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Cystic Fibrosis (CF)
Cystic fibrosis is a hereditary disease that causes certain glands to produce abnormal secretions, resulting in tissue and organ damage, especially in the lungs and the digestive tract.
Cystic fibrosis is caused by inherited genetic mutations that cause thick, sticky secretions to clog the lungs and other organs.
Typical symptoms include vomiting and abdominal bloating, loose stools, and poor weight gain in newborns, as well as coughing, wheezing, and frequent respiratory tract infections throughout life.
The diagnosis is based on sweat test results and/or genetic testing.
Half of the people with this disease live to their early 40s.
Treatments include antibiotics, bronchodilators, drugs to thin lung secretions, airway clearance treatments for respiratory problems, supplements of pancreatic enzymes and vitamins for digestive problems, and a drug to improve cystic fibrosis protein activity in people with certain mutations.
Some people benefit from lung transplantation.
Cystic fibrosis is the most common inherited disease leading to a shortened life span among white people. In the United States, it occurs in about 1 of 3,300 white infants and in 1 of 15,300 black infants. It is rare in Asians. Because improvements in treatment have extended life expectancy for people with cystic fibrosis, about 50% of people in the United States with this disease are adults. Cystic fibrosis is equally common among boys and girls.
Cystic fibrosis results when a person inherits two defective copies (mutations) of a particular gene, one from each parent. This gene is called the cystic fibrosis transmembrane conductance regulator (CFTR). It controls the production of a protein that regulates the movement of chloride and sodium (salt) across cell membranes. Worldwide, about 3 of 100 white people carry one defective copy of the CFTR gene. People with one defective copy are carriers but they themselves do not get sick. About 3 of 10,000 white people inherit two defective copies of the gene and develop cystic fibrosis. In these people, chloride and sodium movement is disrupted, leading to increased stickiness of secretions throughout the body.
Cystic fibrosis affects many organs throughout the body and nearly all the glands that secrete fluids into a duct (exocrine glands).
The organs most commonly affected are the
The lungs are normal at birth, but problems can develop at any time afterward as thick secretions begin to block the small airways (termed mucus plugging). The plugging leads to chronic bacterial infections and inflammation that cause permanent damage to the airways (termed bronchiectasis). These problems make breathing increasingly difficult and reduce the lungs’ ability to transfer oxygen to the blood. People also may have frequent bacterial respiratory infections that affect the sinuses.
In the pancreas, blockage of ducts prevents digestive enzymes from reaching the intestine. A lack of these enzymes leads to poor absorption of fats, proteins, and vitamins (malabsorption). This poor absorption, in turn, can lead to nutritional deficiencies and poor growth. Eventually, the pancreas can become scarred and no longer produce enough insulin, so some people develop diabetes. However, about 5 to 15% of people who have cystic fibrosis do not develop pancreatic digestive problems.
The intestines can become blocked by thick secretions. This blockage is common immediately after birth because the contents of the fetus's digestive tract (called meconium) are abnormally thick. Such intestinal blockage is called meconium ileus. Older children and adults may also have problems with constipation and blockage of the intestines (called distal intestinal obstruction syndrome).
The reproductive organs can be blocked by thick secretions, which can cause infertility. Almost all men are infertile, but infertility is much less common in women.
The sweat glands secrete fluid containing more salt than normal, increasing the risk of dehydration.
The symptoms of cystic fibrosis can vary depending on a person's age.
About 15 to 20% of newborns who have cystic fibrosis have meconium ileus, which causes vomiting, bloating (distention) of the abdomen, and absence of bowel movements. Meconium ileus is sometimes complicated by perforation of the intestine, a dangerous condition causing infection and peritonitis (inflammation of the tissue lining the abdominal cavity and abdominal organs) and, if untreated, shock and death. Some newborns have a twisting of the intestine on itself (volvulus) or incomplete development of the intestine. Newborns who have meconium ileus almost always develop other symptoms of cystic fibrosis.
The first symptom of cystic fibrosis in an infant who does not have meconium ileus is often a delay in regaining birth weight or poor weight gain at 4 to 6 weeks of age. This poor weight gain is due to poor absorption of nutrients related to inadequate amounts of pancreatic enzymes. The infant has frequent, bulky, foul-smelling, oily stools and may have a bloated (distended) abdomen. Without treatment, weight gain in infants and older children is slow despite a normal or large appetite.
