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Cystic Fibrosis: A Disease for a Multidisciplinary Team

Cystic Fibrosis: A Disease for a Multidisciplinary Team. Kim Otsuka, MD Pediatric Pulmonary Fellow September 21, 2004 UoA PPC 2004 Workshop Lectures. Objectives. Brief overview of cystic fibrosis (CF) Review some of the “newer” pulmonary therapies in CF Highlight nutritional issues in CF

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Cystic Fibrosis: A Disease for a Multidisciplinary Team

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  1. Cystic Fibrosis: A Disease for aMultidisciplinary Team Kim Otsuka, MD Pediatric Pulmonary Fellow September 21, 2004 UoA PPC 2004 Workshop Lectures

  2. Objectives • Brief overview of cystic fibrosis (CF) • Review some of the “newer” pulmonary therapies in CF • Highlight nutritional issues in CF • Highlight psychosocial issues in CF • Highlight respiratory care issues in CF

  3. CF Center Team • Center director • Associate center director • Clinic coordinator • Social worker • Respiratory therapist • Nurse • Registered dietitian

  4. Cystic Fibrosis - A recap • Epidemiology • Most common life-threatening inherited disease • Autosomal recessive • Incidence 1:3200 live births (Caucasians)* • Hispanics 1:9200, Blacks 1:15,000, Asians 1:31,000 • 1:28 Caucasians are carriers • Hispanics 1:48, Blacks 1:61; Asians 1:88 *Adapted from Hamosh A, et al. J Pediatr 1998; 132: 255-259

  5. Genetics • Single gene defect on chromosome 7 • Dicovered in 1989 • Cystic fibrosis transmembrane regulator (CFTR) • Most common F508 • Over 1000 mutations identified Zeitlin P, N Engl J Med 2004; 351: 606-8.

  6. Pathophysiology • CFTR mutations affect epithelial cells, thus affecting: • Airways (sinuses, lungs) • Pancreas (endocrine and exocrine) • GI tract (liver/biliary system, intestines) • Reproductive organs • Skin

  7. Pulmonary Pathophysiology • 2 theories • Composition hypothesis • Airway epithelia regulate the airway surface liquid (ASL) salt content that is important for lung defense • Volume hypothesis • Airway epithelia regulate the volume of liquid in the mucus and periciliary liquid layers of ASL for efficient ciliary mucus interactions and airway clearance.

  8. Pulmonary - Pathophysiology Ratjen F, Coring G. Lancet 2003; 361: 681-89.

  9. Pulmonary Pathophysiology • CFTR mutation --> abnormal airway surface microenvironment --> thickened mucus, chronic infection, chronic inflammation --> damages airway ---> bronchiectasis, respiratory failure and often death

  10. Inflammation in CF Konstan MW, Davis PB. Advanced Drug Delivery Reviews 2002; 54: 1409-1423

  11. Ibuprofen Konstan et al, NEJM 1995 85 patients 5 - 39 y/o FEV1 > 60 % predicted 20-30 mg/kg of ibuprofen peak plasma concentrations 50-100 mcg/mL Results FEV1 -2.17 + 0.57 vs. -3.60 + 0.55 (p=0.02) weight better in ibuprofen group (p=0.02) Adverse events No difference between groups in study Increased GI hemorrhage in f/u Treatment: Anti-inflammatories

  12. Azithromycin Multicenter US trial double-blind, randomized, placebo-controlled trial 185 patients, >6 y/o FEV1 >30% predicted weight <40 kg: 250 mg azithromycin 3x/wk weight >40 kg: 500 mg azithromycin 3x/wk Results At 24 weeks into study FEV1 gain 4.77% in azithromycin group FEV1 loss -1.77% in placebo Improved weight gain and decreased hospitalizations in azithromycin group Adverse events: nausea, diarrhea, wheezing Treatment: Anti-inflammatories

