Cystic Fibrosis Best Practices

1. Cystic FibrosisBest Practices Diane Hanfelt-Goade MD Director, Adult CF Center

2. Case presentation • 28 year-old gentleman with cystic fibrosis, genotype Δ F508 homozygous • Diagnosed as an infant with meconiumileus • Followed every 3 months in CF clinic • Colonization with Pseudomonas aeruginosaand Staphylococcus aureus • History of staph schleiferi and aspergillus tares. • Called with increasing cough and SOB for three weeks

3. Problem list • 1. Moderate to severe lung dysfunction • 2. Pancreatic insufficiency. • 3. Chronic sinusitis, nasal polyps • 4. Allergic rhinitis. • 5. Impaired glucose tolerance. • 6. Reactive airway disease. • 7. History of hiatal hernia. • 8. History of H. pylori • 9. Sleep apnea • 10. Low body mass index.

4. Medications and treatments: • 1.Pulmozyme 2.5 milligrams inhaled once daily. • 2. 7% hypertonic saline inhaled once per day. • 3. Oxygen 2 liters nocturnally. • 4. Vest once per day • 5. Acapella once or twice per day. • 6. Tobi 300 milligrams inhaled, 28 days on, 28 days off. This is an off cycle. • 7. Aztreonam 75 milligrams inhaled three times a day 28 days on, 28 days off. • 8. Azithromycin 500 milligrams by mouth Monday, Wednesday, Friday. • 9. Ultrase MT18s, 8-9 with meals and 4-5 with snacks. • 10. Ensure three cans daily. • 11. Multivitamin one tablet by mouth once daily. • 12. Calcium 600 milligrams with 125 of D, once daily. • 13. Flonase 0.5 %, two sprays per nostril once or twice per day. • 14. AquADEK, 2 tablet by mouth daily • 15. Scan Dical as needed. • 16. Vitamin D 50,000 international units reports he took for 8 to 10 days • 17. Vitamin A, dosage unknown, one tablet by mouth every day. • 18. Vitamin E 400 international units one by mouth every day. • 19. Zyrtec 10 mg by mouth as needed for allergies. • 20. Spiriva 18 micrograms inhaled once daily. • 21. Saline nasal washes as needed. • 22. ProAir 90 micrograms inhaled two to three puffs prior to therapy and as needed. • 23. Advair HFA 2 puffs twice daily.

5. Pulmonary function tests • FVC of 2.27 (39%), • FEV1 1.30 (27%), • FEF 25-75% is 0.52 (11%), • RV/TLC % of 46

6. What is cystic fibrosis (CF)? • A multisystem disease • Autosomal recessive inheritance • Cause: mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) • chromosome 7 • codes for a c-AMP regulated chloride channel Rosenstein, BJ and Zeitlin, PL. Cystic fibrosis. The Lancet. 351: 277-82.

7. Diagnosis of cystic fibrosis • One or more clinical features of CF PLUS • Two CF mutations on genetic testing OR • Two positive quantativepilocarpineiontophoresis sweat chloride values OR • An abnormal nasal transepithelial potential difference value Cystic Fibrosis Foundation. Clinical Practice Guidelines for Cystic fibrosis.1997.

8. 1st Descriptions • 17th Century European folklore • “A child that tastes salty when kissed will soon die.“ • Thought to be hexed/bewitched • 18th Century Case Descriptions • Cases of children with severe malnourishment, steatorrhea, meconium ileus Quinton PM. Phys Rev;1999;79:S3-S22.www.cysticfibrosismedicine.com

9. Clinical Description • 1943 Dr. Stanely Farber • “Mucoviscidosis” • Multisystem disease • Major manifestations • Chronic bronchopulmonary infections • Malabsorption and steatorrhea • Growth Failure Farber S. Arch Pathol 1944;37:283-250.

