Cystic fibrosis (CF) is a systemic disease of the exocrine glands characterized by a progressive obstructive lung disease (bronchiectasis), exocrine pancreatic insufficiency, and gastrointestinal secretory defects. The sweat glands, vas deferens, and other organs are also affected to varying degrees.
First described in 1938, CF is the most common inherited autosomal recessive disorder in the North American white population. An estimated 40,000 individuals in the United States are living with CF, and about 12 million people are carriers. CF is also the most common cause of pancreatic insufficiency in children. Because normal absorption and digestion of nutrients, especially fat, are altered by pancreatic insufficiency, failure to thrive, malnutrition, diabetes, and growth problems are common clinical features in the absence of treatment. Altered fatty acid metabolism produces excess arachidonic acid and leads to inflammatory complications in multiple systems. The median age of survival is approximately 39 years.
CF is caused by mutations in a single gene on chromosome 7 that encodes the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which controls the concentration of sodium and chloride across certain epithelial cell membranes. More than 1,000 mutations of this gene have been identified; the most common is the ΔF508 mutation.
The disruption of proper CFTR function causes excessive sodium and chloride resorption. Water, in turn, follows the abnormal movement of sodium and chloride into the epithelial cell layer. This dehydrates airway surfaces, produces thick mucus, and impedes mucociliary transport. Thickened secretions in the airways lead to obstruction and subsequent colonization with pathologic bacteria. The same process in the pancreas leads to severely impaired secretory function and duct obstruction resulting in decreased digestive enzyme delivery to the digestive tract. Severe mutations that cause complete duct obstruction can lead to autolysis of islet cells causing impaired endocrine function as well.
Genetics. CF is an autosomal recessive condition. If both parents are carriers, a child has a 25% chance of having the disease and a 50% chance of also being a carrier. One in 25 white people is a carrier. A family history of cystic fibrosis and unexplained infant death are also risk factors.
Race. The prevalence of CF is approximately 1 in 3,200 for whites, 1 in 15,000 for Blacks, 1 in 10,500 for Native Americans, 1 in 30,000 for Asian Americans, and 1 in 10,000 for Hispanics.
Signs and symptoms of CF reflect sinopulmonary, hepatic, endocrine, and intestinal involvement.
Respiratory problems include:
Persistent, productive cough, hyperinflation of the lung fields seen on chest x-rays, and pulmonary function tests consistent with obstructive airway disease.
Recurrent respiratory infections, which are associated with Haemophilus influenza and Staphylococcus aureus in the first decade of life. Teenage and adult years are characterized by infections with mucoid Pseudomonas aeruginosa and S aureus, which quickly acquire multiple drug resistance. Any sputum culture growing P aeruginosa should prompt an evaluation for bronchiectasis, and, if present, a workup for CF.
Acute exacerbations of respiratory chronic bacterial colonization usually present with increased green-colored sputum, malaise, fatigue, wheezing, dyspnea, pneumothorax, and hemoptysis, due to increased inflammation in the airway.
Concurrent sinus disease, including chronic sinusitis and nasal polyposis, is relatively common and may contribute to progressive lung decline.
Intestinal involvement may lead to:
Bowel obstruction, with meconium ileus and intussusception, is particularly common at birth. Other digestive symptoms are steatorrhea, abdominal cramping and constipation, rectal prolapse, liver and gallbladder disease, and CF-related diabetes.
Malabsorption, which causes failure to thrive, retarded growth, and fatigue.
Male infertility is also a symptom. While spermatogenesis is not affected, most affected men cannot naturally conceive due to incompletely developed genital structures. The most common finding is congenital bilateral absence of the vas deferens.
Women may have some abnormalities of the cervical mucus, but fertility does not appear to be significantly reduced in the absence of severe malnutrition.
Patients with CF have reduced bone mineral content and increased rates of fractures and kyphoscoliosis, increased risk for recurrent venous thrombosis, as well as nephrolithiasis and nephrocalcinosis.
CF is diagnosed by clinical findings, along with biochemical or genetic confirmation. A sweat chloride test, which can be done as early as 48 hours after birth, is the mainstay of laboratory confirmation. Newborn screening is mandatory in all 50 states. A positive sweat test (see below), combined with pulmonary and/or gastrointestinal symptoms, establishes the classic diagnosis in nearly all cases. CF mutations, identified through genetic testing, can also confirm diagnosis, or they can be used to make the diagnosis in patients with mild forms of the disease.
