Etiology and Pathogenesis

Infection and impairment of drainage (frequently due to obstruction) are the two underlying problems that contribute to development of dilated or bronchiectatic airways. The responsible infection(s) may be viral or bacterial. Years ago, measles and pertussis (whooping cough) pneumonia were common problems resulting in bronchiectasis. Currently, a variety of other viral and bacterial infections often are responsible; important examples are tuberculosis and Mycobacterium avium complex. At times, inflammation resulting from hypersensitivity to fungal organisms is the underlying cause, as with allergic bronchopulmonary aspergillosis. This condition, found almost exclusively in patients with clinically apparent asthma or cystic fibrosis, is characterized by colonization of airways with Aspergillus organisms and by thick mucous plugs and bronchiectasis in relatively proximal airways.

When an airway is obstructed, a superimposed infection may develop behind the obstruction, causing destruction of the airway wall and leading to bronchiectasis. Tumors, thick mucus, or foreign bodies commonly cause bronchial obstruction, resulting in bronchiectasis.

Another factor that plays a role in some patients is a defect in the ability of the airway to clear itself of, or protect itself against, bacterial pathogens (see Chapter 22). Such a defect predisposes a person to recurrent infections and eventually to airway dilation and bronchiectasis. The abnormality may involve inadequate humoral immunity and insufficient antibody production (hypogammaglobulinemia) or defective leukocyte function. Another problem that has received significant attention is dyskinetic cilia syndrome, in which ciliary dysfunction affects the ability of the ciliary blanket that lines the airway to clear bacteria and protect the airway against infection. The ciliary dysfunction is not limited to the lower airways; it also affects the nasal mucosa and, in males, may affect sperm motility and hence fertility. Pathologically, the dynein arms that are a characteristic feature of the ultrastructure of cilia are frequently absent in this disorder. One specific syndrome associated with bronchiectasis and ciliary dysfunction is Kartagener syndrome, which includes a triad of sinusitis, bronchiectasis, and situs inversus (usually discovered because of the presence of dextrocardia).

Pathology

The primary pathologic feature of bronchiectasis is evident on gross inspection of the airways, which are markedly dilated in the involved region (Fig. 7-1). Three specific patterns of dilation have been described: cylindrical (appearing as uniform widening of the involved airways), varicose (having irregularly widened airways resembling varicose veins), and saccular bronchiectasis (characterized by widening of peripheral airways in a balloonlike fashion). These terms are still used when describing radiographic patterns but are much less relevant clinically. The dilated airways are generally filled with a considerable amount of secretions that may be grossly purulent. Microscopic changes of the bronchial wall epithelium, consisting of ulceration and squamous metaplasia, are seen.

As a result of the exuberant inflammatory changes in the bronchial wall, the blood supply, provided by the bronchial arteries, is increased. The arteries enlarge and increase in number, and new anastomoses may form between the bronchial and pulmonary artery circulations. Inflammatory erosion or mechanical trauma at the site of these vascular changes is often responsible for the hemoptysis seen frequently in patients with bronchiectasis.

Coexisting disease in the remainder of the tracheobronchial tree is common. Other areas of bronchiectasis may be present, or generalized changes of chronic bronchitis may be seen (see Chapter 6).

Pathophysiology

Once the airways have become irreversibly dilated, their defense mechanisms against infection are disturbed. The normal propulsive action of cilia in the involved area is lost, even if it was intact before development of bronchiectasis. Bacteria colonize the enlarged airways, and secretions pool in the dilated sacs of patients with saccular bronchiectasis. Cough becomes much less effective at clearing secretions because of the abnormally collapsible airways. In many cases the relationship established between the colonizing bacteria and the host is relatively stable over time, but the course may be punctuated by acute exacerbations of airway infection.

Functionally, patients with a localized area of bronchiectasis are not impaired to the same extent as patients with generalized obstructive lung disease. Measurement of pulmonary function may reveal surprisingly few if any abnormalities. When seen, functional abnormalities are the result of either extensive bronchiectasis involving a large area of one or both lungs or coexistent generalized airway disease, primarily chronic bronchitis.

Clinical Features

The most prominent symptoms in patients with bronchiectasis are generally cough and copious sputum production. The sputum may be frankly purulent and tenacious, and often the profuse amount of yellow or green sputum production raises the physician’s suspicion of bronchiectasis. However, not all patients with bronchiectasis have significant sputum production. It has been estimated that approximately 10% to 20% of patients are free of copious sputum production; these patients are said to have “dry” bronchiectasis.

