When the woman gave birth to her first child, all seemed to go well at first. But within a few months, she knew something was wrong. Despite almost constant feeding, the infant was never satisfied and failed to gain weight. He was often inconsolable, and his bowel movements were large and bulky. A physician examined the infant, and a quick lick on the child’s arm revealed a salty taste. Instantly, the practitioner knew there was no hope of survival. The infant died shortly thereafter.

Seventy years ago, this was the typical scenario when a child was born with what is now known as cystic fibrosis. Today, life expectancy is far longer, and treatment of cystic fibrosis has advanced, but patients and their caregivers still face many challenges.

Cystic fibrosis is a genetic disorder. It’s the most common autosomal recessive disease among Caucasians, with an incidence of about one in 3,500 live births.^{1 (Level B)} The disease is less common in other races and ethnic groups: one in 113,500 live births among Hispanics, one in 15,100 in African Americans and one in 31,000 in Asian Americans.^{2 (Level B)} It is a chronic, multisystem disorder that reduces life expectancy. The primary manifestations include progressive obstructive lung disease and pancreatic insufficiency, but patients also may suffer from chronic sinusitis, nasal polyps, malnutrition, distal intestinal obstructive syndrome, diabetes, liver cirrhosis, pancreatitis, gallstones and infertility.^{3 (Level C)}

To be affected with cystic fibrosis, a child must inherit two abnormal cystic fibrosis genes, one from each parent. The parents usually have just one abnormal gene, are asymptomatic and are referred to as carriers. Each time two carriers have a child, there is a 25% chance the baby will have cystic fibrosis, a 50% chance the baby will be a carrier and a 25% chance the baby will be healthy.⁴ One in 31 Americans (more than 10 million people) is a carrier of the abnormal cystic fibrosis gene.^{1 (Level B)} Why has this gene persisted for so long when the result is such a devastating, life-shortening disease? One belief is the carrier state can actually protect a person from diarrhea associated with cholera. This would account for the gene’s persistence through the years.^{3 (Level C)} Today, about 30,000 people in the United States have cystic fibrosis. The median age of survival among people with the disease has improved dramatically, from less than two years in 1930 to almost 37.4 in 2008.^{1 (Level B)} This is a result of better and more comprehensive treatment programs.

The Basic Defect

In 1989, a landmark study reported the identification and cloning of the cystic fibrosis gene.⁵ The gene is located on the long arm of chromosome seven and is responsible for the production of a protein referred to as the cystic fibrosis transmembrane conductance regulator (CFTR). Healthy people have normal, functioning CFTR; people with cystic fibrosis have defective CFTR.

The main function of CFTR is to direct salt (sodium and chloride) across cell membranes. The epithelial cells fail to conduct chloride, and water transport abnormalities occur. In cystic fibrosis, because the CFTR is defective, the chloride cannot exit across the cell membrane into the airway lumen, and the sodium pump is overactive. The sodium, chloride and water are diverted from the airway lumen, and this causes the fluid lining to be dehydrated, thick and sticky.^{3,4,6 (Level C)}

Genetic Mutations

More than 1,500 mutations of the cystic fibrosis gene have been identified.^{7 (Level B)} Most of them are named according to the amino acid sequence in the CFTR gene, and each mutation interferes with proper CFTR synthesis or function in a particular way.^{8 (Level A)} The mutations prevent the proper production of CFTR within the cell. The CFTR protein must also achieve proper conformation for it to be transported to the plasma membrane.

Some mutations interfere with the conformation process, and the protein is unable to get where it needs to go. Other mutations result in an inactive protein. With such mutations, CFTR is localized in the plasma membrane, but it does not respond or function properly.^{8 (Level A)} Regardless of the specific gene defect, the result remains the same: an imbalance in the secretion of chloride and absorption of sodium.

The Respiratory Tract

The epithelial lining of the respiratory tract contains both mucus-secreting goblet cells and ciliated cells. These cells are bathed in fluid, and a layer of mucus rests on top of the cilia. In healthy lungs, the ciliated cells beat the mucus layer that contains inhaled foreign particles and microorganisms up toward the larger bronchi and trachea, where it is either expectorated or swallowed.

