Pediatric Bronchiectasis

René Laennec, inventor of the stethoscope, first described bronchiectasis in 1819 while observing patients with tuberculosis and the sequelae of pneumonia in the pre-antibiotic era. In 1922, Jean Athanase Sicard introduced contrast bronchography, which provided imaging of the destructive changes characteristic of bronchiectasis. The term bronchiectasis is derived from the Greek bronchion, meaning windpipe, and ektasis, meaning stretched. Bronchiectasis is a pathologic term defined by the dilatation of bronchi with destruction of elastic and muscular components of their walls. Bronchiectasis is defined by the findings of bronchiole destruction on pathology or more commonly on radiologic imaging, CT scan, and a clinical syndrome of chronic wet cough, and recurrent airway infections and/or signs of airway inflammation.

The pathophysiology of bronchiectasis is based on the theory of an extended vicious cycle of infection, inflammation and airway destruction. Bronchiectasis exists on a continuum beginning with an acute respiratory infection progressing to protracted bacterial bronchitis then chronic suppurative lung disease and eventually bronchiectasis. Bronchiectasis is more directly the product of obstruction and/or inflammation of the airway; however, it is generally the result of an intricate interaction between the host, pathogens and the environment. The obstruction and inflammation may be due to any of the underlying disorders listed above or to infection, including acute tuberculosis, adenovirus, measles, Mycobacteriumavium, or Aspergillus fumigatus.

Mucus clearance is reduced in the setting of bronchiectasis due to airflow limitation, abnormal quantity and quality of mucus produced, and specific bacterial characteristics that contribute to ciliary dyskinesia. Bronchiectasis associated with bronchial obstruction may have a focal distribution distal to the site of obstruction. Bronchiectasis associated with underlying disease is more likely to be diffuse.

Regardless of the etiology, there is an impairment in the mucociliary clearance ability of the lungs, which leads to a diminished ability to clear the airway of the purulent and inflammatory material, which in turn leads to increased bacterial colonization and infection.[1]  Cole proposed a “vicious cycle” of infection and dysregulated airway inflammation, leading to progressive destruction of bronchial walls resulting in dilatation and airflow obstruction.[2]  

Infection leads to recruitment of neutrophils, T lymphocytes, and monocyte-derived cytokines. Multiple studies have evaluated the inflammatory patterns seen in samples from bronchoscopic and sputum analysis.  These studies have found increased interleukin-8 expression, infiltration by neutrophils, T lymphocytes and mucous gland hypertrophy on mucosal biopsies and sputum and bronchoalveolar lavage fluid with increased concentrations of inflammatory mediators such as neutrophil elastase, interleukin-8, tumor necrosis factor-alpha and prostanoids.[3] The release of inflammatory mediators, elastases, and collagenases leads to inflammation and destruction of elastic and muscular components of bronchial walls. In addition, the outward elastic recoil forces of surrounding lung parenchyma exert traction, which causes expansion of airway diameter. Two different types of bronchiectasis are noted: cylindrical, which is presumably more readily reversible if the underlying disorder can be controlled, and saccular, which is less readily reversible even if the underlying disorder is controlled.

These changes may be accompanied by bronchial arterial proliferation, which predisposes to hemoptysis. Hemoptysis may also occur as a result of the dilating airways impinging on the accompanying blood vessels.

Bronchiectasis may result from multiple etiologies including most commonly infection, congenital or genetic disorders, or idiopathic.  A systematic review (12 studies involving 989 children) found 63% had an underlying cause.[4]  Previous pneumonia (19%), primary immunodeficiency (17%), recurrent aspiration, including an inhaled foreign body (10%), and primary ciliary dyskinesia (7%) were implicated most commonly.  It has been estimated that approximately 30% of cases of bronchiectasis are idiopathic.[5]  

Common theory suggests that a single severe acute lower respiratory tract infection or multiple lower respiratory tract infections early in life can lead to bronchiectasis.  More specifically, a correlation has been found between the overall number of pneumonias rather than the site of pneumonia and bronchiectasis. Although, infections remain the most common etiology of bronchiectasis, there has been a reduction in post-infectious bronchiectasis due to the widespread use of vaccinations and antibiotics.

All causes share the same pathophysiologic pathway: ineffective pulmonary toilet and chronic or recurrent infection and inflammation.

Common infectious causes include the following:

Infectious:

• Varying severity of pneumonia - viral and bacterial
• Mycobacterial and Fungal infections
• Measles, tuberculosis, pertussis, adenovirus, Mycobacterium avium, and Aspergillus fumigatus
• HIV infection: HIV-related Lymphocytic interstitial pneumonitis is associated with subsequent development of bronchiectasis

Congenital/Genetic disorders:

• Cystic Fibrosis
• Young syndrome
• Primary Ciliary dyskinesia
• Marfan syndrome
• Alpha-1 antitrypsin deficiency
• Bruton agammaglobulinemia
• Congenital absence of bronchial muscle (Mounier-Kuhn syndrome) or cartilage (Williams-Campbell syndromes)
• Usher Syndrome

Immune deficiency:

• Immunoglobulin A (IgA) and G (IgG) deficiencies and IgG subclass deficiencies, especially IgG2 deficiency
• Allergic bronchopulmonary aspergillosis (ABPA)/  allergic bronchopulmonary mycoses
• Bruton agammaglobulinemia

Acquired disorders associated with bronchiectasis include the following:

