© 2003 American Thoracic Society
Pathophysiology and Management of Pulmonary Infections in Cystic FibrosisDepartment of Pediatrics, University of Washington School of Medicine, Children's Hospital, and Regional Medical Center, Seattle, Washington Correspondence and requests for reprints should be addressed to Bonnie W. Ramsey, M.D., Professor of Pediatrics, Department of Pediatrics, University of Washington School of Medicine, 2611 NE 125th Street, Suite 90, Seattle, WA 98125. E-mail: bonnie.ramsey{at}seattlechildrens.org
This comprehensive State of the Art review summarizes the current published knowledge base regarding the pathophysiology and microbiology of pulmonary disease in cystic fibrosis (CF). The molecular basis of CF lung disease including the impact of defective cystic fibrosis transmembrane regulator (CFTR) protein function on airway physiology, mucociliary clearance, and establishment of Pseudomonas aeruginosa infection is described. An extensive review of the microbiology of CF lung disease with particular reference to infection with P. aeruginosa is provided. Other pathogens commonly associated with CF lung disease including Staphylococcal aureus, Burkholderia cepacia, Stenotrophomonas maltophilia, Achromobacter xylosoxidans and atypical mycobacteria are also described. Clinical presentation and assessment of CF lung disease including diagnostic microbiology and other measures of pulmonary health are reviewed. Current recommendations for management of CF lung disease are provided. An extensive review of antipseudomonal therapies in the settings of treatment for early P. aeruginosa infection, maintenance for patients with chronic P. aeruginosa infection, and treatment of exacerbation in pulmonary symptoms, as well as antibiotic therapies for other CF respiratory pathogens, are included. In addition, the article discusses infection control policies, therapies to optimize airway clearance and reduce inflammation, and potential future therapies.
Key Words: cystic fibrosis • Pseudomonas aeruginosa • airway disease • cystic fibrosis transmembrane conductance regulator • antibiotics CONTENTS Clinical Presentation Diagnosis Pulmonary Manifestations CFTR Function and Molecular Basis of CF Lung Disease CFTR Structure and Function Impact of Defective CFTR on Airway Physiology and Mucociliary Clearance Impact of Defective CFTR on Initial and Persistent P. aeruginosa Infection Microbiology of CF Lung Disease Early Colonization and Infection Infection with P. aeruginosa Characteristics of P. aeruginosa That Contribute to Initial and Persistent Infections Late-emerging Pathogens Clinical Assessment in the Management of CF Lung Disease Monitoring Pulmonary Health Status Diagnostic Microbiology Current Antibiotic Therapies Prevention of Chronic P. aeruginosa Infection Maintenance Therapy Treatment of Pulmonary Exacerbation Treatment of Other Emerging Pathogens Immunotherapy Infection Control in CF Pulmonary Disease Transmissibility of CF Pathogens Consensus Recommendations Current Therapies to Optimize Airway Clearance and Reduce Inflammation Optimizing Airway Clearance and ASL Hydration Bronchodilators Antiinflammatory Therapy Diagnosis and Treatment of ABPA Future Therapies for CF Pulmonary Disease Gene Transfer Therapy Pharmacologic Approaches New Approaches to Treating P. aeruginosa Infection The cystic fibrosis (CF) scientific community has orchestrated a focused, multidisciplinary effort to understand the molecular basis of this disorder and at the same time improve clinical care for patients with CF. After identification of the CF gene in 1989, the 1990s was a decade associated with rapid expansion of knowledge regarding the structure and function of the CF gene product, CF transmembrane conductance regulator (CFTR) protein. The previous State of the Art assessment of CF in 1996 (1) provided a comprehensive review focusing on significant advances in scientific understanding of the CFTR gene. As we enter the 21st century, both laboratory and clinical investigators are applying this knowledge toward elucidating the critical factors that initiate chronic endobronchial bacterial infection in this genetic disorder and are using this knowledge to develop novel and effective therapies. This State of the Art focuses on the current understanding of the impact of abnormal CFTR function on airway surface liquid (ASL) that initiates a pathophysiologic cascade leading to progressive lung disease. The role of chronic endobronchial bacterial infection with pathogens such as Pseudomonas aeruginosa and the resultant intense neutrophilic inflammatory response, pathognomonic for this lung disease, will be reviewed. In addition, current and future therapies