Cystic Fibrosis

Cystic Fibrosis Cystic fibrosis (CF) is caused by a defective gene and its protein which causes the body to produce abnormally thick and sticky mucus Basic defect is a faulty chloride transport that causes mucus build up that results in lung dysfunction, pancreatic insufficiency, intestinal diseases, and infertility

* Tenacious-not easily pulled apart : cohesive tending to adhere or cling especially to another substance Cystic Fibrosis Most common life-threatening genetic disorder in Caucasians Autosomal-recesesive disorder with more than 1900 mutations in the CFTR (CF transmembrane conductance regulator) gene No identifiable cure is known

What is CFTR? CFTR gene goes for a protein called the cystic fibrosis transmembrane conductance regulator Function of CFTR protein: Channel in membrane of cells that produces mucus, sweat, saliva, tears, and digestive enzymes Transports chloride into and out of cells; helps control movement of water in tissues for thin mucus production Transports sodium ions across cell membranes; important for function of organs http://ghr.nlm.nih.gov/gene/CFTR. Located on chromosome 7

Cystic Fibrosis In 1938- 70% of CF babies died within the first year of life Average life expectancy age today is 37 years old The most prevalent CF-causing mutation in the Caucasian population, 86% of CF alleles of cases is the F508del mutation Cff.org

F508 mutation Mutation in the gene for the CFTR protein. The mutation deletes three nucleotides that code for phenylalanine. Causes a person to produce CFTR without phenylalanine CFTR protein breaks down because of its abnormality and cannot escape to move to its correct cell location

Airway clearance techniques (ACTs) are treatments that help people with cystic fibrosis (CF) stay healthy and breathe easier. ACTs loosen thick, sticky lung mucus so it can be cleared by coughing or huffing. Clearing the airways reduces lung infections and improves lung function. TOBI® (tobramycin inhalation solution) is an inhaled antibiotic for the treatment of cystic fibrosis (CF). TOBI helps fight the germ Pseudomonas aeruginosa AZ=Azithromycin HS=hypertonic saline AI=Ivacaftor is used to treat cystic fibrosis in adults and children who are at least 6 years old. Ivacaftor is for use only in patients with a specific gene mutation related to cystic fibrosis. O'Sullivan BP, Freedman SD. Cystic fibrosis. The Lancet. ;373(9678):1891-1904.

Prevalence & Incidence Approximately 80,000 people in the world are diagnosed with CF. 30,000 of those 80,000 people are in the United States 1 in 3500 live births have Cystic Fibrosis More than 70% of patients are diagnosed by age two. More than 45% of the CF patient population is age 18 or older. 1 in 3000 white Americans, 1 in 4000–10 000 Latin Americans, and 1 in 15 000–20 000 African Americans.11 Cystic fibrosis is uncommon in Africa and Asia, with a reported frequency of 1 in 350 000 in Japan. O'Sullivan BP, Freedman SD. Cystic fibrosis. The Lancet. ;373(9678):1891-1904.

Diagnosis Neonatal cystic fibrosis screening First test: A sample of blood sample is taken from the bottom of the baby's foot or a vein in the arm. The blood sample is examined for increased levels of immunoreactive trypsinogen (IRT), a protein produced by the pancreas that is linked to CF Kleven D, McCudden C, Willis M. Cystic fibrosis: newborn screening in America. Medical Laboratory Observer. 2008;40(7):16.

* In the first part of the test, a colorless, odorless chemical that causes sweating is applied to a small area on an arm or leg. An electrode is then attached to the arm or leg. A weak electrical current is sent to the area to stimulate sweating. People may feel a tingling in the area, or a feeling of warmth. This part of the procedure lasts for about 5 minutes. Diagnosis Gold standard for diagnosis is the sweat chloride test (pilocarpine iontophoresis) Test used to induce sweating then the sweat electrolytes are measured Hjortskov N, Jepsen L, Nielsen B, Juul A, Skakkebaek N. Pilocarpine iontophoresis test: an index of physiological sweat secretion?. Clinical Physiology. 1995;15(4):409-414.