The other frequent symptom in patients with bronchiectasis is hemoptysis, which may be massive and life threatening. Hypertrophied bronchial arterial circulation to the involved area is responsible for this symptom in the majority of cases. Because bronchial arteries are branches of the aorta and therefore perfused at systemic blood pressure, bleeding from these vessels can be brisk. Physical examination of the patient with bronchiectasis may reveal few abnormalities, even over the area of involvement. On the other hand, the examiner may hear strikingly abnormal findings such as wheezes, crackles, or rhonchi in a localized area. Clubbing is frequently present. Although the mechanism is not clear, clubbing is thought to be associated with the chronic suppurative process.

Whether arterial blood gas values are abnormal in these patients often depends on the extent of involvement and the presence or absence of underlying chronic bronchitis. With well-localized disease, both PO₂ and PCO₂ may be normal. At the other extreme, patients with more severe disease may develop hypoxemia and hypercapnia. Cor pulmonale may subsequently develop.

Diagnostic Approach

The diagnosis of bronchiectasis is usually suggested by a history of copious sputum production, hemoptysis, or both. Evaluation on a macroscopic level generally includes a chest radiograph, which often reveals nonspecific abnormalities in the involved area. The radiograph may show an area of increased markings, crowded vessels, or “ring” shadows corresponding to dilated or saccular airways. However, none of the findings on the routine radiograph is considered diagnostic of bronchiectasis.

High-resolution computed tomography (HRCT) provides a definitive diagnosis and is the initial procedure used to define the presence, location, and extent of bronchiectasis (Fig. 7-2). HRCT (with sections 1-2 mm thick) provides excellent detail and is particularly useful for detecting subtle bronchiectasis. In the past, the definitive diagnosis depended on bronchography, a radiographic procedure in which an inhaled opaque contrast material was used to outline part of the tracheobronchial tree (Fig. 7-3). This procedure is uncomfortable, can induce bronchospasm, and is not performed today.

Evaluation on a microscopic level is not particularly helpful for patients with presumed bronchiectasis, except for examination of the sputum for microorganisms, particularly during an acute exacerbation of the disease. Patients with bronchiectasis frequently become colonized and infected with Pseudomonas aeruginosa, and the finding of this otherwise relatively unusual pathogen may be a clue to the presence of underlying bronchiectasis. The findings on functional evaluation were discussed in the sections on pathophysiology and clinical features.

Treatment

The three major aspects of treatment of bronchiectasis are antibiotics, bronchopulmonary drainage (clearance of airway secretions), and bronchodilators. Antibiotics are used in various ways. Some patients are treated only when the quantity or appearance of the sputum clearly changes. Other patients, especially those who have severe disease and frequent exacerbations, are given a regimen of intermittent or even continuous antibiotics in an attempt to control chronic infection. Oral agents such as amoxicillin and trimethoprim-sulfamethoxazole, which are effective against many strains of Streptococcus pneumoniae and Haemophilus influenzae, are often used in patients with bronchiectasis. Inhaled tobramycin is sometimes used prophylactically to diminish the growth of gram-negative organisms. When these patients are infected with Pseudomonas organisms, treatment is generally more difficult. Oral fluoroquinolones such as ciprofloxacin have become useful therapy for Pseudomonas infection as an alternative to parenteral antibiotics, but secondary development of resistance to this class of antibiotics is common. Infection with M. avium complex requires prolonged therapy with multiple drugs (see Chapter 24). Chest physical therapy and positioning to allow better drainage of secretions (postural drainage) are frequently used for patients with copious sputum. Alternatively, inflatable vests or mechanical vibrators on the chest are increasingly being used to facilitate clearance of secretions. Bronchodilators may be useful in patients with coexisting airway obstruction that is at least partially reversible. Inhaled DNase has been used to decrease the viscosity of pulmonary secretions in patients with cystic fibrosis (see section on cystic fibrosis) but has not proven effective in bronchiectasis resulting from other causes.