to control or eradicate Pseudomonas infection and slow disease progression are summarized. This review focuses only on the pulmonary aspects of this genetic disease and does not include other important aspects of this illness including gastrointestinal, endocrine, and metabolic manifestations of CF (2). CF is an autosomal recessive disorder caused by mutations in a single gene on the long arm of chromosome 7 that encodes the CFTR protein (2–5). Despite impressive advances in understanding the molecular basis and pathophysiology of this disorder, it remains the most common life-shortening genetic disorder in the white population with an estimated median survival age of 33.4 years in the United States in 2001 (Figure 1) . This represents an increase of 6 years since the previous State of the Art was written (6). CF affects approximately 30,000 individuals in the United States and 60,000 individuals worldwide with an estimated incidence in the U.S. white population ranging from 1 in 1,900 to 1 in 3,700 (2, 7). CF is present, but less frequent, in Hispanic (8), Asian (9), and African American (7, 10) populations (1 in 9,000, 1 in 32,000, and 1 in 15,000, respectively). The CF gene is large, spans 250 kb, and is composed of 27 exons (11). As shown in Figure 2 , the gene is transcribed into a 6.5-kb messenger RNA (3) that encodes a 1,480 amino acid protein. Since identification of the gene, over 800 disease-associated mutations in the CF gene have been reported to the CF Genetic Analysis Consortium database (www.genet.sickkids.on.ca/cftr/). The vast majority of mutations involves three or fewer nucleotides and result in predominantly amino acid substitutions, frameshifts, splice site, or nonsense mutations.
Although a large number of CF-causing mutations have been described, only 22 mutations have been identified with a frequency of at least 0.1% of known alleles (12). The remaining mutations are extremely rare and often limited to one or a few individuals. The most common and first identified mutation, a three base pair deletion that codes for phenylalanine at position 508 of the CFTR protein,  F508, accounts for 70% of CF alleles in whites (13). It is the presence of F508 that increases the frequency of CF in the white population relative to other races. Although several theories have been proposed suggesting a selective advantage for F508 heterozygotes such as resistance to secretory diarrhea from cholera (14) or protection against bronchial asthma (15), no confirmatory data are available. The other 21 common mutations are often found in higher frequency in particular ethnic groups, such as the W1282X mutation in Askenazi Jewish populations (16), G551D in French Canadians (17), and 3,120 + 1G  A in African/Mediterranean populations (18).
In vitro physiologic studies have demonstrated that mutations in the CF gene can disrupt CFTR function within epithelial cells in different ways, ranging from complete loss of protein to surface expression with poor chloride conductance (19). The five major mechanisms by which CFTR function is altered are summarized in Figure 3
. Class I mutations produce premature transcription termination signals resulting in unstable, truncated, or no protein expression. Class II mutations, usually missense mutations including
Diagnosis Although the genetic basis is now well understood, the diagnosis of CF remains clinical and not genetic. Until the 1990s, the diagnosis was based on clinical criteria (Table 1) and analysis of sweat chloride values (25). The availability of mutational analyses within the CF gene (12, 13) as well as an assessment of bioelectrical properties of respiratory epithelia by measurement of transepithelial potential differences (26) rapidly expanded the clinical spectrum of CF to include milder, atypical presentations. In addition, availability of newborn screening (27) in certain states and countries and prenatal diagnosis afforded the opportunity to diagnose individuals before the onset of clinical symptoms. In 1997, a consensus panel was convened to define the diagnosis of CF in the context of these newer diagnostic tools (28). This group defined the clinical parameters that support the diagnosis (Table 1) and appropriate laboratory tests to document CFTR dysfunction (28, 29). The World Health Organization has developed similar criteria (30). Of the 1,091 newly diagnosed patients from the United States in 2001 (6), only a small percentage were identified by newborn screening (9.1%) or prenatal diagnosis (3.9%). The majority of diagnoses were based on clinical features of which respiratory symptoms (43.8%), failure to thrive (29.3%), steatorrhea (24.4%), and meconium ileus (18.5%) were most common.