  13. Mucolytics King M, Rubin BK. Advanced Drug Delivery Review 2002; 54: 1475-90

  14. Dornase alfa Fuchs, et al 1994 968 patients (youngest 5 y/o) Randomized, double-blinded placebo controlled trial placebo vs. once or twice daily DNAse Results Improved QOL, health economics Pulmonary exacerbations once daily: RR 0.78 (CI 0.57-1.06; p=0.11) twice daily: RR = 0.66 (CI 0.48-0.91; p=0.01) FEV1 (improved p<0.01) once daily 5.8 + 0.7 twice daily 5.7 + 0.7 Adverse events Voice alteration, laryngitis, rash Pulmozyme®

  15. Antibiotics • Often unable to eradicate the organism • Determining optimal delivery mode for a drug is difficult • CF patients require higher doses • Altered volume of distribution • Rapid clearance of drugs

  16. Decreased density of pseudomonas Decreased hospitalizations Additive effect with DNase Adverse events Tinnitus Voice alteration No hearing loss No change in kidney function Ramsey et al, 1999 520 patients, >6 y/o Tobi 300 mg bid x 28 days q o month x 20 weeks Inhaled Tobramycin (Tobi®) Ramsey et al, NEJM 1999; 340: 23-30

  17. Nutritional Issues

  18. Nutritional Issues • Nutrition is closely tied to overall health • Malnutrition in CF associated with • Stunted growth • Pubertal delay • Deterioration of lung function • Early death

  19. ESCF Study • J. Pediatrics 2003 • 931 patients • 3-6 years • Parameters evaluated: • Height, weight, s/sx of lung disease recorded at age 3 and 6 • Respiratory tract culture < 3 y/o • 1 valid spirometry obtained when stable between 5.5 and 7.5 y/o

  20. Results - age 3 Konstan MW, J. Pediatr 2003; 142:624-30

  21. Results - age 6 Konstan MW, J. Pediatr 2003; 142:624-30

  22. Weight gain improves lung function by age 6 Konstan MW, J. Pediatr 2003; 142:624-30

  23. Conclusions • Indexes of growth and nutrition at age 3 associated with lower pulmonary function at age 6 • S/sx of lung disease at age 3 are also associated with lower pulmonary function at age 6 • Relative weight loss was associated with worse lung function • Relative weight gain was associated with improved lung function

  24. Care team responsibilities • Monitor growth • Provide anticipatory counseling and plan interventional strategies for those who are undernourished or are at high risk • Dietitian • Provides discipline-specific expertise needed for optimal nutritional management • Provide expertise concerning developmental and behavioral aspects of eating

  25. Nutritional management • Growth and nutritional status monitored every 3 months • Annual pubertal assessment • Especially important times for monitoring • First 12 months after diagnosis • Birth to 12 months for those diagnosed prenatally or by GDS • Peripubertal growth period

  26. 85-90% affected Malabsorption fats, protein, and other nutrients Diagnostic tests 72 hour fecal fat fecal elastase-1 PS patient re-evaluated annually Treatment Pancreatic enzyme supplementation Improved release with H2 blocker or PPI Proprietary enzymes better than generic Complication: fibrosing colonopathy Taurine supplementation Curcumin Pancreatic Insufficiency

  27. Calorie intake • Greater than RDA for those without CF • Weight goal is 100-110% IBW • Fat intake 35-40% • Protein 15-20% • Supplements • Oral: controversial • Enteral

  28. Vitamin A 15-40% deficient 18% adults deficits in dark field adaptation Negative acute phase reactant (do not draw with acute illness) Vitamin D 10-40% deficient Vitamin E 5-10% deficient Vitamin K PIVKA-II vs. PT Essential Fatty Acids Minerals and Electrolytes Calcium Iron Zinc Sodium The Vitamins

  29. Children > 8 y/o with risk factors Post-organ transplant End-stage lung disease Bone fracture with low-impact activity Chronic corticosteroid use Delayed pubertal development Nutritional failure Screening DEXA lumbar spine Annual serum calcium, phosphorous, intact PTH, 25-hydroxy vit D Dietary assessment of calcium and vit D Treatment Optimize nutrition and intake of vit D, K, calcium Weight bearing physical activity Bone monitoring