Because ongoing airway inflammation is an important feature of bronchiectasis, there is great interest in antiinflammatory treatment. Both oral and inhaled corticosteroid medications have been investigated. Although these drugs may be helpful in some patients, large studies do not support their routine use. Use of oral macrolides (e.g., erythromycin, azithromycin) in bronchiectasis is a promising new area of investigation, since antiinflammatory actions and immunomodulatory effects can be attributed to macrolides when administered long term in low doses. Currently, however, whether these agents have a definite role in treating patients with bronchiectasis is uncertain.

In the past, surgery was used for many patients with localized bronchiectasis. Because medical therapy is frequently effective in limiting symptoms and impairment, resection of the diseased area now is performed much less frequently. In general, surgery is reserved for selected patients who have significant poorly controlled symptoms attributable to a single localized area and who do not have other areas of bronchiectasis or significant evidence of generalized chronic obstructive pulmonary disease.

Etiology and Pathogenesis

Cystic fibrosis is caused by mutations in the gene that codes for the 1480 amino acid protein cystic fibrosis transmembrane conductance regulator (CFTR), which resides on the long arm of chromosome 7. A member of the adenosine triphosphate (ATP)-binding cassette transporter protein superfamily, CFTR is an epithelial ion channel critically important in regulation of chloride and water absorption and secretion. CFTR mutations are categorized into five different classes according to the resultant functional or processing abnormality in the protein (Table 7-1). The specific defects in each class are potential targets for different approaches to therapy (see Treatment).

The most common mutation causing cystic fibrosis, ΔF508, is a three-nucleotide deletion causing a single phenylalanine residue to be missing at position 508. The ΔF508 mutation causes the protein to misfold and be retained in the endoplasmic reticulum. Working by mechanisms not yet fully elucidated, this mutation leads to impermeability of epithelial cells to chloride transport, which is thought to be responsible for both high electrolyte concentrations in sweat and abnormally thick secretions produced by exocrine glands. Although the ΔF508 mutation is responsible for approximately 70% of cases of cystic fibrosis, more than 1700 different cystic fibrosis mutations have been identified.

Two major consequences of abnormal CFTR are recognized as responsible for the clinical manifestations of cystic fibrosis. The first relates to the quality of secretions produced by various exocrine glands, which are thick and tenacious and block the tubes into which they are normally deposited (especially airways and pancreatic ducts). Second, the sweat produced by affected patients has an abnormal electrolyte composition, specifically, elevated concentrations of sodium, chloride, and potassium. These abnormalities in the composition of sweat have proved to be crucial in diagnosing the disorder.

The mechanisms by which abnormal CFTR leads to all manifestations of the disease are not completely understood. Thick, tenacious secretions appear to play a major role. However, CFTR-related changes in cellular fatty acid metabolism causing abnormalities in control of inflammation and susceptibility to infection may also contribute. In addition, other genetic differences, such as variants in tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-β genes, appear to influence disease severity.

Pathology

The pathologic findings in cystic fibrosis appear to result from obstruction of ducts or tubes by tenacious secretions and the accompanying inflammation. In the pancreas, obstruction of the ducts eventually produces fibrosis, atrophy of the acini, and cystic changes. In the airways, thick mucous plugs appear in the bronchi, obstructing both airflow and normal drainage of the tracheobronchial tree. Early in the course of the disease, airway changes are found predominantly in the bronchioles, which are plugged and obliterated by secretions. Later, the findings are more extensive. Superimposed areas of pneumonitis appear, and frank bronchiectasis and areas of abscess formation may be found. Cardiac complications of cor pulmonale frequently occur, and pathologic examination of the heart shows evidence of right ventricular hypertrophy.

Pathophysiology

In the pancreas, the pathologic process leads to exocrine pancreatic insufficiency, with maldigestion and malabsorption of foodstuffs, particularly fat and the fat-soluble vitamins A, D, E, and K. Diabetes mellitus due to destruction of islet cells may develop in later stages. In the lung, the major problem is recurrent episodes of tracheobronchial infection and bronchiectasis resulting from bronchial obstruction and defective mucociliary transport. In addition, evidence suggests that the CFTR mutation contributes to airway infection by altering the binding and clearance of microorganisms by airway epithelial cells, and the altered chloride concentration of airway fluid appears to impair the activity of antimicrobial peptides (especially human β-defensin-1). The major organisms that eventually colonize the airways are Staphylococcus aureus and P. aeruginosa. Difficulty with these organisms seems to be entirely the result of local (airway) host defense mechanisms; the humoral immune system (i.e., ability to form antibodies) appears to be intact.