With these expanded criteria, the borders between normal and abnormal CFTR function have become less distinct (29). A particularly interesting group is males with obstructive azoospermia secondary to congenital bilateral absence of the vas deferens who have no other clinical features of CF. Nearly half the individuals with congenital bilateral absence of the vas deferens carry two CFTR mutations (31), and even patients with unilateral absence of the vas deferens (32) have increased incidence of CFTR mutations. Adults with chronic pancreatitis (33) and rhinosinusitis (34) have been reported to commonly carry at least one CFTR mutation. At the other end of the spectrum, CF phenotypes have been characterized in the absence of CFTR mutations (35). To address this conundrum, a continuum of diagnoses from a pre-CF to subclinical CF to classic presentation has been proposed (36). Thus, it is clear that the diagnostic criteria will continue to evolve as molecular and physiologic understanding expands.
Pulmonary Manifestations
Soon after birth, initial infection with bacterial pathogens commences and is associated with an intense neutrophilic response localized to the peribronchial and endobronchial spaces (42–44). Early airway infection and inflammation in CF can have regional heterogeneity that complicates understanding the causal and temporal relationship between initial infection and airway inflammatory response (45–47). Several studies in toddlers and older children with CF have shown a robust inflammatory response in the airways in both bacterial culture–positive and culture-negative patients; some studies show a greater inflammatory response in those patients with at least 5 x 104 cfu/ml of bacteria in their bronchoalveolar lavage (BAL) fluid (43, 48–50). At this point, pathologic changes become more evident with mucopurulent plugging of small and medium size bronchioles (Figure 4). In older individuals with CF, persistent neutrophils dominate airway inflammation with elevated interleukin (IL)-8 and neutrophil elastase (51–53). Airways become dilated and bronchiectatic, secondary to proteolysis and chondrolysis of airway support tissue (54, 55) (Figure 5) . In later stages, lung parenchyma becomes affected by atelectasis, pneumonia, and encroachment by enlarging airways. Many secondary consequences of bronchiectasis ensue, including hypertrophy of bronchial circulation and formation of bronchial cysts. A later and less common consequence is pulmonary hypertension.
In effect, the CF airway represents a prolonged primary inflammatory response usually observed in acute infections. The CF host inflammatory response is unable to mature and promote a macrophage-driven granulomatous response seen in other chronic infections. It has been suggested that this inflammatory response remains orchestrated by local airway epithelium–pathogen interactions, rather than driven by T cells as part of the systemic immune response (52).
The critical mediators for neutrophil influx in the CF lung include IL-8, tumor necrosis factor– The clinical manifestations of CF lung disease are highly variable in onset and intensity. Affected individuals rarely demonstrate respiratory symptoms in the newborn period, but infants less than 6 months of age may demonstrate tachypnea, wheezing, increased work of breathing, hyperinflation, and cough. These symptoms may be initiated or exacerbated by respiratory viral infections (59) and, if undiagnosed, these babies may be labeled as having recurrent or persistent bronchiolitis. At some point in the course of all affected individuals' lives, cough becomes a prominent symptom. Patients with mild disease may only cough during exacerbations (see TREATMENT OF PULMONARY EXACERBATION), but eventually cough becomes a daily occurrence, usually associated with expectoration of sputum. With disease progression, daily sputum volume increases and becomes green to tan in color. Blood-streaked sputum and hemoptysis are not unusual in later stages of illness. Similar to other chronic obstructive lung diseases, patients experience increasing dyspnea on exertion and shortness of breath as the illness progresses. They are often oxygen dependent (at least nocturnal) with retention of carbon dioxide in the late stages of the illness and experience decreasing life quality as the frequency of exacerbations and intensity of respiratory therapy increases. Respiratory failure still accounts for over 80% of deaths for patients with CF in the United States (6).
