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Chapter 1. Unusual Lung Infection, Bronchiectasis, and Cystic Fibrosis Free To View

COL Lisa K Moores, MC, USA, FCCP
DOI: 10.1378/pulm.26.1
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Synopsis 

Pulmonary nocardiosis and actinomycosis are rare but often severe infections that occur in immunocompromised (the former) and immunocompetent hosts. They are often not suspected initially and can present with extensive local or disseminated disease. They share many common clinical and radiographic features and can be difficult to delineate from one another. It is important to do so, however, as the antimicrobials of choice and duration of therapy differ. The epidemiology, clinical presentation, imaging, diagnosis, and treatment of both are reviewed. Bronchiectasis is a syndrome, with many underlying etiologies and associations, that has been defined as an irreversible dilation and destruction of one or more bronchi, and inadequate clearance and pooling of mucus in the airways. Cystic fibrosis (CF) is a common genetic disorder that accounts for many cases of bronchiectasis. Treatment of CF involves chest physiotherapy, mucolytic agents, antibiotics, and antiinflammatory agents. Gene therapy is a promising approach still being investigated. Treatment of non-CF bronchiectasis has been less well studied, and many of the recommendations are extrapolated from studies of patients with CF.

Objectives 
  • Review the presentation, diagnosis, and treatment of actinomycosis and nocardiosis infection in the lung.

  • List the causes of bronchiectasis.

  • Review the therapeutic options for the treatment of bronchiectasis.

  • Review the genetic disorders that lead to cystic fibrosis (CF).

  • Introduce the newer therapeutic approaches in the treatment of pulmonary disease in patients with CF.

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Unusual Lung Infections

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Nocardiosis

Nocardiosis refers to invasive disease caused by members of the genus Nocardia. Respiratory tract disease and extrapulmonary dissemination are the most common manifestations. Pulmonary infection is increasingly being seen in immunosuppressed patients, particularly those with defects in cellular immunity. Other presentations include cellulitis, the lymphocutaneous syndrome, actinomycetoma, and keratitis. Nocardia spp are aerobic, nonmobile, and non-spore-forming organisms that live as soil saprophytes. In tissue specimens, the organisms reveal delicate branching filamentous forms that are gram-positive and usually acid fast if weak decolorizing agents are used for the stains.1 Seven species have been associated with human disease. Nocardia asteroides is the most common species associated with invasive disease. Nocardia farcinica is less common and is associated with dissemination. Other species known to cause human infection are Nocardia pseudobrasiliensis and Nocardia brasiliensis.2

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Epidemiology/Pathogenesis

Nocardia spp are common natural inhabitants of the soil throughout the world. The aerosol route is the main portal of entry, although ingestion of contaminated food or direct inoculation of the organism due to trauma can also lead to infection.1,2 Epidemics within the hospital environment are rare, and person-to-person transmission has only rarely been suggested. The disease has been reported worldwide and is more common in men than women (approximately 3:1, respectively).3 Although Nocardia can occur as a primary pulmonary pathogen in patients with no underlying disease, it is frequently recognized as an opportunistic disease, especially among patients with cell-mediated immune deficiencies, including transplantation (highest frequency in those who have undergone lung transplantation), lymphoma, and AIDS. Therapy with corticosteroids is the most important risk factor.3 High-dose corticosteroids, cytomegalovirus infection in the past 6 months, and high calcineurin inhibitor levels (cyclosporine or tacrolimus) are independent risk factors for Nocardia infection in organ transplant recipients. In HIV-positive persons, nocardiosis most often presents with a CD4+ lymphocyte concentration of <100 cells/μL, but can occur in patients with counts <250 cells/μL. Nocardiosis has also been reported to be associated with pulmonary alveolar proteinosis, mycobacterial diseases, and chronic granulomatous disease. Finally, nocardiosis is not uncommon in COPD patients receiving chronic corticosteroid treatment, but it is also increasingly being seen in patients with COPD who have received a recent short course of corticosteroids for an exacerbation. Case series over time reveal an increasing percentage of patients with COPD as the underlying risk. When COPD is the main underlying infection, the disease is almost always isolated to the lungs.3 Impairment of local lung defenses plays a role.4 Lesions are characterized by necrotizing abscesses that are not well encapsulated and spread easily. Granuloma formation and fibrosis are infrequent.1 Because of its propensity for hematogenous dissemination, Nocardia is often associated with metastatic spread, especially to the brain (in up to one-third of cases). Dissemination is more common in patients with underlying HIV and in patients with alcoholism.2,4 Chest wall invasion may occur but is uncommon.1

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Clinical Manifestations

Important features of Nocardia infection include diverse clinical and radiographic presentations, the ability to disseminate to any organ system in the body, and the tendency to relapse or remain unresponsive to therapy. The nonspecific features make diagnosis challenging, and the disease is often not suspected early on in the patient's course of symptoms. The median time to diagnosis ranges from 40 to 55 days in reported series.2 Nocardial pneumonia is the most common respiratory tract presentation.3 Although the clinical course may be acute in immunosuppressed patients, typically, the patients have a subacute presentation consisting of several weeks of symptoms. Cough, purulent sputum, occasional hemoptysis, night sweats, and pleuritic pain are common symptoms.3 Superior vena cava syndrome, mediastinitis, and pericarditis have been reported from direct spread from the lungs. Nocardia rarely involves the chest wall. In approximately 50% of pulmonary cases, extrapulmonary dissemination occurs. In a significant number of cases of disseminated disease, the initial respiratory tract involvement does not elicit symptoms. As noted above, nocardiosis has the propensity for dissemination to the brain, but other extrapulmonary sites include the skin, bone, and muscle. In the CNS, Nocardia brain abscesses may be single or multiple. Nocardia is not usually recovered from the cerebrospinal fluid.

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Radiographic Manifestations

The chest radiographic patterns are variable. The most frequent manifestation is an airspace consolidation, usually homogeneous, but occasionally patchy. Bilateral involvement is common.3 Nodules, either single or multiple, maybe confused with metastatic carcinoma.1 The most common radiographic manifestation is cavitation, which is found in both consolidations and nodules. Pleural involvement with an empyema is present in approximately one-third of cases.2

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Diagnosis

In most cases of pneumonia, sputum smear findings are negative. Bronchoscopy may be necessary to obtain an adequate specimen for the characteristic gram-positive filaments that may be acid fast and often take up silver stains.1 Cultures for Nocardia require special handling because colonies may not appear for 2 to 4 weeks. Blood cultures require incubation aerobically for up to 4 weeks. Advances in DNA extraction and real-time PCR assays may allow for identification of most Nocardia spp within hours.3 The isolation of Nocardia from the sputum in a nonimmunosuppressed patient without radiographic abnormalities may represent colonization. However, a sputum culture that is positive for Nocardia in an immunosuppressed patient more often indicates disease.4 A number of serologic tests have been evaluated, but the diversity of species known to cause disease and the potential lack of sensitivity for detecting an antibody response in immunocompromised patients have limited their practical use.3

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Treatment

Sulfonamide agents remain the drugs of choice for nocardiosis (sulfadiazine or sulfisoxazole, 6 to 8 g/d, then decreasing to 4 g/d as the disease is controlled). The combination of trimethoprim and sulfamethoxazole (TMP-SMX) is thought to be an equally effective alternate choice.2 Unfortunately, disease does occasionally occur in patients receiving TMP-SMX prophylaxis, particularly in patients with malignancy or HIV infection.3 Minocycline is an alternative choice for an oral medication in those patients who have sulfa allergies. IV regimens include amikacin, ceftriaxone, cefotaxime, ceftizoxime, and imipenem. Linezolid has now been shown in vitro to be highly effective against most strains of Nocardia. However, the high cost and serious potential toxicities currently relegate this agent to refractory cases. Because of the risk of relapse, patients who have intact host defenses are generally treated for 6 to 12 months, whereas deficient hosts and those with CNS involvement are treated for 12 months. If ongoing steroid or cytotoxic therapy is required, prolonged maintenance therapy may be needed.3 When the CNS is involved, treatment with cefotaxime or ceftriaxone in addition to the TMP-SMX is recommended.4 Surgical drainage should be considered for patients with brain abscesses, empyema, and subcutaneous abscesses.1 Mortality due to pulmonary nocardiosis is high (15%–40%), and increases significantly with CNS involvement. Delay in diagnosis and treatment affects prognosis. It is therefore imperative that practitioners have a high index of suspicion in evaluating patients who are immunosuppressed or have significant chronic lung disease.

