INTRODUCTION — Cystic fibrosis (CF) is a multisystem disease affecting the lungs, digestive system, sweat glands, and reproductive tract. Patients with CF have abnormal transport of chloride and sodium across secretory epithelia, resulting in thickened, viscous secretions in the bronchi, biliary tract, pancreas, intestines, and reproductive system [1,2]. Although the disease is systemic, progressive lung disease continues to be the major cause of morbidity and mortality for most patients. The clinical findings described here are characteristic of the disease before the advent of CF transmembrane conductance regulator (CFTR) modulator therapies. These descriptions are still very relevant for patients who do not carry genetic mutations amenable to these medications. The effects of CFTR modulator therapy on disease course has yet to be determined, but it is likely that symptoms and disease progression will be greatly attenuated or slowed .
Clinical manifestations of pulmonary disease are reviewed here. The treatment of CF-associated lung disease is discussed in the following topic reviews:
Other aspects of CF care are discussed in these topic reviews:
PROGRESSION OF PULMONARY DISEASE
Alterations in respiratory secretions — CF is caused by mutations in a single, large gene on chromosome 7 that encodes the CF transmembrane conductance regulator (CFTR) protein [4-6]. CFTR is a regulated chloride channel, which, in turn, may regulate the activity of other chloride and sodium channels at the cell surface. The net result of these changes is an alteration in the rheology of airway secretions, which become thick and difficult to clear . Ultimately, these viscid secretions obstruct the small airways and promote infection, which leads to tissue destruction and eventually to bronchiectasis. (See "Cystic fibrosis: Genetics and pathogenesis".)
Infection — The chronic airway obstruction caused by viscous secretions is soon followed by colonization with pathogenic bacteria, including Haemophilus influenzae, Staphylococcus aureus, Pseudomonas aeruginosa, and Burkholderia cepacia complex species. Methicillin-resistant S. aureus is encountered with increasing frequency in many regions. Other organisms frequently encountered in the CF airways include Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and Klebsiella spp, although the contribution of these pathogens to the development of bronchial disease is not always clear. Chronic bacterial infection within the airways occurs in most patients with CF (table 1), and the prevalence of each bacterial type varies with the age of the patient (figure 1). Even among asymptomatic infants identified by newborn screening, there is evidence of subclinical lung disease within the first few months of life [8-10] (see 'Pulmonary function testing' below). Infection with S. aureus and P. aeruginosa are common even in young children with CF. The presence of P. aeruginosa with a mucoid phenotype is particularly suggestive of CF. Nontuberculous mycobacteria and fungal species such as Aspergillus also contribute to clinical disease in many patients. A subset of patients colonized with Aspergillus develop a hypersensitivity reaction known as allergic bronchopulmonary aspergillosis (ABPA), which causes acute or subacute deterioration of pulmonary function. (See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection", section on 'Pathogens' and "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection", section on 'Aspergillus species'.)
Bronchiectasis — Once infection is established, neutrophils are unable to control the bacteria even though there is massive infiltration of these inflammatory cells into the lung tissue. Recruited neutrophils subsequently release elastase, which overwhelms the antiproteases of the lung and contributes to tissue destruction. In addition, large amounts of DNA and cytosol matrix proteins are released by degranulating neutrophils, contributing to the increased viscosity of the airway mucus .