As a result of airway obstruction, functional changes characteristic of obstructive airways disease and air trapping develop. Patients also exhibit ventilation-perfusion mismatch, hypoxemia (sometimes with CO₂ retention), pulmonary hypertension, and cor pulmonale.

Clinical Features

Approximately 10% to 20% of patients with cystic fibrosis develop their first clinical problem in the neonatal period, manifested as intestinal obstruction with thick meconium (the newborn’s intestinal contents composed of ingested amniotic fluid). This obstruction is called meconium ileus. The remainder of patients usually have a childhood presentation, manifested as pancreatic insufficiency, recurrent bronchial infections, or both. Occasionally, patients are first diagnosed when they are adults. Almost all males with the disease are sterile because of congenital absence of the vas deferens. Females are capable of having children, but their fertility rate is decreased.

Physical examination of patients with cystic fibrosis reveals the findings expected with severe airflow obstruction and plugging of airways by secretions. Wheezing and coarse crackles or rhonchi occur frequently, and clubbing is common.

Several complications may develop as a result of the disease. Pneumothorax and hemoptysis, which may be massive, can be major problems in management. Eventually, frank respiratory insufficiency and cor pulmonale develop. Although most patients live into adult life when good care has been provided, their lifespan is significantly reduced, with a median survival of 37 years.

Diagnostic Approach

Definitive diagnosis of cystic fibrosis is made by the combination of compatible clinical features and one of the following: (1) identification of mutations known to cause cystic fibrosis in both CFTR genes, (2) characteristic abnormalities in measurements of nasal mucosal electrical potential difference, or (3) abnormal sweat electrolytes. The concentrations of sodium, chloride, and potassium are elevated in sweat from these patients, and a sweat chloride concentration greater than 60 mEq/L is generally considered diagnostic. Only individuals homozygous for the cystic fibrosis gene demonstrate this abnormality; heterozygous carriers have normal sweat electrolytes. Identification of heterozygotes (i.e., carriers of the cystic fibrosis gene) and in utero detection of homozygotes are possible with current DNA probe techniques.

The chest radiograph often shows an increase in markings and the findings of bronchiectasis described in the previous section (Fig. 7-4). Evidence of focal pneumonitis may be seen during the course of the disease.

Functional assessment of these patients early in the disease shows evidence of obstruction of small airways. As the disease progresses, evidence of more generalized airway obstruction (decreased forced expiratory volume in 1 second [FEV₁], forced vital capacity [FVC], and FEV₁/FVC ratio) and air trapping (increased residual volume [RV]/total lung capacity [TLC] ratio) is seen. The elastic recoil of the lung is generally preserved, and TLC most commonly is within the normal range. Because emphysematous changes generally are not seen in patients with cystic fibrosis and the alveolar-capillary interface remains relatively preserved, most frequently the diffusing capacity is relatively normal. Arterial blood gas values often indicate hypoxemia, and hypercapnia may be seen as the disease progresses.

Treatment

Therapy for cystic fibrosis is based on an attempt to diminish the clinical consequences and to manage complications when they occur. Other than a sustained focus on adequate nutrition, the principles of therapy are similar to those used for bronchiectasis: bronchopulmonary drainage (using chest physical therapy and postural drainage, a flutter valve, or a vibrating vest), antibiotics, and bronchodilators. Agents used to decrease the viscosity of the sputum appear to offer benefit in some patients. In particular, because DNA released from inflammatory cells contributes significantly to the viscosity of mucus, inhalation of recombinant deoxyribonuclease (DNase) has been used to degrade DNA, decrease mucus viscosity, and improve clearance of secretions. Inhaled hypertonic saline also may be useful as a mucolytic agent. Oral macrolide antibiotics such as azithromycin may offer some benefit that is believed related to their antiinflammatory effects rather than their antimicrobial properties.

In a recent conceptual breakthrough, a new drug, ivacaftor, has been shown to improve respiratory symptoms and lung function in patients with a less common CFTR mutation (G551D-CFTR). This mutation results in a protein that is present in typical amounts on the cell surface but does not function normally. Ivacaftor acts as a “potentiator” to increase the time activated CFTR channels at the cell surface remain open, thus improving the function of the abnormal channel. Unfortunately, the drug does not appear to be effective treatment for patients with the most common defect, ΔF508. However, the success of ivacaftor provides hope that an understanding of the different classes of CFTR mutations (see Table 7-1) may lead to other allele-specific therapies.