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Actinomycosis

Actinomycosis is a slowly progressive infectious disease that is caused by anaerobic, gram-positive, non-spore-forming bacteria. They were originally misclassified as fungi.5 The word actinomycosis is derived from the Greek terms aktino (the radiating appearance of the sulfur granule) and mykos (mycotic disease). The classic clinical picture is a cervicofacial disease in which the patient presents with a large mass on the jaw. It is now recognized that the organisms colonize in the mouth, colon, and vagina. Infection results from mucosal disruption and can occur at any site in the body. The pulmonary form of the disease is actually quite rare.1 Infection is characterized by a pyogenic response and necrosis, followed by intense fibrosis. Actinomycosis is difficult to diagnose, and is often confused with TB, lung abscess, or malignancy.1

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Epidemiology/Pathogenesis

The organisms are a normal inhabitant of the human oropharynx, and are frequently found in dental caries and at the gingival margins of persons with poor oral hygiene. Actinomycosis is most commonly caused by Actinomyces israelii. Actinomycotic infections in the lung are, however, usually polymicrobial. In tissue, actinomycotic infection grows in microcolonies or granules. Because these granules are yellow, they are often called sulfur granules, although they contain minimal amounts of sulfa. Actinomycosis of the respiratory tract is acquired most commonly by aspiration, but direct extension of the disease from the head and neck or abdominal cavity can occur. The peak incidence is reported in the fourth and fifth decades of life; nearly all series have reported a male predominance (3:1, respectively). The pulmonary form typically constitutes only 15% of reported cases, but has been as high as 50% in some series. Most infections occur in individuals who are immunocompetent. However, some cases have been reported in patients with impaired host defenses. Patients with alcoholism and poor dental hygiene are at increased risk. The pulmonary form has also been reported in patients with chronic lung disease, including COPD and bronchiectasis.1 The presentation of pulmonary actinomycosis has changed in recent years to a less aggressive infection, which is likely related to improved oral hygiene and increased use of penicillin, even when the specific diagnosis is not suspected.

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Clinical Manifestations

Actinomycosis most commonly presents as a disease of the cervicofacial region following dental extraction, with osteomyelitis of the mandible or a soft tissue abscess that drains through the skin. Pulmonary actinomycosis usually presents with an indolent progressive course. The initial manifestations include a nonproductive cough and low-grade fever, subsequently followed by a productive cough, which can be associated with hemoptysis.1 With chest wall involvement, pleuritic pain will develop in the patient. Rarely, a sinus tract may appear as a bronchocutaneous fistula. When this occurs, it is highly suggestive of actinomycosis. Late in the disease, the patient may present with weight loss, anemia, and clubbing of the digits.

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Radiographic Manifestations

The usual pattern of acute pulmonary actinomycosis consists of airspace consolidation, commonly in the periphery of the lung and often in the lower lung fields. The typical CT scan feature is a chronic segmental airspace consolidation containing necrotic low-attenuation areas with frequent cavity formation. Other findings include hilar or mediastinal adenopathy, bronchiectasis within the consolidation, and localized pleural thickening and/or effusion. If not treated with appropriate antibiotics, a lung abscess may develop, and the infiltrate may extend into the pleura with an associated empyema. Subsequently, actinomycosis will extend into the chest wall with osteomyelitis of the ribs, abscess formation, and draining sinus formation. This is highly suggestive of actinomycosis.1 Chest CT scan may be a more sensitive imaging modality, especially if bone windows are obtained (which might reveal early rib erosion). Actinomycosis is often mistaken for pulmonary carcinoma; the presence of an air bronchogram in the mass lesion should suggest the possibility of a nonneoplastic process. Actinomycosis can also present as an endobronchial infection, which is often associated with a broncholith or other foreign body. Both actinomycosis and nocardiosis are often confused with TB, cryptococcosis, anaerobic pulmonary infection, bronchogenic carcinoma, and lymphoma.1

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Diagnosis

A diagnosis of actinomycosis is rarely suspected; in one series, it was suspected on hospital admission in <7% of the patients in whom it was ultimately diagnosed.1 Because actinomycosis often mimics malignancy, diagnosis may not be made until surgical resection. Because these organisms are normal oropharyngeal flora, isolation in specimens of sputum or bronchial washings is not considered significant, unless sulfa granules are found. Actinomyces are fastidious bacteria that are difficult to culture, and thus correlation with the clinical and radiographic presentation is essential. Bronchoscopy is usually not diagnostic unless endobronchial disease is present, and samples must be obtained anaerobically with a protected specimen brush and delivered to the laboratory under anaerobic conditions. Histologic examination of lung tissue by either transbronchial lung biopsy or open lung biopsy may be necessary to confirm the diagnosis. There is no reliable serologic test.1

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Treatment

Untreated, actinomycosis is ultimately fatal, but early treatment can result in cure rates of >90%.1 Prolonged treatment with high doses of antimicrobial agents is necessary. Penicillin is the drug of choice. Regimens include IV administration of 18 to 24 million units of penicillin for 2 to 6 weeks, followed by oral penicillin for an additional 6 to 12 months. Tetracyclines, erythromycin, clindamycin, imipenem, and chloramphenicol are acceptable alternatives. The organisms are generally not sensitive to the fluoroquinolones, metronidazole, or the aminogycosides.1 Whether patients should be treated for the co-pathogens usually associated with Actinomyces is not resolved, but most experts do not recommend additional antibiotics. Patients with actinomycosis have a tendency to relapse, and prolonged therapy optimizes the likelihood of a cure. However, small trials have shown success with relatively brief courses of therapy (6 weeks).1 Some cases may require both medical and surgical therapies. Patients with bulky disease should probably not receive short courses of therapy unless surgical debulking is also performed. A comparison of the main features of actinomycosis and nocardiosis is shown in Table 1.

Table Graphic Jump LocationTable 1 Distinguishing Features of Nocardiosis and Actinomycosis
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Bronchiectasis

Bronchiectasis is a syndrome, with many underlying etiologies and associations, that has been defined as an irreversible dilation and destruction of one or more bronchi, and inadequate clearance and pooling of mucus in the airways.6 Bronchiectasis results from the occurrence of one of three main pathologic mechanisms: bronchial wall injury, bronchial lumen obstruction, and traction from adjacent fibrosis. Three important pathogenic components, infection, inflammation, and enzymatic/lytic enzyme release, cause a chronic, self-perpetuating destruction to the airways.6 This leads to the unique progressive airway dilation that is associated with the inflammation in bronchiectasis, as opposed to the small airway narrowing seen in asthma and COPD.6,7 Bronchiectasis is also characterized by persistent microbial infection and inflammatory response with release of microbial toxins and immune mediators. It is estimated that the prevalence in the United States ranges from 4 per 100,000 persons aged 18 to 34 to 271 per 100,000 among those over age 75. Prevalence in underdeveloped countries is likely higher.6 Bronchiectasis is often divided into a form associated with cystic fibrosis (CF) and a non-CF form. Non-CF bronchiectasis will be reviewed first.