Chronic inflammation causes lung damage, first identified on imaging studies as peribronchial cuffing and mild bronchiectasis. Bronchiectasis is an abnormality of the bronchial tree, associated with impairment of mucociliary clearance in the airway. This begins as mild dilatation of areas of the bronchial walls (fusiform bronchiectasis) and can progress to almost globular expansions of the bronchial tree (saccular bronchiectasis). The walls of bronchiectatic airways are chronically inflamed, and they become weak and easily collapsible, which further limits the effectiveness of mucociliary transport and leads to increased infection. Mild, early bronchiectasis may not be easily visualized on a routine chest radiograph but may be seen on computed tomography (CT) scan. More advanced bronchiectasis may be noted by the radiographic finding of abnormal dilation and distortion of the bronchial tree. Associated findings include atelectasis, emphysema, fibrosis, and hypertrophy of the bronchial vasculature. Clinically, bronchiectasis manifests as daily productive cough in almost all patients (see "Bronchiectasis in children: Clinical manifestations and evaluation"). Prospective studies have identified evidence of bronchiectasis by CT in 50 to 75 percent of children with CF by three to five years of age [9,12]. In a study of infants with CF identified by newborn screening, the point prevalence of bronchiectasis on a single CT was approximately 30 percent at 3 months and 12 months of age, 44 percent at two years, and 61 percent at three years. Thirty-two percent had CT evidence of persistent bronchiectasis at three years of age. Important predictors of early bronchiectasis included a history of meconium ileus at birth (odds ratio [OR] 3.17, 95% CI 1.51-6.66), severe genotype (OR 2.54, 95% CI 1.57-4.11), respiratory symptoms at the time of the study (OR 2.57, 95% CI 1.50-4.39), and neutrophil elastase activity in fluid obtained by bronchoalveolar lavage (OR 4.21, 95% CI 1.45-12.21) .
Over time, chronic mucus plugging and chronic infection cause irreparable changes to the airways and damage advances to the stage of irreversible bronchiectasis and progressive respiratory failure . Terminal findings often include severely congested parenchyma with grossly purulent secretions in and around dilated airways (picture 1). The airway epithelium is hyperplastic, often with areas of erosion and squamous metaplasia. Plugs of mucoid material and inflammatory cells are often present in the airway lumen (picture 2). Submucosal gland hypertrophy and hyperplasia of airway smooth muscle may also be noted . (See "Bronchiectasis in children: Pathophysiology and causes", section on 'Pathophysiology'.)
With the advent of new CFTR modulator medications, which modify the function of the abnormal CFTR protein, we anticipate that the progression of lung disease may be significantly delayed in those patients who are eligible for therapy. (See "Cystic fibrosis: Treatment with CFTR modulators".)
Variability in progression — Progressive lung disease continues to be the major cause of morbidity and mortality for most patients. The rate of progression varies widely, depending in part on genotype (including gene modifiers), as well as environmental factors and the frequency and aggressiveness of treatment of the recurrent infections. Registry data from CF centers in the United States indicate a median predicted survival for an individual born in 2021 of approximately 65 years (figure 2) . National registry data from Canada, Italy, and the United Kingdom also note increases in predicted survival over the past decade . Some of these changes have been attributed to earlier diagnosis by means of newborn screening. Females with CF appear to have higher morbidity and mortality than males during the first three decades of life . This sex difference is modest but consistent across many populations, even in the face of improved survival in recent years, and is hypothesized to be due to the proinflammatory effects of estrogens. Interestingly, among people who are diagnosed with CF in adulthood, female patients may actually have a survival advantage compared with their male peers [19,20]. (See "Cystic fibrosis: Genetics and pathogenesis".)
RESPIRATORY SYMPTOMS AND SIGNS — Respiratory symptoms of CF usually begin early in life, although in milder cases, the onset of persistent lung disease may be delayed until the second or third decade . Newborn screening is now performed in many countries, and this identifies most infants before they develop symptoms. Where newborn screening is not performed, pulmonary disease is the primary presenting symptom for approximately 40 percent of children diagnosed with CF. (See "Cystic fibrosis: Clinical manifestations and diagnosis".)
Chronic endobronchial suppurative disease — Respiratory manifestations of CF usually start with a recurrent cough that gradually becomes persistent. In young infants, this may manifest as prolonged or recurrent episodes of bronchiolitis with tachypnea and wheezing. Eventually, coughing occurs on a daily basis, becoming productive and often paroxysmal. The productive nature of the cough may be overlooked in young children, who tend to swallow sputum.
Progressive airway damage and mucus plugging eventually cause chronic obstruction of the airways. As a result, the anteroposterior diameter of the thorax may increase due to progressive air trapping and hyperinflation from airway collapsibility [21,22]. Many older patients have a barrel-shaped chest. Other complications that occur in a minority of patients include spontaneous pneumothorax and hemoptysis, which may be massive [23,24]. (See "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Other pulmonary complications'.)
Airway reactivity — Many patients with CF have airway hyperreactivity, which is typically modest. In one study of young children with CF (mean age 16 months), 50 percent had wheezing and 43 percent of children who wheezed were responsive to bronchodilator therapy . Many patients continue to demonstrate bronchial hyperresponsiveness into adolescence and adulthood, with positive correlations between the degree of airway reactivity and overall severity of lung disease. Beta-agonist medications, which are thought to enhance ciliary function and airway patency, are usually part of daily airway clearance for children with CF. Inhaled corticosteroids have been associated with an increased rate of lower respiratory infection, however, so their use is not recommended for CF patients unless they have classic symptoms of asthma (episodic wheezing, often with other atopic symptoms) or allergic bronchopulmonary aspergillosis (ABPA).
Patients with CF sometimes become less responsive to bronchodilators over time . This phenomenon may occur when progressive airway damage leads to a loss of cartilaginous support, resulting in an increased dependence on muscle tone for maintenance of airway patency. In this setting, the muscle relaxation caused by bronchodilators may cause collapse of such "floppy" airways, leading to increased airflow obstruction.
Allergic bronchopulmonary aspergillosis — Although invasive fungal disease is rare in patients with CF, ABPA is increasingly recognized in CF patients. Symptoms are similar to the progressive pulmonary disease that is typical in CF. However, marked exacerbation of wheezing or otherwise unexplained deterioration in lung function despite antibiotic therapy in CF patients should prompt a careful evaluation for this disorder, which causes acute or subacute deterioration of pulmonary function and should be treated. Patients who grow Aspergillus species from respiratory cultures but who do not have evidence of ABPA should be observed closely but usually do not warrant treatment. In most CF centers, patients are screened with annual evaluation of total serum immunoglobulin E (IgE); a sudden increase should prompt further investigation for possible ABPA. (See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection", section on 'Aspergillus species' and "Clinical manifestations and diagnosis of allergic bronchopulmonary aspergillosis".)
Obstructive sleep apnea — Children and adults with CF may be at higher risk than typical peers for obstructive sleep apnea (OSA) [26,27]. One study employed polysomnography to evaluate sleep in 40 children with mild and stable CF-associated lung disease . Nearly 70 percent of the CF patients were found to have mild or moderate OSA (defined as an apnea-hypopnea index >2), substantially more than in age-matched controls. OSA was more severe in CF patients younger than six years. The presence of OSA may exacerbate nocturnal hypoxemia and sleep fragmentation, particularly in patients with more severe lung disease . The mechanisms for the association between CF and OSA have not been established, but chronic inflammation and nasopharyngeal obstruction may play a role. Presenting symptoms of OSA are similar to those in individuals without CF. (See "Evaluation of suspected obstructive sleep apnea in children", section on 'Clinical manifestations'.)
Pulmonary hypertension — Advanced chronic lung disease in CF can be complicated by pulmonary hypertension, which is correlated with severity of lung disease, likely mediated by alveolar hypoxia, acidosis, hypercapnia, and chronic systemic inflammation . As an example, among CF patients listed for lung transplantation, approximately 10 percent had pulmonary hypertension . (See "Cystic fibrosis: Management of advanced lung disease", section on 'Indications for referral to a lung transplant center'.)
The development of pulmonary hypertension is associated with significantly worse survival. In one study, patients with mild pulmonary hypertension had a hazard ratio (HR) for death of 1.9 (95% CI 1.29-2.85) compared with CF patients without pulmonary hypertension and those with severe pulmonary hypertension had an HR for death of 4.17 (95% CI 1.71-10.16) . In most cases, CF patients with pulmonary hypertension have severe pulmonary compromise (eg, forced expiratory volume in one second [FEV1] <40 percent predicted, hypoxemia, or hypercapnia), and the pulmonary hypertension is often identified in the context of evaluation for lung transplantation. If pulmonary hypertension is identified in a CF patient who is not already being considered for transplant, the patient should be offered a referral for transplant evaluation.