A patient with the symptoms and/or signs presented above may require the following tests (additional tests are available if the diagnosis remains in doubt):
Sweat chloride test. The test is performed by collecting sweat using pilocarpine iontophoresis and by chemical determination of the chloride concentration. A value 60 mmol/L (on 2 occasions) supports the diagnosis.
Genetic testing. Patients who exhibit signs and symptoms but do not have a positive sweat test should have a genetic test. Prenatal testing and newborn screening may be used. Early detection renders a better clinical course.
While not widely available, nasal potential difference measurements can confirm the diagnosis if sweat testing and genetic testing results are inconclusive.
Stool tests. Fecal fat analysis can be used to confirm pancreatic insufficiency. Low levels of fecal elastase support a CF diagnosis, although a normal level does not exclude the diagnosis.
Bone density evaluation may reveal osteopenia or osteoporosis.
The cornerstones of treatment for CF patients are airway clearance therapies and techniques, bronchodilators, anti-inflammatory therapies, specific antibiotic and infection prevention regimens and nutritional support. CF patients should be cared for at a comprehensive CF care center by a multidisciplinary health care team that includes a physician, nurse, respiratory therapist, dietitian, and social worker. Many clinical care guidelines are available from the Cystic Fibrosis Foundation.
The pulmonary status of patients should be regularly monitored by an assessment of symptoms, a physical examination, and spirometry. Percent predicted forced expiratory volume in 1 second (FEV1) is accepted as the single most useful objective measure of pulmonary status. Oxygen saturation at rest, during exercise, and/or during sleep should be measured routinely in patients with moderate-to-severe pulmonary disease to assess the need for supplemental oxygen.
Participation in regular exercise may help preserve pulmonary function. A review of exercise benefits indicated that, over 3 years of physical training, the mean annual rate of decline in forced vital capacity was significantly greater in the control group compared with the exercise group. Both aerobic exercise and resistance exercise appear to benefit CF patients. Children who received aerobic training had significantly better peak aerobic capacity, whereas those who received resistance training had better weight gain, lung function, and leg strength than children who received aerobic training.
Antibiotics are used both for pulmonary exacerbations and chronic suppressive therapy. During acute exacerbations of chronic infections, therapy is typically aggressive, and treatment should be guided by each patient’s most recent sputum culture. Aggressive management of chronic lung infections is helpful in preventing lung function decline. A complete microbiologic assessment of expectorated sputum, including antibiotic susceptibility testing, should be performed every 3 months. More than 75% of CF patients are chronically infected by P. aeruginosa by adulthood, and this represents the most significant cause of infection over the life of the patient. Staphylococcus aureus is the most prevalent bacterial infection in childhood.
Chronic treatment with oral antibiotics is not recommended because the benefits do not outweigh the associated antibiotic resistance that it may cause, with two exceptions:
A regular azithromycin regimen (typically 3 times per week) is recommended in all CF patients 6 years and older, regardless of colonization with P. aeruginosa. Patients as young as 6 months may be so treated if they are found to be colonized. This recommendation is based on the evidence that suggests lower rates of pulmonary exacerbations and hospitalization with regular use. This efficacy may be attributable to antibiotic effects, anti-inflammatory effects, or both.
Inhaled tobramycin or aztreonam are cornerstones of standard CF care. In a clinical trial, inhaled tobramycin (TOBI) 300 mg twice daily led to a 12% improvement in FEV1. Treatment is given every other month in order to avoid antibiotic resistance.
CF is an obstructive airway disease. Bronchodilators (see Asthma chapter) are used by the great majority of patients.
Inhaled recombinant human DNase I decreases sputum viscosity by degrading extracellular DNA into smaller pieces. Along with hypertonic saline, this mucolytic is recommended for daily use to optimize airway clearance.
Chest physiotherapy may be administered through a variety of techniques and should be performed daily to help clear airway mucus. The method should be individualized, based on efficacy and compliance. Financial assistance for modalities such as mechanical vests may be available through the Cystic Fibrosis Foundation.
In advanced disease, when FEV1 drops below 50% of predicted values, bilateral lung transplant is an option, but an imperfect one at best. Thorough risk/benefit evaluation is required.