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Classification

A classification system has been devised that classifies bronchiectasis according to anatomic and morphologic patterns or airway dilatation as follows: (1) cylindrical bronchiectasis, in which there is uniform dilatation of the bronchi, which are thick walled and extend to the lung periphery without normal tapering (on a high-resolution CT [HRCT] scan, it has parallel “tram track” lines or “signet ring” appearance); (2) varicose bronchiectasis, which has an irregular and beaded outline of bronchi with alternating areas of constriction and dilatation similar in appearance to saphenous varicosities; (3) cystic bronchiectasis, which is the most severe form and is common in patients with CF, characterized by bronchial dilatation and clusters of round air-filled and fluid-filled cysts, with a honeycomb appearance in patients with CF; and (4) follicular bronchiectasis, which has extensive lymphoid nodules and follicles within thickened bronchial walls. Cystic, cylindrical, and varicose forms may coexist in the same patient. The fourth pattern, follicular bronchiectasis, usually occurs following childhood pneumonia, measles, pertussis, or adenovirus infection.

Although insightful, these definitions are not particularly helpful from a clinical or therapeutic standpoint. Four clinical stereotypes have been defined and are more useful. These are (1) rapidly progressive (early-onset and rapidly progressive diffuse disease with frequent exacerbations and copious sputum); (2) slowly progressive (slow, insidious progression, with an increase in sputum production and exacerbations over decades); (3) indolent disease (patients can be asymptomatic and do not show deterioration); and (4) predominant hemoptysis (recurrent hemoptysis in the setting of very little sputum).7

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Etiology

The most common causes of non-CF bronchiectasis810 are listed in Table 2. In general the causes can be divided into idiopathic, postinfectious, or due to an underlying anatomic or systemic disease.11 The condition is most commonly idiopathic in adults.6,8 The prevalence of undiagnosed CF is not known, but studies have suggested it is very low. Patients with focal bronchiectasis, which is localized to a segment or lobe, should undergo bronchoscopy to evaluate for and eliminate an obstructing bronchial lesion. Other indications for bronchoscopy are to obtain a biopsy specimen to determine ciliary disorders and obtain specimens for the diagnosis of mycobacterial disease.12

Table Graphic Jump LocationTable 2 Common Causes of Bronchiectasis

The factor most commonly associated with bronchiectasis in childhood is infection,6 although it is being seen more commonly in adults now, especially with the increased use of HRCT scanning. Radiographic findings obtained with an HRCT scan of the chest have been described in patients with Mycobacterium avium-intracellulare complex (MAC). The most notable finding in bronchiectasis is the presence of small nodular opacities or the “tree-in-bud” appearance. Abnormalities most often occur in the lower lung fields. Treatment with multiple antimicrobial agents may lead to the resolution of these abnormalities, but prolonged therapy for up to 18 months may be necessary.6

There are an increasing number of immune deficiencies that have been associated with bronchiectasis. Ciliary disorders are considered to be primary disorders of immune defense, as airway clearance mechanisms contribute an important component of barrier immunity. Acquired adult-onset hypogammaglobulinemia may involve one or more of the immunoglobulin classes. IgG subclass deficiencies may be present even with normal total IgG levels. Patients with HIV infection have been found to have a high incidence of bronchiectasis, which may in part be due to recurrent bronchopulmonary infections (especially Pneumocystis-proved pneumonia and Mycobacterium intracellulare infection). The bronchiectasis observed in HIV-infected patients is particularly aggressive. Allergic bronchopulmonary aspergillosis (ABPA) predisposes patients to bronchiectasis as a consequence of a persistent complex immune response to airway colonization by Aspergillus. This type of bronchiectasis most commonly involves the central airways, distinguishing it from other types of bronchiectasis.6

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Diagnosis

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Clinical Manifestations

Clinical findings from a retrospective chart review of patients with confirmed bronchiectasis included cough (90%), chronic daily sputum production (76%), dyspnea (72%), hemoptysis (56%), and pleuritic chest pain (46%). Two symptoms that are also very common are rhinosinusitis and fatigue. The most common physical findings were crackles (70%) and wheezing or rhonchi (<50%). Daily cough and sputum production have been reported in HIV-positive patients with bronchiectasis confirmed by CT scan in <39% of cases. The disease is more common in women and most commonly presents in the sixth decade of life.6

Pulmonary function study results may be normal if the involvement of bronchiectasis is localized and mild. With diffuse disease, pulmonary function tests may reveal an obstructive ventilatory defect with hyperinflation and impaired diffusing capacity of the lung for carbon monoxide. Airway hyperresponsiveness has been seen in up to 40% of patients with bronchiectasis in some series. On the other hand, some patients with diffuse disease may present with a combined obstructive and restrictive ventilatory defect. Pulmonary function tests are not useful in distinguishing bronchiectasis from other obstructive airway diseases.6 Laboratory studies in patients with bronchiectasis include a mild degree of leukocytosis, usually without a left shift; an increase in the erythrocyte sedimentation rate; mild anemia; and hypergammaglobulinemia.

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Radiographic Findings/Imaging

Routine chest radiographs can be used but are insensitive to exclude the diagnosis, detecting abnormalities in only 50% of patients. Findings are abnormal in approximately 50% of patients with proven bronchiectasis. The classic finding of tram tracks, representing thickened dilated bronchial walls, is best seen on radiographs obtained from a lateral view. Other findings include hyperinflation and air trapping, increased linear markings, rounded opacities that represent areas of focal pneumonia, and ring shadows that represent dilated airways seen en face. Although bronchography was the historical gold standard for confirming the diagnosis, HRCT scanning has become the current diagnostic standard for the detection of bronchiectasis. It is both highly sensitive and specific for the diagnosis of bronchiectasis.

Today, HRCT scanning is the method used in nearly all cases of bronchiectasis. Given the high sensitivity of HRCT scanning, it has become much easier to diagnose the disorder, which may account for the increased awareness and prevalence of the disease. Standard criteria for the diagnosis of bronchiectasis on HRCT scans have been established. The most specific criteria are an internal bronchus diameter that is wider than its adjacent artery (signet ring formation), the failure of the bronchi to taper as they move toward the periphery of the lung parenchyma, and bronchi visualized in the outer 1 to 2 cm of the lung fields.13 Secondary criteria include excessive bronchial wall thickening, impacted mucus, and crowding of the bronchi. Figure 1 shows the characteristic large bronchi in a patient with Kartagener syndrome. MRI has similar sensitivity and specificity and can be used in cases where radiation must be avoided.

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Figure Jump LinkFigure 1 Large internal diameter of the bronchi (greater than the accompanying vessel), which is diagnostic of bronchiectasis (large arrows). From the author's personal files.Grahic Jump Location

The pattern of distribution of the bronchiectatic changes on HRCT can help narrow the differential diagnosis.14 Focal changes suggest mechanical obstruction, congenital bronchial atresia, or a necrotizing pneumonia. Diffuse changes that have a central predominance suggest ABPA or cartilage deficiency syndromes. More peripheral changes seen predominantly in the upper lung regions suggest CF, sarcoidosis, or postradiation fibrosis. Peripheral middle lobe changes are seen with atypical mycobacterial infections and immotile cilia syndrome. Peripheral changes in the lower lung fields should prompt consideration of aspiration, fibrotic lung disease (traction bronchiectasis), HIV, hypogammaglobulinemia, transplant rejection, and prior infection. Most cases of diffuse lower lobe bronchiectasis will be idiopathic.