In cystic fibrosis, the fluid and the mucus layer are dehydrated. The dehydrated mucus is thick and sticky, which inhibits the cilia from propelling it up and out of the airway.^{3 (Level C)} It accumulates and progressively obstructs the bronchioles and bronchi. The sticky mucus also creates an ideal environment for the proliferation of bacteria.

Research has shown that excess mucous production contributes to obstruction and inflammation, leading to chronic infections.^{6 (Level C)} Bacterial organisms have increased adherence to cystic fibrosis epithelial cells or the airway mucins. The airways quickly become colonized with bacteria, and once the pathogens are established within the lung, they become difficult to eradicate.^{8 (Level A)}

Patients with cystic fibrosis are often colonized with numerous organisms at once. The most common are Pseudomonas aeruginosa (52.5% of patients), Staphylococcus aureus (50.9%) and Haemophilus influenzae (16.3%). Other microorganisms — such as Stenotrophomonas maltophilia (12.5%), Burkholderia cepacia (2.8%), methicillin-resistant Staphylococcus aureus (22.6%), nontuberculous mycobacteria and fungi, such as Aspergillus — can also be present.^{1 (Level B)}

In addition to chronic infection, airway inflammation plays a role in cystic fibrosis lung disease. The inflammation was thought to be a consequence of infection, but research has shown that inflammation occurs very early in life and may actually precede chronic infection.^{6 (Level C)} The chronic infection and inflammation in cystic fibrosis lung disease is a vicious cycle, leading to permanent damage. Lung damage accounts for most of the morbidity and mortality associated with cystic fibrosis.^{9 (Level B)} It usually occurs over many years, but it is relentless, eventually causing patients to succumb to respiratory failure.

The Skin

Sweat is produced in the coil of the sweat gland. As the secretions move toward the skin surface, the sodium and chloride are absorbed back into the bloodstream from the ductal portion of the gland. In people with cystic fibrosis, the chloride is not reabsorbed into the bloodstream, because of the CFTR defect, nor is the sodium. This causes the sweat to have a high concentration of salt. Patients with cystic fibrosis can quickly become dehydrated if they are not mindful of the possibility of salt depletion through sweat.^{3 (Level C)}

The Pancreas

The pancreas is another organ often severely affected in cystic fibrosis. The abnormal CFTR transport mechanism results in obstruction of the pancreatic ducts by thick, sticky mucus. This causes cyst formation, fibrosis and atrophy of the pancreas. Pancreatic enzymes, necessary for digestion, are prevented from reaching the intestine by the thick mucus. If untreated, this can lead to severe malnutrition. About 90% of patients develop pancreatic insufficiency and require oral pancreatic enzyme supplementation with each meal. In time, the progressive fibrosis of the pancreas also can destroy the islet cells that are responsible for insulin secretion. This leads to cystic fibrosis-related diabetes mellitus.¹⁰

Other Organ Systems

Abnormal CFTR functioning can lead to problems in many other organ systems. Sinus mucus is thick and sticky, leading to impaired mucociliary transport and chronic sinusitis. There can be blockage of the bile ducts within the liver, contributing to fat malabsorption and causing biliary fibrosis and cirrhosis.³ Dehydration of the intestinal contents is relatively common, causing meconium ileus in 10% to 15% of infants with cystic fibrosis in the newborn period and constipation or distal intestinal obstruction syndrome in older children and adults.³ More than 95% of men with cystic fibrosis are infertile because of the bilateral absence of the epididymal ducts and vas deferens. In women, cervical mucus is thicker than normal. This impedes sperm migration and makes pregnancy more difficult.^{9 (Level B)}