10. History • 1948 Dr. Paul di Sant’ Agnese • High chloride/sodium in sweat CF patients • Standardization of sweat test by 1959 1954 1st comprehensive CF center

11. Cystic fibrosis transmembrane conductance regulator (CFTR) gene • The CFTR gene is located on the long arm of chromosome 7. • There are 1522 mutations in CFTR listed on the mutation database (http://www.genet.sickkids.on.ca/cftr/) • The most common mutation is Δ F508-70% CF alleles in caucasians.1 • Causes loss of aa phenylalanine at position 508 in protein 1. Gibson, RL, Burns, JL, and Ramsey, BW. Pathophysiology and Management of Pulmonary Infections in Cystic Fibrosis. AJRCCM 168 (918-951); 2003. http://www.ornl.gov/sci/techresources/ Human_Genome/posters/chromosome/cftr.shtml

12. CFTR CFTR functions as a regulated chloride channel Also regulates the activity of other chloride and sodium channels at the cell surface Gibson, RL, Burns, JL, and Ramsey, BW. Pathophysiology and Management of Pulmonary Infections in Cystic Fibrosis. AJRCCM 168 (918-951); 2003.

13. Airway surface liquid low volume hypothesis and consequences • Cilia do not beat well when PCL volume is depleted • Mucins are not diluted and cannot be easily swept up the airway • Mucus becomes concentrated • Results in increased adhesion to airway surface • Promotes chronic infection Donaldson,SH and Boucher,RC. Update on the pathogenesis of cystic fibrosis lung disease. Current Opinion in Pulmonary Medicine. 9: 486-491; 2003.

14. Airway surface liquid low volume hypothesis • Mucus---helps clear airway of bacteria • Clearance of mucus depends on • Ciliary function • Mucin secretion • Volume of airway surface liquid (ASL) • Forms periciliary liquid layer • Dilutes mucus---facilates entrapment of bacteria and clearance • Optimal volume of ASL regulated by Na+ absorption and Cl- secretion Donaldson,SH and Boucher,RC. Update on the pathogenesis of cystic fibrosis lung disease. Current Opinion in Pulmonary Medicine. 9: 486-491; 2003.

15. CFTR and Airway Surface Liquid Donaldson,SH and Boucher,RC. Update on the pathogenesis of cystic fibrosis lung disease. Current Opinion in Pulmonary Medicine. 9: 486-491; 2003.

16. Burden of CF • Most common “life-shortening” recessive genetic disease in Caucasians • 1:3,500 newborns in the US • 1 in 10,500 Native Americans • 1 in 11,500 Hispanics • 1 in 14,000 to 17,000 African Americans • 1 in 25,500 Asians http://www.cff.org

17. Burden of CF (continued) • About 30,000 people affected in United States • >10,000,000 people carriers of mutant CFTR • 80% cases diagnosed by age 3 • Almost 10% diagnosed ≥18 years • “atypical disease” • UNM Adult care center has approx 66 patients http://www.cff.org

18. CF Survival • Overall trend is improved survival • Female survival worse than male between 2-20 years of age1 • 35% of patients are older than 18 years of age2 • Median survival 36.8 years3 • 1930s life expectancy was about 6 months2 • The impact of usual adult diseases in CF is virtually unknown 1.Goss, CH and Rosenfeld, M. Update on cystic fibrosis epidemiology. Current Opinion in Pulmonary Medicine. 10:510-514; 2004. 2. Davis, P. Cystic Fibrosis Since 1938. AJRCCMss. Doi: 10.1164/rccm.200505-840OE; 2005. 3.www.cff.org/news/general_news

19. CF clinical manifestations • Chronic Sinusitis • Chronic pulmonary infections • Endobronchial disease • GI disease • Nutritional deficiencies • Liver disease • CFRD, pancreatic dysfunction • Obstructive azospermia

20. Chronic Sino-Pulmonary Disease • Chronic infection with CF pathogens • Endobronchial disease • Cough/sputum production • Air obstruction---wheezing; evidence of obstruction on PFTs • Chest x-ray anomalies • Digital Clubbing • Sinus disease • Nasal Polyps • CT or x-ray findings of sinus disease Cystic Fibrosis Foundation. Clinical Practice Guidelines for Cystic fibrosis.1997.