Unless a diagnosis is made through newborn screening, about half the children with cystic fibrosis are first taken to the doctor because of frequent coughing, wheezing, and respiratory tract infections. Coughing, the most noticeable symptom, is often accompanied by gagging, vomiting, and disturbed sleep. Children may have difficulty breathing, wheezing, or both. As the disease progresses, children develop a declining tolerance for exercise, lung infections tend to occur more frequently, the chest becomes barrel-shaped, and insufficient oxygen may make the fingers clubbed (see Clubbing) and the nail beds bluish. Polyps may form in the nose. The sinuses may fill with thick secretions, leading to chronic or recurring sinus infections.
Older children and adults may have episodes of constipation or develop recurring and sometimes chronic blockage of the intestines. Symptoms include a change in stooling pattern, crampy abdominal pain, a decreased appetite, and sometimes vomiting. Gastroesophageal reflux is relatively common among children and adults.
When a child or adult with cystic fibrosis sweats excessively in hot weather or because of a fever, dehydration may result because of the increased loss of salt and water. Parents may notice the formation of salt crystals or even a salty taste on their child’s skin.
Adolescents often have slowed growth and delayed puberty. As the disease progresses, lung infection becomes a major problem. Recurring bronchitis and pneumonia gradually destroy the lungs.
There are many complications of cystic fibrosis.
Inadequate absorption of the fat-soluble vitamins A, D, E, and K may lead to night blindness, osteopenia (decrease in bone density), osteoporosis, anemia, and bleeding disorders. In about 20% of untreated infants and toddlers, the lining of the rectum protrudes through the anus, a condition called rectal prolapse. Infrequently, infants with cystic fibrosis who have been fed soy formula or hypoallergenic formula may develop anemia and swelling of the extremities, because they are not absorbing enough protein.
Complications of cystic fibrosis in adolescents and adults include rupture of the small air sacs of the lung (alveoli) into the pleural space (the space between the lung and chest wall). This rupture can allow air to enter into the pleural space (called pneumothorax), which collapses the lung. Other complications include heart failure and massive or recurring bleeding in the airways.
About 2% of children, 20% of adolescents, and 40% of adults with cystic fibrosis develop insulin-dependent diabetes because the scarred pancreas can no longer produce enough insulin.
The blockage of bile ducts by thick secretions can lead to inflammation of the liver and eventually to scarring of the liver (cirrhosis) in about 2 to 3% of people with cystic fibrosis. Cirrhosis may increase the pressure in the veins entering the liver (portal hypertension), leading to enlarged, fragile veins at the lower end of the esophagus (esophageal varices), which can rupture and bleed profusely.
In almost all people with cystic fibrosis, the gallbladder is small and filled with thick bile and does not function well. About 10% of people develop gallstones, but only a small percentage develops symptoms. Surgical removal of the gallbladder is rarely needed.
People with cystic fibrosis often have impaired reproductive function. Almost all men have a low sperm count (which makes them sterile) because one of the ducts of the testis (the vas deferens) has developed abnormally and blocks the passage of sperm. In women, cervical secretions are too thick, causing somewhat decreased fertility. However, many women with cystic fibrosis have carried pregnancies to term. The outcome of the pregnancy for both the mother and the newborn is related to the mother's health status during pregnancy. Otherwise, sexual function is not impaired in men or women.
Screening tests for cystic fibrosis are done on all newborns in the United States. A drop of blood is collected on a piece of filter paper and the level of trypsin (a digestive enzyme) is measured. If the trypsin level in the blood is high, newborns undergo confirmatory testing. Confirmatory tests include sweat testing and/or genetic testing. Over 90% of new cases of cystic fibrosis are now identified by newborn screening tests.
If newborn screening was not done, the diagnosis of cystic fibrosis is usually confirmed in infancy or early childhood, but cystic fibrosis goes undetected until adolescence or early adulthood in about 10% of people with the disease.