CFTR Structure and Function CFTR is a member of the ATP-binding cassette transporter family of membrane proteins (2, 60). CFTR contains the characteristic two nucleotide-binding domains and two membrane-spanning domains, as well as a unique regulatory R domain with multiple phosphorylation sites (Figure 2). cAMP-dependent phosphorylation of the R domain governs channel activity (61), and ATP binding and hydrolysis by the two nuclear-binding domains controls channel gating (62, 63). CFTR structure and function, the regulatory activity of CFTR on other ion channels, and the impact of CFTR dysfunction on the composition and pH of ASL are reviewed elsewhere (2).
Impact of Defective CFTR on Airway Physiology and Mucociliary Clearance
Two competing hypotheses have been proposed: (1) the isotonic "low volume" hypothesis with resultant abnormalities in mucociliary clearance (64, 65), and (2) the "compositional" hypothesis with increased ASL salt concentrations in CF inactivating salt-sensitive antimicrobial peptides (Figure 7) (67). Both hypotheses can in part explain the early and persistent endobronchial infection in CF (68–70). In the first hypothesis, water-permeable airway epithelia regulate the volume of the ASL by isotonic transport to maintain optimal ciliary mucus layer interactions and mucociliary clearance. This hypothesis predicts the salt composition of control and CF ASL to be similar with each other and plasma. The second or "compositional" hypothesis proposes that airway epithelia regulate ASL salt concentration that is critical for optimal function of innate antimicrobial peptide defenses in the lung. This hypothesis predicts a higher ASL salt concentration in patients with CF compared with individuals who are not infected.
There is no final consensus on the tonicity of ASL in subjects with CF relative to healthy control individuals. Technical limitations of collecting and assaying ASL from the upper and lower airways are a significant obstacle. It is also uncertain if ASL composition varies along the respiratory tract (i.e., nasal epithelium to distal airways), in response to chronic inflammation and infection, and within local microenvironments such as submucosal glands or mucus plugs (68). There is increasing evidence from nasal and bronchial epithelium derived from human and animal sources that ASL is similar in healthy control individuals and subjects with CF and is isotonic (64, 71–75). However, using a novel isotopic technique, one investigator suggests that normal ASL concentrations of sodium and chloride are approximately 50 mM and that the ASL concentrations of these ions are elevated to approximately 100 mM in CF (76). Therefore, the "compositional" hypothesis has not been entirely refuted, especially when considering local microenvironments such as submucosal glands. Additional studies on the ionic composition and volume of ASL are necessary, as the answer will influence approaches to treatment of CF lung disease. Evidence is accumulating for the important role of submucosal glands in the pathophysiology of airway disease in CF (71). CFTR is highly expressed in the serous epithelial cells of submucosal glands compared with other tissues of the lung (38, 68). Abnormalities in submucosal gland secretions are proposed to contribute to airway disease in CF. Loss of CFTR function may alter the macromolecular composition of the submucosal gland secretions and thereby change viscosity, gel hydration, and adversely effect mucociliary clearance (Figure 6D) (66, 71, 77). Submucosal gland secretions from explanted human CF airways have sodium content and pH similar to control tissue, but CF submucosal gland secretions have approximately a twofold increase in viscosity (77). Further studies are needed on submucosal gland secretions from CF airways before chronic infection, however, to determine if the increased viscosity of submucosal gland secretions in CF is due to decreased fluid secretion or altered protein/glycoprotein composition. Mucociliary clearance is a primary innate airway defense that most studies show is reduced in CF (Figure 6) (64, 66, 78). In CF, there is abnormal regulation of the periciliary liquid volume that contributes to reduced mucociliary clearance (64, 66). Altered viscosity and regulation of submucosal gland secretion may also impair host defense (77, 79). In addition, the reduced periciliary liquid volume promotes interactions between gel mucins in the mucus layer with cell-surface mucins that hinder clearance of particles from the airways (66). Clearance of particles from normal peripheral airways by mucociliary clearance can require up to 6 hours, and this can be significantly prolonged in CF airways (66). Endogenous antimicrobial peptides can suppress bacterial growth for 3 to 6 hours (80). Thus reduced mucociliary clearance in CF may contribute to overwhelming innate antimicrobial peptides and thereby promote the initial endobronchial infection in young children with CF.
Impact of Defective CFTR on Initial and Persistent P. aeruginosa Infection
Abnormal bacterial adherence to epithelial cells.