21. Endobronchial disease • Hyperinflation • Peribronchial cuffing • Bronchiectasis • Diffuse fibrosis • Atelectasis From: http://www.meddean.luc.edu/lumen/meded/elective/pulmonary/cf/cf_f.htm

22. Nasal Polyps • Benign lesions in nasal airway • If large enough, can be associated with significant nasal obstruction, drainage, headaches, snoring • Likely associated with chronic inflammation • May need surgical intervention • High recurrence rate From: http://www.emedicine.com/ ped/topic1550.htm

23. GI disease • Intestinal abnormality • Meconiumileus • Distal intestinal obstruction syndrome (DIOS) • Rectal prolapse • Hepatobiliary disease • Focal biliary cirrhosis • Multilobular cirrhosis • Pancreatic endocrine dysfunction • Cystic fibrosis related diabetes

24. Nutritional deficiency • Pancreatic insufficiency • Autopsy of malnourished infants--1938--- “cystic fibrosis of the pancreas”---mucus plugging of glandular ducts1 • Davis, P. Cystic Fibrosis Since 1938. AJRCCM Articles in Press. • Doi: 10.1164/rccm.200505-840OE; 2005.

25. Nutritional deficiency • Chloride impermeability affects HCO3- secretion and fluid secretion in pancreatic ducts2 • Pancreatic enzymes stay in ducts and are activated intraductally • Autolysis of pancreas • Inflammation, calcification, plugging of ducts, fibrosis • Malabsorption • Failure to thrive • Fat soluble vitamin deficiency • Davis, P. Cystic Fibrosis Since 1938. AJRCCM Articles in Press. • Doi: 10.1164/rccm.200505-840OE; 2005. • 2. Quinton, P. Physiologic Basis of Cystic Fibrosis. Physiol Rev 79:3-22, 1999.

26. Complications • Endocrine • Glucose intolerance/CFRD • Reduction in insulin secretion due to pancreatic damage • Insulin resistance related to infection and CF exacerbations • Associated with accelerated pulmonary decline and increased mortality • Arthropathy (2-9%) • Osteopenia/osteoporosis

27. Cystic fibrosis related liver disease • Focal inspissation of bile • Obstructs biliaryductules • Second leading cause of death in CF1 • Prevalence 9-37%1 • Spectrum of disease • increased liver enzymes • biliary cirrhosis • portal hypertension 1. Efrati, O et al., Liver Cirrhosis and portal hypertension in CF. European Journal of Gastroenterology and Hepatology. 15(10): 1073-1078; 2003.

28. Electrolyte abnormality • Clinically---hypochloremic metabolic alkalosis • CFTR on luminal side of sweat duct • Chloride goes in from lumen via CFTR and out to blood by other transporters • Sodium goes in via ENaC • Defective CFTR---Na and Cl- movement and reabsoprtion into lumen impeded Goodman, B and Percy, WH..CFTR in Teaching Membrane Transport. Adv Physiol Educ. 29 (79-82); 2005

29. Pathophysiology Genetic and Protein Defect Abnormal Salt and Water Transport Persistent Airway Infection, invasion of neutrophils Accumulation of Leukocyte-DerivedDNA and Elastase-Rich Secretions Airway Obstruction Exacerbations of Infections ProgressiveLung Destruction Early Death Murphy TM and Rosenstein BJ

30. GENE MODIFIERS  • Modify phenotype and disease expression in CF • TGF-beta 1 • potent suppressor of T cell activation • can decrease T cell proliferation and cytokine production • In a study of 808 patients w delta F 508 mutation, polymorphisms in the TGF-beta 1 gene were associated with more severe CF lung disease • MBL — Mannose-binding lectin • important component of the complement system • deficiencies increase the risk for pyogenic infections • In CF, variant MBL alleles associated with reduced lung function, increased risk for complex infections, and early death • polymorphisms of TNF-a • increase susceptibility to Ps. aeruginosa infection and contribute to the clinical manifestations of CF