A sweat test is done in newborns who have a positive screening test and in infants, children, and older people who have symptoms that suggest cystic fibrosis. This test, which is done on an outpatient basis, measures the amount of salt in sweat. The drug pilocarpine is placed on the skin to stimulate sweating, and filter paper or thin tubing is placed against the skin to collect the sweat. The concentration of salt in the sweat is then measured. A salt concentration higher than normal confirms the diagnosis of cystic fibrosis in people who have symptoms of cystic fibrosis or who have a sibling with cystic fibrosis. Although the results of this test are valid any time after a newborn is 48 hours old, collecting a large enough sweat sample from a newborn younger than about 2 weeks old may be difficult.
Genetic testing for an abnormal CFTR gene can help diagnose cystic fibrosis in a person who shows one or more typical symptoms or has a sibling with cystic fibrosis. Finding two abnormal cystic fibrosis genes (mutations) is consistent with the diagnosis of cystic fibrosis. However, a positive sweat test is still needed to confirm the diagnosis. In addition, because typical genetic testing does not look for all of the more than 1,900 different cystic fibrosis mutations, failure to detect two mutations does not guarantee the person does not have cystic fibrosis (although the chance of having cystic fibrosis is very low). The disease can be diagnosed prenatally by doing genetic testing on the fetus using chorionic villus sampling or amniocentesis.
Some infants with a positive newborn screening test for cystic fibrosis can be hard to classify, even after sweat testing and genetic testing. These are infants who have no cystic fibrosis-related symptoms, sweat test results that are in-between the positive and negative ranges, and either no or only one cystic fibrosis gene mutation. Doctors diagnose this group as having CFTR-related metabolic syndrome. Although most of these infants remain healthy, later in life some develop certain symptoms of cystic fibrosis and have the diagnosis confirmed. Thus, all of these children should be monitored regularly in a cystic fibrosis care center. When people do develop symptoms, they are usually older and often only one organ is affected. For example, they may develop pancreatitis, bronchiectasis (lung damage), or male infertility.
Carrier testing can be done for people who want to become parents or are looking for prenatal care. In particular, relatives of a person with cystic fibrosis may want to know whether they are at increased risk of having children with the disease, and they should be offered genetic testing and counseling. A blood sample is taken to help determine whether a person has a defective cystic fibrosis gene (mutation).
Unless both potential parents have at least one such mutation, their children will not have cystic fibrosis. If both parents carry a defective cystic fibrosis gene, each pregnancy has a 25% chance of producing a child with cystic fibrosis, a 50% chance of producing a child who is a carrier, and a 25% chance of producing a child with no defective cystic fibrosis genes.
Because cystic fibrosis can affect several organs, other tests may be helpful. Pancreatic enzyme levels are usually reduced, and an analysis of the person’s stool may reveal low or undetectable levels of the digestive enzyme elastase (secreted by the pancreas) and high levels of fat.
Blood tests are done to determine whether insulin secretion is reduced and blood sugar levels are high. Tests are also done to measure liver function and fat-soluble vitamin levels.
Doctors routinely take samples of material from the throat or coughed up from the lungs and culture it to identify bacteria in the airways and help them decide which antibiotics may be needed.
Pulmonary function tests may show that breathing is compromised and are good indicators of how well the lungs are functioning.
The severity of cystic fibrosis varies greatly from person to person regardless of age. The severity is determined largely by how much the lungs are affected. In the United States, half of the people with cystic fibrosis live about 41 years or longer. The outlook for longer survival has improved steadily over the past 50 years, mainly because treatments can now postpone some of the changes that occur in the lungs. Long-term survival is significantly better in people who do not develop pancreatic problems.
However, deterioration is inevitable, leading to loss of lung function and eventually death. People with cystic fibrosis usually die of respiratory failure after many years of deteriorating lung function. A small number, however, die of heart failure, liver disease, bleeding into the airways, or complications of surgery. Despite their many problems, people with cystic fibrosis usually attend school or work until shortly before death.
Antibiotics, inhaled drugs to thin airway secretions, and airway clearance techniques
Drugs that help prevent airways from narrowing (bronchodilators) and sometimes corticosteroids
Pancreatic enzyme supplements
In people with specific mutations, ivacaftor or an ivacaftor/lumacaftor combination
A person with cystic fibrosis should have a comprehensive program of therapy directed by a doctor experienced with cystic fibrosis care—usually a pediatrician or an internist—along with a team of other doctors, nurses, a dietitian, a respiratory therapist, and ideally a social worker, genetics counselor, pharmacist, psychologist, and physical therapist. The goals of therapy include long-term prevention and treatment of lung and digestive problems and other complications, maintenance of good nutrition, and encouragement of physical activity.