Positive Results For infants up to 6 months of age Chloride levels of: Less than 29 mmol/L=CF is very unlikely 30-59 mmol/L= CF is possible Greater than 60 mmol/L= CF to be diagnosed For people older than 6 months of age Less than 39 mmol/L= CF is very unlikely 40-59 mmol/L= CF is possible

Diagnosis Other Tests Prenatal Screening Chest x ray Sinus x-ray Genetic testing can show if the fetus has CF Amniocentesis- removing small amounts of fluid from the sac around the baby Tested to see if the CFTR genes are normal Chorionic villus testing- removing a tissue sample from placenta to test for CF Chest x ray Sinus x-ray Lung function tests Sputum culture Trypsin and chymotrypsin in stool http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001167/

Quality of Life Back pain and headaches in 89% of adults with CF Chest pain in 16-64% of CF adults Pain can cause anxiety and depression Females are observed to have a lower quality of life 1. Gee L, Abbott J, Conway SP, Etherington C, Webb AK. Quality of life in cystic fibrosis: The impact of gender, general health perceptions and disease severity. Journal of Cystic Fibrosis. 2003;2(4):206-213.

Quality of Life Sleep disturbances can occur Patients with airflow limitation; have sleep related hypoventilation, hypovolemia and hypoxemia Mucus and gastric reflux can cause nocturnal cough episodes Pain

Infertility Congenital bilateral absence of the vas deferens (CBAVD) accounts for 1-2% of male infertility Men: All men with CF are azoospermia, infertile, and have CBAVD 50% of men with CBAVD carry two or more CFTR mutations Women can be fertile; controversial to whether or not they should become pregnant

Figure 2. Approximate age of onset of clinical manifestations of cystic fibrosisABPA=allergic bronchopulmonary aspergillosis. CBAVD=congenital bilateral absence of the vas deferens. CFRD=cystic fibrosis-related diabetes mellitus. DIOS=distal intestinal obstruction syndrome. HPOA=hypertrophic pulmonary osteoarthritis. The Lancet Brian P O'Sullivan, MD, Steven D Freedman, MD

CFTR Cystic Fibrosis Transmembrane Regulator Water follows chloride Thick mucus develops http://peds.stanford.edu/Rotations/yellow_team/documents/PulmInfections.pdf http://learn.genetics.utah.edu/content/disorders/whataregd/cf/

Signs and Symptoms Salty sweat Frequent Infections (Pneumonia, Bronchitis) Nasal polyps Cough and sputum production Wheezing and air trapping Digital clubbing Infertility http://health-7.com/imgs/17/3257.jpg

Nutritional S/S Failure to Thrive Edema (hypoproteinemia) Chronic pancreatitis Cirrhosis Pancreatic exocrine insufficiency Steatorrhea

Organs Affected Lungs Pancreas Liver Intestines Sinuses Sex Organs http://permanent.access.gpo.gov.erl.lib.byu.edu/LPS107877/LPS107877_CysticFibrosis.pdf

Lungs Airway Surface Liquid Cilia Bacteria Inflammation Bronchioles in Young Adult with CF: Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis. American journal of respiratory and critical care medicine. 2003;168(8):918.

Infections The mucous is so thick that it is typically anaerobic Biofilms form easily in this environment Neutrophils have poor mobility to fight off infections

Infections Pseudomonas aeruginosa Staphylococcus aureus Haemophilus influenzae Burkholderia cepacia Flu and staph are first to appear in CF patients

Infections Pseudomonas aeruginosa Present in 80% of adult patients Gradual decrease in lung function Poor clinical status Drug resistant (antibiotics treatment usually ineffective) CF: E, D&T

Infections Aspergillus species, noninvasive Allergic bronchopulmonary apergillosis (ABPA) causes lung deterioration Or aspergilloma can occur in cystic space CF: E D&T; “CF Everything you need to know” p 164

Pancreas Pathophysiology

Pancreas Pathophysiology Bicarbonate Volume pH The Pancreas in CF

Pancreas Anatomy Secretions obstruct flow from acini, causing degradation of acinar cells, then pancreatic fibrosis

Pancreas Lipase excretion must be below 10% before symptoms appear 85% of CF patients require enzyme replacement therapy due to pancreatic insufficiency (PI) “The Pancreas in CF”

Pancreatic Insufficiency Meconium Ileus Maldigestion/absorption Failure to Thrive/Growth Retardation Steatorrhea Deficiencies in fat soluble vitamins Meconium is the fecal matter produced by infants in the womb Cistic Fibrosis: Etiology, Diagnosis and Treatments; picture: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002118/figure/A001132.B9809/?report=objectonly