• Intrinsic airway luminal obstruction by a retained bronchial foreign body ^[6] or extrinsic compression by mass
• Chronic aspiration, which is associated with swallowing dysfunction, gastroesophageal reflux disease, or tracheoesophageal fistula
• Connective tissue disorders, including rheumatoid arthritis and systemic lupus erythematosus
• Extrinsic airway narrowing (vascular ring, adenopathy, compressive mass)
• Endobronchial mass or tumor
• Tracheal stenosis with impaired mucociliary clearance
• Severe tracheomalacia or bronchomalacia with impairment of mucociliary clearance
• Fibrosing lung diseases associated with sarcoidosis or idiopathic pulmonary fibrosis

United States statistics

The true prevalence of bronchiectasis in children has been difficult to determine due to the frequent delay in diagnosis, difference in prevalence among various populations, physician awareness, and the availability of high resolution CT scans as the diagnostic modality of choice.  Current population-based estimates of occurrence are not available. In 1963, Clark estimated an incidence of 1.06 cases per 10,000 population.[7] The incidence of bronchiectasis associated with underlying systemic disease reflects the incidence of the particular disease. The most common genetic disease associated with bronchiectasis is cystic fibrosis (CF). One study estimates that 110,000 people in the United States have bronchiectasis, including adults.[8] The incidence of non-cystic fibrosis bronchiectasis in childhood has been estimated to range from 0.2 to 4.2 per 100,000 in the United States.

In most high-resource countries, the overall prevalence of childhood bronchiectasis has significantly declined over the last 4 decades due to earlier detection and treatment and public health measures including broader immunization programs, improved control and treatment of infectious diseases, sanitation, reduced crowding, improved nutrition, and easier access to medical care. The exception to this is indigenous populations and disadvantaged groups where the prevalence has not decreased as dramatically.   

Indigenous populations within North America have been reported to have the highest incidence of pediatric bronchiectasis. The incidence among Alaskan Native children in the Yuskon-Kuskokwim region is about 140 cases per 10,000 population.[9]  The incidence of bronchiectasis in southwest Alaskan Natives is 16 cases per 1000 population.[10]

International statistics

In high resource countries, the frequency is similar to that in the United States with bronchiectasis being more common among indigenous populations and disadvantaged groups.  Similarly to the United States, the most clinically significant cause of bronchiectasis in developed affluent countries is cystic fibrosis. However, throughout the world, bronchiectasis is predominantly associated with non-CF related conditions rather than CF.

The frequency is higher in the resource limited countries, where measles, adenovirus infection, pneumonia, tuberculosis, and HIV infection are highly prevalent and are associated with bronchiectasis.

In a study from the United Kingdom that started in 1949, Field studied children with bronchiectasis for almost 2 decades and documented a fall in the annual hospitalization rate for bronchiectasis in 5 British hospitals. During the study period, as broad-spectrum antibiotics became widely available, the hospitalization rate decreased from approximately 48 cases per 10,000 population to 10 cases per 10,000 population.[11]  More recent estimates of annual incidence of pediatric bronchiectasis in the United Kingdom are appoximately 15 per 100,000.[12]  In high-income countries the annual incidence ranges from 0.2 per 100,000 to 15.0 per 100,000.[12, 13, 14]

In New Zealand, Twiss and colleagues reported the incidence of bronchiectasis in children younger than 15 years at 3.7 cases per 100,000 population in 2001-2002.[15] The incidence was highest among Pacific children, at 17.8 cases per 100,000 population. The incidence was 4.8 cases per 100,000 population in Maori children and 1.5 cases per 100,000 in New Zealand overall, compared with 2.4 cases per 100,000 in other Pacific regions. 

Twiss and colleagues noted that the incidence of bronchiectasis in New Zealand children was nearly twice the rate of CF and 7 times that of bronchiectasis in Finland, which is the only other country reporting a childhood national rate. They further noted that in central Australian Aboriginal children, the incidence is 14 cases per 1,000 population, compared with 0.1 cases per 1,000 in Scotland and 4.9 cases per 1,000,000 in Finnish children.[15]  More recently, extrapolated data from Janu et al. found the incidence of pediatric bronchiectasis among the indigenous population of Australia to be as high as 410 per 100,000. [5]  [16]

Ethnicity-, sex-, and age-related demographics

Bronchiectasis is more common in patients of Polynesian and Alaskan Native ancestry. A study in Turkey suggests possible genetic predisposition in some populations and found that 43% of children with bronchiectasis had parents who were first-degree or second-degree relatives but presumably without any other known underlying disorder.[17]

Non-CF bronchiectasis is more common and more virulent in women. The differences may result from inflammatory-immune, environmental, anatomic, or other genetic factors.[18]

Overall, the prognosis is good for a child with non-cystic fibrosis bronchiectasis. There is very limited data on the prognosis of non-CF pediatric bronchiectasis, yet with increasing earlier detections and multi-disciplinary management, the lung function in children with bronchiectasis often stabilizes and patients have an overall good prognosis. A few studies have found evidence of reversibility and normalization on imaging however many studies have found that while clinical symptoms improve there is a persistence of signs of bronchiectasis on CT scan and improvement in lung function tests without complete normalization.[19, 20, 21, 22]  Reversibility is most likely associated with early diagnosis and management.

