A Simple Glance at Cystic Fibrosis

Cystic fibrosis is a progressive, genetic disease that causes persistent lung infections and limits the ability to breathe over time. CF is the result of 2 disease-causing CFTR gene mutations that produce defective CFTR proteins. These proteins are too few in number, don't work right, or both.

According to the Cystic Fibrosis Foundation Patient Registry, in the United States: More than 30,000 people are living with cystic fibrosis (more than 70,000 worldwide). Approximately 1,000 new cases of CF are diagnosed each year. More than 75 percent of people with CF are diagnosed by age 2. More than half of the CF population is age 18 or older. 

Prevalence of CF in United States In the United States, the number of people who carry a CF gene mutation is about: 1 in 29 Caucasian-Americans 1 in 46 Hispanic-Americans 1 in 65 African-Americans 1 in 90 Asian-Americans In the United States, the number of people who have CF is about: 1 in 2,500 - 3,500 Caucasian-Americans 1 in 4,000 - 10,000 Hispanic-Americans 1 in 15,000 - 20,000 African-Americans 1 in 100,000 Asian-Americans

History of Cystic Fibrosis European folklore from the Middle Ages warned “woe is the child who tastes salty from a kiss on the brow, for he is cursed, and soon must die”. References have been found in medical texts as early as 1595 that linked salty skin and damage to the pancreas with death in childhood by infants who were “hexed” or “bewitched” . Scholars have proposed that the Polish composer Frederic Chopin (1810-1849), who died of respiratory failure after a lifetime of malabsorption and lung infection, likely had a mild form of CF. In 1938, the American Pathologist Dr. Dorothy Andersen provided the first description of the disorder in the medical literature, calling the disease “cystic fibrosis of the pancreas” based on her autopsy findings of children that died of malnutrition. Other physicians of the era referred to the disease as “mucoviscidosis”, which called attention to the presence of thickened mucous.

History of CF cont.... The modern history of CF is dominated by the definition of the underlying genetic defect, and the rapid increase in survival following the introduction of improved therapies. During a heat wave in the summer of 1948, Dr. Paul di Sant’Agnese observed infants presenting with dehydration to a New York City emergency room. This lead to his discovery that the sweat of children with CF had abnormally high concentrations of salt, and validated the ancient folklore of the disease. In the 1980s, the protein defect was described, and in 1989 the responsible gene (CFTR) was identified and its genetic code was sequenced. With each decade, new therapies have been introduced, leading to a dramatic increase in survival.

Did You Know? All 50 states perform newborn screening for cystic fibrosis. More than 1,700 different mutations have been identified in the CF gene, and more continue to be found. These mutations can be grouped into different types, based on how confident scientists are that the change in the gene actually causes the CF disease. 

10 Million People in U.S. are carriers CF carriers can pass their copy of the CF gene mutation to their children. Each time two CF carriers have a child together, the chances are: 25 percent (1 in 4) the child will have CF 50 percent (1 in 2) the child will be a carrier but will not have CF 25 percent (1 in 4) the child will not be a carrier of the gene and will not have CF

PATHOPHYSIOLOGY OF CYSTIC FIBROSIS Inherited Recessive Disease Mutations in gene on chromosome 7

CF and the CFTR Protein Cystic fibrosis is caused by abnormalities in a protein called CFTR (cystic fibrosis transmembrane conductance regulator). When working properly, the CFTR protein moves to the surface of cells in the lungs -- and in the pancreas and other organs -- where it helps move chloride, water and other small molecules out of the cells and onto the surface. But in people with CF, this protein doesn't get to the cell surface, or it doesn't function properly if it does reach the cell surface. The right amounts of chloride, water and other molecules do not move into the airways. This results in the buildup of thick, sticky mucus. The mucus becomes so thick that the cilia cannot easily move the mucus to the throat. So, instead of the cilia cleaning the airways, the mucus clogs the airways.

