Respiratory system involvement in cystic fibrosis is the leading cause of morbidity and mortality. Defects in the cystic fibrosis transmembrane regulator (CFTR) gene throughout the sinopulmonary tract result in recurrent infections with a variety of organisms including Pseudomonas aeruginosa , methicillin-resistant Staphylococcus aureus, and nontuberculous mycobacteria. Lung disease occurs earlier in life than once thought and ideal methods of monitoring lung function, decline, or improvement with therapy are debated. Treatment of sinopulmonary disease may include physiotherapy, mucus-modifying and antiinflammatory agents, antimicrobials, and surgery. In the new era of personalized medicine, CFTR correctors and potentiators may change the course of disease.
Key points
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Defects in the cystic fibrosis transmembrane regulator (CFTR) lead to airway surface liquid depletion, abnormal pH, inflammation, and chronic infection, causing the pulmonary symptoms/signs of cystic fibrosis (CF).
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Patients with CF are living longer, although respiratory disease remains as the leading cause of mortality; survival bias exists owing to those with “milder” mutations.
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Early lung disease occurs in children with minimal or absent symptoms; the ideal combination of monitoring with lung function, imaging, and bronchoscopy is controversial.
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Pulmonary exacerbations are a major cause of morbidity and expense, although the definition is debated.
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Chronic treatments with physiotherapy, mucolytic, antiinflammatory, and antimicrobial agents are recommended; CFTR potentiators and correctors may change the face of the disease.
Video content accompanies this article at http://www.pediatric.theclinics.com .
Pathophysiology
Cystic fibrosis (CF) is an autosomal recessive disease occurring in approximately 1 in 3500 people and 70,000 people worldwide. The gene for CF was discovered in 1989 and encodes the cystic fibrosis transmembrane regulator (CFTR) protein. As of 2015, there are nearly 2000 identified mutations in CFTR, approximately 200 of which are disease causing (see www.CFTR2.org ). The cascade of events by which CFTR defects lead to irreversible airway wall damage is shown in Fig. 1 . Lack of chloride and bicarbonate secretion through CFTR and excessive sodium absorption through the epithelial sodium channel leads to airway surface liquid (ASL) depletion. Deficient transport of bicarbonate and abnormal pH prevent proper antimicrobial function. The pH in the nasal ASL is lower in CF infants compared with normal infants; in older children and adults, the correlation of pH and genotype is variable, possibly owing to secondary effects of infection and/or inflammation. ASL depletion and abnormal pH contribute to impaired mucociliary clearance. Recent data have suggested that mucociliary transport in piglets with CF is abnormal not only owing to ASL depletion, but also to abnormal adherence of mucus to the submucosal glands and increased mucus viscosity, owing to bicarbonate secretion abnormalities. Reduced MCC effectiveness, amino acid–rich and iron-rich sputum, as well as reduced antimicrobial activity allow typical CF-associated bacteria to grow.
Airway inflammation adds to the cycle of excessive mucus production and infection. Neutrophil elastase, a protease released from neutrophils, causes neutrophil transmigration into the airways, mucus secretion, goblet cell hyperplasia, and CFTR degradation. Other proteases such as cathepsins and matrix metalloproteases are involved in the inflammatory cascade. Irreversible airways obstruction leads to bronchiectasis, resulting in loss of lung function. See [CR] from the CF Foundation (CFF) website demonstrating normal versus abnormal ciliary movement: https://www.youtube.com/watch?feature=player_embedded&v=YzjnxegMWfk .
Lung Disease, Mortality, and Determinants of Lung Disease Severity
The median predicted age of survival in people with CF has steadily increased over the last 25 years from approximately 28 to 39 years of age. These data do not reflect the new corrector/potentiator therapies (see Ong T, Ramsey BW: New Therapeutic Approaches to Modulate and Correct CFTR , in this issue), but reflect earlier diagnosis by newborn screening. In 2014, 64% of new CF diagnoses in the United States were detected by newborn screening. The Wisconsin newborn screening cohort showed that the significant determinants of lung disease were genotype, poor growth, hospitalizations, meconium ileus, and infection with mucoid Pseudomonas aeruginosa . The median age of patients with CF is higher in people who have class IV or V mutations compared with class I, II, or III mutations. However, pulmonary phenotype can be either mild or severe among individuals with the same mutation. On a population level, children with 1 or no copies of the F508del mutation have a slower decline in lung function; low body mass index, female gender, and presence of various organisms on culture are associated with a more rapid decline. Hispanic ethnicity is associated with higher mortality in patients with CF.