The prognosis of non-CF bronchiectasis primarily depends on the underlying cause and whether that etiology is an acute or chronic condition.  The key to a successful outcome is determining whether the cause of the damage is ongoing (eg, chronic aspiration) and then treating the underlying problem. In the absence of an underlying condition, children with isolated or localized bronchiectasis often have a better prognosis compared to those with more diffuse disease.

Growth of new pulmonary tissue in children proceeds rapidly until about age 6 years and then tapers off through childhood. Injury at an early age may be compensated for in part by growth of normal healthy lung parenchyma in the absence of ongoing damage.

Progressive bronchiectasis from underlying disease (eg, CF) or ongoing pulmonary insult (eg, aspiration syndromes) causes a progressive obstructive defect and, ultimately, respiratory compromise.  In these cases bronchiectasis is an irreversible process associated with progressive and persistent lung damage. The progression of the lung damage that occurs with bronchiectasis is associated with significant morbidity as it usually manifests as recurrent infectious exacerbations and progressive obstructive lung disease.  Respiratory compromise may manifest as dyspnea at rest or with exercise or sleep-disordered breathing. Ultimately, patients may experience chronic hypoxemia, pulmonary hypertension, cor pulmonale, hypercarbia, respiratory failure, and death.

Progressive focal disease may lead to progressive infection with fever and abnormal growth. The area may contribute enough ventilation/perfusion mismatch to cause hypoxemia with exercise. Although not yet proven, infected secretions from the abnormal portion of the lung could spill over to other portions of the lung, causing more widespread infection.

Limited mortality data are available. In Field's original group, who were studied at the beginning of the antibiotic era, 4% of children with medically treated bronchiectasis died (mostly from infection), and 3% of children who were surgically treated died (many immediately following or as a late result of surgery) in the ensuing two decades.[23]  In the countries of England, New Zealand, and India between 0.2% to 11% of pediatric subjects within population stiudies on pediatric bronchiectasis died. [24, 25]

A poorer prognosis is associated with the presence of asthma, bilateral lung involvement, and saccular bronchiectasis. Akalin and colleagues reported decreased left ventricular function and exercise capacity in bronchiectasis, which has subsequently been found to present late in the disease course.[17]

Complications

Complications that can develop solely from bronchiectasis range from mild such as focal atelectasis to severely life threatening such as massive hemoptysis.  Other complications associated with disease progression consist of heart related morbidity and respiratory failure. In those with more diffuse involvement, significant impairment in lung function may affect physical activity and quality of life.

Additional morbidity occurs from side effects of medications used in the management of bronchiectasis, predominantly related to the well-documented side effects of antibiotics.

Non-CF bronchiectasis in children presents as a wide spectrum of disease severity. Some children have intermittent symptoms of cough and occasional lower respiratory tract infections. Others experience daily cough and produce purulent fetid sputum, requiring frequent hospitalizations for respiratory exacerbations.

The diagnosis should be considered in children with a daily productive cough (chronic cough) for longer than 4 weeks. The cough is frequently described as productive in older children or loose in toddlers and infants. Because small children rarely expectorate, the clinician may observe the child with a loose-sounding cough who swallows after coughing.  Bronchiectasis should also be considered in children with chronic or persistent cough in whom another diagnosis has been made but who are not responding to therapy. If children with cough responsive to antibiotics on a recurrent basis, bronchiectasis should be considered.

Recurrent cough with fetid sputum, hemoptysis, or recurrent pneumonia are important clues to early diagnosis of this disease. Tsao and associates reported that hemoptysis is the second most common symptom of bronchiectasis.[18] The frequency of hemoptysis varies and become more common as bronchiectasis progresses due to the increasing diameter of the bronchial artery. Other common symptoms and signs include: exertional dyspnea, recurrent wheezing, digital clubbing, and recurrent lung infections.

Smyrnios and colleagues concluded that cough is much more common in patients with asthma (24%), gastroesophageal reflux disease (15%), and viral bronchitis (11%) than in patients with bronchiectasis (4%). However, if children with gastroesophageal reflux disease or asthma do not respond to therapy, bronchiectasis should be considered. Furthermore, recurrent aspiration can lead to bronchiectasis.[26]

Acute exacerbations of bronchiectasis are defined by symptomatic changes, including increased thick sputum production with change in color, shortness of breath, pleuritic chest pain, and generalized malaise.  The patient may or may not have fever or chills.

During history taking, those suspected of having bronchiectasis should be screened for any underlying conditions. In addition to detecting co-morbidities, clinicians should investigate for exposures to tobacco smoke or other pollutants and for modifiable exacerbating factors.

Physical examination findings in patients with bronchiectasis may include variable degrees of crackles or coarse rhonchi and digital clubbing. However, the lung exam may be normal. Crackles and wheezing rank among the most frequent findings of the physical examination.[27] An inspiratory "honk" has been described in some children with bronchiectasis, the etiology of which is unclear.  Recurrent wheezing may be present even without the presence of asthma.  Chest deformity described as increased anterior-posterior diameter, appearance of hyperinflation and presence of Harrison's sulci can be present. Additionally, chest pain, dyspnea and growth failure or failure to thrive have often been reported.

Digital clubbing is reported in 37-51% of patients with bronchiectasis. Edwards and associates found that children with digital clubbing and chest deformity showed significantly higher scores for extent of bronchiectasis, bronchial wall dilatation and thickness, and overall changes based on CT score.[23]  In Field's 1949 series, clubbing was present in 78 cases (43.7%).[11] In many of her cases, the clubbing cleared after the affected section of the lung was surgically removed. The high frequency of this finding has been replicated in multiple studies. In medically treated cases, clubbing often improved and, in some cases, disappeared despite persistent bronchographic evidence of bronchiectasis. Although Field concluded that clubbing in the absence of congenital heart disease signifies irreversible bronchiectasis, a myriad other entities are now known to cause clubbing.