How CF Mutations Affect Symptoms of the Disease Certain types of CF mutations are associated with different symptoms of the disease. Researchers continue to study the relationship between CF mutations and how mild or severe an individual's CF symptoms are likely to be. For example, some mutations are more likely to affect the gastrointestinal (GI) tract than the lungs. However, knowing an individual's CF mutations cannot fully tell you how severe that person's CF symptoms will be. The most common CF mutation is F508del (sometimes called Delta F508). F508del causes the most common CF symptoms. But the effects of this mutation can vary in different people, and some people with the F508del mutation may have more severe CF symptoms than others. Some less common CF mutations may cause milder symptoms.

Clinical Manifestations

If not cleared from the lungs, mucus plugs can lead to lung infections and lung damage. Lung infections cause serious problems for people with CF because: Infections cause inflammation, which can damage the cilia and airways, making them even less able to clear mucus, particles and germs from the lungs. Infections often cause more mucus to be made. This can lead to more mucus plugs and worse infections. This infection-inflammation cycle causes lung damage. Mucus plugs airways, allowing germs to grow and cause infection. When the body's defense system -- white blood cells -- attack the germs, the lungs become inflamed. This inflammation spurs the creation of more mucus, which then blocks the airways and allows more germs to grow. As you can see, it's a vicious cycle.

Symptoms of a Pulmonary Exacerbation of CF •Increased cough •Increased sputum production •Change in sputum appearance (darker or blood streaked) •Coughing up blood (hemoptysis) •Increased shortness of breath •Decreased appetite •Weight loss •Unable to attend school or work •Weakness and fatigue

Signs on Physical Exam Increased respiratory rate Increased heart rate Fever Weight loss Retraction of intercostal muscles Increased chest crackles People with cystic fibrosis often have pulmonary exacerbations -- a period when lung disease worsens. Exacerbations can include an infection, increase in cough and sputum, drop in lung function and weight loss. To treat exacerbations and improve lung function, the clinical care guidelines for the treatment of pulmonary exacerbations provide evidence-based recommendations on: Treatment of an exacerbation -- antibiotics and airway clearance Chronic medication use during an exacerbation

Laboratory Tests •Decreased FEV1- good measure of how much mucus is blocking the large airways •Decreased oxygen saturation •Increased white blood cell count •New changes on chest X-ray

Treatment for CF Patients Airway clearance to help loosen and get rid of the thick mucus that can build up in the lungs. Some airway clearance techniques require help from family members, friends or respiratory therapists. Many people with CF use an inflatable vest that vibrates the chest at a high frequency to help loosen and thin mucus. Inhaled medicines to open the airways or thin the mucus. These are liquid medicines that are made into a mist or aerosol and then inhaled through a nebulizer. These medicines include antibiotics to fight lung infections and therapies to help keep the airways clear. Pancreatic enzyme supplement capsules to improve the absorption of vital nutrients. These supplements are taken with every meal and most snacks. People with CF also usually take multivitamins.

CFTR Modulator Therapies CFTR (cystic fibrosis transmembrane conductance regulator) modulator therapies are designed to correct the function of the defective protein made by the CF gene. Because different mutations cause different defects in the protein, the medications that have been developed so far are effective only in people with specific mutations. There are currently two FDA-approved CFTR modulators: ivacaftor (Kalydeco®) and lumacaftor/ivacaftor (Orkambi®).

CFTR Modulator Therapies Ivacaftor (Kalydeco®) Lumacaftor / Ivacaftor (Orkambi®) Ivacaftor is prescribed for people ages 2 and older who have at least one of the following mutations in the CFTR gene: G551D G1244E G1349D G178R G551S R117H S1251N S1255P S549N S549R The lumacaftor/ivacaftor combination therapy is prescribed for people ages 6 and older who have two copies of the F508del mutation, which is the most common CF mutation. Several problems are caused by the F508del mutation, which prevents CFTR from achieving the correct shape and reaching the cell surface. The combination therapy works to correct this in two ways. Lumacaftor moves the defective CFTR protein to the correct place on the cell surface, and ivacaftor increases the protein's activity once it is in place.