Pathophysiology
Cystic fibrosis (CF) is an autosomal recessive disease occurring in approximately 1 in 3500 people and 70,000 people worldwide. The gene for CF was discovered in 1989 and encodes the cystic fibrosis transmembrane regulator (CFTR) protein. As of 2015, there are nearly 2000 identified mutations in CFTR, approximately 200 of which are disease causing (see www.CFTR2.org ). The cascade of events by which CFTR defects lead to irreversible airway wall damage is shown in Fig. 1 . Lack of chloride and bicarbonate secretion through CFTR and excessive sodium absorption through the epithelial sodium channel leads to airway surface liquid (ASL) depletion. Deficient transport of bicarbonate and abnormal pH prevent proper antimicrobial function. The pH in the nasal ASL is lower in CF infants compared with normal infants; in older children and adults, the correlation of pH and genotype is variable, possibly owing to secondary effects of infection and/or inflammation. ASL depletion and abnormal pH contribute to impaired mucociliary clearance. Recent data have suggested that mucociliary transport in piglets with CF is abnormal not only owing to ASL depletion, but also to abnormal adherence of mucus to the submucosal glands and increased mucus viscosity, owing to bicarbonate secretion abnormalities. Reduced MCC effectiveness, amino acid–rich and iron-rich sputum, as well as reduced antimicrobial activity allow typical CF-associated bacteria to grow.
Airway inflammation adds to the cycle of excessive mucus production and infection. Neutrophil elastase, a protease released from neutrophils, causes neutrophil transmigration into the airways, mucus secretion, goblet cell hyperplasia, and CFTR degradation. Other proteases such as cathepsins and matrix metalloproteases are involved in the inflammatory cascade. Irreversible airways obstruction leads to bronchiectasis, resulting in loss of lung function. See [CR] from the CF Foundation (CFF) website demonstrating normal versus abnormal ciliary movement: https://www.youtube.com/watch?feature=player_embedded&v=YzjnxegMWfk .
Lung Disease, Mortality, and Determinants of Lung Disease Severity
The median predicted age of survival in people with CF has steadily increased over the last 25 years from approximately 28 to 39 years of age. These data do not reflect the new corrector/potentiator therapies (see Ong T, Ramsey BW: New Therapeutic Approaches to Modulate and Correct CFTR , in this issue), but reflect earlier diagnosis by newborn screening. In 2014, 64% of new CF diagnoses in the United States were detected by newborn screening. The Wisconsin newborn screening cohort showed that the significant determinants of lung disease were genotype, poor growth, hospitalizations, meconium ileus, and infection with mucoid Pseudomonas aeruginosa . The median age of patients with CF is higher in people who have class IV or V mutations compared with class I, II, or III mutations. However, pulmonary phenotype can be either mild or severe among individuals with the same mutation. On a population level, children with 1 or no copies of the F508del mutation have a slower decline in lung function; low body mass index, female gender, and presence of various organisms on culture are associated with a more rapid decline. Hispanic ethnicity is associated with higher mortality in patients with CF.
Clinical presentation
Early Pulmonary Disease
Most infants diagnosed by newborn screening are asymptomatic. Universal adoption of CF newborn screening in the United States has led to earlier diagnosis and treatment. Animal models have shown that structural lung damage occurs in utero and in piglets before symptoms develop. Data from the Australian Respiratory Early Surveillance Team for Cystic Fibrosis suggest early lung disease occurs in infants and preschoolers with no symptoms. Computed tomography (CT) evidence of bronchiectasis was reported in 44% of patients at initial assessment; at the 1-year follow-up, 26% of these findings had resolved. Of the remaining 18%, 74% persisted and 63% progressed. Air trapping was the most common finding, reported in 88% of the scans, and persisted in 81% of subsequent scans. In a longitudinal multicenter observational study in England, volumetric CT scans obtained at 1 year of age in infants with CF showed similar prevalence of bronchiectasis. Air trapping was less common. A study from the Netherlands showed that peripheral bronchiectasis progresses despite normal pulmonary function tests.