  30. Cystic Fibrosis Related Diabetes • Leading comorbidity associated with CF • Prevalence increased by 173% from 1992-2002 • Prevalence increases with age • 3-12% are reported to have diabetes • 14% of CF patients >14 years old • 25% of CF patients 35-44 years old • Average age of onset 18-21 y/o • Females > Males

  31. Glucose Intolerance Increases with Age Moran, et al. J. Pediatrics. 133(1998)

  32. Survival Analysis of survival at University of Minnesota has demonstrated that the rapid decline in survival can be attributed to females with CFRD since males with CFRD has ~equivalent suvival rates to males without CFRD Finnkelstein et al. . J Pediatr 1988; 112: 373-7

  33. Rate of Decline in Pulmonary Function is Related to Oral Glucose Tolerance Status Milla CE et al: Am J Resp Crit Care Med 162:891-5, 2000

  34. Comparison of CFRD with type 1 and type 2 DM Moran T: Mountain West Consortium June 24, 2004

  35. Therapy - CFRD • Treatment: insulin • Control glucose to avoid acute/chronic complications • FPG 80-120 mg/dl • Post-prandial FSBS with + 30 mg/dl from pre-meal value • HgA1c < 7% • Maintain optimal nutritional status and growth • Continue high energy intake

  36. Respiratory Care Issues

  37. Pulmonary Function Tests • Spirometry • Respiratory rate • Pulse oximetry • Lung volume • Exercise studies

  38. Aerosol Delivery Systems • They are not all equal • 2 important considerations • Volume • Concentration of therapeutic agent

  39. Airway Clearance • Standard daily therapy for patients with cystic fibrosis • CF --> viscous airway secretions + poor clearance --> airway obstruction and infection --> airway injury, fibrosis --> bronchiectasis • Goal: enhance clearance of airway secretions

  40. Airway Clearance Wagener JS, Headley AA. Respir Care 2003; 48: 234-45

  41. Chest physiotherapy Accepted standard Goal move peripheral mucus into central airways Active cycle breathing Autogenic drainage PEP and flutter low, high pressure oscillating Intrapulmonary percussive ventilation High-Frequency Chest Compression Shears mucus away from airways Modifies viscoelastic properties of mucus Exercise Airway Clearance

  42. Typical Day Airway Clearance/Aerosols • Albuterol 2x/day (15-20 minutes each) • Dnase 1x/day (15-20 minutes) • Inhaled tobramycin 2x/day (15-20 minutes) • Chest clearance 2x/day (20-30 minutes) • Step up to 3-4x/day will illnesses

  43. Psychosocial Issues

  44. Social Issues • Address social concerns every 3 months • Complete assessment by an MSW or psychologist should be performed annually including • Changes in family structure and coping • School and work performance • Participation in age appropriate activities • Developmental and emotional issues • Vocational training and preparation for adult life

  45. Social Issues • Other • Concerns about CF patient care and understanding of disease manifestations and treatment • Compliance with treatment regimens • Financial issues related to the illness • Family planning when reaching reproductive age

  46. Psychosocial Aspects • WHO definition of health “A State of complete physical, mental, and social well being and not merely the absence of disease or infirmity” • Health related quality of life (HRQOL) • Physical health • Mental health • Social function • Role function • General health perceptions

  47. Overall psychosocial function is good Problem areas Exacerbations - neg impact on general and physical health Increased vulnerability to stress of life More dysfunction seen in families with older patients Lower PFT’s had a greater impact on the parents than the patients Patients >12 years increased distress with hospitalization Compliance of treatment regimens improved in mother with less frequent social contacts and less satisfactory marital relationships Psychosocial Aspects

  48. Psychosocial Aspects • Intellectual function distributed normally • Inversely related to age • Academic function distributed normally • No changes with age • Lower levels of academic and intellectual functioning in lower SES classes • Age and SES account for 21% and 43% of variance in level of functioning

  49. Risk Behaviors • Cystic fibrosis patients vs. age-matched adolescent peers • Alcohol use 45.5% vs. 63.1% • Cigarettes 21.1% vs 53.3% • Marijuana use 9.7% vs 29.4% • Cocaine and other injectable drugs 2.6% vs. 5.7%

  50. