acute exacerbations. Oral fluoroquinolones such as ciprofloxacin can be useful as an alternative to parenteral antibiotics for treatment of Pseudomonas infection, but development of resistance to this class of antibiotics is common. Infection with nontuberculous mycobacteria such as M. avium complex may require prolonged therapy with multiple drugs (see Chapter 25). Just as for patients with other chronic lung diseases, pneumococcal, SARS-CoV-2, and seasonal influenza vaccines are particularly important for patients with bronchiectasis.
Chest physical therapy and positioning to allow better drainage of secretions (postural drainage), often preceded by inhalation of a mist of hypertonic saline, are frequently used for patients with copious sputum. Alternatively, mucus-clearing devices that provide oscillating positive pressure during exhalation, inflatable vests, or mechanical vibrators on the chest are commonly used to facilitate clearance of secretions. Inhaled deoxyribonuclease (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 anti-inflammatory treatment. Both oral and inhaled corticosteroid medications have been investigated, but large studies do not support their routine use. Oral macrolides (e.g., azithromycin) are increasingly being used in bronchiectasis because anti-inflammatory actions and immunomodulatory effects can be attributed to macrolides when administered for long term in low doses. Studies have demonstrated a significant reduction in exacerbations in patients receiving chronic macrolide therapy, although there is a potential for emergence of resistant bacteria from the long-term use of antibiotics and a risk of adverse cardiac effects due to QT interval prolongation. Other more targeted approaches to anti-inflammatory interventions are under study, but none have yet been proven safe and effective.
Treatment of bronchiectasis includes antibiotics, mobilization and clearance of secretions, suppression of the inflammatory response, and bronchodilators. Surgical therapy with resection of the diseased area is infrequent.
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 a discrete diseased area now is performed infrequently. 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.
Cystic fibrosis
Cystic fibrosis, an autosomal recessive genetic disorder that affects all races and ethnic groups, is the most common lethal genetic disease affecting persons of European ancestry. An epidemiologic survey of cystic fibrosis in the United States found a frequency in newborns of approximately 1 in 3200 whites, 1 in 9200 Hispanics, 1 in 11,000 Native Americans, 1 in 15,000 African Americans, and 1 in 30,000 Asian Americans. Manifestations of the disease are usually seen in childhood, although increasingly more cases are being recognized in adults, and children with the disease are living longer into adulthood. The clinical presentation is dominated by severe lung disease and pancreatic insufficiency resulting from thick and tenacious secretions produced by exocrine glands.
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, sodium, bicarbonate, and water absorption and secretion. CFTR mutations are categorized into six 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).
TABLE 7.1
Classes of Cystic Fibrosis Transmembrane Conductance Regulator Mutations
Class |
Effect on CFTR |
Functional |
Presence of CFTR on |
|
CFTR |
Cell Membrane |
|||
|
|
|||
I |
Defective protein production due to premature |
No |
No |
|
|
termination of CFTR messenger RNA |
|
|
|
|
|
|
|
|
II |
Impaired protein processing due to misfolding |
No |
No, CFTR is degraded |
|
|
(e.g., ΔF508 deletion) |
|
in the cytoplasm |
|
|
|
|
|
|
III |
Defective regulation with reduced channel opening |
No |
Yes |
|
|
time (e.g., G551D mutation) |
|
|
|
|
|
|
|
|
IV |
Impaired function causing reduced chloride |
Yes, but |
Yes |
|
|
transport |
reduced in |
|
|
|
|
function |
|
|
|
|
|
|
|
V |
Reduced synthesis of normally functioning CFTR |
Yes, but |
Reduced in number |
|
|
|
reduced in |
|
|
|
|
number |
|
|
|
|
|
|
|
VI |
Impaired membrane insertion or stability |
Yes, but |
Reduced in number |
|
|
|
reduced in |
|
|
|
|
number |
|
|
|
|
|
|
CFTR, cystic fibrosis transmembrane conductance regulator.
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. Whatever the responsible mutation, a deficiency in the quantity or function of CFTR leads to decreased secretion of chloride into airways and increased reabsorption of sodium from airway secretions. As movement of water follows the concentration of ions, the decrease in sodium and chloride in the liquid covering the airway surface leads to a dehydrated airway surface, viscous mucous secretions, and impaired mucociliary clearance. The defective CFTR also leads to decreased secretion of bicarbonate into the airways, resulting in a lower pH in the mucus layer and impaired bacterial killing. Although a double copy (i.e., homozygous) ΔF508 mutation is responsible for approximately 50% of cases of cystic fibrosis, at least one allele with the ΔF508 mutation, when combined with another abnormal allele, is present in approximately 90% of cases. To date, more than 2000 different cystic fibrosis mutations have been identified.
Two major consequences of abnormal CFTR function are responsible for the clinical manifestations of
cystic fibrosis. The first relates to the quality of secretions produced by various exocrine glands, which
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are thick and tenacious and block the tubes into which they are normally deposited (especially airways and pancreatic ducts). Second, because of disrupted sodium and chloride transport and reabsorption along the sweat duct, the sweat produced by affected patients has elevated concentrations of sodium, chloride, and potassium. The abnormal electrolyte composition of sweat has proven to be crucial in diagnosing the disorder.