Bronchiectasis results from recurrent or persistent respiratory inflections or inflammation. The evaluation for the etiology and co-morbidities are guided by the history and physical examination. Identifying the etiology has management implications and should follow an algorithmic approach.. European guidelines recommend a minimal panel of tests that comprises the following: (1) high resolution chest CT, (2) sweat test, (3) spirometry, (4) complete blood cell count, (5) immunologlobulin levels and specific antibodies to vaccine antigens, and (6) lower airway bacteriology via sputum culture or bronchoscopic alveolar lavage.

Because bronchiectasis is defined as an abnormal dilatation of airways, the diagnosis depends on radiographically or anatomically visualizing the typical changes. In patients with suspected bronchiectasis, a high-resolution CT (HRCT) scan is the diagnostic procedure of choice. Where available, multi-detector (MDCT) with HRCT is considered the gold standard.

Obtain a routine posteroanterior and lateral chest radiograph. A dilated airway, with thickened airway walls can be noted. When seen laterally, the bronchiectatic airway has been described as tram tracks. However, normal radiograph findings do not rule out bronchiectasis. Risk factors for bronchiectasis on chest radiography include atelectasis and persistent lobar abnormalities.

A posteroanterior chest radiograph of a child with bronchiectasis due to chronic aspiration is shown below.

Posteroanterior chest radiograph of a child with bronchiectasis due to chronic aspiration.

The diagnosis of bronchiectasis is usually established using high-resolution CT (HRCT) scanning, which has a sensitivity and specificity of more than 90%. The gold standard in Europe, Australia and New Zealand is a multidetector chest computed tomography (MDCT) scan with high resolution CT scan which provides a continuous image and improves sensitivity to over 95%.[28, 29]  The key feature on HRCT scanning is an enlarged internal bronchial diameter with bronchi that appear larger than the accompanying artery (an increased broncho-arterial ratio), called the signet sign. European guidelines define an abnormal broncho-arterial ratio in pediatric patients to be greater than 0.8.[28]  Other HRCT scan findings include the failure of the larger airways to taper while progressing to the lung periphery, air fluid levels in the dilated airways, and the identification of airways in the extreme lung periphery.

The most common and consistent radiographic findings on high resolution CT scan of the chest in a patient with bronchiectasis as found by Smith et al include: enlarged internal bronchial diameter relative to the adjacent artery, the signet ring sign, lack of bronchial tapering while progressing towards the lung periphery, bronchi seen at the lung periphery, bronchial wall thickening or mucous plugging or impaction, mosaic perfusion defects, and air trapping on expiration.[30]

Other nonspecific signs of bronchiectasis on high resolution CT scan include air fluid levels in distended bronchi.

Radiographic findings including distribution have been used to define severity of disease.[31, 32] Brconchiectasis progresses from cylindrical to varicose then cystic (or saccular) changes as the broncho-arterial ratio increases. As  severity increases reversibility decreases.

In settings where a high resolution CT scans with pediatric specific protocols regarding radiation exposure is not always readily available, a presumptive diagnosis of bronchiectasis can be made by relevant clinical history and physical exam findings.

A CT scan of the chest of a child with bronchiectasis due to chronic aspiration is shown below. 

CT scan of the chest of a child with bronchiectasis due to chronic aspiration.

Evaluate patients suspected of having bronchiectasis for gastroesophageal reflux disease, especially infants and young children. Studies may include barium esophagraphy, gastric scintiscanning, or intraesophageal pH or impedance monitoring. Suspicion of poor oromotor coordination should lead to a swallow function study.

Flexible bronchoscopy may help assess the caliber and appearance of the airways and provide bronchoalveolar lavage fluid for evidence of chronic aspiration or infection. Significant numbers of lipid-laden macrophages or significant amounts of pepsin or amylase may suggest recurrent aspiration.

A study evaluated the value of flexible bronchoscopy and bronchoalveolar lavage (BAL) in indigenous children as part of the workup at the first diagnosis of bronchiectasis.[33] BAL eosinophilia was found in 34% of the children; of these, 42% were found to have positive serology to Strongyloides, which was not known beforehand. BAL microbiology led to a change in antibiotic therapy in 9%. These data suggest a larger role for bronchoscopy in the diagnosis of pediatric bronchiectasis.

Bronchoscopy can also help identify foreign bodies or underlying structural anomalies, while providing a macroscopic view of the airways. If a retained foreign body is strongly suspected, rigid rather than flexible bronchoscopy should be considered. 

In the past, fluoroscopically guided selective bronchography, using water-soluble contrast media and performed by an experienced bronchoscopist, provided excellent anatomic definition. This study has been virtually eliminated by CT imaging.

Examination of the bronchoalveolar fluid reveals inflammatory cells. Hemosiderin-laden macrophages generally suggest nonacute bleeding. Lipid-laden macrophages suggest chronic aspiration but may also be observed in other forms of severe airway disease associated with inflammation.  Therefore there remains some controversy over the usefulness of lipid-laden alveolar macrophages given its high sensitivity but low specificity as an indicator of aspiration, as they are often found in acute or chronic lung disease not related to aspiration and even healthy persons.