Children with cystic fibrosis need psychologic and social support because they may be unable to participate in normal childhood activities and may feel isolated. Much of the burden of treating a child with cystic fibrosis falls on the parents, who should receive adequate information, training, and support so they can understand the disorder and the reasons for the treatments.
Adolescents need guidance and education as they transition to independence and assume responsibility for their care.
Adults need support as they deal with issues related to employment, relationships, health insurance, and deteriorating health.
The treatment of lung problems focuses on
The person should receive all routine immunizations, particularly for infections such as Haemophilus influenzae,influenza, measles, pertussis, pneumococcus, and varicella, which cause respiratory problems.
Airway clearance techniques, which include postural drainage, chest percussion, hand vibration over the chest wall, and encouragement of coughing (see Chest Physical Therapy), are started when cystic fibrosis is first diagnosed. Parents of a young child can learn these techniques and carry them out at home every day. Older children and adults can carry out airway clearance techniques independently, using special breathing devices, a compression vest, or special breathing maneuvers. Aerobic exercise, done regularly, can also help keep the airways clear.
Bronchodilators are drugs that help prevent the airways from narrowing. People usually take bronchodilators by inhaling them. People with severe lung problems and a low level of oxygen in the blood may need supplemental oxygen therapy. In general, people with chronic respiratory failure do not benefit from using a ventilator (breathing machine). However, occasional, short periods of mechanical ventilation in the hospital may help during an acute infection, after a surgical procedure, or while waiting for a lung transplant.
Aerosol (nebulized) drugs, such as dornase alfa (recombinant human deoxyribonuclease I) or a highly concentrated (hypertonic) salt solution (in people older than 6 years of age), are widely used to help thin the thick mucus in the airways. Such drugs make it easier to cough up sputum, improve lung function, and may also decrease the frequency of serious respiratory tract infections.
Corticosteroids, such as prednisone or dexamethasone, given by mouth can relieve symptoms in infants with severe bronchial inflammation, in people who have narrowed airways that cannot be opened with bronchodilators, and in people who have an allergic lung reaction to a type of fungus (allergic bronchopulmonary aspergillosis). Allergic bronchopulmonary aspergillosis is also treated with an antibiotic by mouth.
The nonsteroidal anti-inflammatory drug (NSAID) ibuprofen is sometimes used to slow the deterioration of lung function.
Antibiotics must be started as early as possible to treat respiratory tract infections. At the first sign of a respiratory tract infection, a sample of coughed-up sputum or a swab of a sample from the back of the throat and tonsils is collected and tested, so that the infecting organism can be identified and the doctor can choose the drugs most likely to control it. Staphylococcus aureus, including methicillin-resistant strains, and Pseudomonasspecies are commonly found. Many different antibiotics can be given by mouth to treat staphylococcal infections. To treat a Pseudomonas infection, an antibiotic such as a fluoroquinolone often can be given by mouth (orally), or an antibiotic such as tobramycin or aztreonam can be given in an aerosol mist.
However, if the infection is severe, antibiotics given by vein (intravenously) may be needed. For this treatment, tobramycin or gentamicin is combined with a type of penicillin that specifically targets Pseudomonas. This treatment often requires hospitalization, but part of the treatment may be given at home. Taking the aerosol form of tobramycin or aztreonam for a long time, usually every other month, and also continuously taking an oral form of the antibiotic azithromycin 3 times each week may help prevent recurrences of pseudomonas infection and slow the decline in lung function.
Ivacaftor is a drug that improves the function of the protein that regulates the movement of chloride and sodium (salt) across cell membranes and is recommended for people age 2 years and older who have 1 or 2 copies of these specific cystic fibrosis mutations: G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, G1349D, or R117H. These mutations are present in only a small proportion of people who have cystic fibrosis. In these people, the drug can improve lung function, increase weight, and decrease lung infections.