ACT = airway clearance techniques BASIC LUNG CARE Although CF affects many parts of the body, the focus is often on the lungs because of the disease’s effect on breathing. Medications ACT = airway clearance techniques Bronchodilators should be inhaled before starting ACTs Mucolytics help thin and then move the mucus out of the airways so it can be coughed out Inhaled antibiotics should be taken after ACTs are finished and the lungs are as clear of mucus as possible Coughing or Huffing Chest Physical Therapy High-frequency Chest Wall Oscillation (“the VEST”) (PEP) Positive Expiratory Pressure Oscillating PEP (Flutter,™ Acapella™ AerobikA™ and Cornet™) Autogenic Drainage Active Cycle Breathing

The role of malnutrition in the progression of lung disease and health decline in CF Although likely a multifactorial process with complex interactions, malnutrition can be best understood if viewed as a vicious spiral that is incrementally affected by the development of nutritional deficiencies from early in life. As malnutrition develops, the effects and rate of progression of the process is magnified with each cycle.

CF Care Guidelines CF care center at least four times a year Care centers use pulmonary function tests (PFTs), sputum or throat cultures and blood tests to monitor a CF patient’s health ACT should be preformed at least 2 times per day even when “healthy”, increased home therapy when feeling ill Clean and disinfect nebulizers daily.

CF CARE TEAM CF care team approach means that health care professionals work together in partnership with the patient to provide comprehensive and high quality care for them

People with cystic fibrosis are living longer and more fulfilling lives, thanks in part to specialized CF care and a range of treatment options.  To stay healthy, people of all ages with CF must follow a regular treatment routine. In addition to a nutrition and fitness plan, there are drugs that help clear the thick, sticky mucus from airways and reduce inflammation, antibiotics to treat CF lung infections and emerging therapies that target the defective cystic fibrosis transmembrane conductance regulator (CFTR) protein in CF to improve different symptoms of the disease. 

Life Expectancy statements Historically Children with CF died in infancy As recently as 1980, the median survival rate for CF patient’s was less than 20 years The median survival rate for patient’s with CF in 2006 increased to 37.5 years of age In the past, females with CF have a significantly shorter lifespan than males (reasons are not completely understood)

CF-ABLE SCORE The ABLE score uses clinical parameters that are measured at every clinic visit and scored on a scale from 0 to 7. If FEV1 is < 52%, then 3.5 points are added; if the number of exacerbations in the past 3 months is > 1, then 1.5 points are added; if BMI is < 20.1 kg/m2 or age < 24 years, each receive 1 point. Patients with a low score have a very low risk of death or lung transplantation within 4 years; however, as the score increases, the risk significantly increases. Patients who score > 5 points have a 26% risk of poor outcome within 4 years. This score is simple and applicable and better predicts outcome than FEV1 alone

Time Line of Life Expectancy for CF Patients

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Work Cited "Cystic Fibrosis Foundation." Homepage | CF Foundation. N.p., n.d. Web. 10 Apr. 2017. "Basic Science: CFTR." Johns Hopkins Cystic Fibrosis Center. N.p., n.d. Web. 10 Apr. 2017. Quintana-Gallego, Esther, Isabel Delgado-Pecellín, and Carmen Calero Acuña. "CFTR Protein Repair Therapy in Cystic Fibrosis." Archivos De Bronconeumología (English Edition) 50.4 (2014): 146-50. Web "Treatment Archives." AirPhysio. N.p., n.d. Web. 10 Apr. 2017. Mccarthy, C., B.d. Dimitrov, C. Gunaratnam, and N.g. Mcelvaney. "WS3.6 The CF-ABLE Score: A Novel Clinical Prediction Tool in Cystic Fibrosis." Journal of Cystic Fibrosis 11 (2012): n. pag. Web.