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Differential Diagnosis/Additional Testing

Additional testing includes a workup to detect the underlying cause and microbiologic examination of the sputum. Additional tests include sweat chloride testing, ciliary structure and function examination, immunoglobulin levels, HIV, α1-antitrypsin, rheumatoid factor and ANA levels, barium swallow, and Aspergillus antigen.12 The choice of additional testing should be prompted by the history, associated symptoms, and radiographic patterns.9,10 Studies have shown that a specific cause can be identified in many cases, and this has led to a modification in the treatment in up to 50% of patients.13 In some cases, such as ABPA or immunodeficiencies, specific therapy may prevent disease progression.15 Bronchiectasis should be distinguished from COPD (particularly chronic bronchitis).6 Both diseases present with cough, sputum production, wheezing, and dyspnea. Exacerbations are common in both disorders, although the volume of sputum production is greater in patients with bronchiectasis. Recurrent fever and hemoptysis are less likely to be found in patients with chronic bronchitis. The presence of Pseudomonas in the sputum may be helpful to the diagnosis. The incidence of Pseudomonas aeruginosa is approximately 31% in patients with bronchiectasis, but only 2% to 4% in patients with COPD.

Bronchiectasis can also be confused with interstitial fibrosis, especially in patients with end-state fibrosis who have a honeycomb appearance seen on a chest radiograph. This parenchymal honeycomb appearance may mimic the air-filled cysts of bronchiectasis.

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Therapy

The objectives of management for bronchiectasis are the relief of symptoms, the prevention of complications, the control of exacerbations, and a reduction in mortality. Unfortunately, only a small number of well-designed trials in small numbers of patients have been performed in patients with non-CF bronchiectasis. Many of the current recommendations are extrapolated from those done in patients with CF.13

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General Supportive Measures

Vaccination against influenza and pneumococcal pneumonia are also recommended, although they have not been proven to change important outcomes in these patients.13

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Airway Clearance Techniques

Postural drainage and chest physiotherapy are useful to enhance the gravity-aided clearance of secretions. Alternative treatment includes the use of a flutter device, a positive expiratory pressure mask, chest oscillation, and humidification of inspired air.6,8

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Exercise Training

The role of pulmonary rehabilitation and inspiratory muscle training has been investigated in only one well-designed trial, but it has been suggested that rehabilitation increases exercise tolerance in patients with bronchiectasis.8

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Bronchodilators

Most patients with bronchiectasis have significant airway hyperresponsiveness, presumably as a result of transmural airway inflammation. The routine use of bronchodilators has the added potential advantage of the stimulation of mucociliary clearance, which is associated with the use of p-adrenergic agents. Both aerosolized p-agonist therapy and aerosolized anticholinergic therapy should be tried when there is evidence of reversible airway obstruction.6,8

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Antibiotics

Antibiotics are the cornerstone for the treatment of exacerbations of bronchiectasis. They are used to treat acute exacerbations, to prevent exacerbations, or to reduce the bacterial burden.10 Early in the disease process, patients are typically colonized with Haemophilus influenzae. As the disease progresses, Psuedomonas spp predominate. Other pathogens include Moraxella catarrhalis, Aspergillus, and MAC.7Staphylococcus aureus is uncommon, and if repeatedly isolated, should prompt the consideration of undiagnosed CF.11 Early, when the bacterial flora include Streptococcus pneumoniae and H influenzae, treatment with TMP-SMX, ampicillin-clavulanate acid, or one of the newer macrolide agents is effective. In patients who have been colonized with Pseudomonas, oral therapy requires the use of a fluoroquinolone.10 In some cases, IV administration of antipseudomonal antibiotics is required.6 Whether prophylactic antibiotic therapy is necessary remains an unresolved question. Strategies that have been tried include a high oral or IV dose for a prolonged period (4 weeks), pulsed courses of antibiotics with on/off periods, and regular aerosolized therapy.6,11,16 Strategies for prophylaxis with low-dose antibiotics range from daily to 1 week of each month. Daily inhaled antibiotic prophylaxis is now recommended in patients with CF who have been colonized with P aeruginosa. In non-CF bronchiectasis, this approach is reserved for patients with severe disease, manifested by copious purulent sputum and frequent exacerbations, who fail to respond to other approaches. Both inhaled tobramycin and gentamicin have been shown to decrease bacterial density, but the benefits seem to be less than those seen in patients with CF. In addition, adverse events such as bronchospasm are more common.17

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Antiinflammatory Agents

Although intense airway inflammation characterizes bronchiectasis, few studies have looked at the efficacy of corticosteroids in the treatment of this disorder. Inhaled steroids have been suggested as alternative therapy and may be useful in some patients, especially those with significant airway hyperreactivity. It has been shown that inhaled corticosteroids can reduce the levels of inflammatory mediators and improve dyspnea and cough. However, a systematic review found no significant improvement in pulmonary function.8,13 Short courses of oral corticosteroid therapy are often used during acute exacerbations. Nonsteroidal antiinflammatory agents, such as indomethacin (not available in the United States), have been used in Europe, either orally or by inhalation.8 Leukotriene receptor antagonists may be of benefit in patients with bronchiectasis because they can inhibit neutrophil-mediated inflammation. However, there have been no randomized controlled trials published concerning patients in this population.8 Macrolides suppress inflammation, independent of their antimicrobial action, and have improved the clinical status and lung function of patients in a few small studies of bronchiectasis.16,17 Long-term use needs to be balanced against potential side effects, including gastrointestinal, cardiac, and auditory. The possibility of MAC infection must also be excluded as macrolide monotherapy increases the likelihood of resistance.17 Further study is needed before they can be recommended routinely.

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Mucolytic Agents and Hydration

Adequate oral hydration and the use of nebulized solutions may improve airway mucus clearance.6 Acetylcysteine is beneficial in some patients. To date, there have been no randomized, controlled clinical trials showing mucolytics to be of benefit in the treatment of non-CF bronchiectasis. Recombinant human DNase breaks down DNA that is released from degenerating bacteria and neutrophils. DNA has a tendency to form thick, viscous gels. DNase improves the clearance of secretions and pulmonary function and reduces the number of hospitalizations in patients with CF, but has not been found to be useful in non-CF bronchiectasis. One study has suggested that DNase was ineffective and potentially harmful in >300 adult outpatients with idiopathic bronchiectasis who were in stable condition.18 Therapy with inhaled mannitol may improve impaired mucociliary clearance by inducing an influx of fluid into the airways and has shown clinical promise in patients with non-CF bronchiectasis.8,17 This is particularly exciting because it is easier to inhale a dry powder than to use a nebulizer. One small study has also shown benefit with nebulized hypertonic saline.17

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Surgery

In patients with localized bronchiectasis, surgical removal of the most affected segment or lobe may be considered. The major indications for surgery include the partial obstruction of a segment or lobe due to a tumor or the presence of a highly resistant organism in the affected area, such as MAC or Aspergillus. Patients require significant pulmonary function to withstand surgery. Surgery may also be performed for massive hemoptysis in patients with adequate pulmonary reserve, although the increased success of bronchial artery embolization for hemoptysis makes surgery less desirable.6,10,11

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Lung Transplantation

Patients with bronchiectasis and CF were initially considered not to be good transplant candidates because of concerns about overwhelming infection after the use of prolonged immunosuppression. However, double-lung transplantation has been successful in patients with CF, and the St. Louis International Transplant Registry lists >1,000 patients with CF and >200 non-CF bronchiectasis patients who have undergone lung transplantation, with a 1-year survival rate of 72% and a 4-year survival rate of 49% in patients with CF.9,11

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Cystic Fibrosis

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Genetics

CF is the most common genetic disease in the United States, with an incidence of 1 in 3,000 births in a white population. The incidence is much lower in African Americans, Asians, Hispanics, and Native Americans. CF is an autosomal-recessive disorder with variable penetrance. Carriers of the CF gene are phenotypically normal. About 5% of persons in the white US population are carriers of the CF gene, and approximately 20,000 individuals are affected by this disorder.19,20

