Cystic fibrosis (CF) is the most common autosomal-recessive disease in white persons. Significant advances in therapies and outcomes have occurred for people with CF over the past 30 years. Many of these improvements have come about through the concerted efforts of the CF Foundation and international CF societies; networks of CF care centers; and the worldwide community of care providers, researchers, and patients and families. There are still hurdles to overcome to continue to improve the quality of life, reduce CF complications, prolong survival, and ultimately cure CF. This article reviews the epidemiology of CF, including trends in incidence and prevalence, clinical characteristics, common complications, and survival.
Key points
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Survival for people with CF has improved greatly and for the first time adults with CF outnumber children with CF.
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The introduction of newborn screening has changed how CF is recognized; today, most people with CF are diagnosed in the neonatal period.
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Changes in CF therapies, disease measures, and outcomes can be tracked longitudinally using large registries, such as the CF Foundation Patient Registry.
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Progressive lung disease can be detected in early life via sensitive measures, such as chest CT scans and the lung clearance index.
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CF is a multisystem disease with complications that include pancreatic insufficiency, sinusitis, CF-related diabetes, infertility, and depression and anxiety.
Introduction
Cystic fibrosis (CF) is the most common autosomal-recessive cause of early mortality in caucasians worldwide. However, significant advances in therapies and outcomes for people with CF over the past 30 years have brought hope and optimism to clinicians, researchers, and most importantly, individuals and families with CF. In just the past few years, therapies that directly correct errors caused by mutations of the Cystic Fibrosis Transmembrane Conductance Regulator ( CFTR ) gene have received regulatory approval, the current median predicted survival is approaching 40 years (and even longer in Canada and some other countries), and the number of adults with CF outnumber the number of children with CF in the United States for the first time.
These recent successes illustrate the great strides that have occurred since “cystic fibrosis of the pancreas” was first described by Dorothy Anderson in 1938. At that time, few children with CF lived beyond 5 years, and it was not until the introduction of airway clearance, pancreatic enzyme replacement therapy, nutritional supplements, and anti- Staphylococcus antibiotics in the 1960s to 1970s that life expectancy began to extend into adolescence.
Introduction
Cystic fibrosis (CF) is the most common autosomal-recessive cause of early mortality in caucasians worldwide. However, significant advances in therapies and outcomes for people with CF over the past 30 years have brought hope and optimism to clinicians, researchers, and most importantly, individuals and families with CF. In just the past few years, therapies that directly correct errors caused by mutations of the Cystic Fibrosis Transmembrane Conductance Regulator ( CFTR ) gene have received regulatory approval, the current median predicted survival is approaching 40 years (and even longer in Canada and some other countries), and the number of adults with CF outnumber the number of children with CF in the United States for the first time.
These recent successes illustrate the great strides that have occurred since “cystic fibrosis of the pancreas” was first described by Dorothy Anderson in 1938. At that time, few children with CF lived beyond 5 years, and it was not until the introduction of airway clearance, pancreatic enzyme replacement therapy, nutritional supplements, and anti- Staphylococcus antibiotics in the 1960s to 1970s that life expectancy began to extend into adolescence.
Cystic Fibrosis Foundation Patient Registry
Many of the developments in CF have occurred at care centers accredited by the CF Foundation (CFF). Modeled on the first successful therapeutic program developed in the 1950s, CF care centers follow CFF Care Guidelines, deliver multidisciplinary care, and have appropriate inpatient and outpatient medical, diagnostic, and laboratory facilities. They are part of a network that includes pediatric, adult, and affiliate programs. As of 2014, there were 121 CF care centers geographically dispersed within the United States. All accredited care centers must contribute data to the CFF Patient Registry (CFFPR). The CFFPR is an ongoing, observational study that is the primary tool for monitoring the health of individuals with CF in the United States. Starting in the 1960s, the CFFPR has evolved to expand the quantity and frequency of the information collected from individuals with CF. Data entered into the CFFPR include demographic and diagnostic information, anthropometric values, pulmonary function test (PFT) results, cultures of respiratory secretions, CF complications, comorbidities, and prescribed CF medications. Thus, the CFFPR is a valuable resource used extensively to inform clinical care, support quality improvement initiatives, and conduct research. Outside of the United States, CF registries exist in Canada, the United Kingdom, Europe, and Oceania, all of which are used to better the understanding of individuals with CF and the course of the disease.
Incidence
Among white persons, CF occurs in approximately 1 in 3000 to 4000 live births. Approximately 1 in 25 to 30 white persons are carriers of a pathogenic mutation of the CFTR gene. In other races and ethnicities CF occurs less commonly, including approximately 1 in 4000 to 10,000 Latin Americans, 1 in 15,000 to 20,000 African Americans, and even less commonly in Asian Americans. In the United States, approximately 1000 individuals are diagnosed with CF each year ( Fig. 1 ).