CFTR may serve as a receptor for P. aeruginosa internalization. The relative importance of epithelial cell phagocytosis in the innate defense against P. aeruginosa is uncertain compared with mucociliary clearance and antimicrobial peptides. It is unlikely that epithelial phagocytosis is important in established infection, as mucoid P. aeruginosa and Staphylococcus aureus are observed primarily within endobronchial mucus and not adherent to the epithelium (97, 98).
Innate immunity and persistence of bacterial infections. The central tenet of the "compositional" theory (see IMPACT OF DEFECTIVE CFTR ON AIRWAY PHYSIOLOGY AND MUCOCILIARY CLEARANCE) is that the elevated sodium chloride content in CF ASL (Figure 7) leads to inactivation of salt-sensitive antimicrobial peptides permitting initial bacterial colonization within the CF airway (2, 67, 70). There are limited in vivo data to corroborate this theory (76). It has been postulated, however, that local microenvironments such as mucus plaques or submucosal glands in the CF airway, not easily reached for in vivo sampling, may demonstrate conditions (salt content or binding to actin/DNA) that can inactivate innate antimicrobial peptides to promote initial bacterial infection (106). New data showing steep oxygen gradients in mucus plagues within the CF airway has led proponents of the "isotonic, low ASL volume" hypothesis to propose a scheme for early and persistent endobronchial infection in CF (97). In this model, the hyperabsorption of sodium and absent chloride secretion in the CF airway result in reduced periciliary liquid volume and impaired mucociliary clearance leading to a cascade of events that provides a unique microenvironment to promote P. aeruginosa adaption and persistent infection as illustrated in Figure 6.
Acquired immunity. There are multiple factors, however, contributing to the ineffective acquired immune response (109). Opsonophagocytosis of bacteria requires intact complement and Fc receptors on phagocytes. In the CF airway, with neutrophil-dominated inflammation, there is proteolytic cleavage of complement and Fc receptors resulting in reduced opsonophagocytosis (52). Local tissue destruction and reduced mucociliary clearance reduces the effectiveness of the immune response in the clearance of P. aeruginosa from the airway. Chronic P. aeruginosa antigen exposure in patients with CF appears to result in a lack of avidity maturation of anti–P. aeruginosa antibodies that may contribute to reduced function in P. aeruginosa clearance (110).
All of the proinflammatory cytokines and chemokines elevated in the CF airway have their synthesis regulated by the transcription factor nuclear factor-
CF has a unique set of bacterial pathogens that are frequently acquired in an age-dependent sequence. The pattern of age-specific prevalence as well as overall prevalence of these pathogens in the CF population in the United States is demonstrated in Figure 8 from the Cystic Fibrosis Foundation Patient Registry data (6). Of the organisms causing infection in CF, only S. aureus may be pathogenic in immunocompetent individuals. P. aeruginosa, B. cepacia, nontypeable Haemophilus influenzae, Stenotrophomonas maltophilia, and Achromobacter xylosoxidans are all considered opportunistic pathogens. Other organisms seen in CF that are also generally nonpathogenic in the healthy host include Aspergillus and nontuberculous mycobacteria.
Early Colonization and Infection Early infections in CF airways are most frequently caused by S. aureus and H. influenzae, organisms that may be seen in other young children with chronic illnesses and in adults with non–CF bronchiectasis. S. aureus is often the first organism cultured from the respiratory tract of young children with CF (48). However, there continues to be debate about the significance of S. aureus in the pathogenesis of CF lung infection (115). Historically, significant improvements in patient longevity have been associated with the advent of antistaphylococcal therapy (116). However, several recently published studies of the efficacy of prophylactic antistaphylococcal antibiotics question the benefit of this therapeutic approach (see BRONCHODILATORS) (117, 118). H. influenzae is also isolated from the respiratory tract early in the course of CF. In a natural history study of CF diagnosed in 40 children in the first year of life, either for clinical reasons or because of a family history, H. influenzae was the most common organism isolated from lower airway cultures at age 1 year (50, 107). Similar numbers have been reported in studies of children with CF identified by neonatal screening (119). The H. influenzae infecting patients with CF is nontypeable, thus not prevented by childhood immunization against H. influenzae type b. The role of H. influenzae in progressive airway infection and inflammation in patients with CF has not been clearly demonstrated, although it is known to be pathogenic in patients with non–CF bronchiectasis (120).