The CF gene, which was sequenced in 1989, is located in the long arm of chromosome 7 and encodes for the CF transmembrane regulator (CFTR) protein.19 The CFTR is located at the cell surface and acts as an ion channel that regulates liquid volume on epithelial surfaces through chloride secretion and the inhibition of sodium absorption. The CFTR protein may also regulate the function of other epithelial cell proteins. The defective transport of ions across the epithelial membrane leads to thick viscous secretions in many organs and to excessive chloride concentration in the sweat of patients with CF. This abnormality is the basis for the laboratory test that is most frequently performed to diagnose this disorder. The CFTR protein is expressed in all of the epithelial cells affected in patients with CF, including those in the lung, pancreas, sweat glands, and liver. It is also found in the large intestine and testes.19

More than 1,600 mutations of the CFTR gene have been described. The ΔF508 mutation is the most common and accounts for about 90% of CF chromosomes in patients of northern European descent, but only 60% of CF chromosomes worldwide. The mutation is due to the deletion of a single phenylalanine residue at position 508. The Δ508 mutation is a Class II mutation that results in improper folding and thus degradation of the protein (see below). CFTR mutations are categorized into six classes19:

  • Class I: absent or defective protein synthesis

  • Class II: abnormal processing or transport of the protein to the cell membrane

  • Class III: abnormal regulation of CFTR function, inhibiting chloride channel activation

  • Class IV: normal amount of CFTR but reduced function (abnormal conductance)

  • Class V: reduced synthesis of fully active CFTR

  • Class VI: decreased stability of fully processed and functional CFTR

These multiple mutations lead to varying phenotypic presentations of the disease. Even patients with similar genetic mutations may manifest different clinical manifestations of the disease. The degree of organ involvement and perhaps the disease severity correlate with the individual's sensitivity to the CFTR dysfunction, as well as the amount of functional CFTR, which is influenced by the specific type of mutation. It is now recognized that some patients may present with only one characteristic feature of CF and a borderline abnormal sweat test finding in the presence of either a known CFTR mutation or an abnormal nasal potential difference (PD), which has led to use of the term atypical or nonclassic CF. Nonclassic CF is often associated with Class IV or V mutations. These patients typically present later in life, and will display typical CF symptoms in at least one organ, but often have a normal or borderline sweat chloride test. They are typically pancreatic sufficient and have milder pulmonary disease and a better overall prognosis.21,22 Additionally, patients with only one mutation and mild symptoms with indeterminate testing may have another CFTR-related disease, such as chronic sinusitis, ABPA, or asthma. It is now thought that other modifier genes and environmental exposures determine the phenotypic expression of the underlying genotypic mutation.22

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Pathogenesis

CF is initiated by a defect in the gene that is normally responsible for encoding CFTR protein, which is necessary for the flow of electrolytes and fluid across cell membranes. The resultant abnormalities in salt and water transport lead to an alteration in the composition of secretions in the respiratory tract, pancreas, GI tract, sweat glands, and other exocrine tissues.23 In the lung, these alterations change the properties of the mucus layer lining the epithelia and the composition of the airway surface fluid, ultimately resulting in the clinical features of CF. The net fluid loss on the airway surface leads to the collapse of cilia and impaired mucociliary clearance, persistent bacterial infection, excessive host inflammatory response (characterized by the accumulation of leukocyte-derived DNA and secretions rich in elastase), and airway obstruction, leading to progressive lung destruction/bronchiectasis. Although bacterial infection clearly leads to an intense inflammatory response, there is mounting evidence that patients with CF have increased basal and inducible airway inflammation independent of infection.19,20,24,25Figure 2 is a nice summary of the interaction between airway obstruction, infection, inflammation, and destruction.

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Figure Jump LinkFigure 2 Products of polymorphonuclear cells and their effects on inflammation of the airways in patients with CF. Adapted from Ramsey.27Grahic Jump Location
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Diagnostic Tests

Prior to the mid-1990s, most patients were diagnosed with CF after presenting with typical symptoms. Since that time, newborn screening (NBS) has become much more widespread. Newborns with CF will have elevated levels of serum immunoreactive trypsinogen (IRT), which can be detected via a radioimmunoassay or enzyme-linked immunosorbent assay performed on samples of dried blood. After an abnormal IRT, most NBS programs perform DNA testing to identify the known CFTR mutations, although some repeat the IRT after 2 weeks. NBS is not a diagnostic test, and thus only identifies newborns at risk for CF. An elevated IRT must be followed by direct diagnostic testing (typically with the sweat chloride test).26

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Sweat Test (Pilocarpine Iontophoresis)

The sweat chloride test remains the gold standard diagnostic test, because genetic screening only identifies a small number of the most common mutations. The results of this test are abnormal in the large majority of patients with CF. A level of >60 mEq/dL is usually diagnostic for CF. However, the test must be repeated at least twice, and an adequate sample containing at least 75 mg of sweat must be collected over a 30-min period. The cutoff values are different in infants and older patients. In infants, a level ≤29 mmol/L makes CF unlikely; levels between 30 and 59 mmol/L are indeterminate, and levels ≥60 mmol/L are indicative of CF. In patients over 6 months of age, who will have higher concentrations of chloride, levels ≤39 mmol/L indicate that CF is unlikely, levels between 40 and 59 mmol/L are indeterminate, and levels ≥60 mmol/L remain indicative of CF.26 About 1% of patients with CF have normal sweat chloride test results. Abnormal sweat test results are seen in patients with other disorders (as listed in Table 3). Therefore, a diagnosis should only be made if the clinical history is suggestive of CF.

Table Graphic Jump LocationTable 3 False-Positive or False-Negative Sweat Test Results
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Molecular Diagnosis

Approximately 1,600 mutations have been identified after sequencing the entire gene in a research laboratory. Genotyping at commercial laboratories usually can identify only 20 to 30 of the most common mutations. This accounts for approximately 90% of CF mutations in the general population. DNA analysis can be particularly helpful in cases where the sweat chloride testing is indeterminate. Two separate mutations on two separate chromosomes are generally associated with disease. A single mutation on one chromosome or two mutations on a single chromosome may be associated with atypical disease or with other CFTR-related diseases, or may not manifest with symptoms at all.26 It is important to note that the phenotypes associated with CFTR gene mutations have expanded, and genotype analysis cannot predict prognosis in individual patients.26

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PD Across the Respiratory Epithelium

This is a research tool that may be available at few centers to aid in the diagnosis of CF. The abnormal transport of chloride leads to a very negative PD across the nasal epithelium. The measurement of this PD can establish a CF diagnosis. Nasal perfusion with amiloride hydrochloride and with chloride-free solutions leads to characteristic changes in the PD.

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Ancillary Tests

In cases where the diagnosis may be elusive, ancillary testing may be helpful. This might include genital evaluation in males, pancreatic function testing or imaging, HRCT of the chest to evaluate for bronchiectasis, and lower airway sampling for classic pathogenic organisms.26

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Clinical Diagnosis of CF

In infants with a positive NBS, with either a repeat positive NBS or DNA testing that reveals known mutations, the diagnosis of CF can be confirmed with sweat chloride testing. In infants with an indeterminate sweat chloride test, the diagnosis of CF can be made if two CF-causing mutations are identified. Infants with indeterminate sweat chloride testing and no or one CF-causing mutation cannot be diagnosed definitively. These infants are at risk for developing CF or a CFTR-related disease and should be followed closely.