Although current forms of therapy have significantly improved prognosis in cystic fibrosis, the natural history of the disease at present is still one of progressive pulmonary dysfunction and eventual death due to the disease or its complications. Despite initial concern about lung transplantation in these patients because of their chronic pulmonary infection, experience with bilateral lung transplantation suggests posttransplantation survival is similar to that of other patients undergoing this procedure.

Identification of the genetic basis for the disease in the majority of patients raised hopes that gene therapy would provide a means for reversing the primary defect as well as the characteristic abnormality in airway secretion. Unfortunately, initial enthusiasm for gene therapy as a “cure” for cystic fibrosis has been tempered by difficulty finding an effective and nontoxic method (vector) for delivering the gene to the airway and achieving sufficient and durable expression of the normal gene. Thus, as with ivacaftor, much current therapeutic research is focused on posttranslational modifications of the defective protein or its effects.

Etiology

The upper airway can be affected by either acute problems or those following a more subacute or chronic course. On an acute basis, the larynx is probably the major area subject to obstruction. Potential causes include infection (epiglottitis, often due to H. influenzae), thermal injury and the resulting laryngeal edema from smoke inhalation, aspiration of a foreign body, laryngeal edema from an allergic (anaphylactic) reaction, or physical trauma associated with endotracheal intubation.

On a chronic basis, the upper airway may be partially obstructed by hypertrophy of the tonsils, by tumors (particularly of the trachea), by strictures of the trachea (often resulting from prior instrumentation of the trachea), or by vocal cord paralysis. Tracheomalacia, another chronic condition that may be congenital or acquired, is characterized by flaccidity of supporting airway cartilage and results in upper airway narrowing, especially on forced exhalation. Some patients are subject to recurrent episodes of upper airway obstruction during sleep; this entity is one variety of what is termed sleep apnea syndrome, which is considered further in Chapter 18.

Pathophysiology

The resistance of a tube to airflow varies inversely to the fourth power of the radius; hence, even small changes in airway size may produce dramatic changes in resistance and in the work of breathing. If the airways under consideration were always stiff or if a disorder did not allow any flexibility in the size of the airway, inspiration and expiration would be impaired by the same amount, and the flow rate generated during inspiration would be essentially identical to the flow rate during expiration. This type of obstruction is termed a fixed obstruction.

On the other hand, if airway diameter changes during the respiratory cycle, the greatest impairment to airflow occurs when the airway diameter is smallest. This type of obstruction is termed a variable obstruction. If the obstruction is located within the thorax, changes in pleural pressure during the respiratory cycle affect the size of the airway and therefore the magnitude of the obstruction. During a forced expiration, the positive pleural pressure causes airway narrowing, making the obstructing lesion more critical. In contrast, during inspiration, the airways increase their diameter, and the effects of a partial obstruction are less pronounced (see Fig. 3-20).

If the obstruction is located above the level of the thorax (i.e., outside the thorax), changes in pleural pressure are not directly transmitted to the airway in question. Rather, the negative airway pressure during inspiration tends to create a vacuum-like effect on extrathoracic upper airways, narrowing them and augmenting the effect of any partial obstruction. During expiration, the pressure generated by the flow of air from the intrathoracic airways tends to widen the extrathoracic airways and decrease the net effect of a partially obstructing lesion (see Fig. 3-20).

Clinical Features

Patients with upper airway obstruction may have dyspnea or cough. On physical examination they may have evidence of flow through narrowed airways. If the lesion is variable and intrathoracic, the primary difficulty with airflow occurs during expiration, and patients demonstrate expiratory wheezing. If the lesion is variable and extrathoracic, obstruction is more marked during inspiration, and patients frequently manifest inspiratory stridor, a high-pitched, monophonic, continuous inspiratory sound often best heard over the trachea. With acute upper airway obstruction, such as that seen with inhalation of a foreign body, anxiety and respiratory distress often are apparent, signaling a medical emergency. In patients with epiglottitis, respiratory distress often is accompanied by sore throat, change in voice, dysphagia, and drooling.