Diabetes in CF Cystic Fibrosis Related Diabetes (CFRD) Affects about 1/3 of adult CF patients Due to beta cell degradation Frequent OGTT recommended As CF longevity increases more microvascular complications are present CF: E, D&T; “Diabetes in Cystic Fibrosis”

CFRD Treatment Typical diabetic diets are inappropriate Increased energy needs through a high fat diet, also high starch Limited treatment is typical because of treatment demands of CF risk noncompliance/overwhelming patient Insulin is used when necessary “Diabetes in Cystic Fibrosis”

Liver Liver disease is the 3rd cause of death in CF Fatty liver causes hepatomegaly Commonly asymptomatic Focal Biliary Fibrosis Severe scarring can lead to cirrhosis Verices, hemorrhaging Best treatment: Liver transplant “Cystic Fibrosis: Everything you need to know”

Instestines Distal Intestinal Obstructive Syndrome DIOS Due to thickened fecal matter Adult equivalent of maconeum ileus Rectal Prolapse CF: E D&T

Medical Care

Goals of Treatment Preventing and controlling lung infections Loosening and removing mucus from the lungs Preventing and treating intestinal blockage Providing adequate nutrition and absorption

Medications Antibiotics Mucus thinning drugs Bronchodilators Oral pancreatic enzymes Inflammatory treatment

Physical Therapy Postural Drainage and Percussion 4-5 minutes in 2-3 positions Cystic Fibrosis Care: A practical guide PD&P: should not disrupt breathing p. 61-65

Breathing Techniques Active Cycle of Breathing Cystic Fibrosis Care: A practical guide PD&P: should not disrupt breathing p. 68 Mobilizes secretions from smaller to larger airways.

Breathing Techniques Positive Expiratory Pressure Masks increase force required to exhale

Mechanical Devices Mechanical Percussor

Mechanical Devices Inflatable Vest

Pulmonary Rehabilitation Long term program to improve lung function and overall well-being Attended weekly Includes: Exercise training Nutritional counseling Energy conserving techniques Breathing strategies Psychological counseling or group support or both Education on how to manage disease

Other Medical Treatments Surgery/transplant Oxygen therapy Endoscopy and lavage Lung transplant Feeding tube Bowel surgery

Exercise

Is exercise good for those with CF? Yes, exercise is always recommended. It helps clear the airway and improve lung function It also helps improve quality of life Higher levels of aerobic exercise have been associated with prolonged survival VO2 peak is a valuable predicator of disease prognosis

What kind of exercise is best? Aerobic training is essential to increase VO2 peak (increase survival) Those with CF can also benefit from strength training. Anaerobic training can help increase aerobic capacity IMF strength training is also crucial IMF= inspiratory muscle function Intense breathing exercises that strengthen the muscles around the lungs Without IMF, pulmonary compliance decreases and residual volume increases If the program is enjoyable to the patient, they are more willing to exercise regularly

Lung Transplants

Who is eligible? Those who are likely to die from lung disease within 1 or 2 years Their conditions are so severe that other therapies no longer work CF is the most common reason in children for needing a lung transplant Must be healthy enough for a transplant (only affected by the disease causing the demise of the lung)

Tests for lung transplant approval Lung function tests Measure amount air you can breathe, how fast you can breath air out, and how well your lungs can deliver oxygen Blood tests Chest CT scan EKG Echocardiography Right cardiac catheterization

General Facts About 1,800 lung transplants were done in the United States in 2010 Most people who receive transplants are between the ages of 18-65 OPTN (Organ Procurement and Transplantation Network) oversees the organ-sharing process. Also maintains the waiting list. Both the recipient and the donor must go through a careful screening process Every year, about half of the people on the waiting list receive a lung

Types of Transplants Single-lung transplant Usually takes 4-8 hours to complete the process Double-lung transplant Usually takes 6-12 hours The number of double-lung transplants has increased over the years More double transplants are done than single transplants Heart-lung transplant For those who have severe heart disease and lung disease Living donor lobar lung transplant Healthy adult donates a segment, or lobe, of one lung to another person

Outlook Lung transplants are a last resort option They can improve quality of life They also have serious risks The recipients body may reject the lung Infections Survival Rates About 78% of patients survive the first year 63% of patients survive 3 years 51% of patients survive 5 years Survival rates for double-lung transplant are a little better than single transplants

Current Research A study in the New England Journal of Medicine states that lung transplants may not be beneficial for children. Median survival after lung transplantation is 2.84 years, and survival at 5 years is 32.9%, less than that reported for all patients with CF. The question is whether children who undergo lung transplantation do worse because of the condition of their disease before the transplant, or because of the transplant itself?

