaccination: a systematic review Members of the Massachusetts Department of Public Health: Vaccination, underlying comorbidities, and risk of invasive pneumococcal disease Improving immunity to Haemophilus influenzae in children with chronic suppurative lung disease Surgical treatment of noncystic fibrosis bronchiectasis in Brazilian children Surgical management of bronchiectasis: analysis and short-term results in 238 patients Surgical treatment in bronchiectasis: analysis of 166 patients The radiological follow-up of aboriginal children with bronchiectasis treated surgically or medically Lung transplantation for advanced bronchiectasis Socioeconomic disparities in health behaviors Risk factors for mortality from acute lower respiratory infections (ALRI) in children under five years of age in low and middle-income countries: a systematic review and meta-analysis of observational studies Ventilatory mechanics in patients with bronchiectasis starting in childhood Non-cystic fibrosis bronchiectasis in childhood: longitudinal growth and lung function Longitudinal pulmonary function of childhood bronchiectasis and comparison with cystic fibrosis Management of bronchiectasis and chronic suppurative lung disease (CSLD) in Indigenous children and adults from rural and remote Australian communities Lower airway inflammation in infants and young children with cystic fibrosis Understanding the impact of infection, inflammation, and their persistence in the pathogenesis of bronchopulmonary dysplasia Neutrophil TLR4 expression is reduced in the airways of infants with severe bronchiolitis Respiratory syncytial virus binds and undergoes transcription in neutrophils from the blood and airways of infants with severe bronchiolitis Airway inflammation in children and adolescents with bronchiolitis obliterans Salivary amylase level in bronchoalveolar fluid as a marker of chronic pulmonary aspiration in children Blood eosinophil counts rarely reflect airway eosinophilia in children with severe asthma Pulmonary aspergillosis: a clinical review Eosinophilic pneumonias in children: a review of the epidemiology, diagnosis, and treatment Lymphocytic inflammation in childhood bronchiolitis obliterans Idiopathic chronic cough and organ-specific autoimmune diseases: a case control study Contribution of neuroimmune mechanisms to airway inflammation and remodeling during and after respiratory syncytial virus infection Calcitonin gene-related peptide relates to cough sensitivity in children with chronic cough Cough quality in children: a comparison of subjective vs. bronchoscopic findings A bronchoscopic scoring system for airway secretions-airway cellularity and microbiological validation Accuracy of cough reporting by carers of Indigenous children Randomised controlled trial of amoxycillin-clavulanate in children with chronic wet cough British Thoracic Society Guidelines recommendations for the assessment and management of cough in children Protracted Bacterial Bronchitis (PBB) in children: natural history and risk for bronchiectasis We are grateful to Dr. Rosalyn Singleton for her expert comments and critique on the chapter published in the 7th edition of this textbook.