Laboratory evaluation of bronchiectasis may include the following tests:

• Sweat chloride
• With underlying asthma or cystic fibrosis (CF), evaluation for allergic bronchopulmonary aspergillosis should include immunoglobulin E (IgE) and serum precipitins for Aspergillus species , sputum culture for fungus, and an aspergillus skin test
• Complete blood cell count
• Serum immunoglobulin G (IgG) with IgG subclasses, immunoglobulin M (IgM), and IgA
• Speech pathologist assessment for identification of possible dysphagia with aspiration
• HIV test
• Sputum culture or deep oropharyngeal swab in younger children
• Spirometry for children older than 6 years of age
• Ciliary biopsy
• Antinuclear antibody and rheumatoid factor
• Vaccine antigens
• Flexible fiberoptic bronchoscopy

Obviously, not every patient with bronchiectasis requires each of the above studies. The history and physical examination should help guide the clinician to choose the appropriate studies.

Often spirometry may be normal early in the course of patients with bronchiectasis.  As the disease progresses, it is obstructive in the earlier stages and becomes mixed obstructive and restrictive disease process later in the disease.  Other lung function abnormalities include high residual lung volume, lower aerobic capacity.

Spirometry can be used to monitor disease control with acute drops in function and worsening obstructive pattern associated with acute exacerbations.

In addition to the treatment of an identified underlying disorder in patients with bronchiectasis, therapy is aimed at preventing further airway damage and optimizing lung growth by reducing airway secretions and facilitating their removal through airway clearance techniques. The principles of managing bronchiectasis are to identify and treat any underlying cause and associated conditions, prompt diagnosis, treatment and prevention (when possible) of acute exacerbations, managing nutritional and psychosocial issues, improving airway clearance and capacity for physical activity, regular surveillance for complications of bronchiectasis, ongoing education and promotion of general health measures, including avoiding tobacco smoke, encouraging exercise, cough hygiene and recommended vaccinations, and as much as possible normalizing psychological development. 

Pharmacotherapy may be used to enhance bronchodilation and to improve mucociliary clearance.

Antibiotics can be used to prevent and treat recurrent infections, often polymicrobial, and diminish bacterial load and the associated cycle of infection and inflammation. Choice of antibiotics is usually based on the findings of bronchoalveolar lavage or sputum culture. Secretions can be mobilized with chest physiotherapy and mucolytic agents. The goal of therapy is to mobilize secretions and to reduce the infectious and inflammatory load, thereby preventing progression of airway destruction. The main pathogens associated with bronchiectasis are non-typeable H influenzae, Streptococcus pneumoniae, Moraxella catarrhalis, and Pseudomonas in later disease. Occasionally, surgery may be considered.

As previously stated, treatment for bronchiectasis primarily revolves around antibiotics for infections, airway clearance measures, and bronchodilators for any airway hyperreactivity, with the caveat that this approach is not fully evidence based. Randomized trials of these treatment options lack proper control groups. In children, many of the therapies have been used in cystic fibrosis (CF). However, non-CF bronchiectasis may not always respond the same as CF. The markers used to assess therapy effectiveness have included the volume of sputum production and the clearance of a radiolabeled aerosol from the lung. More meaningful studies that focus on measures such as rate of respiratory exacerbations and quality of life and improvement in lung function and radiographic findings are needed.

Randomized placebo-controlled trials of inhaled corticosteroids in patients with non-CF bronchiectasis showed no significant improvement in lung function. Inhaled corticosteroids may have a role in regulating the host response and halting inflammatory damage to the lung. However, Cochrane reviews and guidelines found no evidence for the effective use of inhaled corticosteroids with or without a long acting beta agonist in children with non-CF bronchiectasis without a history of asthma.[34, 35] In children with underlying asthma, it is important to continue inhaled corticosteroids on a chronic basis.

A study of 27 children with stable non-CF bronchiectasis looked at the effects of withdrawal of inhaled corticosteroids.[36] After 12 weeks, they found the patients had increased airway reactivity and decreased neutrophilic apoptosis in induced sputum, but no change in symptom scores, forced expiratory volume in 1 second (FEV1), oxygen saturation, sputum neutrophil ratios, sputum tumor necrosis factor-alpha, or interleukin 8. Systemic corticosteroids may be used to treat any acute reactive airway component, when appropriate.

Bronchodilators are indicated when bronchial hyperreactivity is evident. These agents are used to improve ciliary beat frequency and, thus, facilitate mucus clearance. However, no randomized studies have validated their usefulness in the management of bronchiectasis. 

Although beta agonists may improve ciliary function and airway clearance, ensure that they are not adversely affecting lung function. Some patients with bronchiectasis experience paradoxic bronchoconstriction with beta-agonist therapy. This is likely secondary to loss of airway tone due to beta-agonist relaxation of bronchial smooth muscle superimposed on already weakened bronchial cartilage in the bronchiectatic airway. Therefore, assessing bronchodilator response before beginning such therapy is critical. If no significant bronchodilator response is observed, the ciliary effects by themselves are not great enough to warrant such therapy.