MNT for Cystic Fibrosis Goal: control malabsorption, maldigestion, provide adequate nutrients, promote optimal growth or maintain weight, support pulmonary function, and prevent nutrient deficiencies. * MNT is specific to each patient; coordinated with other treatments, medications, and chest physical therapy. Krause, Stallings VA

Types of MNT: replacing digestive enzymes respiratory therapy COX inhibitors to decrease inflammation Agenst that increase cAMP (like theophylline) to open chloride channels Krause

How to administer MNT: Monitor ongoing nutrition status Supply pancreatic enzyme replacement therapy (PERT) Meet increased energy requirements Provide vitamin/mineral supplements

Pancreatic Enzyme Replacement Therapy..... (PERT) PERT is first step taken to correct maldigestion/malabsorption. Microspheres are taken orally, designed to withstand the acidic stomach, and release enzymes in the duodenum for digestion of macronutrients. The degree of pancreatic insufficiency, amount of food eaten, and types of enzymes taken determine the quantity to take. krause

PERT continued... the enzyme dosage per meal is adjusted to control GI symptoms (steatorrhea) and promote growth. monitoring fecal elastase, fecal fat, or nitrogen balance may help evaluate adequate enzyme dosage and efficacy. Fecal elastase is the enzyme secreted by the pancreas to digest proteins and is involved in hydrolysis of peptide bonds. Krause

MNT for children Evaluate and monitor growth and development (body composition, BMI, wt, ht, head circumference, bone status, etc) Identify degree of pancreatic insufficiency Determine PERT recommendation Borowitz D. reference: Borowitz D, Baker RD, Stallings V. Consensus report on nutrition for pediatric patients with cystic fibrosis. J Pediatr Gastroenterol Nutr 2002;35:246-259. and.... Borowitz D, Grand RJ, Durie PR. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the contect of fibrosing colonopathy. J Pediatr 1995;127:681-684

Macronutrient needs Energy Intake: Based on sex, age, BMR, physical activity, respiratory infection, severity of disease, and severity of malabsorption There are equations to calculate energy needs when labs aren't available. CF patients shouldn't decrease PA but rather increase energy intake For Children: high energy (based on growth needs), moderate to high fat, and complementary PERT For Adults: high energy (to maintain weight) Krause, Borowitz D

Macronutrient needs CHO needs: Protein needs: FAT needs: needs change as disease progresses CF patients may develop lactose intolerances Protein needs: Slightly increased, but 15--20% should meet DRI for protein requirements FAT needs: CF patients have increased fat needs; 35-40% of total kcals (especially sources of EFA) Check for EFA deficiencies in regular lipid profiles Also watch for fat-soluble vitamin deficiencies since there is likely fat malabsorption. Fat intolerances found in stool samples. Borowitz D, Krause

Specific Vitamin Recommendations Water soluble vitamins: Adequately absorbed; requirements are met by diet and multivitamin/mineral supplement. Fat soluble vitamins: Usually inadequately absorbed (fat malabsorption) Low serum vitamin A - impaired mobilization and transportation from liver. Decreased vitamin D - related to decreased bone mineral content Low vitamin E - hemolytic anemia and abnormal neurologic findings. Vitamin K deficiency - secondary to antibiotics or liver disease. Borowitz D, Krause

Mineral needs Intake should meet CF patients gender/age recommendations. Minerals to watch: Na requirements increase because increased losses in sweat. Deficiency is evident with lethargy, vomiting, and dehydration. Supplemental salt is required only in some conditions (infants b/c low Na content in BM, Formula and baby food, adults and children during fever, hot weather, or exercise)

Minerals to watch (cont) Calcium - watch for decreased bone mineralization during childhood esp. Iron - check yearly in children, and monitor hgb and hct Zinc - decreased absorption and increased zinc in stools (esp in children and infants). Also related to vitamin A levels. Borowitz D, Krause

Feeding Strategies - MEET THE NUTRIENT REQUIREMENTS Infants: PERT by mouth or added to baby food, supplementation of high-calorie formula. Children and adults: Regular and enjoyable mealtimes, larger food portions, extra snacks, high-nutrient density, fortified beverages, puddings, etc. *feeding tube is alternative for patients who can't meet nutrient needs orally. *TPN is used short term & after GI surgery. Krause

Results Results can be evidenced in improved weight gain, slowed decline in pulmonary function, decreased respiratory infection, and improved sense of well being and quality of life. Krause

Case Study: LJ Age: 14 Female Student Mother is 41, grandmother is 66, half-brother is 5 Caucasian "I caught a cold, and it has just gotten worse. My regular treatments were not working, and my doctor says I probably have pneumonia."