Lumacaftor is a drug that can be given to people who have the specific cystic fibrosis gene mutation F508del. A combination of lumacaftor and ivacaftor is recommended for people who have cystic fibrosis and are 6 years of age or older and have 2 copies of this mutation.
Doctors are working to develop drugs similar to ivacaftor and lumacaftor that will help people with other mutations that cause cystic fibrosis.
Injections of human growth hormone may improve lung function, increase height and weight, and reduce the rate of hospitalization. However, this drug is costly and inconvenient for people to receive, so doctors do not commonly prescribe it.
Newborns who have blocked intestines may be treated with special enema solutions but often require surgery.
The diet should provide enough calories and protein for normal growth. Because digestion and absorption can be abnormal even when pancreatic enzyme supplements are used, most children need to consume 30 to 50% more calories than the usually recommended amount to ensure adequate growth. The proportion of fat should be normal to high. High-calorie oral supplements can provide extra calories for children and adults.
People who cannot absorb enough nutrients from food may need supplemental feedings given through a tube inserted into the stomach or small intestine.
People with cystic fibrosis should take double the usual recommended daily amount of fat-soluble vitamins (A, D, E, and K) in a special formulation that is more easily absorbed.
Drugs that stimulate the appetite may be helpful. When people exercise, have a fever, or are exposed to hot weather, they should increase their fluid and salt intake.
People whose pancreas has been affected by cystic fibrosis must take capsules of pancreatic enzyme supplements with all meals and snacks. For infants, parents open the capsules and mix the contents with an acidic food such as applesauce so that the special coating on the pancreatic enzyme supplement does not dissolve before reaching the intestines. For some people, drugs that reduce stomach acid, such as a histamine-2 blocker or a proton pump inhibitor, can improve the effectiveness of the pancreatic enzymes. Special milk formulas containing protein and fats that are easy to digest may help infants who have pancreatic problems and poor growth.
People with cystic fibrosis who have diabetes need to take insulin injections. Oral drugs for diabetes are not adequate treatment.
In addition to insulin, management includes nutrition counseling, a diabetes self-management program, and monitoring for eye and kidney complications. People also need special nutrition counseling because standard dietary recommendations for people with only diabetes or only cystic fibrosis are not adequate.
At times, surgery may be needed to treat a collapsed lung, chronic sinus infection, severe chronic infection restricted to one area of the lung, bleeding from blood vessels in the esophagus, gallbladder disease, or obstruction of the intestine. Massive or recurring bleeding in the lung can be treated by a procedure called embolization, which blocks off the bleeding artery.
Liver transplantation has been successful for people who have severe liver damage.
Double lung transplantation for severe lung disease is becoming more routine and more successful with experience and improved techniques. About 50 to 60% of people are alive 5 years after transplantation of both lungs, and their condition is much improved.
People who have heart failure are given drugs (diuretics) to reduce the amount of fluid they retain. Diuretics help by increasing the amount of water the kidneys can get rid of from the body. People should also limit their intake of table salt and salty foods.
Some people with low oxygen levels in their blood may need supplemental oxygen that is usually given through a two-pronged nasal tube (cannula). Some people are treated with a tight-fitting mask placed over the nose or nose and mouth. A mixture of oxygen and air is delivered under pressure through the mask. This technique, called bilevel positive airway pressure or continuous positive airway pressure, can help people maintain normal oxygen levels while they sleep.
People who have CF and their family members need to have discussions with their doctor and care team about their prognosis and what types of treatment they want to receive. These discussions are especially important for people whose lung function is worsening. People need to be prepared for what is to come and know what treatments may be done to extend life. With advanced CF, people and their families need to discuss the potential benefits and burdens of lung transplantation.
Doctors should give people who have CF the information they need to make care choices and should help people determine how and when to accept dying and how to talk about dying. Most people facing the end of life with CF are older adolescents or adults who are responsible for and usually capable of making their own choices.
When aggressive treatments are no longer helpful, doctors may begin giving people treatments that aim only to relieve symptoms (called palliative care). People usually do best when they make such decisions for end-of-life care well in advance of needing to. Such early discussions are very important because, later on, the illness often prevents people from explaining their wishes. This process of making decisions in advance for end-of-life care is called advance care planning. Such planning should involve the execution of appropriate legal documents that reflect the person's wishes regarding end-of-life care.