Infection with P. aeruginosa
Characteristics of P. aeruginosa That Contribute to Initial and Persistent Infections
Phenotypic changes. Although growth of P. aeruginosa in microcolonies has been proposed for many years (131), support for the existence of biofilms in CF has recently been reported (132, 133). Biofilms are sessile communities of bacteria that form in aggregates on surfaces using a hydrated polymeric matrix of their own synthesis (Figures 6D and 6E). Some common clinical characteristics of biofilm infections have been identified: slow growth of organisms, stimulation of production of antibodies that are ineffective in clearing bacteria, inherent resistance to antibiotics, and an inability to eradicate biofilm infections even in hosts with intact immune systems (134–137). These are characteristic of CF airway infections. The presence of P. aeruginosa biofilms in infected CF airways was first suggested because of the quorum-sensing signals that the organisms produce to signal cell-density–dependent gene expression (132). In addition, both transmission and scanning electron microscopy have demonstrated organized clusters and microcolonies of P. aeruginosa in expectorated CF sputum consistant with biofilm formation (138). Subsequently, the presence of local hypoxia within mucus plaques in the airways has been suggested to increase Pseudomonas alginate production (97), which may lead to increased biofilm formation (Figure 6) (138). It has recently been reported that antibiotic-resistant phenotype variants of P. aeruginosa with an enhanced ability to form biofilms arise at high frequency in the lungs of patients with CF (133).
Genetic advantages. A high frequency of hypermutability has been identified in P. aeruginosa isolates from patients with CF. This is likely caused by the milieu of the CF airway with large numbers of infecting organisms and compartmentalization of infection, combined with ineffective host defenses and ongoing antibiotic selective pressure (141).
Late-emerging Pathogens S. maltophilia and A. xylosoxidans are seen more commonly than B. cepacia in patients with CF with advanced lung disease but are generally less virulent. Epidemiologic studies examining their association with morbidity and mortality in CF have not demonstrated a correlation between infection and outcome (149, 150). Like P. aeruginosa, person-to-person spread of these organisms is rarely documented in patients with CF, other than siblings (151). Fungal colonization and infection of the CF airway late in disease progression is not surprising given the exposure of this population to frequent broad-spectrum antibiotic therapy (152). Whereas Candida spp. are the most frequent colonizers, isolated from almost 50 to 75% of patients with CF who were cultured (153, 154), they are usually considered to be harmless commensals. However, Aspergillus spp., most frequently Aspergillus fumigatus, are isolated from more than 25% of patients (154). There is not sufficient evidence to generally recommend treatment of an Aspergillus-postive sputum culture in the absence of allergic bronchopulmonary aspergillosis (ABPA) (155). Invasive infections caused by Aspergillus are rare in the immunocompetent nontransplant CF population, but ABPA can be a significant problem (156, 157). ABPA is not an invasive fungal infection but rather a syndrome, including wheezing, pulmonary infiltrates and, potentially, bronchiectasis and fibrosis, that develops because of sensitization against allergens from A. fumigatus in the environment (156, 157). Exposure of the airways to high levels of Aspergillus allergens, due in part to reduced mucociliary clearance in CF, may be a key element in the development of ABPA. In patients with atopy, exposure to fungal spores and hyphal elements leads to the production of specific IgE and an increase in the CD4+ Th2 cell response to A. fumigatus (157). The overall prevalence of ABPA in CF is reported between 2 and 8% on the basis of three large clinical databases (157–159). The true prevalence of ABPA in the CF population is uncertain due to the lack of standardized diagnostic criteria and the lack of uniform surveillance and laboratory procedures (see DIAGNOSIS AND TREATMENT OF ABPA). Another filamentous fungus isolated commonly from the respiratory tract of patients with CF (8.6% of patients in one study) whose significance is unknown is Scedosporium apiospermum (160). For both Aspergillus and Scedosporium, no clustering of isolates has been identified by genotyping (161, 162). Other molds that have been reported from CF respiratory samples include Wangiella dermatitidis and Penicillium emersonii (163, 164). Nontuberculous mycobacteria have been increasingly reported from the respiratory secretions of patients with CF. In a prospective prevalence study conducted at 21 CF centers across the United States, 13% of patients cultured nontuberculous mycobacteria from sputum (165). The most common species isolated were Mycobacterium avium complex (72%) and Mycobacterium abscessus (16%). Nontuberculous mycobacteria