LJ Anthropometric Data Current anthropometrics: Ht: 5'5" Wt: 102 # 3 months ago: UBW: 110-115 #

LJ - pt. history Diagnosed with CF at 6 mos. Since then uneventful disease course. Hospitalized several times for respiratory infections but otherwise has been maintained by outpatient therapy. Seen yearly in CF clinic Uses high-frequency chest compression for 1 hour twice daily PMH - seen in hospital over year ago. Very active, runs 3-5 miles 5-6x week.

LJ continued Meds: Pancrease (1-3 capfuls after meals), Prevacid (20mg daily), Humabid (1/2 tablet every 12 hours), multivitamin and Proventil PRN. Family Hx: T2DM maternal grandmother, and CF paternal great aunt (deceased) Nutrition Hx: Not good appetite, Never knows how much Pancrease to take. Likes most foods, but never drinks milk. Likes F/V but doesn't eat many. “I am not really home for meals that much” “I take more pancrease if I eat more fat”

Typical Diet for LJ AM - rarely eats Lunch - 3 T crunchy PB or 2 oz ham + 2 oz swiss cheese sandwich, 2-3 oz chips, 1 orange or other fruit, water Dinner - 5-6 oz of chicken, pork or beef (grilled or baked), 1-2 c raw vegetables on lettuce, 1/4 c ranch dressing, 1 c pasta, potatoes, or rice, usually with 1-2 T margarine, water. *really depends on whether eats at home or friends'

PES statement for LJ Inappropriate administration of medication related to repeated infection as evidenced by pneumonia and cold. Inadequate oral intake related to lack of nutrient absorption as evidenced by weight loss.

Sample diet for LJ AM - 1 slice toast with margarine, 1 piece of fruit, 1 c milk Lunch - 2 slices bread, 3-4 oz ham or other lunch meat, 2-3 oz swiss cheese, lettuce, tomato, mayonnaise, mustard (sandwich), 1 piece of fruit, caloric drink Dinner - 3-4 oz chicken or beef, 1 cup pasta or rice, cream sauce, steamed vegetables with margarine, 1 cup milk. *avoid "diet" or low fat items, and increase fat intake.

Sources Mayo Clinic. Cystic Fibrosis. Available at http://www.mayoclinic.com/health/cystic-fibrosis/DS00287. Accessed February 18, 2013. Ramsey B, Davies J, Elborn J, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. The New England Journal of Medicine. 2011;365:1663-1672. National Heart, Lung, and Blood Institute. What is pulmonary rehabilitation?. Available at w.nhlbi.nih.gov/health/health- topics/topics/pulreh/. Accessed February 18,2013. Van Doorn N. Exercise programs for children with cystic fibrosis; a systematic review of randomized controlled trials. Disability and Rehabilitation. 2010;32:41-49. Enrigh S, Chatham K, Ionescu A, Unnithan V, Shale D. Inspiratory muscle training improves lung function and exercise capacity in adults with cystic fibrosis. Chest. 2004;126:405-411. Klijn P, Oudshoorn A, Van Der Ent C, Van Der Net J, Kimpen J, Helders P. Effects of anaerobic training in children with cystic fibrosis: a randomized controlled study. Chest. 2004;125:1299-1305. Adler F, Aurora P, Barker D, Barr M, Blackwell L, Bosma O, Brown S. Lung transplantation for cystic fibrosis. Proc Am Thorac Soc. 2009;6:619-633. Allen J, Visner G. Lung transplantation in cystic fibrosis-primum non nocere?. The New England Journal of Medicine. 2007;357:2186-2188. Taylor-Cousar J, Von Kessel K, Young R, Nicholas D. Potential of anti-inflammatory treatment for cystic fibrosis lung disease. Journal of Inflammation Research. 2010;3:61-74.