Diagnosis

Most children are diagnosed by age 2. The three primary methods for diagnosis are genetic testing, newborn screening and the sweat test. The sweat test is considered the diagnostic gold standard. The test involves placement of a small electrode on the skin to stimulate the sweat glands. The sweat is collected, and the amount of chloride is measured. For children of all ages, chloride levels at or above 60 mmol/L indicate a positive result for cystic fibrosis. For infants less than 6 months old, levels between 30 mmol/L and 59 mmol/L are considered borderline, and require further testing. For children older than 6 months, borderline is 40 mmol/L to 59 mmol/L. When the sweat test results are unclear, a genetic test using a blood sample or cells from inside the mouth are used to confirm or deny a diagnosis.¹¹

In 2007, the state of California established a newborn cystic fibrosis screening program in the hopes that early diagnosis and treatment will improve patient outcomes.¹² Since then, 37 states have adopted similar newborn screening programs.²

Treatment

The treatment focuses on preventing or delaying lung damage and optimizing growth and nutrition.^{3 (Level C)} Patients receive antibiotics for the frequent pulmonary exacerbations they experience. The symptoms usually associated with an exacerbation include increased cough, increased shortness of breath, increased sputum production, decreased pulmonary function tests, fever, hemoptysis and changes in activity level and appetite. The antibiotics may be delivered by oral, inhaled, or IV routes, and they are given in large doses because of the increased clearance of these medications in patients with the disease. Sputum is cultured frequently, and the antibiotic sensitivities of the specific organisms guide the antibiotic choice. Oral trimethoprim-sulfamethoxazole (Septra) is often used against Staphylococcus or Haemophilus infections, and oral quinolones, such as ciprofloxacin (Cipro), are effective against Pseudomonas aeruginosa, the most common bacterial organism found in the cystic fibrosis lung.

Inhaled antibiotics, such as tobramycin (Tobi), allow high doses of the drug to be delivered directly to the airways with a lower risk of systemic adverse effects, such as ototoxicity or nephrotoxicity. Inhaled tobramycin has been shown to improve lung function and reduce the need for hospitalization and IV antibiotics. For more severe exacerbations, IV antibiotics are required. Combinations of medications usually are used to achieve a synergistic effect, and the length of treatment depends on the severity of the illness. Researchers are developing new and more effective antibiotic therapies. Controlling bronchial infection helps fight the inflammation problem. However, specific anti-inflammatory medications also can help prevent lung damage. Corticosteroids are effective in controlling inflammation and swelling in the bronchi, and can prevent bronchospasm. Inhaled steroids often are used to minimize the possibility of adverse effects, such as cataracts and growth retardation.^{3 (Level C)} Azithromycin (Zithromax) is often used for respiratory infections. In addition to its antibacterial properties, it seems to provide anti-inflammatory benefits when it is used as a long-term maintenance therapy. Other agents are being studied that also may help decrease the inflammatory response.

Patients use a variety of methods to combat mucus plugging and increase airway clearance. Postural drainage — accompanied by percussion, vibration, coughing, deep breathing maneuvers, forced expiration, physical therapy vests and exercise — loosens and promotes expectoration of secretions.^{6 (Level C)} Dornase alfa (Pulmozyme) also helps remove mucus secretions from the lungs. It is a recombinant form of a naturally occurring human enzyme that reduces the viscosity of cystic fibrosis sputum by cutting up neutrophil DNA into short strands. This thinned sputum is easier to expectorate. Aerosolized medications that help loosen the secretions are dornase alfa and hypertonic saline solutions.^{13 (Level A)}

Many patients benefit from using bronchodilators. They often have episodes of recurrent wheezing, especially during pulmonary exacerbations. Bronchodilators, such as albuterol (Proventil, Ventolin) and levalbuterol (Xopenex), relax the smooth muscle surrounding the bronchi, relieve obstruction and improve gas exchange.^{9 (Level B)} The short-acting bronchodilators are often used before chest physiotherapy to open up the airways and help with mucociliary clearance.