Before the widespread use of newborn screening (NBS), individuals with CF were diagnosed either after presenting symptomatically, or via family history. The list of presenting signs and symptoms indicates the multiorgan system nature of the disease ( Box 1 ). In 2004, the Centers for Disease Control and Prevention recommended that all states consider NBS for CF. Since then, the proportion of individuals diagnosed via NBS has risen to account for nearly two-thirds of all diagnoses. The early diagnosis of CF after NBS is associated with improved nutritional outcomes and may improve later pulmonary function. Similar to NBS, prenatal screening is also widely available, although it accounts for only a minority of diagnoses (4% in 2014). Overall, reports are inconsistent regarding the impact prenatal screening and NBS have had on incidence rates; some reported differences may be in part caused by changes in racial and ethnic distributions over time.
General
Family history of CF
Salty-tasting skin
Clubbing of fingers and toes
Productive cough
Pseudomonas aeruginosa isolated from airway secretions
Hypochloremic metabolic alkalosis
Neonatal
Meconium ileus
Prolonged neonatal jaundice
Abdominal or scrotal calcifications (secondary to meconium peritonitis)
Intestinal atresia
Infancy
Persistent infiltrate on chest radiographs
Failure to thrive
Anasarca or hypoproteinemia
Chronic diarrhea
Abdominal distention
Cholestasis
Staphylococcus aureus pneumonia
Pseudotumor cerebri (vitamin A deficiency)
Hemolytic anemia (vitamin E deficiency)
Childhood
Chronic pansinusitis
Nasal polyps
Steatorrhea
Rectal prolapse
Distal intestinal obstruction syndrome
Recurrent or chronic pancreatitis
Liver disease
Adolescence or adulthood
Allergic bronchopulmonary aspergillosis
Chronic pansinusitis or nasal polyps
Bronchiectasis
Hemoptysis
Recurrent or chronic pancreatitis
Portal hypertension
Delayed puberty
Congenital bilateral absence of the vas deferens
The introduction of NBS for CF has also led to the recognition of patients who have abnormal NBS results, but do not meet the diagnostic criteria for CF. The terms “CFTR metabolic syndrome” in the United States and “CF screened positive, inconclusive diagnosis” in Europe have been introduced to characterize the symptoms of these individuals ( Table 1 ). Although the frequency of the diagnosis of CFTR metabolic syndrome/CF screened positive, inconclusive diagnosis depends on the NBS algorithm used ( Box 2 ), both the CFF and European CF Society recommend that these individuals be followed at specialized CF centers. This population of patients is different than the patients who present clinically with some degree of CFTR dysfunction, such as congenital bilateral absence of the vas deferens, recurrent pancreatitis, or bronchiectasis; these patients are considered to have CFTR-related disorders (see Table 1 ).
| CF | CRMS | CFTR-RDs | |
|---|---|---|---|
| Identified via NBS | + | + | − |
| Sweat test results a | |||
| Abnormal | + | − | − |
| Intermediate | + | + | + |
| Normal | − | + | − |
| Typical CFTR mutation analysis | 2 disease-causing mutations | 1–2 mutations, 1 of which is not clearly disease-causing | 1–2 mutations, 1 of which is not clearly disease-causing |
| Symptomatic at presentation | + or − | − | + |
| Diagnostic criteria | Abnormal sweat test and/or 2 disease-causing mutations | Intermediate sweat test and <2 disease-causing mutations or normal sweat test and 2 CFTR mutations, including <2 disease-causing mutations | Intermediate sweat test and 2 CFTR mutations, including <2 disease-causing mutations |
a Abnormal sweat chloride test ≥60 mmol/L: intermediate, 40–59 mmol/L in children >6 months of age and adults or 30–59 mmol/L in children <6 months of age; normal, <40 mmol/L in children >6 months of age and adults or <30 mmol/L in children <6 months of age.
New York state, 0.5:1
California, 2.9:1
Canada/Italy, 0.3–0.7:1
Entire United States, 0.2:1
Prevalence and trends
The CFFPR captures most individuals with CF living in the United States, but does not include those who seek care outside of a CFF care center, who do not consent to participate in the CFFPR, or who are lost to follow-up in a given calendar year. To estimate the total number of individuals with CF living in the United States, the CFF combined CFFPR data with national data sources. They estimated that there were around 33,200 individuals with CF living in the United States in 2012, of whom approximately 28,700 had data entered into the CFFPR.