Diagnostic Approach

In the evaluation of suspected disorders of the upper airway, radiography and direct visualization provide the most useful information about the macroscopic appearance of the airway. Lateral neck radiographs or CT scans of the upper airway may reveal the localization, extent, and character of a partially obstructing lesion. A CT scan may offer particularly useful information by providing a cross-sectional view of the airways from the larynx down to the carina. Direct visualization of the upper airway may be obtained by laryngoscopy or bronchoscopy, which may reveal the presence of edema, vocal cord paralysis, or an obstructing lesion such as a tumor. However, direct visualization of the airways by these techniques is not without risk. The instrument used occupies part of the already compromised airway and may induce airway spasm or swelling that further obstructs the airway. This is especially true in cases of suspected epiglottitis, in which direct visualization should not be attempted unless the examiner is prepared to perform an emergency tracheostomy.

Functional assessment of the patient with presumed upper airway obstruction can be useful in quantifying and localizing the obstruction, because the functional consequences of a fixed versus a variable obstruction and an extrathoracic versus an intrathoracic obstruction are quite different. To understand these differences, the flow-volume loop and the principles discussed in the pathophysiology section must be understood. This type of physiologic evaluation is appropriate for chronic upper airway obstruction, not for acute life-threatening obstruction.

When a fixed lesion is causing a relatively critical obstruction, maximal flow rates generated during inspiration and expiration are approximately equal, and a “plateau” marks both the inspiratory and expiratory parts of the flow-volume curve. When the lesion is variable, the effect of the obstruction depends on whether the lesion is intrathoracic or extrathoracic. With an intrathoracic obstruction, critical narrowing occurs during expiration, and the expiratory part of the flow-volume curve displays a plateau. With an extrathoracic obstruction, the expiratory part of the loop is preserved, and the inspiratory portion displays the plateau. A schematic diagram of the flow-volume loops observed in these types of upper airway obstruction is shown in Figure 3-21.

Treatment

Because many different types of disorders result in upper airway obstruction, treatment varies greatly depending on the underlying problem, particularly its acuteness and severity. In acute severe upper airway obstruction, an emergency procedure such as endotracheal intubation or tracheostomy may be necessary to maintain a patent airway. A procedure such as bronchoscopic laser therapy or airway stenting also may be used. Discussion of each disorder and further consideration of management can be found in other textbooks and in some articles listed in the references.

Bronchiectasis

Barbato, A, Frischer, T, Kuehni, CE, et al. Primary ciliary dyskinesia: a consensus statement on diagnostic and treatment approaches in children. Eur Respir J. 2009;34:1264–1276.

Barker, AF. Bronchiectasis. N Engl J Med. 2002;346:1383–1393.

Feldman, C. Bronchiectasis: new approaches to diagnosis and management. Clin Chest Med. 2011;32:535–546.

Feldman, C. The use of antiinflammatory therapy and macrolides in bronchiectasis. Clin Chest Med. 2012;33:371–380.

Fujimoto, T, Hillejan, L, Stamatis, G. Current strategy for surgical management of bronchiectasis. Ann Thorac Surg. 2001;72:1711–1715.

Fuschillo, S, De Felice, A, Balzano, G. Mucosal inflammation in idiopathic bronchiectasis: cellular and molecular mechanisms. Eur Respir J. 2008;31:396–406.

Gould, CM, Freeman, AF, Olivier, KN. Genetic causes of bronchiectasis. Clin Chest Med. 2012;33:249–263.

Lillington, GA. Dyskinetic cilia and Kartagener’s syndrome. Bronchiectasis with a twist. Clin Rev Allergy Immunol. 2001;21:65–69.

Metersky, ML. The initial evaluation of adults with bronchiectasis. Clin Chest Med. 2012;33:219–231.

Moulton, BC, Barker, AF. Pathogenesis of bronchiectasis. Clin Chest Med. 2012;33:211–217.

O’Donnell, AE. Bronchiectasis. Chest. 2008;134:815–823.

Pasteur, MC, Bilton, D, Hill, AT, British Thoracic Society Bronchiectasis non-CF Guideline Group. British Thoracic Society guideline for non-CF bronchiectasis. Thorax. 2010;65:i1–58.

Rosen, MJ. Chronic cough due to bronchiectasis: ACCP evidence-based clinical practice guidelines. Chest. 2006;129:122s–131s.

Smith, MP. Non-cystic fibrosis bronchiectasis. J R Coll Physicians Edinb. 2011;41:132–139.

Strippoli, MP, Frischer, T, Barbato, A, et al. for the ERS Task Force on primary ciliary dyskinesia in children: Management of primary ciliary dyskinesia in European children: recommendations and clinical practice. Eur Respir J. 2012;39:1482–1491.