Adequate nutrition is essential in the treatment of cystic fibrosis. Patients with poor nutrition have a worse prognosis. Nutrition therapy can improve growth and development, improve strength and make a patient with cystic fibrosis strong enough to better resist lung infections.  Patients should follow a diet without restrictions and add extra calories during periods of rapid growth and exacerbations. This may require the use of oral supplements, nasogastric/gastrostomy tube placement or parenteral nutrition.^{9 (Level B)}

Patients who have pancreatic enzyme insufficiency require the replacement of fat-soluble vitamins and pancreatic enzymes. For patients who have problems with constipation and distal intestinal obstructive syndrome, an increase in fluid intake and stool softeners or enemas are options.^{3,9 (Level B)}
 
Because the majority of patients now survive into adulthood, cystic fibrosis-related diabetes is the most common nonpulmonary complication with a mix of features of type 1 and 2. Insulin deficiency alters protein and fat metabolism, resulting in weight loss and a decline in pulmonary function. The recommended treatment is insulin. Cystic fibrosis patients who have diabetes have no dietary restrictions.^{14 (Level B)} Research continues in patients with prediabetes to determine whether treatment with insulin or oral hypoglycemics will improve body mass and pulmonary function.

Teaching and Community Support

The teaching role of the therapist is to instruct patients and families in the self-management of cystic fibrosis. Therapists must encourage patients to be active in meeting their own care needs. The appropriate therapies will help the patient to maintain optimal lung function, reduce the incidence of infection, treat infections early, manage cystic fibrosis-related diabetes and promote healthy growth and development. To provide comprehensive teaching, therapists must be aware of the patient’s current care protocols and participation in any clinical trials. The Cystic Fibrosis Foundation has current guidelines available for patients, families and providers.

About 30,000 children and adults in the United States have cystic fibrosis.¹¹ In 2009, the Cystic Fibrosis Foundation collected data on more than 25,500 people who received care at one of the 115 accredited foundation care centers. The patient information from these centers helps caregivers and researchers to develop care guidelines and test new therapies. The foundation recommends that every year people with cystic fibrosis have:¹

• Four physician visits to their specialist
• Four respiratory cultures
• Two pulmonary function tests
• Flu vaccinations
• Fat-soluble vitamin blood levels
• A glucose tolerance test to screen for cystic fibrosis-related diabetes if age 10 or older

In addition, people with the disease should have a yearly liver function test to measure the liver enzymes in the blood.¹

The supportive role of the therapist is to foster independence in their patients by encouraging them to become more involved in their own care and participate as partners in the cystic fibrosis care team. The therapist should help patients to locate community resources for support outside the hospital. Community resources throughout the United States are dedicated to helping patients manage the physical illness, the emotional strain of dealing with the illness and the financial implications of obtaining medications and medical care. The Cystic Fibrosis Foundation provides a listing of local chapters and accredited care centers, research institutes, clinical trials and state-by-state resources. Pharmacy resources include the Cystic Fibrosis Services Pharmacy, a subsidiary of the foundation, which helps patients with medication needs. Another pharmacy resource is the Cystic Fibrosis Pharmacy. The National Institutes of Health also offers cystic fibrosis information.

The Future

Gene therapy trials in cystic fibrosis are continuing, but with greater caution than in years past. Getting the correct copy of the gene where it needs to go without causing complications is proving to be more difficult than originally thought. The Cystic Fibrosis Foundation Therapeutics Inc. National BioInformatics Center, located at the University of North Carolina Chapel Hill, has become the repository for data derived from gene expression studies around the world. By pooling information, researchers hope to accelerate the process of finding a cure for cystic fibrosis.¹⁵ Despite all the treatments and therapies available, the damage to the lungs, pancreas and liver with the disease is progressive and permanent. For patients who have end-stage lung disease, transplantation is the only option. With lung transplantation, the survival rate is 90% at one year post-transplant and 50% at five years.¹⁶

Recent advances in the understanding and treatment of the disease have significantly improved survival and quality of life for patients. Cystic fibrosis manifests itself differently in each patient; the treatment course needs to be individualized. Therapists must understand the complexity of this disease and be familiar with treatments and research to provide optimal care to patients and families.

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