culture-positive patients were more frequently older and had a higher frequency of S. aureus and a lower frequency of P. aeruginosa compared with culture-negative control subjects. Molecular typing demonstrated a pattern of infrequent spread among patients. There appeared, however, to be a distinct geographic distribution of the prevalence of nontuberculous mycobacteria. Prevalence ranged from 7% in Boston to 24% in New Orleans, and the majority of centers with a rate greater than 15% were in coastal states. A substudy that followed 60 nontuberculous mycobacteria–positive patients for 15 months and compared them with an uninfected control group identified no difference in the rate of decline of FEV1 (166). Abnormalities on high-resolution computerized tomography (HRCT) scan, however, were predictive of progression. Thus, current recommendations suggest that adult patients with CF be screened on a regular basis with both acid-fast smear and appropriately processed sputum or BAL fluid culture (see NONTUBERCULOUS MYCOBACTERIA). Findings suggestive of infection rather than colonization include: multiple positive cultures, a single positive culture associated with a pulmonary exacerbation that is not responsive to conventional antibacterial therapy or HRCT scan demonstrating peripheral pulmonary nodules, and/or a mucosal biopsy demonstrating granulomatous disease.
Monitoring Pulmonary Health Status There is no approved therapy to correct the underlying genetic defect or reverse the ion transport abnormalities associated with dysfunctional CFTR. Thus, therapy is directed toward slowing the progression of secondary organ dysfunction and its sequelae such as pancreatic insufficiency with maldigestion and chronic endobronchial infection. This treatment approach has been enhanced by the establishment of comprehensive, multidisciplinary CF care centers worldwide. The Cystic Fibrosis Foundation has also established Clinical Practice Guidelines (167) followed by CF centers throughout the United States emphasizing routine quarterly monitoring of health status, patient and family education, and early intervention to slow illness progression (2). Routine laboratory evaluations are key to assessing pulmonary status and are used to monitor disease progression and response to therapeutic interventions. These studies include radiologic examinations, pulmonary function testing, and microbiologic cultures of airway secretions. Assessment of blood oxygen and carbon dioxide values are useful in patients with more severe disease or acute pulmonary decompensation. Management of endstage lung disease including intensive care management–assisted ventilation and transplantation is beyond the scope of this review and has been reviewed (168–173).
Imaging. HRCT is more sensitive and specific than chest radiographs in identifying changes such as airway wall thickening and gas trapping in early CF lung disease and is particularly useful in identifying localized areas of bronchiectasis and parenchymal abnormalities (177–179). HRCT changes may also precede changes in pulmonary function, which assess an overall change in function rather than regional changes in structure (46, 180). For these reasons, HRCT is being used to document early bronchiectasis, localized disease, and response to antibiotic interventions during acute exacerbations (178, 181). Despite this progress, there are still no consensus guidelines for use of HRCT in CF care; the risk versus benefit ratio must continue to be addressed in terms of additional cost and radiation exposure (182).
Lung function testing. Changes in FEV1 will become evident as patients begin to develop obstructive lung disease. FEV1 is the most widely used pulmonary function testing parameter of lung status (186–188) in CF because of the universal accessibility of spirometric equipment, standardized criteria for performance, availability of reference values (189–191), and reproducibility. In addition to day-to-day clinical management, FEV1 serves two other important functions. First, it is the primary marker for disease progression identified in numerous epidemiologic studies to predict survivorship and decline in health status (122, 188, 192–195). Second, it is the primary outcome measure used for defining clinical efficacy for new therapeutic modalities in CF (187, 196, 197). Across the entire U.S. CF population, the average decline in FEV1 is 2% per annum (186). Factors that may negatively impact the rate of decline include nutritional status (198), comorbidity from diabetes mellitus (199, 200), colonization with P. aeruginosa (122, 124), and B. cepacia (142, 143) and frequency of pulmonary exacerbations (122). Other factors such as mild genotype and pancreatic sufficiency are associated with slower rates of decline (122, 201). Patients may be stable for many years and then show periods of more rapid progression. As FEV1 continues to decline, patients will begin demonstrating a decline in FVC presumably due to progressive scarring, gas trapping, and increased dead space ventilation.