The London Cystic Fibrosis Collaboration showed objective measures of decreased lung function in 3-month-old infants with CF diagnosed by newborn screening. These abnormalities indicate the presence of early lung disease in patients with CF compared with normals. Lower infant lung function was also associated with infection from either Staphylococcus aureus or P aeruginosa . Bronchoalveolar lavage in infants with CF showed neutrophilic inflammation as early as 4 weeks of age, in patients with and without pathogens. Active elastase and increased interleukin-8 levels were present, confirming the presence of inflammation early in life.
Later Pulmonary Disease
Before newborn screening, infants and children were diagnosed clinically with respiratory symptoms such as cough (either dry or productive) in 45% of patients. Recurrent bronchiolitis with wheezing or airway reactivity can be seen. Diagnosis may be delayed in patients with milder or rarer mutations, false-negative newborn screens, and birthdate preceding newborn screening implementation in their state of birth. As lung disease progresses, exercise intolerance and shortness of breath develop. Chronic bronchitis progressing to obstructive lung disease and bronchiectasis is the hallmark of CF lung disease. Bronchiectasis ( Fig. 2 ) leads to reduced lung function and respiratory failure. Typical physical findings include increased anteroposterior diameter of the chest, seen as hyperinflation on chest radiographs ( Fig. 3 ), scattered or localized crackles, and digital clubbing. Other manifestations of CF are listed in Box 1 .
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Bronchiectasis/airways obstruction
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Sinus disease (chronic pansinusitis)
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Pancreatic insufficiency (85%)
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Growth failure
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Pancreatitis
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Digital clubbing
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Infertility
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Meconium ileus/distal intestinal obstructive syndrome
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Cystic fibrosis-related diabetes
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Hepatobiliary disease
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Rectal prolapse
Sinus disease
The unified airway theory proposes that organisms colonizing the upper airway lead to chronic infection in the lower airways. Chronic rhinosinusitis is common in CF and may lead to decreased appetite and cough. Chronic rhinosinusitis is defined in Box 2 along with information on treatment of sinusitis and polyps. In some patients with CF, nasal endoscopy will demonstrate a nose filled with polypoid tissue that bleeds easily; CT of the sinuses is the best imaging modality for diagnosis of anatomic sinus abnormalities in CF, such as sinus hypoplasia, medial bowing of the lateral nasal wall, lower fovea ethmoidalis, and uncinated process reabsorption. Sinus disease in CF can be treated with nonsurgical or surgical measures ( Box 3 ).
| Subjective Symptoms | Objective Symptoms |
|---|---|
| Mucopurulent nasal drainage Nasal congestion Facial pain Decreased sense of smell | Mucosal inflammation on nasal endoscopy Radiographic findings of mucosal inflammation |
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Nonsurgical treatment for chronic rhinosinusitis and polyposis in CF
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Saline irrigation (Neti-Pot, saline rinses, etc)
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Topical steroids (nasal steroids)
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Irrigations with 3% hypertonic saline
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Sinusitis treatment with antibiotics for 3 to 6 weeks: penicillins, cephalosporins, quinolones, aminoglycosides
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Irrigations with tobramycin
Surgical treatment for chronic rhinosinusitis and polyposis in CF
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Indications
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Persistent nasal congestion/obstruction, headache, uncontrolled pain, infection, mucocele, unresolved fevers, awaiting lung transplantation
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Purpose
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Widen natural sinus ostia to improve drainage, reduced inflammation and to remove nasal polyps
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Maximize postoperative medical therapy
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Approaches
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Polypectomy
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Widening of the natural sinus ostia (“wide antrostomies”)
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Endoscopic medial maxillectomy
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FESS: chronic sinus disease success rates of 80% to 93%, but with sinonasal polyposis, 40% to 70% resolution of symptoms and recurrence rates are greater than 50%
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Abbreviations: CF, cystic fibrosis; FESS, functional endoscopic sinus surgery.
Assessment and monitoring of lung disease
Lung Function Testing
Spirometry
Spirometry measures the forced expiratory volume in 1 second (FEV 1 ), using height, gender, and age as standards (FEV 1 % predicted). Box 4 describes key points about spirometry. Height changes rapidly during childhood; thus, absolute values for FEV 1 always increase. Predicted values are used to interpret whether the increases are appropriate or show signs of decline. Spirometry is the core measurement of lung function in patients with CF; however, children need to be able to cooperate with the maneuvers. Thus, detection of lung disease in early childhood is challenging. Testing in younger children includes infant lung function testing, preschool spirometry and lung clearance index ( Table 1 ). At present, these tests are not done routinely but are used in research.