In patients presenting with symptoms of CF or a family history of CF, the following is used to make a diagnosis: CF can be diagnosed if the sweat chloride value is greater than 60 mmol/L (on two occasions, or once with two mutations identified by DNA analysis) and excluded if the value is ≤39 mmol/L. Patients with an indeterminate level should undergo DNA analysis (if not already done). As with infants, the presence of two known mutations is diagnostic of CF. If only one or no mutation is identified, these patients are at risk for CF or may have another CFTR-related disease. In this situation, ancillary testing may help confirm or exclude the diagnosis. If a diagnosis cannot be made at the time of presentation, these patients should also be monitored periodically for the development of symptoms.26

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Nonpulmonary Clinical Manifestations

In the pancreas, dysfunction of the exocrine portion leads to fat malabsorption and malnutrition. Glucose intolerance is present in as many as 50% to 70% of older patients with CF; diabetes mellitus occurs in about 15%. Malabsorption of fat-soluble vitamins such as A, D, E, and K can lead to vitamin deficiency and coagulopathy. The liver is affected by biliary cirrhosis as a result of thick secretions in the biliary ducts. This is manifested by abnormal liver function test results. Diffuse liver involvement can lead to portal hypertension. Meconium ileus is present in about 20% of infants with CF and is pathognomonic for this disorder. A similar syndrome occurs in older patients with CF because of inspissated mucus in the GI tract. This results in the distal intestinal obstruction syndrome, often requiring surgical treatment.

About 95% of male patients with CF are infertile. Although sperm maturation is normal, the Wolffian structures are often not developed. The vas deferens is often completely absent. This may indicate a role for the CFTR protein in the development of the male genital tract. In fact, in subjects with congenital bilateral absence of the vas deferens but without any other abnormalities of CF, mutations in the CFTR gene have been reported.19 Women with CF are not infertile, although they may have difficulty conceiving because of thick cervical mucus and/or anovulatory cycles if their nutritional status is poor. Pregnancies can be successful, and pulmonary function has not been found to deteriorate after pregnancy.

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Pulmonary Manifestations

The primary cause of morbidity and mortality in patients with CF is bronchiectasis and obstructive lung disease. Pulmonary disease is present in 98% of patients with CF by the time they reach adulthood. Despite the great advances in the management of this disorder, the majority of the patients succumb to respiratory complications. A recurrent cough that becomes persistent is often the first manifestation. Airway hyperreactivity and wheezing are common in children. Bronchodilator responsiveness tends to decrease with age, perhaps as a result of the destruction of the cartilage. Pansinusitis with opacification of the paranasal sinuses is a universal finding in patients with CF. Nasal polyps are present in up to 30% of patients with CF.19,23

In patients with CF, the lungs are normal at birth, but infection occurs early in life and is persistent. The abnormal ionic environment and chronic airway obstruction by thick secretions promote colonization with pathogenic bacteria, which leads to the accumulation of inflammatory cells. These cells release inflammatory mediators that cause inflammation and damage to the airway wall, leading to the development of bronchiolitis and subsequently bronchiectasis (Figure 2).

H influenzae, S aureus, and, later, P aeruginosa are the pathogens that are most commonly found in the airways of patients with CF. The abnormal CFTR may be partly responsible for colonization with Pseudomonas, as the normal CFTR appears to be involved in the clearance of this organism from the airways. The high sodium content in CF secretions may contribute to chronic infection, as low sodium content is required for the effective killing of bacteria in airway epithelia. Colonization with P aeruginosa is not benign, as it has been found to be an independent risk factor for the accelerated loss of lung function and decreased survival. Colonization with Burkholderia cepacia denotes an even worse prognosis. Many Burkholderia spp have innate antibiotic resistance, are transmissible from person to person, and are highly virulent. Occasionally infection with the complex can cause an invasive, fatal bacteremia—the “cepacia syndrome.”23

The mucoid appearance of Pseudomonas is due to the production of alginate. This bacterium is difficult to eradicate because of the poor penetration of antibiotics into purulent airway secretions and to the interference in phagocytic killing by alginate. Bacteria may have native or acquired antibiotic resistance. In addition, pharmacokinetics differ in patients with CF, as the volume of distribution of hydrophilic drugs (eg, penicillins, cephalosporins, and aminoglycosides) is increased because of decreased amounts of adipose tissue. The renal clearance of aminoglycosides is increased, and therefore the dosage has to be adjusted, usually at triple the normal dose.19,23

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Management of Pulmonary Disease

Although the focus of this section is on the treatment of pulmonary disease in patients with CF, it should be kept in mind that management in general will be suboptimal unless all aspects of the disease are addressed (ie, exocrine pancreatic supplementation, nutritional support, glucose control, psychosocial issues, and treatment compliance). Progress has been made in attempts at addressing the underlying defect of CF with gene therapy, but current clinical treatment is aimed at treating the effects of the CFTR dysfunction—thickened airway mucus, infection, and inflammation.

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Clearance of Airway Secretions

The chief nonpharmacologic means of enhancing airway secretion clearance has been chest physiotherapy (either manual or with use of an oscillatory vest) and postural drainage. Other techniques include forced expiratory techniques, positive expiratory pressure, and flutter valves. A Cochrane review in early 200927 noted that there is no high-level evidence that any of these techniques are superior to the others. All patients who produce daily sputum should be instructed in clearance techniques. All of the techniques require a great deal of time, and treatment compliance can be an issue. Therefore, several methods can be introduced to each patient.28

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Bronchodilator Therapy

As noted earlier, many patients with CF will demonstrate a degree of bronchial hyperactivity and reversibility. The obstructive airway disease is typically only partially reversible, as the underlying causes include the chronic infection, inflammation, and resulting structural damage. Bronchodilator therapy should be considered in patients who have at least a 10% increase in FEV1 in response to an inhaled bronchodilator. In addition, bronchodilators are often used in all patients with CF prior to chest physiotherapy and immediately prior to the inhalation of hypertonic saline solution, antibiotics, or dornase alfa (as these medications have the potential to induce nonspecific bronchial constriction). The role of these medications in improving mucociliary clearance has not been well defined. Current guidelines recommend the use of β-adrenergic receptor antagonists over anticholinergic agents.28,29

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Reduction in the Viscosity of Secretions

The increased viscosity of the sputum in patients with CF is due in part to the presence of many polymorphonuclear neutrophils and their degradation products, including DNA from dying cells. Recombinant DNase (recombinant human DNase or dornase alfa) digests extracellular DNA and can help to reduce the viscosity. A meta-analysis of randomized trials of dornase alfa has concluded that treatment improves lung function and is well tolerated. There is some controversy about when to initiate dornase alfa, but most clinicians will consider a trial in patients with documented chronic infection and obstruction on spirometry. A guideline committee for the CF Foundation recommends chronic dornase alfa for all children with CF over the age of 6 years. The recommended dosage is 2.5 mg daily.28,29

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Osmotic Therapy

A decreased amount of airway surface liquid is an important factor in the under lying pathophysiology of CF. Therefore, osmotically drawing water onto the airway surface via inhalation of a hypertonic substance might help to clear secretions and restore mucociliary transport. Inhaled hypertonic saline solution has been used for this purpose in patients with CF, and has been associated with increased mucus clearance and improvement in lung function, and, in one long-term study, with fewer exacerbations requiring antibiotic therapy. Prescribing patterns vary, but twice-daily treatments (4 mL of 7% saline solution) in patients with chronic cough and sputum production should be considered. There have been no randomized controlled trials comparing dornase alfa with hypertonic saline solution. As the mechanism of action differs somewhat between the two, it is reasonable to assume that they may be complementary.29

