Cystic Fibrosis (CF)

Cystic fibrosis results when a person inherits two defective copies (variants) of a particular gene, one from each parent. This gene is called the cystic fibrosis transmembrane conductance regulator (CFTR). There are a number of variants of the CFTR gene. For example, the most common one is called the F508del variant. The CFTR gene controls the production of a protein that regulates the movement of chloride, bicarbonate, and sodium (salt) across cell membranes. Variants of the CFTR gene cause the protein to become dysfunctional. If the protein does not work correctly, the movement of chloride, bicarbonate, and sodium is disrupted, leading to thickening and increased stickiness of secretions throughout the body. 

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, as a result, develop cystic fibrosis.

Cystic Fibrosis: Thickening Mucus

3D Model

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

• Lungs

• Pancreas

• Intestines

• Liver and gallbladder

• Reproductive organs

The lungs are normal at birth, but problems can develop at any time afterward as thick secretions begin to block the small airways (mucus plugging). The plugging leads to chronic bacterial infections and inflammation that cause permanent damage to the airways (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 small 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, a small percentage of people who have cystic fibrosis and carry certain variants 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 blockage in the small intestine is called meconium ileus and in the large intestine is called meconium plug syndrome. Older children and adults may also have problems with constipation and blockage of the intestines (distal intestinal obstruction syndrome).

The liver and gallbladder can be blocked by thick secretions, which eventually can cause liver scarring (fibrosis). Gallstones may develop.

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.

Cystic Fibrosis in the Lungs

3D Model

About 10% 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 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 concern. Recurring lung infections gradually destroy the lungs.

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 from the pancreas) is measured. If the trypsin level in the blood is high, newborns undergo confirmatory testing, which includes sweat testing and/or genetic testing. Most 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.

Genetic testing for an abnormal CFTR gene can help diagnose cystic fibrosis in a newborn who has a positive newborn screening test result, in a person who shows one or more typical symptoms, or in a person who has a sibling with cystic fibrosis. Finding 2 abnormal cystic fibrosis genes (variants) 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 2,000 different cystic fibrosis variants, failure to detect 2 variants 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 variant. Doctors diagnose this group as having CFTR-related metabolic syndrome (CRMS), also called cystic fibrosis screen positive, inconclusive diagnosis (CFSPID). Although most of these infants remain healthy, later in life about 10% develop symptoms related to cystic fibrosis and are diagnosed with cystic fibrosis or a cystic fibrosis–related disorder. Thus, all of these children should be monitored regularly in a cystic fibrosis care center.

Some people, usually adults, develop symptoms that affect only one organ, often with an intermediate sweat test result and without 2 cystic fibrosis–causing variants. For example, symptoms may affect only the pancreas (resulting in pancreatitis), the lungs (resulting in bronchiectasis), or the male reproductive organs (resulting in infertility). They are diagnosed with a CFTR-related disorder.

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 (variant).

Unless both potential parents have at least one such variant, 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. Blood tests are also done to look for problems with the liver and to measure 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. These tests are done several times a year and whenever there is a decline in a person's health.

Chest x-rays and computed tomography (CT) of the chest may be helpful to document lung infection and the extent of lung damage. CT of the sinuses is done for people who have serious sinus symptoms, particularly if they have nasal polyps or are being considered for sinus surgery.

The treatment of lung problems is focused on

• Preventing airway blockage

• Controlling infection

The person should receive all routine immunizations, particularly for infections that can cause respiratory problems such as Haemophilus influenzae, influenza, measles, pertussis, pneumococcus, varicella, and COVID-19.

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 by using special breathing devices, an inflatable vest that vibrates at a high frequency (a high-frequency oscillation vest), or special breathing maneuvers. Aerobic exercise, done regularly, can also help keep the airways clear.

Bronchodilators are medications 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.

Medications that help thin the thick mucus in the airways,

Corticosteroids,allergic bronchopulmonary aspergillosis). Allergic bronchopulmonary aspergillosis is also treated with an antifungal medication given by mouth, by vein, or both.

a nonsteroidal anti-inflammatory drug (NSAID), is sometimes used to slow the deterioration of lung function.

Antibiotics are often used to treat both acute and chronic respiratory tract infections in people with cystic fibrosis. A sample of coughed-up sputum or a swab of a sample from the back of the throat and tonsils is collected and tested at regular intervals during stable health, and also during periods of increasing symptoms, so that the infecting organism can be identified and the doctor can choose the medications most likely to control it. Staphylococcus aureus, including methicillin-resistant or methicillin-sensitive strains, and Pseudomonas species are commonly found. Many different antibiotics can be given by mouth to treat staphylococcal infections. To treat a new Pseudomonas

However, if the infection is severe, or results in significant worsening of symptoms or lung function, antibiotics given by vein (intravenously) may be needed. For this treatment, the aminoglycosidePseudomonas. These other antibiotics include cephalosporins, penicillins, fluoroquinolones, and monobactams. This treatment often requires hospitalization, but part of the treatment may be given at home.

Pseudomonas infection and slow the decline in lung function.

CFTR modulators are oral medications taken chronically that improve the function of the defective protein made by variants in the CFTR gene.

can be given to people 1 month of age and older who have at least 1 copy of a specific cystic fibrosis variant.

The combination of lumacaftor and ivacaftor can be given to people 1 years of age and older who carry 2 copies of the F508del variant.

The combination of tezacaftor and ivacaftor can be given to people 6 years of age and older who carry 2 copies of the F508del variant or other specified variants.

The combination of elexacaftor, tezacaftor, and ivacaftor can be given to people 2 years of age and older who carry at least 1 copy of the F508del variant or 1 copy of certain rare variants.

CFTR modulators can improve lung function, pancreas function, and quality of life; increase weight; and decrease the salt concentration in sweat and the frequency of lung infections and hospitalizations. Although all of these drugs can be helpful, only ivacaftor and the combination of elexacaftor, tezacaftor, and ivacaftor are considered to be highly effective therapy.

Doctors are working to develop drugs that will help people with other variants that cause cystic fibrosis.

Newborns who have blocked intestines may be treated with special enema solutions but often require surgery.

Older children and adults who have constipation or partially blocked intestines may be treated with stool softeners, enemas, and special solutions given by mouth or via a small, flexible plastic tube (nasogastric tube) that is passed through the nose or mouth into the stomach.

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.

Medications that stimulate the appetite may be helpful (although many people with cystic fibrosis have a strong appetite without any such medications). 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, medications 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

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 infections, 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 bleeding resulting from esophageal varices or severe liver damage.

Double lung transplantation for severe lung disease is becoming more routine and more successful with experience and improved techniques. For adults who have cystic fibrosis, average survival after a double lung transplant is about 9 years.

Medications to treat chronic inflammation of the sinuses

People who have heart failure are given medications (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.

Injections of human growth hormone may improve lung function, increase height and weight, and reduce the rate of hospitalization. However, this medication is costly and inconvenient for people to receive, so doctors do not commonly prescribe it.

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 (BiPAP) or continuous positive airway pressure (CPAP), can help people maintain normal oxygen levels while they sleep.

People who have cystic fibrosis 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 cystic fibrosis, people and their families need to discuss the potential benefits and burdens of lung transplantation.

Doctors should give people who have cystic fibrosis 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.

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.