31. Infections in CF • Individuals with CF are livinglonger • most common cause of death in CF is respiratoryfailure secondary to pulmonary infection. • Pseudomonasaeruginosa and Burkholderiacepacia complex are the pathogensmost commonly associated with a shortened life span • With prolonged infection, P. aeruginosa converts to a mucoid phenotype by the production of alginate • Conversion to mucoidy is associated with worsening lung function • increase in the prevalence of several potentially pathogenicmicroorganisms in CF

32. Infection Gibson, RL, Burns, JL, and Ramsey, BW. Pathophysiology and Management of Pulmonary Infections in Cystic Fibrosis. AJRCCM 168 (918-951); 2003.

33. Burkholderiacepacia complex • B. cepacia syndrome: fevers, rapidly progressive necrotizing pneumonia, death • Chronic cepacia infection—decreased lung function and increased mortality • Several closely related species termed genomovars1 • III has been associated with more severe disease Holmes, A, Govan, J, and Goldstein, R. Agricultural Use of Burkholderia (Pseudomonas) cepacia: A Threat to Human Health? Emerging Infectious Diseases. 4(2):221-227; 1998 1. Gibson, RL, Burns, JL, and Ramsey, BW. AJRCCM 168 (918-951); 2003.

34. Other infections • NTM in about 13% of patients • 75% is MAC • Treat if criteria for disease is met: pulm nodules, deteriorating function • Aspergillus • Infection vs. colonization • ABPA • Nationwide, MRSA increased from 2.1 percent in 1996 to 21.2 percent in 2007

35. ACUTE PULMONARY EXACERBATIONS • Increased cough • Increased sputum production or chest congestion • Increased dyspnea with exertion • Increased fatigue • Decreased appetite • Increased respiratory rate or dyspnea at rest • Change in sputum appearance • Fever (present in a minority of patients) • Absenteeism from school or work • Increased nasal congestion or drainage • Reductions in FEV1 • Reduction of greater than 10% = admission

36. ACUTE PULMONARY EXACERBATIONS • Admitted for 14 days • antibiotics • chest phsyiotherapy and inhaled meds 4 times daily • Aggressive nutrition, physical therapy • Blood sugar control • After 14 days of treatment, patients receiving antibiotics had greater increases in several pulmonary function measures than those treated with placebo • Standard of care, so covered by most insurances • Majority of patients with some second payer coverage

37. ACUTE PULMONARY EXACERBATIONS: antibiotic considerations • Directed to culture results • Recognize that multiple species often present • We are now using synergy data as well • Most common: tobra + anti-PA ES PCN (zosyn) or 3rd or 4th gen ceph • The clearance of aminoglycosides is accelerated in CF patients • Once daily dosing endorsed by the CFF • Patients hypermetabolic, increased hepatic clearance of sulfonamides • No changes: vanco, quinolones • ? Absorption of oral antibiotics

38. UNM data • 18 months: data on 65 patients with at least one positive culture • Most with persistent positive cultures • Most with polymicrobial infections • 52 PA • 90% mucoid • Increasing MDRO – now almost 50% • 18 MSSA and PA • 5 MRSA and PA

39. UNM data • 23 MSSA • 14 MRSA • 2 B. cepacia patients • MSSA, PA, B. cepacia • MRSA , B. cepacia • Aspergillusfumigatus, B. cepcia • 4 Stenotrophomonas • 1 small colony variant • 4 H. flu

40. UNM data • Klebpneumo • Flavobacteriummeningosepticum • Achromobacter • Morganella • Aspergillusfumigatus • Aspergillusterus • Scedosporiumapiospermum • Nocaridatransvalensis – R to bactrim