Major consequences of abnormal CFTR in cystic fibrosis are as follows:
1.Production of thick, tenacious secretions from exocrine glands
2.Decreased pH of mucus
3.Elevated concentrations of sodium, chloride, and potassium in sweat
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, predisposing to difficulty clearing microbes and chronically infected airways. Inflammation and release of mediators from inflammatory cells, particularly neutrophils, not only are triggered by chronic infection but may result from abnormalities in mucosal defenses that are related to CFTR dysfunction. In addition, CFTR-related changes in cellular fatty acid metabolism causing abnormalities in control of inflammation and susceptibility to infection may also contribute. 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 result from obstruction of ducts or airways 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 lungs, thick mucus plugs appear in the airways, 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. Bacterial and sometimes fungal colonization of the airways and secondary infection results, accompanied by infiltration primarily with neutrophils. Superimposed areas of pneumonitis appear, and frank bronchiectasis and areas of abscess formation may be found.
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, Pseudomonas aeruginosa, Stenotrophomonas (Xanthomonas) maltophilia, and
Burkholderia cepacia. 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.
Major clinical problems from cystic fibrosis are as follows:
1.Pancreatic insufficiency
2.Recurrent episodes of tracheobronchial infection
3.Bronchiectasis
4.Intestinal obstruction
5.Sterility in males
As a result of airway obstruction, functional changes characteristic of obstructive airways disease and air trapping develop and can be tracked longitudinally with pulmonary function testing. 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 infertile because of congenital bilateral absence of the vas deferens. Females have reduced fertility due to abnormally tenacious cervical mucus as well as malnutrition, which is frequently present to some degree.
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 problems may complicate the course of cystic fibrosis. Pneumothorax and hemoptysis, which may be massive, can pose major challenges in management. Eventually, progressive respiratory insufficiency and cor pulmonale develop. Although most patients with access to good care live into adult life, their life span is significantly reduced, with a current median survival of approximately 40 years. As noted below, with the recent introduction of CFTR modulator drugs, improvement in life expectancy is forecast.
Serious complications of cystic fibrosis are as follows:
1.Pneumothorax
2.Massive hemoptysis
3.Respiratory insufficiency
4.Cor pulmonale
Diagnostic approach
In the United States and many countries in Europe, all newborns now are screened for cystic fibrosis, which is leading to earlier diagnosis and intervention. The definitive diagnosis of cystic fibrosis is made
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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 analytic techniques.
The chest radiograph often shows an increase in markings and the findings of bronchiectasis described in the previous section (Fig. 7.5). Evidence of focal pneumonitis may be seen during the course of the disease.
FIGURE 7.5 Posteroanterior chest radiograph of patient with cystic fibrosis shows
diffuse increase in markings throughout both lungs. These findings represent
extensive fibrotic changes and bronchiectasis.
Diagnosis of cystic fibrosis is made by demonstration of an elevated concentration of sweat chloride, a culprit mutation in the CFTR gene, or an abnormal electrical potential difference in the nasal mucosa.
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 has been focused on diminishing the clinical consequences and managing complications when they occur. In addition to a sustained focus on adequate nutrition, the principles of therapy were traditionally similar to those used for bronchiectasis of other causes: bronchopulmonary drainage (using chest physiotherapy and postural drainage, a mucus-clearing device, 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 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 anti-inflammatory effects rather than their antimicrobial properties.
More recently, therapy of cystic fibrosis has been revolutionized by the development of medications that improve the function of abnormal CFTR in most patients, frequently to within the normal range. These CFTR modulator drugs, such as ivacaftor, tezacaftor, and elexacaftor, can be used individually or in combination (depending on the specific mutation[s] present) to restore normal CFTR function and improve respiratory symptoms, lung function, nutritional status, and quality of life, frequently with normalization of sweat chloride testing.
Although current forms of therapy have significantly improved prognosis in cystic fibrosis, the natural history of the disease at present without disease-modifying therapy is still one of progressive pulmonary dysfunction and eventual death due to the disease or its complications. However, there is great optimism that the introduction of CFTR modulator medications earlier in the course of the disease, perhaps even in presymptomatic infants identified via newborn screening, may markedly improve prognosis. Importantly, even in adults with established advanced disease, the number of pulmonary exacerbations and hospitalizations tends to fall quickly after CFTR modulator therapy is initiated.
Bilateral lung transplantation may be considered for advanced cystic fibrosis. Despite initial concern for infectious complications due to preexisting chronic sinopulmonary infections, experience with bilateral lung transplantation in cystic fibrosis suggests post-transplantation survival is similar to that of patients with other diagnoses undergoing this procedure. Unfortunately, median survival after lung transplantation in cystic fibrosis remains less than 10 years, emphasizing that transplantation in this young population cannot be viewed as a cure.
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. With the correction of ion transport abnormalities with CFTR modulators such as ivacaftor, cystic fibrosis may become a less optimal candidate disease for gene therapy approaches to treatment.
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