Infant pulmonary function testing. Current methods of infant lung function testing cannot be extended beyond 3 to 4 years of age because of the inability to provide adequate oral sedation and loss of the Hering–Breuer reflex (relaxation of inspiratory muscles with repeated sigh breaths). Promising measures of lung function in preschool patients with CF (ages 3–6 years) that can be performed without sedation and during tidal breathing are being developed. These techniques include modified spirometry (211, 212) and respiratory resistance measured by plethysmography (202, 213), forced oscillation (214, 215), and interrupter resistance (216).
Diagnostic Microbiology
Source of specimens. Recently, hypertonic saline induction of sputum has been reported to be a good surrogate for lower airway sampling for both microbiology and inflammatory markers in both adult and older pediatric patients with CF (222, 225–227). In a comparison of culture results from expectorated and induced sputum samples and BAL fluid, similar detection rates for bacteria and fungi were identified with all three sample sources (222).
Isolation/identification techniques.
Once organisms are isolated, identification, particularly of Gram-negative bacteria, may also be difficult because of the presence of a large number of unique organisms combined with the phenotypic changes that even the more common organisms may undergo. The use of standard biochemical testing rather than commercial systems has been recommended for identification of Gram-negative nonfermenting bacteria (217, 218). In addition, molecular techniques, especially polymerase chain reaction, have proved useful for bacterial identification, both directly in sputum and for isolated organisms growing in pure culture (231–233).
Antibiotic susceptibility testing. Whereas clinical laboratories have not been routinely looking for methicillin resistance in S. aureus isolated from patients with CF, a survey of isolates from multiple CF centers suggested that the rate of resistance in CF is comparable with that in the general population (153). Vancomycin tolerance and resistance have both been described in human isolates of S. aureus (235–237), and there is no reason to believe that patients with CF will be protected from acquiring them, as well. Other nonstandard methods for susceptibility testing in CF include synergy testing of multiply-resistant Gram-negative isolates and multiple combination bactericidal testing of P. aeruginosa and B. cepacia complex (238). Ongoing trials of the clinical utility of multiple combination bactericidal testing testing for the management of B. cepacia complex lung infections are being conducted in Canada. More recently, evidence of biofilm formation by organisms in the CF airway has prompted the investigation of biofilm susceptibility testing (239). Different drugs and drug combinations appear to be efficacious against P. aeruginosa growing in biofilms; this may help explain nonbactericidal mechanisms of activity of antimicrobial therapy. At this time, many of these nonstandard techniques cannot be recommended for routine use in CF because their clinical efficacy has yet to be tested.
Pseudomonas serology.
Nontuberculous mycobacteria.
Appropriate antibiotic therapy directed against bacterial pathogens isolated from the respiratory tract is an essential component in the management of CF lung disease. Most clinicians prescribe antibiotic therapies in three distinct clinical settings during the lifespan of an individual with CF. First, during early lung disease patients may receive antibiotics to delay onset of chronic colonization with P. aeruginosa. Second, once patients are colonized with pathogens such as S. aureus and P. aeruginosa, chronic maintenance antibiotics are administered to slow decline in pulmonary function and reduce frequency and morbidity of pulmonary exacerbations. Third, at the time of periodic exacerbations in pulmonary symptoms, intensive antibiotic regimens are frequently administered during hospitalization to relieve symptomatology and restore pulmonary function to baseline values. The current recommendations for antibiotic therapy in each of these settings and the body of scientific knowledge on which the reco |
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ABSTRACT
CLINICAL PRESENTATION
and IL-1, complement-derived chemoattractants, and leukotriene B4 (
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