Demographics
The prevalence of CF varies throughout the 50 United States and the District of Columbia ( Fig. 2 ), ranging from 1.2 per 100,000 people in Hawaii to 24.6 per 100,000 in Vermont. The variability across states is likely related to the proportion of the state that is white. In 2014, a total of 93.9% of the individuals in the CFFPR were white, 4.6% were African American, 3.1% were other races, and 8.2% were Hispanics. This is in contrast to the population of the United States that is 62% white, 12% African American, and 17% Hispanic.
In 1966, CF was a disease primarily affecting children with only 6% of the CFFPR population older than age 18 and only 0.1% older than age 30. However, over the last 30 years, there have been steady increases in the adult population of people with CF, leading to an increase in the prevalence of CF. For the first time in 2014, the adult population made up more than half of individuals in the CFFPR ( Fig. 3 ).
CF care is multifaceted and involves substantial costs for outpatient medical care, hospitalizations, and medications thereby making health insurance for individuals with CF a necessity. Federal- and state-supported insurance is used extensively within the population ( Fig. 4 ). In 2014, CFFPR data showed 41% of children received Medicaid only, 8% received insurance through state special needs programs, and an additional 6% received both types. Among adults, 18% received Medicare disability benefits and an additional 21% received Medicaid. Only a small percentage of individuals report no insurance for the entire year (0.4% of children and 1.3% of adults). The impact of the costs of care are even wider-reaching because of days missed from school and work for patients and caregivers.
Clinical characteristics
Lung Disease
Lung disease is the major source of morbidity and mortality for people with CF. The most commonly tracked measure of lung disease forced expiratory volume in 1 second (FEV 1 ). Expressed as percent predicted or z scores adjusted for age, gender, race, and height, FEV 1 can first be measured in children approaching school-age. FEV 1 % predicted has improved markedly: the average FEV 1 is nearly 100% predicted (ie, normal) among 6 year olds in the most recent birth cohort ( Fig. 5 ). Among 18 year olds, the proportion with FEV 1 greater than or equal to 70% predicted increased from 43% in 1994% to 72% in 2014.
Children less than 6 years of age are unable to reliably perform spirometry, and FEV 1 has poor sensitivity for early CF lung disease. There are several complementary measures that overcome these limitations, including infant PFTs, chest imaging, and lung clearance index (LCI), a research tool that identifies abnormalities in the distribution of ventilation. The Australian Respiratory Early Surveillance Team for CF (AREST CF) and London CF Collaborative studies have followed children with CF prospectively from diagnosis after NBS with routine infant PFTs, bronchoscopies, chest computed tomography (CT) scans, and LCI measurements. These studies have shown that infant PFTs are abnormal in approximately 25% of 3 month olds and in greater than 50% of 2 year olds with CF, although they may stabilize with conventional CF evaluations and treatment. LCI is abnormal even in 3 month olds. Early abnormalities in LCI may correlate with later abnormalities on chest CT scans, and are more likely to be abnormal than traditional spirometry in the early school years. Results of chest CT scans are inconsistent between the two studies; bronchiectasis, the most severe manifestation of CF lung disease, is often present in infants of the AREST CF cohort but not in the 1 year olds of the London CF Collaborative cohort. The use of complementary measures, although not yet used widely, has advanced the understanding of early CF lung disease.
Nutrition
People with CF can develop malnutrition and failure to thrive even in the first few weeks after birth. This is caused by pancreatic insufficiency, which prevents the absorption of fats, proteins, and fat-soluble vitamins. Approximately 85% of individuals with CF are prescribed pancreatic enzyme replacement therapy to treat pancreatic insufficiency. As demonstrated by Corey and colleagues, improved survival is associated with better measures of nutrition among people with CF. Furthermore, nutritional status and severity of lung disease are tightly linked ( Fig. 6 ) and there are data to suggest that improvements in nutritional status are associated with improved lung function. As a result, the CFF nutrition guidelines recommend that all children maintain a body mass index (BMI) greater than or equal to 50th percentile for age on the Centers for Disease Control and Prevention growth charts and that all adult females and males achieve a BMI greater than or equal to 22 and 23 kg/m 2 , respectively. Substantial progress has been made toward this goal, with a median weight for length percentile of 63% among children younger than age 2, a median BMI percentile of 50% among individuals aged 2 to 19, and a median BMI of 22.3 among adults. However, despite the improvements, there is still evidence of stunting with median height percentiles of 32% in children younger than age 2 and 35% among individuals aged 2 to 19. At the other end of the spectrum, there is concern that the number of people with CF who are overweight or obese is increasing.