Corticosteroids are generally reserved for treatment of asthma in CF because of their poor side-effect profile.
CFTR modulators. These medications improve function of the defective CFTR protein. Ivacaftor, lumacaftor and tezacaftor-ivacaftor are the first CFTR modulating drugs to be FDA approved. Use of these medications is dependent on individual genotype.
Influenza and pneumococcal vaccines are recommended for all patients with CF.
Exogenous pancreatic enzyme replacement therapy allows for the digestion of lipids and prevents symptoms of steatorrhea.
A significant percentage of patients develop CF-related diabetes mellitus (CFRD). An oral glucose tolerance test should be done yearly, starting by age 10, and treatment instituted when 2-hour glucose levels surpass 200 mg/dL. Frequently, HbA1c levels are normal. CFRD is typically preceded by decline in lung function several years prior to CFRD diagnosis. CF patients should not automatically be placed on diabetic diets (due to high caloric needs). Instead, insulin therapy should be increased to achieve optimal glycemic control.
In the absence of steatorrhea, constipation is common. This can be avoided and/or treated with an osmotic laxative, such as polyethylene glycol electrolyte solution (e.g., MiraLAX or Golytely). Constipation must be differentiated from distal intestinal obstruction syndrome (DIOS), an acute complete or incomplete obstruction of the ileocecum by inspissated intestinal contents unique to CF. DIOS must be managed more aggressively to prevent intestinal ischemia and/or need for surgical intervention.
Primary biliary cirrhosis can be treated with ursodeoxycholic acid, which improves biliary excretion and bile acid composition, even in asymptomatic or minimally symptomatic patients.
Proper nutrition (see below) and exercise may help prevent decreased bone density. Bisphosphonates are effective when indicated.
Nutritional management has a dramatic effect on growth and survival in patients with CF, but it is often challenging due to malabsorption. Survival is markedly poorer in patients who are underweight for their height. Thus, a high-energy diet is commonly recommended, along with nutritional supplements. Additional calories and protein from enteral nutrition may be indicated to improve nutritional status and growth in both adults and children and should be used if necessary.
Assessing nutritional status is important to determine proper therapy for patients with CF. Height z-score, weight z-score, and BMI percentile should be measured in children (weight-for-length z-score in children under 2), and BMI in adults. Cystic Fibrosis Foundation guidelines recommend that all children achieve a weight-for-length z-score at or above the 50th percentile by 2 years old and that all children and adolescents aged 2 to 20 years maintain a BMI at or above the 50th percentile. Dietary intake (calories and fat), micronutrient and essential fatty acid status, quality of life, and pulmonary status can also determine what supplements are indicated.
Maintenance of a high-calorie diet is a cornerstone of therapy. A study of adults with CF found that 60% failed to meet recommended calorie needs, and 72% failed to meet recommendations for both protein and energy. Patients with CF are susceptible to weight loss for several reasons, including ongoing steatorrhea and azotorrhea (despite enzyme therapy); a 10-30% increase in elevated resting energy expenditure (REE), particularly during pulmonary exacerbations; treatment with bronchodilators (which cause an 8-20% increase in REE); infection-related anorexia; gastrointestinal disturbances; and clinical depression.
With proper nutrition therapy, including an energy intake of 110-200% of the requirements for a general healthy population, patients with CF may have better pulmonary function and survival. Nutritional supplements are recommended for children who have growth deficits and for adults who have weight deficits. Additionally, high-fat diets have typically been used, although this approach may increase the susceptibility to oxidative stress. The kind of fat that should be given is also a matter of debate (see below).
Provision of a diet high in essential fatty acids helps with weight maintenance and prevention of deficiency symptoms. Biochemical evidence of deficiency of both the essential omega-6 fatty acid linoleic acid and docosahexanoic acid, a derivative of the essential omega-3 fatty acid alpha-linolenic acid, is common in patients with CF, although clinical signs and symptoms are rare.