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Antibiotic Therapy

Patients with CF have frequent exacerbations of infection. Acute exacerbations are manifested by increased cough and sputum volumes, sometimes associated with hemoptysis, and are often accompanied by systemic symptoms such as decreased energy, anorexia, and weight loss. Spirometry demonstrates a decrease in lung function. In order to standardize the definition of acute exacerbations, a mnemonic has been proposed: CF of the PANCREAS (Cough, Fever, pulmonary function studies, Appetite, Nutrition, Complete blood count, Radiograph, Examination, Activity, and Sputum).23 Chronic therapies should be continued.30 Parenteral antibiotics are generally administered for 14 to 21 days to reduce the burden of bacteria, to decrease symptoms, and to improve lung function. The most recent respiratory tract cultures should be used to guide therapy. Cephalothin and nafcillin are used for the treatment of infection with S aureus, and vancomycin is used for patients with a penicillin allergy. For patients colonized with Pseudomonas, an antipseudomonal penicillin is combined with an aminoglycoside. Combination therapy reduces the risk of the development of resistance. Intensified bronchodilator therapy and chest physiotherapy are indicated during the treatment of exacerbations. Short-term corticosteroids may be added in patients with hyperreactive airways, but are not recommended for routine use in acute exacerbations.28,30

Chronic infection with Pseudomonas is associated with a more rapid decline in pulmonary function and increased mortality; delaying the onset of chronic infection is critical. When the organism is first isolated, a prolonged course of antibiotics that eradicates the organism has been shown to delay the onset of chronic infection. Repeated attempts to eradicate the organism may also be successful and beneficial. A combination therapy consisting of an oral quinolone and an inhaled aminoglycoside is typically used. Some patients with CF are given long-term antibiotic therapy in the hopes of suppressing bacterial growth and recurrent infections, although this practice is controversial. The most common current practice involves the use of nebulized antipseudomonal antibiotics in patients with documented chronic infection. The inhaled route is attractive as it allows the delivery of higher concentrations to the airways with low systemic absorption, thus reducing the risk of ototoxicity and nephrotoxicity. A 2009 Cochrane review confirmed that long-term use is associated with improved lung function and a decreased number of hospitalizations.31 Inhaled tobramycin and inhaled aztreonam are currently approved for use in the United States. Ongoing research in inhaled therapy is focusing on other classes of antimicrobial agents, more rapid and efficient delivery methods, and liposomal formulations that may allow more effective penetration of the mucoid biofilm.32

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Antiinflammatory Agents

There is a neutrophil-predominant inflammation in the airways of patients with CF. These neutrophils perpetuate the inflammatory cycle through the release of cytokines, chemotactants, and proteolytic enzymes (Figure 2). As noted earlier, patients with CF have abnormal basal and inducible airway inflammation. This inflammation is not entirely independent from infectious stimulation, as neutrophils and inflammatory mediators increase significantly during infectious exacerbations. When considering potential antiinflammatory strategies, several key concepts must be kept in mind: the inflammatory process is primarily endobronchial; it is characterized by persistent neutrophil influx; intracellular signaling pathways are a key component; and the inflammatory response is prolonged and involves heightened oxidative and proteolytic stress.

Several early studies evaluated the effects of systemic glucocorticoids in patients with CF. Although a beneficial effect on lung function was seen in some patients, the adverse effects (glucose intolerance, growth retardation, cataracts) limit widespread use. Therefore, therapy with systemic glucocorticoids is recommended only for patients with asthma or ABPA complicating their disease. There is a lack of good clinical trials of inhaled corticosteroids in patients with CF, and these also are only recommended in patients with asthma or ABPA.29,33,34

Ibuprofen has also been studied because of its ability to inhibit the migration and activation of neutrophils. In high doses, ibuprofen appears to slow the progressive decline in lung function, particularly in younger patients with more mild disease. The 2007 Cochrane review, which is based on four trials enrolling a total of 287 patients, confirms this finding.19,35 The beneficial effects are dependent on achieving adequate serum levels, and thus the drug must be individually dosed based upon measured pharmacokinetics (desired peak plasma concentrations between 50 and 100 μg/mL). This therapy has not been used widely (only 6% based upon current CF patient registry data) because of concerns about the logistics of dosing and fear of gastrointestinal and renal toxicity. However, several clinical trials have suggested that renal impairment does not occur at an increased rate, and most gastrointestinal complaints are related to the underlying disease. There is a statistically significant increase in GI bleeding, but the event rates remain very low. The CF Foundation currently recommends high-dose ibuprofen therapy for children 6 to 12 years of age with moderate to severe lung disease.29,34,36

Macrolide therapy was found to be beneficial in patients with panbronchiolitis, which led to empiric use by some physicians in patients with CF. Several well-conducted clinical trials have now shown that the long-term use of azithromycin (which appears to act primarily as an antiinflammatory agent by inhibiting neutrophil migration and elastase production and reducing the production of proinflammatory cytokines) is associated with improved lung function and a reduction in the number of exacerbations. The CF Foundation currently recommends azithromycin (500 mg orally 3 d/wk) for patients chronically infected with Pseudomonas. Prior to the initiation of therapy, some experts have recommended that sputum be examined for nontuberculous mycobacteria (as macrolide antibiotics are a vital in the treatment of nontuberculous mycobacteria).29,34

Other antiinflammatory agents are being investigated in patients with CF. Increased oxidative stress and reduced levels of glutathione in the lungs of patients with CF have led to trials of the antioxidant N-acetylcysteine, aerosolized glutathione, and oral supplementation with antioxidant vitamins. Evidence suggests that these agents might attenuate lung inflammation, but further study is needed. Pharmacologic therapies that target proinflammatory and regulatory cytokines have been developed for other diseases (rheumatoid arthritis, psoriasis, inflammatory bowel disease). No published data on their use in CF is available. In addition, there is some concern that these agents might overly suppress the inflammatory response, leading to secondary infectious complications. Finding ways to interrupt intracellular signaling pathways that lead to increased inflammation may also be an effective strategy, but more understanding of the complex roles these play in other important cellular mechanisms is needed. The increased levels of neutrophils in the lung lead to massive amounts of proteases that overwhelm native antiproteases. Several trials have examined the use of inhaled α1-antitrypsin in patients with CF. Although it appears to be well tolerated, no clear benefit on important outcomes have yet been demonstrated. In addition, this therapy is limited by expense, supply, and the risks of using plasma-derived products. Some of this may be overcome in the future with recombinant α1-antitrypsin.33,34

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New Therapies in Development

Because CFTR mutations lead to defective or absent CFTR protein, the most logical way of treating CF would be to replace the CFTR gene to restore normal production. There are multiple steps to achieving this goal: sufficient gene product must be delivered to the primary target cells and it must be incorporated so as to allow normal gene expression. Although progress has been made, gene therapy is still some years away from clinical practice. Other approaches in development include correction of the abnormal protein folding of the CFTR, improvement in the ion channel function, and induction of alternative ion channels.23,37 A recently completed randomized trial of ivacaftor, a CFTR potentiator, showed statistically and clinically important improvements in lung function, quality of life, and weight gain along with a reduction in pulmonary exacerbations and sweat chloride concentrations over a 48-month period (with no increase in adverse events or side effects). This study is an important milestone in the development of therapies that address the underlying CFTR dysfunction rather than just the downstream effects of infection and inflammation.38

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Pulmonary Complications

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Hemoptysis

Hemoptysis occurs frequently during bronchitic exacerbations and usually is self-limited. Conservative measures such as bed rest, cough suppression, antibiotics, and correction of coagulopathy, if present, are adequate treatment for most patients. Massive hemoptysis is associated with a high mortality rate but may respond favorably to bronchial artery embolization. It is successful in as many as 90% of cases, but recurrences can occur in about 20% of cases. Repeated procedures can be performed if necessary. If this proves unsuccessful, lung resection of the involved lobe may be the only alternative, but it is often difficult to ascertain with certainty which lobe or segment is responsible for the hemorrhage.39