Diagnosis and management of pulmonary hypertension in children and adults is described separately. (See "Pulmonary hypertension in children: Classification, evaluation, and diagnosis" and "Pulmonary hypertension in children: Management and prognosis" and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults" and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)
Conventional chest radiography — Most CF centers monitor patients with chest radiographs at least every two years.
In patients with mild lung disease, the chest radiograph may appear normal for many years, but, in most patients, at least mild radiographic findings are evident in the first decade of life. The first discernible change is usually hyperinflation, which may initially be reversible with treatment for acute exacerbations of infection. As the disease progresses, hyperinflation becomes persistent and the bronchovascular markings become more prominent. For unclear reasons, abnormalities tend to appear in the upper lobes first, progressing to the lower lobes with advancing disease.
With time, the bronchovascular markings progress to a pattern of bronchiectasis and cyst formation. Peribronchial cuffing and "tram tracks" (parallel lines caused by thickened bronchial walls in longitudinal section) appear, followed by the rounded shadows of saccular bronchiectasis (image 1). (See "Bronchiectasis in children: Clinical manifestations and evaluation".)
Increasing hyperinflation leads to progressive flattening of the diaphragms, a prominent retrosternal space, and kyphosis in late stages of disease (image 2A-B). Thin-walled cysts (most common in the upper lobes) may appear to extend to the lung surface, and pneumothorax is observed with increasing frequency in older patients. In advanced stages of disease, the chest radiograph may demonstrate little or no correlation with acute clinical changes.
With good clinical care and careful attention to daily airway clearance, progression of lung disease may be delayed such that the classic radiographic signs of CF do not develop for many years.
Computed tomography — CT of the chest may be helpful in defining the extent of bronchiectasis in some patients . It is typically performed in selected patients when a detailed understanding of the extent of lung disease is needed to make a clinical decision. As an example, chest CT is of particular interest in patients who have focal areas of advanced disease, which may sometimes be amenable to surgical resection, although this is rarely undertaken. CT surveillance may also be useful to monitor the presence and/or progression of disease caused by atypical mycobacteria.
High-resolution CT (HRCT) scanning is the most useful technique and may demonstrate evidence of unsuspected air trapping and inhomogeneities of lung inflation even in very young asymptomatic children; it is thus a sensitive indicator of early disease in children too young to perform pulmonary function testing . As the lung disease progresses, HRCT findings typically include mucus plugging, centrilobular nodules, peribronchial thickening, air-trapping, and bronchiectasis (characterized by increased diameter of the airway compared with the adjacent artery and/or bronchi) (image 3)  (see "Clinical manifestations and diagnosis of bronchiectasis in adults", section on 'Computed tomography'). Increased pulmonary artery diameter suggests pulmonary hypertension. More studies will be needed to determine the role of serial CT scanning in the evaluation and care of CF patients, balancing the risk of repeated exposure to radiation with the potential benefits of earlier identification of bronchiectasis .
The degree of bronchiectasis noted on CT is associated with infection with mucoid strains of P. aeruginosa . However, the degree of bronchiectasis is only weakly correlated with measures of pulmonary function and is not well correlated with exercise performance [35,36]. Serial HRCT scans often display progressively severe disease despite apparently stable pulmonary function [37-39]. Thus, changes in pulmonary function may be more subtle than or lag behind the CT abnormalities.
Magnetic resonance imaging — Magnetic resonance imaging (MRI) of the chest has not been well validated as an approach to tracking CF pulmonary disease. The few existing studies indicate that MRI may overestimate the degree of bronchiectasis in patients with relatively mild disease and underestimate bronchiectasis in patients with more severe disease. Improving technology allows better imaging of the lung using MRI, producing better concordance between CT and MRI images of the lung. Newer MRI techniques can provide improved functional imaging of the lung (eg, superior evaluation of regional perfusion), but the imaging detail is still somewhat inferior to CT for imaging structural disease [40,41]. Preliminary data from a study that used both techniques suggest that bronchiectasis scores on both MRI and CT are correlated with pulmonary function, but MRI still tended to overestimate bronchiectasis compared with CT . In this study, MRI bronchiectasis scores were also correlated with pulmonary exacerbations, P. aeruginosa infection, and patient-reported respiratory symptoms. As clinicians increasingly seek to identify structural changes in the lungs of CF patients, lifetime exposure to radiation is becoming a serious concern. MRI may become a useful, safer alternative to serial CT scanning but is not yet appropriate for widespread use.