Mucolytic drugs are given with the intent of improving tracheobronchial clearance via alteration of sputum consistency. Aerosolized recombinant DNase breaks down DNA released by neutrophils, which accumulates in the airways in response to chronic bacterial infection; however, treatment with this agent has not shown significant benefit in non-CF bronchiectasis. This is presumably due to a lesser component of neutrophils in the airway than in CF. Furthermore, studies have documented evidence of increased exacerbations and hospitalizations when used in patients with non-CF bronchiectasis. [37]

Nebulized acetylcysteine and hypertonic saline are other agents aimed at altering mucous consistency to facility mucus clearance. Nebulized acetylcysteine has not been well studied in patients with non-CF bronchiectasis.  Its use in patients with CF as a mucolytic is based on it’s mechanism of action to depolymerize mucin oligomers. Hypertonic saline is thought to induce liquid flux from the epithelial wall into the mucus allowing increased hydration of airway surface liquid. Hypertonic saline has been shown to aid in the expectoration of secretions, reduce sputum viscosity, improve lung function, decrease sputum pathogenic bacteriology, and improve quality of life in patients with non-CF bronchiectasis.[38]

The initial course of treatment may be oral antibiotics and aggressive airway clearance. When possible, antibiotic therapy agents should be tailored to the results of sputum culture.  Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis are the most common organisms documented in pediatric patients with non-CF bronchiectasis. Staphylococcus aureus and Pseudomonas aeruginosa are most often detected in older children with co-morbidities.[39]   Intravenous antibiotic therapy and hospitalization may be necessary for children experiencing exacerbations of endobronchial disease. Exacerbation may be characterized by increased cough or sputum production or changes in pulmonary function. Home intravenous antibiotic therapy may be an option in some situations. Although up to approximately 50% of cases of bronchiectasis exacerbation may be initiated or exacerbated by viruses, antibiotics are considered standard of care due to the perceived high bacterial load density. For an acute exacerbation, antibiotics are recommended for a course of 14 days. 

Antibiotics may be prescribed for long-term use in patients with bronchiectasis to reduce frequency of exacerbations, improve quality of life, and diminish lung function decline. A Cochrane review found that long-term therapy with antibiotics is effective in reducing sputum volume and purulence but has limited impact on the frequency of exacerbations and the natural history of the disease process.[40] In addition, long-term antibiotic use may result in the emergence of resistant organisms. A review determined that available evidence shows benefit associated with use of prolonged antibiotics in the treatment of patients with bronchiectasis, at least halving the odds of exacerbation and hospitalization. However, the authors also add that the risk of emerging drug resistance is increased more than threefold.[41]  

The most commonly used and recommended long-term antibiotic is azithromycin. Davies and colleagues and Anwar and colleagues suggested that long-term triweekly therapy with azithromycin can be helpful in patients with bronchiectasis.[42, 43]  This has also been helpful in CF. Macrolide antibiotics, such as erythromycin and azithromycin, have been found to have anti-inflammatory effects, which have been helpful in CF and in some patients with non-CF bronchiectasis. Guidelines suggest long-term macrolide antibiotics in pediatric patients who have been hospitalized more than once or had more than two outpatient exacerbations within a 12-month period.[28, 29]

However, a study reported that long-term erythromycin treatment changes the composition of respiratory microbiota in patients with non-CF bronchiectasis. In patients without P aeruginosa airway infection, erythromycin did not significantly reduce exacerbations and promoted displacement of H influenzae by more macrolide-tolerant pathogens, including P aeruginosa. The authors added that these findings argue for a cautious approach to chronic macrolide use in patients without P aeruginosa airway infection.[44]

Some clinicians treat bronchiectasis with prolonged oral antibiotics on a rotating basis. This is falling into disfavor, as it is in CF. Broad-spectrum antibiotics can be given for a month, followed by a second broad-spectrum drug, followed by a third, and so forth. Another option is to use alternating antibiotics for 7-10 days, with antibiotic-free periods of 7-10 days between each course.

Antibiotics are important parts of therapy during exacerbations of bronchiectasis, with the selection of agents based on culture results.[2] It is recommended to attempt eradication of Pseudomonas when first detected using protocols similar to CF protocols.[28] Inhaled tobramycin was associated with decreased Pseudomonas aeruginosa load in sputum, improved lung function, and fewer hospitalizations. However, the researchers concluded that inhaled tobramycin is not indicated in non-CF bronchiectasis unless Pseudomonas is detected in the sputum or bronchoalveolar lavage samples.[2]  

Aztreonam and Colistin (colistimethate) have come into frequent use as an inhaled antibiotic in patients with cystic fibrosis, and it may find its way into therapy for non-CF bronchiectasis. Other inhaled antibiotics are also in development for cystic fibrosis.

Manual and mechanical interventions such as chest percussion, vibration, postural drainage, cough-assist devices, and airway oscillation (ie, Flutter®, acapella®, Aerobika® devices) are used to facilitate sputum volume and mucous expectoration. The goal is to facilitate individualized effective airway clearance.[45] These techniques or devices are often used daily in order to be most effective and may be used in combination.  These devices serve as adjuncts to the cough, which is the most effective and efficient manner of clearing the airway.  Patients can be trained to do huff coughing with airway clearance to help expectorate loosened mucus.

Prior to the wide availability of broad-spectrum antimicrobials, both Field and Clark demonstrated a gradual symptomatic improvement of some children who did not undergo surgical therapy for bronchiectasis.[7, 11] In 1993, Lewiston recommended that surgery be delayed, unless symptomatically necessary, until the patient is aged 6-12 years because of the possibility for clinical improvement. Surgery is also delayed in children with stable disease that can be controlled with medical therapy.