Todd, JL, Palmer, SM. Bronchiolitis obliterans syndrome: the final frontier for lung transplantation. Chest. 2011;140:502–508.

Cystic Fibrosis

Boucher, RC. New concepts of the pathogenesis of cystic fibrosis lung disease. Eur Respir J. 2004;23:146.

Boyle, MP. Adult cystic fibrosis. JAMA. 2007;298:1787–1793.

Chmiel, JF, Konstan, MW. Inflammation and anti-inflammatory therapies for cystic fibrosis. Clin Chest Med. 2007;28:331.

Cohen-Cymberknoh, M, Shoseyov, D, Kerem, E. Managing cystic fibrosis: strategies that increase life expectancy and improve quality of life. Am J Respir Crit Care Med. 2011;183:1463–1471.

Corbyn, Z. Promising new era dawns for cystic fibrosis treatment. Lancet. 2012;379:1475–1476. 21

Davis, PB, Yasothan, U, Kirkpatrick, P. Ivacaftor. Nat Rev Drug Discov. 2012;30(11):349–350.

Donaldson, SH, Boucher, RC. Sodium channels and cystic fibrosis. Chest. 2007;132:1631–1636.

Drumm, ML, Konstan, MW, Schluchter, MD, et al. Genetic modifiers of lung disease in cystic fibrosis. N Engl J Med. 2005;353:1443.

Elizur, A, Cannon, CL, Ferkol, TW. Airway inflammation in cystic fibrosis. Chest. 2008;133:489–495.

Farrell, PM, Rosenstein, BJ, White, TB, et al. Cystic Fibrosis Foundation: Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report. J Pediatr. 2008;153:S4–S14.

Flume, PA, Liou, TG, Borowitz, DS, et al. for the VX08–770–104 Study Group: Ivacaftor in Subjects with Cystic Fibrosis who are Homozygous for the F508del-CFTR Mutation. Chest. 2012. Mar 1. [Epub ahead of print]

Flume, PA, Mogayzel, PJ, Jr., Robinson, KA, et al. Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations. Clinical Practice Guidelines for Pulmonary Therapies Committee. Am J Respir Crit Care Med. 2009;180:802–808.

Freedman, SD, Blanco, PG, Zaman, MM, et al. Association of cystic fibrosis with abnormalities in fatty acid metabolism. N Engl J Med. 2004;350:560.

Kerem, E. Pharmacological induction of CFTR function in patients with cystic fibrosis: mutation-specific therapy. Pediatr Pulmonol. 2005;40:183.

Mehta, A. CFTR: more than just a chloride channel. Pediatr Pulmonol. 2005;39:292–298.

Pier, GB. The challenges and promises of new therapies for cystic fibrosis. J Exp Med. 2012;209:1235–1239.

Ramsey, BW, Davies, J, McElvaney, NG, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. VX08–770–102 Study Group. N Engl J Med. 2011;365:1663–1672.

Rogan, MP, Stoltz, DA, Hornick, DB. Cystic fibrosis transmembrane conductance regulator intracellular processing, trafficking, and opportunities for mutation-specific treatment. Chest. 2011;139:1480–1490.

Yarden, J, Radojkovic, D, De Boeck, K, et al. Association of tumour necrosis factor alpha variants with the CF pulmonary phenotype. Thorax. 2005;60:320.

Upper Airway Disease

Ernst, A, Feller-Kopman, D, Becker, HD, et al. Central airway obstruction. Am J Respir Crit Care Med. 2004;169:1278–1297.

Gaissert, HA, Burns, J. The compromised airway: tumors, strictures, and tracheomalacia. Surg Clin North Am. 2010;90:1065–1089.

Grenier, PA, Beigelman-Aubry, C, Brillet, PY. Nonneoplastic tracheal and bronchial stenoses. Radiol Clin North Am. 2009;47:243–260.

Hsia, D, Musani, AI. Interventional pulmonology. Med Clin North Am. 2011;95(6):1095–1114.

Morris, MJ, Christopher, KL. Diagnostic criteria for the classification of vocal cord dysfunction. Chest. 2010;138:1213–1223.

Weinberger, M, Abu-Hasan, M. Pseudo-asthma: when cough, wheezing, and dyspnea are not asthma. Pediatrics. 2007;120:855–864.