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Pneumothorax

Spontaneous pneumothorax occurs in about 16% of patients with CF. The vast majority of these patients have severe pulmonary involvement antecedent to the pneumothorax, with an FEV1 of <50% predicted. The average recurrence rate is nearly 50%, and, despite treatment, the mortality rate is high at 30% to 60%. This high mortality rate relates more to the severe underlying parenchymal involvement than to the pneumothorax itself. Chemical pleurodesis may be necessary for treating recurrences and does not necessarily preclude future lung transplantation.39

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Nontuberculous Mycobacterial Infections

Recently, there has been a marked increase in the isolation of nontuberculous Mycobacterium spp (primarily MAC and Mycobacterium chelonei) in adult patients with CF. Several centers have reported positive culture findings from up to 18% of patients studied. Distinguishing airway colonization from infection can be difficult. HRCT scanning may be useful in the evaluation. Nodular opacities or a tree-in-bud appearance suggests the presence of infection rather than colonization. Transbronchial lung biopsies may be required to demonstrate the presence of infection. If pulmonary function declines and atypical Mycobacterium spp are found in cultures from at least three sputum samples, treatment with antimycobacterial agents is recommended.19

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ABPA

ABPA develops in a small portion of patients in the United States (1.8% in a 1995 report). ABPA should be suspected if there is evidence of bronchospasm, peripheral eosinophilia, sputum cultures positive for Aspergillus fumigatus, and an immediate skin test response to A fumigatus. Diagnosis is confirmed by total serum IgE levels of >1,000 ng/mL and IgE or IgG specific to A fumigatus.19

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Respiratory Failure and Cor Pulmonale

Respiratory insufficiency develops as lung disease progresses, initially with hypoxemia on exercise, then at rest, and eventually with carbon dioxide retention. Right ventricular failure represents the culmination of the pathologic sequence of lung disease with progressive respiratory failure. In most cases, this process heralds the terminal stage in a patient's course with only limited survival beyond a few months.

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Transplantation

Patients with CF are generally good transplant candidates, as they are young and otherwise healthy, and are used to undergoing complex medical regimens. The transplanted lung does not develop the CF defect. However, transplantation in CF is not without controversy, especially because some prediction models suggest that transplantation rarely improves survival in patients less than 18 years of age with CF. Others have found that only those patients with a predicted 5-year survival of <50% and without B cepacia are likely to have increased survival. These patients require bilateral lung transplantation using a clamshell incision.40

Indications for transplantation include deteriorating respiratory status despite aggressive medical therapy, and an FEV1 of <30% predicted in compliant patients with good nutritional status and no other organ impairments. Patients can also be considered if they have an exacerbation requiring an intensive care unit admission or manifest major life-threatening pulmonary complications (eg, massive hemoptysis), pulmonary hypertension, or increasing antibiotic resistance of bacterial infecting the lungs. Female patients and those under 18 years of age have a worse prognosis and should be considered for earlier listing. In May 2005 the United Network for Organ Sharing began using a lung-allocation score rather than simply time on the waiting list in order to better distribute organs to those who would receive the most benefit. Traditionally pediatric patients were not included in the lung allocation system, so patients less than 12 years of age continue to be transplanted on the basis of time on the waiting list. Patients between 12 and 17 years of age have a lung allocation score, but receive preference for pediatric donors. The system appears to be beneficial as the average wait for patients with CF has decreased from an average of 900 to 300 days and fewer patients are dying while awaiting transplant.40

Contraindications to transplantation include other organ failures, noncompliance with therapy, psychosocial instability, or profound malnutrition. An increased risk for transplantation is associated with colonization with resistant organisms (particularly B cepacia complex), but only colonization with Burkholderia cenocepacia is considered an absolute contraindication to transplantation. Patients who have undergone previous thoracic surgery or pleurodesis, an illness requiring mechanical ventilation, or who have concomitant diabetes mellitus are at increased risk for complications but are considered viable candidates for transplantation at most centers.40

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Prognosis

Most patients still die of respiratory complications. The degree of pulmonary impairment is predictive of survival. In 1992, Kerem et al41 published the results of a study that demonstrated that when the FEV1 decreased to <30% predicted, the 2-year survival rate was <50%. Women appear to experience a greater deterioration of lung function with age. When the first accurate description of CF was published by Andersen in 1939, >80% of patients died within 1 year of birth. Since then, advances in diagnosis and therapy have been accompanied by a gradual improvement in prognosis and increased survival time. According to data from the CF Patient Registry, the median survival time in the United States was approximately 20 years in 1970 and had increased to 37.4 years by 2007. Recent estimates have projected that children born with CF in the United States today will survive into their sixth decade of life.42

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Nothing to Disclose

The author has disclosed that no relationships exist with any companies/organizations whose products or services may be discussed in this chapter.

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Konstan MW. Ibuprofen therapy for cystic fibrosis lung disease: revisited. Curr Opin Pulm Med. 2008;14(6):567-573. [PubMed] [CrossRef]
 
Ratjen F. New pulmonary therapies for cystic fibrosis. Curr Opin Pulm Med. 2007;13(6):541-546. [PubMed] [CrossRef]
 
Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365(18):1663-1672. [PubMed] [CrossRef]
 
Flume PA, Mogayzel PJ Jr, Robinson KA, et al. Cystic fibrosis pulmonary guidelines: pulmonary complications: hemoptysis and pneumothorax. Am J Respir Crit Care Med. 2010;182(3):298-306. [PubMed] [CrossRef]
 
Rosenblatt RL. Lung transplantation in cystic fibrosis. Respir Care. 2009;54(6):777-786 discussion.:786-787. [PubMed] [CrossRef]
 
Kerem E, Reisman J, Corey M, Canny GJ, Levison H. Prediction of mortality in patients with cystic fibrosis. N Engl J Med. 1992;326(18):1187-1191. [PubMed] [CrossRef]
 
Elston C, Simmonds N, Geddes D. The future for a child born with cystic fibrosis today. Breathe. 2007;4(1):17-23
 
Figure Jump LinkFigure 1 Large internal diameter of the bronchi (greater than the accompanying vessel), which is diagnostic of bronchiectasis (large arrows). From the author's personal files.Grahic Jump Location
Figure Jump LinkFigure 2 Products of polymorphonuclear cells and their effects on inflammation of the airways in patients with CF. Adapted from Ramsey.27Grahic Jump Location
Table Graphic Jump LocationTable 1 Distinguishing Features of Nocardiosis and Actinomycosis
Table Graphic Jump LocationTable 2 Common Causes of Bronchiectasis
Table Graphic Jump LocationTable 3 False-Positive or False-Negative Sweat Test Results

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Konstan MW. Ibuprofen therapy for cystic fibrosis lung disease: revisited. Curr Opin Pulm Med. 2008;14(6):567-573. [PubMed] [CrossRef]
 
Ratjen F. New pulmonary therapies for cystic fibrosis. Curr Opin Pulm Med. 2007;13(6):541-546. [PubMed] [CrossRef]
 
Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365(18):1663-1672. [PubMed] [CrossRef]
 
Flume PA, Mogayzel PJ Jr, Robinson KA, et al. Cystic fibrosis pulmonary guidelines: pulmonary complications: hemoptysis and pneumothorax. Am J Respir Crit Care Med. 2010;182(3):298-306. [PubMed] [CrossRef]
 
Rosenblatt RL. Lung transplantation in cystic fibrosis. Respir Care. 2009;54(6):777-786 discussion.:786-787. [PubMed] [CrossRef]
 
Kerem E, Reisman J, Corey M, Canny GJ, Levison H. Prediction of mortality in patients with cystic fibrosis. N Engl J Med. 1992;326(18):1187-1191. [PubMed] [CrossRef]
 
Elston C, Simmonds N, Geddes D. The future for a child born with cystic fibrosis today. Breathe. 2007;4(1):17-23
 
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