Otgun and associates, in a retrospective study, concluded that the decision for bronchiectasis surgery should be made in cooperation with the chest disease unit.[3] Furthermore, anatomic localization of disease should be mapped with radiography and scintigraphic studies. Otgun and associates found the morbidity and mortality rates to be within acceptable ranges. In unilateral bronchiectasis, total excision and pneumonectomy, as opposed to leaving residual disease, was found to be well tolerated and most beneficial to the child.  Consideration of future transplant candidacy should be made before proceeding with thoracic surgery. 

Pulmonary segmental resection

Pulmonary segmental resection may be beneficial when damage is severe, well localized and the etiology non-recurring in a symptomatic patient. Preoperative documentation of severe abnormalities in ventilation and/or perfusion to the affected portion of the lung, such as with a lung scan, is often helpful.

Transplantation

For patients with severe progressive disease, transplantation has worked as well as selected patients with other lung diseases.[4] Transplantation has predominantly been used in patients with CF.  At times the underlying condition such as certain immunodeficiency states may preclude consideration for lung transplant. 

No specific activity limitations are necessary. Exercise generally promotes increased mucociliary clearance, which may enhance airway clearance in patients with bronchiectasis. However, exercise-induced dyspnea may require further investigation using exercise testing to evaluate for limitation or hypoxemia.  Those with advanced disease generally will limit themselves as needed.  If a patient has very low lung function, assessment of oxygen saturation during activity should be done to identify possible desaturation requiring O2 supplementation. 

Childhood immunization for pneumococci, Haemophilus influenzae  type B, measles, and pertussis has reduced bronchiectasis. Screening for tuberculosis and other successful public health measures minimizes the risk of this disease in children.

Aggressive appropriate therapy of lower respiratory tract infections may prevent bronchiectasis. However, because some viruses predispose to bronchiectasis, this therapy is not always successful.

Therapy of the child with chronic or recurrent respiratory problems due to recurrent aspiration and/or gastroesophageal reflux disease is important to reduce the likelihood of developing bronchiectasis.

Although routine care of patients with bronchiectasis is successfully provided by a primary care physician, a pediatric pulmonologist must be consulted for all infants and children with bronchiectasis. The subspecialist should be an integral part of the child's care and should manage most of the pulmonary aspects of the bronchiectasis and the underlying disease.

If recurrent aspiration is a contributing factor, a pediatric gastroenterologist should have input into the child's care. Pediatric immunologists should help manage children with HIV infection or immunoglobulin deficiencies. If the child has an underlying rheumatologic disorder, a pediatric rheumatologist should be consulted on a regular basis.

Physical therapists or respiratory therapists are important and helpful in the chest physiotherapy techniques. Whether manually performed or performed with one of the mechanical devices, the procedure needs to be thoroughly learned and periodically reviewed with the therapist.

Consider transferring the care of the child with refractory bronchiectasis to a pediatric pulmonary center for clinical deterioration, frequent or increased symptoms, or hemoptysis.

Children with bronchiectasis should be monitored throughout their lives by a clinician comfortable with the management of chronic lung disease. Children should be seen frequently, generally every 3-6 months, when stable and should be seen more frequently if they are not stable.  The CF Foundation recommends quarterly visits including lung function for all persons with CF.

Spirometry is recommended at every visit in children older than 6 years. Chest radiograph need not be empirically repeated. If the clinical course changes, a radiograph should be part of the assessment.

European Respiratory Society guidelines

The European Respiratory Society (ERS) released guidelines for the management of bronchiectasis in children and adolescents.[28] Highlights of the guidelines include the following:

• The ERS suggests that multidetector chest computed tomography scans with high-resolution CT (HRCT) be used to diagnose bronchiectasis in pediatric patients rather than conventional HRCT.
• The suggested CT criterion for abnormal broncho-arterial dilatation in children and adolescents is >0.8 instead of the adult cut-off of >1-1.5.
• In pediatric patients with bronchiectasis, the ERS advises against the routine use of inhaled corticosteroids either alone or coupled with long-acting β2-agonists. Inhaled corticosteroids may be of benefit in patients who have eosinophilic airway inflammation.
• The ERS recommends against the use of recombinant human DNase and bromhexine in children and adolescents with bronchiectasis. Neither inhaled mannitol nor hypertonic saline should be used routinely.
• Children and adolescents should be taught airway clearance techniques (ACT) and receive airway clearance regularly. During acute exacerbations of bronchiectasis, ACT should be performed more frequently.
• The ERS recommends a 14-day course of antibiotic therapy for an acute respiratory exacerbation of bronchiectasis in children and adolescents.
• Following an initial or new detection of Pseudomonas aeruginosa, the ERS suggests eradication therapy in pediatric patients with bronchiectasis.
• For children and adolescents who have recurrent exacerbations of bronchiectasis, the ERS recommends long-term therapy with macrolide antibiotics.

Class Summary

These agents may be beneficial in treating chronic inflammation in bronchiectasis. They elicit anti-inflammatory and immunosuppressive properties and cause profound and varied metabolic effects. They also modify the body's immune response to diverse stimuli.

Fluticasone (Flovent HFA, Flovent Diskus)

This agent inhibits bronchoconstriction mechanisms, produces direct smooth muscle relaxation, and may decrease the number and activity of inflammatory cells, in turn decreasing airway hyperresponsiveness. Fluticasone is available as an aerosol, Flovent HFA (44, 110, or 220 mcg/actuation); it is also available as Flovent powder for inhalation (Diskus) that delivers 50 mcg/actuation, 100 mcg/actuation, or 250 mcg/actuation.