Contrast bronchography — Since the advent of CT scanning, there is no clinical indication for contrast bronchography. When used in the past, they often provided evidence of saccular bronchiectasis in patients with advanced CF (image 4).
PULMONARY FUNCTION TESTING — Pulmonary function testing is used in serial fashion to assess disease severity and progression. Reliable spirometry can be performed by many children aged three to six years using modified acceptability criteria [43,44], and the majority of children ages six and older can perform reliable spirometry and plethysmographic lung volumes. Once the patient is old enough for reliable testing, spirometry is performed at regular intervals, typically approximately every three months. (See "Overview of pulmonary function testing in children".)
In infants with CF, subtle changes in lung structure and function may be identifiable from a very early age, even before clinical signs of disease are apparent [45-47]. Pulmonary function tests (PFTs) in infants are performed using a technique of forced expiration and are well validated. In infants with CF, the tests typically are normal at the time of diagnosis by newborn screening but may deteriorate by six months of age . The decline in infant pulmonary function is associated with signs of pulmonary inflammation and infection . Infant lung function tests have been shown to correlate with results of standard PFTs performed six years later . While infant PFTs are sometimes used for routine clinical management in centers where they are available, they are more often used for research purposes.
Over time, the majority of CF patients develop an obstructive pattern on PFT. The most sensitive measures of early airway obstruction are increases in the ratio of residual volume to total lung capacity (RV/TLC) and decreases in the forced expiratory flow at 25 to 75 percent of lung volume (FEF25-75). As the disease progresses, spirometry reveals a decline in the forced expiratory volume in one second (FEV1) and the ratio of FEV1 to forced vital capacity (FEV1/FVC) . Lung volumes demonstrate increases in TLC and RV as hyperinflation progresses. (See "Overview of pulmonary function testing in children" and "Overview of pulmonary function testing in adults".)
A technique of multiple-breath inert gas washout has been employed to detect early lung disease in infants and young children with CF. This technique appears to have greater sensitivity to detect early airway obstruction as compared with spirometry and may have future research applications in evaluating new therapies [50,51].
CF patients demonstrate greater within-patient variability in pulmonary function than do normal subjects, even with extensive practice in performance of the maneuvers. These variations reflect fluctuations in the degree of airway inflammation, so PFTs are reliable indicators of acute changes in respiratory function. As an example, the FEV1 and FVC may drop 10 to 15 percent with acute exacerbations and return to "baseline" values after several weeks of treatment. These fluctuations are often used as indicators for the adequacy of treatment during acute flares of bronchitis.
Despite intensive therapy, pulmonary function gradually decreases as patients get older, although the pattern of change is unpredictable and varies greatly among individuals. The patterns that may be seen include :
●Linear decreases in FVC and FEV1
●Near-normal pulmonary function for many years, followed by a rapid decline
●Stepwise decreases in measurements of pulmonary function, separated by years of stability at a new level of function
The FEV1 is correlated with survival in CF patients. In a large observational study, predictors of the rate of decline in FEV1 included poor nutritional status, P. aeruginosa infection, persistent crackles on examination, and frequency of pulmonary exacerbations . Patients with mild pulmonary function abnormalities (high FEV1) sometimes experience rapid declines, suggesting that even patients with apparently high lung function as well as young children should be followed regularly with spirometry. Referral to a lung transplant center has been suggested for patients with FEV1 <50 percent predicted and rapidly declining, or an FEV1 persistently <30 percent predicted . (See "Cystic fibrosis: Management of advanced lung disease", section on 'Lung transplant evaluation'.)