41. CF standard of care CF Foundation guidelines • UNM is a certified care center • Certification requires demonstration of an integrated team approach • Compliance with guidelines and standards of care • Standards developed using evidence based care practices, committee review • Current guidelines and supporting data at the CF Foundation website • http://www.cff.org/treatments/CFCareGuidelines

42. UNM CF Care Team • Diane Hanfelt-Goade, adult clinic director • Charles Gallegos CFNP, CF care specialist • Linda Reineke, nutritionist and diabetes educator • Bill Demary, resp therapy • Felisha Martinez, social work

43. Cystic Fibrosis Pulmonary Guidelines: Treatment of Pulmonary Exacerbations Patrick A. Flume1, Peter J. Mogayzel, Jr.2, Karen A. Robinson3, Christopher H. Goss4, Randall L. Rosenblatt5, Robert J. Kuhn6, Bruce C. Marshall7, and the Clinical Practice Guidelines for Pulmonary Therapies Committee* “A systematic review was performed addressing a series of questions related to treatment of pulmonary exacerbations. For each question, the body of evidence was evaluated by the full Committee. Recommendations were drafted using the U.S. Preventive Services Task Force (USPSTF) grading scheme, which provides a mechanism to weigh the quality of evidence and the potential harms and benefits in determining recommendations (Table 1)” Am. J. Respir. Crit. Care Med. 2009 Nov;180(9):802-8. Epub 2009 Sept. 3

44. Although they did not meet criteria for this systematic review, there are observational studies that suggest better outcomes for patients treated in a hospital than for those treated at home (10, 11). If there is any doubt, admission to the hospital is the suggested option. This may be particularly relevant for patients with comorbidities that complicate care and for patients with more severe exacerbations who may be too fatigued or in too much distress to be able to perform the therapies adequately. For example, nutritional needs, elevated in most patients with CF, are even greater during an exacerbation (8)

45. Treatment: Airway clearance • Chest physiotherapy • Postural drainage and percussion • P.E.P valve, Acapella valve, Flutter valve • High frequency chest wall oscillation • Albuterol • Bronchodilation • Increase ciliary efficiency • Dornase alpha/recombinant DNase (pulmozyme) • Breaks down excess DNA from neutrophils and bacteria • Hypertonic Saline by nebulization • Thins secretions

46. Treatment: Azithromycin • Saiman et al., 2003 double blind placebo controlled trial of azithromycin • 185 patients randomized to receive 3 times weekly azithromycin or placebo • Improvements in lung function, weight, and number of pulmonary exacerbations (decreased courses of antibiotics and days in hospital) Saiman et al., Azithromycin in Patinets with Cystic Fibrosis Chronically Infected with Pseudomonas Aeruginosa. JAMA 290(13):1749; 2003.

47. Treatment: Nutrition • Follow nutrition parameters closely • Pancreatic enzymes • Vitamin supplementation • Fat soluble vitamins ADEK daily • Other nutritional supplementation • Tube feedings • High calorie supplemental shakes, formulas

48. Treatment: Pancreatic enzymes • Initiate if have malabsorption history • Fecal fat • Fecal elastase • May need H2 blocker or PPI to activate enteric coated enzyme • Enzymes with meals and snacks, usually keep at bedside • Patients bring their own, as hospital typically does not carry the branded enzymes • Fibrosingcolonopathy • Strictures in the colon associated with high dose enzyme use (enzyme gets to colon and causes damage leading to scarring/stricture)

49. Treatment: Cystic fibrosis related liver disease • Ursodiol • Increased bile flow • Decrease toxicity of bile acids • Sclerotherapy, portosystemic shunts • Liver transplantation---only curative treatment for portal hypertension

50. Psychosocial issues • Quality of life • Frequent hospitalizations • Time spent on therapies • Morbidity from disease • Restrictions secondary to disease • Adherence to therapies • Family planning • End of life issues