Although a diet high in fat (including animal fat) is often recommended as a means of delivering concentrated calories, it has potential disadvantages for patients with CF. Researchers who examined the dietary intakes of children and adolescents with CF found that while intake of fat recommendations were met (35-40% of calories), saturated fat consumption was well above the recommended amount of less than 10% of total energy. Additionally, the omega-6 fatty acid arachidonic acid found in fatty foods may adversely affect CF patients by contributing to oxidative stress and a pro-inflammatory effect in lung tissue through an increase in leukotriene B4. Omega-3 fats, however, appear to be of clinical benefit in patients with CF. Reduction of sputum volume, improved lung function, a decrease in leukotriene B4, and a decrease in use of antibiotics have been observed in patients given supplements of eicosapentanoic and docosahexanoic acids. Increasing the intake of plant sources of omega-3 fats (alpha-linolenic acid) and monounsaturated fats has been suggested as an alternative approach to improving fatty acid nutrition in CF patients. The Cystic Fibrosis Foundation consensus panel has made similar recommendations, suggesting that oils rich in both omega-3 and monounsaturated fats (e.g., flax, canola, soy) benefit CF patients.
Patients should be monitored for evidence of vitamin deficiency and treated accordingly. Patients with CF require supplemental nutrients for various reasons. The fat-soluble vitamins A, D, E, and K are a priority, mainly because pancreatic enzyme insufficiency often results in malabsorption of these nutrients. Current vitamin supplementation recommendations include: vitamin A—500 to 1000 IU/d; vitamin E—400 to 800 IU/d; vitamin D—400 to 800 IU/d and adequate sunlight exposure; and vitamin K—2.5 to 5 mg/wk. Commercially available vitamins containing A, D, E, and K that are specially formulated for CF patients are sufficient for most adult patients when 2 per day are taken. Occasionally, patients require additional supplementation, most commonly with vitamin D.
Oxidative stress occurs to a greater degree in patients with CF than in healthy controls. Consequently, deficiencies of antioxidants (e.g., vitamin C) and low concentrations of antioxidant enzymes (e.g., glutathione peroxidase) have been found in patients with CF, along with poor selenium and zinc status. The amounts of vitamins required in supplements follow.
Vitamin D. Vitamin D deficiency is common among individuals with CF, especially at northern latitudes. Low vitamin D status is associated with reduced lung function in people with CF, and supplementation may help. Lack of vitamin D also aggravates the already greater risk for osteoporosis and fractures seen in CF patients. Low concentrations of vitamin D have been found in persons with CF taking 1000 IU of vitamin D per day, and the deficiency appears not to be corrected even with megadoses of the vitamin. For increasing calcium absorption and bone density and decreasing markers of bone resorption, the active hormone (D3) form of vitamin D and vitamin D analogues appear more effective than vitamin D2.
Vitamin D status should be checked annually using the serum 25-hydroxyvitamin D measurement with 30 ng/ml (75 nmol/liter) considered adequate for people with CF.
Vitamin K. Vitamin K deficiency is also common in CF. Supplements in the range of 0.1-0.3 mg/d may not be sufficient; a dose of 1 mg/d may be necessary for normalization of vitamin K status.
Patients with CF are at risk for excessive salt loss from the skin. Infants less than 6 months of age should take 0.125 teaspoons of sodium chloride per day and infants and children older than 6 months should take 0.25 teaspoons. Hyponatremic dehydration can occur and contribute to poor weight gain. Adults and children who exercise or live in warm climates may need to consume sports drinks that contain sodium.
Nutrition consultation to assess nutrient status, advise patient in dietary change, and arrange follow-up. The diet should be individualized based on clinical status.
Exercise prescription: Patient-specific aerobic and resistance training.
What To Tell the Family
CF is an inherited disease that frequently causes respiratory tract infection, resulting in poor appetite and weight loss. Poor absorption of nutrients is also common, requiring pancreatic enzyme replacement and supplements of fat-soluble (and possibly water-soluble) vitamins. Patients with CF should follow a high-calorie, high-fat, nutrient-dense diet to help meet needs for energy, growth, and vitamins and minerals. Meeting calorie and nutrient requirements may be accomplished with small, frequent meals. Healthy fats from avocados, nuts, and nut butters can be added to meals to enhance calories. Additional supplementation with fatty acids and minerals may be required if clinical examination or laboratory studies indicate a state of deficiency or insufficiency. Long-term complications of CF that may be delayed through proper diet, exercise, and medical care include osteoporosis, diabetes, and accelerated loss of pulmonary capacity. Care of patients in close consultation with an accredited CF center is recommended.
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