Budesonide inhaled (Pulmicort Flexhaler, Pulmicort Respules)

Budesonide reduces inflammation in airways by inhibiting multiple types of inflammatory cells and decreasing production of cytokines and other mediators involved in bronchospasm. This agent is available as Pulmicort Flexhaler, powder for inhalation (90 mcg/actuation and 180 mcg/actuation; each actuation delivers 80 mcg and 160 mcg respectively) or Pulmicort Respules inhalation susp (0.25 mg/2 mL, 0.5 mg/2 mL, or 1 mg/2 mL). Nebulization has been used in children aged 1-8 y.

Class Summary

Bronchodilators act to decrease muscle tone in the small and large airways in the lungs, thereby increasing ventilation. Spirometry is recommended before and after use of an inhaled bronchodilator before beginning long-term therapy. If no response is noted, or if paradoxical bronchoconstriction occurs, these agents should be avoided.

Albuterol (Proventil HFA, Ventolin HFA, ProAir HFA)

Albuterol relaxes bronchial smooth muscle by action on beta2-receptors. It has little effect on cardiac muscle contractility.

Levalbuterol (Xopenex)

Levalbuterol is used for treatment or prevention of bronchospasm. It is a selective beta2-agonist agent. Albuterol is a racemic mixture, while levalbuterol contains only the active R-enantiomer of albuterol. The S-enantiomer does not bind to beta2-receptors, but it may be responsible for some of the adverse effects of racemic albuterol, including bronchial hyperreactivity and reduced pulmonary function during prolonged use.

Class Summary

Systemic and inhaled antibiotics are used in bronchiectatic disease to prevent or treat exacerbations caused by bacterial colonization that result in airway inflammation and injury. Antibiotics are generally chosen based on organisms and sensitivities from sputum cultures. The antibiotics used more commonly are listed below.

Amoxicillin and clavulanic acid (Augmentin)

Amoxicillin inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins. The addition of clavulanate inhibits beta-lactamase–producing bacteria.

The product is a good alternative antibiotic for patients who are allergic or intolerant to the macrolide class. It is usually well tolerated and provides good coverage against most infectious agents. It is not effective against Mycoplasma and Legionella species. For children older than 3 months, base dosing on the amoxicillin content. Because of different amoxicillin/clavulanic acid ratios in 250-mg tablet (250/125) versus the 250-mg chewable tablet (250/62.5), do not use the 250-mg tablet until the child weighs more than 40 kg.

Ciprofloxacin (Cipro)

Amoxicillin inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins. The addition of clavulanate inhibits beta-lactamase–producing bacteria.

The product is a good alternative antibiotic for patients who are allergic or intolerant to the macrolide class. It is usually well tolerated and provides good coverage against most infectious agents. It is not effective against Mycoplasma and Legionella species. For children older than 3 months, base dosing on the amoxicillin content. Because of different amoxicillin/clavulanic acid ratios in 250-mg tablet (250/125) versus the 250-mg chewable tablet (250/62.5), do not use the 250-mg tablet until the child weighs more than 40 kg.

Trimethoprim and sulfamethoxazole (Bactrim DS, Septra DS)

This agent is a synthetic combination antibiotic: each tab contains 80 mg of trimethoprim and 400 mg of sulfamethoxazole. It is rapidly absorbed after oral administration. The mechanism of action involves blockage of 2 consecutive steps in biosynthesis of nucleic acids and proteins needed by many microorganisms.

This agent provides coverage for common forms of both gram-positive and gram-negative organisms, including susceptible strains of Streptococcus pneumoniae and Haemophilus influenzae. It is indicated in treatment of acute and chronic bronchitic symptoms in patients with bronchiectasis.

Levofloxacin (Levaquin)

Fluoroquinolones should be used empirically in patients likely to develop exacerbations due to organisms resistant to other antibiotics. Levofloxacin is rapidly becoming a popular choice in pneumonia. This is the L stereoisomer of the D/L parent compound ofloxacin, the D form being inactive. It is good monotherapy, with extended coverage against pseudomonal species and excellent activity against pneumococcal species. It acts by inhibition of DNA gyrase activity. The oral form has bioavailability that reportedly is 99%.

Azithromycin (Zithromax, Zmax)

Azithromycin, a macrolide, has bacteriostatic properties due to prevention of mRNA translation and thus stopping bacterial protein synthesis by binding the bacterial 50S ribosomal subunit. At high doses, Azithromycin can be bactericidal. Clinical use as an anti-inflammatory drug takes advange of macrolide inhibition of cell function of macrophages and inflammatory cytokines. Some guidelines do caution against use without negative docuementation of nontuberculous mycobacteria (NTM) infection and normal electrocardiogram (ECG). 

Class Summary

These agents are indicated in bronchiectasis, specifically in patients with CF for Pseudomonas aeruginosa –positive sputum cultures.

Tobramycin (TOBI)

Tobramycin is an aminoglycoside specifically developed for administration with a nebulizer system. When inhaled, it is concentrated in airways, where it exerts antibacterial effect by disrupting protein synthesis. This agent is active against a wide range of gram-negative organisms, including P aeruginosa. It is indicated for the treatment of patients with CF and P aeruginosa infection.