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Forced expiratory flow between 25 to 75 of forced vital capacity (FEF 25–75 ) is more variable than FEV 1 , but also more sensitive to changes in the small airways.
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FEV 1 % predicted predicts future morbidity and mortality.
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Increasing numbers of children have normal spirometry until adolescence.
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Spirometry is useful in those with moderate to severe lung disease, but it is not a sensitive tool for monitoring disease in patients with mild lung disease.
Abbreviations: FEF, forced expiratory flow; FEV 1 , forced expiratory volume in 1 second.
| Infant Lung Function Testing | Preschool Spirometry | Lung Clearance Index | |
|---|---|---|---|
| Technique | Raised volume rapid thoracoabdominal compression | Spirometry | Multiple breath inert gas washout test |
| Parameter measured | FEF: FEV at 0.5 s (FEV 0.5 ) used in infants owing to short time for lung emptying |
|
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| Evidence | Improvement in FEV 0.5 in CF patients given hypertonic vs normal saline as part of a randomized clinical trial |
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| Advantages |
| Good reference ranges in people with CF 3–95 y old across the world |
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| Disadvantages |
| 50% of children can reliably perform on their first attempt |
|
Radiology
Chest radiographs and chest computed tomography
The CFF recommends that chest radiographs be done annually. Scoring systems have been developed for objectivity. Although less sensitive than chest CT, chest radiographs can detect mucus plugging, atelectasis, consolidation, and bronchial wall thickening. Chest CT scans are not recommended on a routine basis owing to radiation dose, need for sedation, and need to control for volume, especially in young children. However, chest CT may be considered on a case-by-case basis, because it is more sensitive to the presence and severity of disease compared with FEV 1 %, shows improvement with therapy, and predicts future disease progression. CT also correlates with true endpoints, like survival, pulmonary exacerbations (PEx), quality of life, FEV 1 , lung clearance index, and bronchoalveolar lavage inflammatory markers. The role of MRI in the monitoring of lung disease in CF and its response to treatment is being evaluated. The clear advantage of MRI over chest CT is the lack of ionizing radiation; however, sedation is needed for most young children.
Airway Cultures
A broad range of bacteria colonize the respiratory tract in patients with CF and are found in throat cultures, sputum, or bronchoalveolar lavage samples. By adulthood, 50% to 70% of CF patients are chronically infected with P aeruginosa ( Fig. 4 ), which has negative effects on disease severity, survival and frequency of exacerbations. Methicillin-resistant Staphylococcus aureus , Burkholderia cepacia , Stenotrophomonas maltophilia , and Mycobacterium abscessus are associated with deteriorating lung function. The CFF recommends surveillance airway bacterial cultures be obtained in all patients every 3 months and mycobacterial cultures be obtained yearly in some patients. A full review of CF microbiology is found in the article (see Zemanick ET, Hoffman LR: Cystic Fibrosis: Microbiology and Host Response , in this issue).
Bronchoscopy
Bronchoscopy is used to obtain lower airway samples for culture and to assess airway inflammation and look for anatomic abnormalities. However, it requires sedation, which has inherent risks and expense. No improved outcomes or cost benefits have been identified in asymptomatic young patients who underwent bronchoscopy to identify pathogens versus those who did not. However, bronchoscopy should be considered in patients who have a decline in FEV 1 or have recurrent PEx despite standard therapy.
Pulmonary Exacerbations
PEx are characterized by increased pulmonary symptoms such as cough, dyspnea, sputum production, change in sputum color or consistency, worsening of lung function (>10% decline in FEV 1 % predicted), and systemic symptoms like fatigue, anorexia, and weight loss. There have been challenges to defining PEx and distinguishing mild, moderate, and severe categories. PEx are associated with poor health-related quality of life, disease progression, and survival. Despite the central role that PEx plays in CF, no consensus diagnostic criteria exist. Empiric definitions of PEx have been used in clinical trials evaluating new CF treatments, but they have not been validated formally ( Table 2 ).
| Study 1 | Study 2 |
|---|---|
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