MONITORING GAS EXCHANGE — Oxygen saturation should be measured using pulse oximetry when a patient presents with an acute pulmonary exacerbation. It should also be monitored routinely in patients with moderate to severe pulmonary disease to assess the need for supplemental oxygen . For those with severe pulmonary disease, the possible presence of hypercapnia should be evaluated by measuring end-tidal carbon dioxide (CO2) or via arterial blood gas analysis. If hypercapnia is present, the patient may benefit from noninvasive ventilation during sleep. A six-minute walk test can be used to assess oxygenation during physical activity and is often used to monitor functional status after transplant. (See "Cystic fibrosis: Management of advanced lung disease", section on 'Supplemental oxygen'.)
As bronchiectasis and airway obstruction become more pronounced, ventilation-perfusion mismatch leads to hypoxemia. This may initially occur only during sleep or exercise, but patients with advanced disease often require continuous oxygen supplementation. Hypercapnia occurs relatively late in the course of CF lung disease. (See "Long-term supplemental oxygen therapy".)
Regions of chronic alveolar hypoxemia may eventually lead to muscular hypertrophy of the pulmonary vasculature with pulmonary hypertension, right ventricular hypertrophy, and, eventually, cor pulmonale with right heart failure. (See 'Pulmonary hypertension' above.)
Polycythemia typically occurs in patients with congenital heart disease as a physiologic compensation for chronic hypoxemia. By contrast, polycythemia is a rare finding in CF [55,56]. Several factors may prevent the polycythemic response in patients with CF, including the anemia of chronic disease and iron deficiency. In addition, blood volume tends to increase as the disease progresses, so absolute increases in red cell mass may not be reflected in the hematocrit.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cystic fibrosis".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword[s] of interest.)
●Basics topic (see "Patient education: Cystic fibrosis (The Basics)")
•Cystic fibrosis (CF) is characterized by chronic airway obstruction caused by viscous respiratory secretions. This predisposes to chronic pulmonary infection with pathogenic bacteria, including Haemophilus influenzae, Staphylococcus aureus, Pseudomonas aeruginosa, and Burkholderia cepacia complex species (table 1); the prevalence of each bacterial type varies with the age of the patient (figure 1). (See 'Infection' above.)
•Chronic inflammation causes lung damage that ultimately advances to the stage of irreversible bronchiectasis (abnormal dilation and distortion of the bronchial tree) and progressive respiratory failure. Terminal findings often include severely congested parenchyma, with grossly purulent secretions in and around dilated airways (picture 1). (See 'Bronchiectasis' above.)
•Respiratory manifestations of CF usually start with a recurrent cough that gradually becomes persistent. In young infants, this may manifest as prolonged or recurrent episodes of bronchiolitis with tachypnea and wheezing. Eventually, coughing occurs on a daily basis, becoming productive and often paroxysmal. (See 'Respiratory symptoms and signs' above.)
•Airway hyperreactivity is a common finding in CF patients, manifested by wheezing that is initially responsive to bronchodilator therapy. However, as the disease progresses, the airway tends to become floppier and patients may become unresponsive to bronchodilator administration. (See 'Airway reactivity' above.)
•Conventional chest radiographs are used to monitor disease progression in patients with CF lung disease. The chest radiograph may appear normal for the first few years of life or longer in patients with mild disease. The first discernible change is usually hyperinflation. Later, bronchovascular markings become more prominent. In advanced disease, the chest radiograph reveals peribronchial cuffing and "tram tracks," followed by the rounded shadows of saccular bronchiectasis (image 1). (See 'Conventional chest radiography' above.)
•High-resolution CT (HRCT) is performed in selected patients when a sensitive measure of CF lung disease is required for clinical purposes. Serial HRCT scans may detect progressive disease before changes are noted in pulmonary function tests (PFTs) or clinical symptoms. The clinical utility of HRCT in making management decisions has not been established. (See 'Computed tomography' above.)
●PFTs – CF is characterized by progressive obstructive abnormalities on PFT testing. PFT findings vary with acute changes in respiratory function. In addition, patients exhibit an overall declining trend in pulmonary function as their disease progresses, but the decline may not be linear. Decline in FEV1 is associated with diminished survival and is an important indicator for determining referral to a lung transplant center. (See 'Pulmonary function testing' above.)
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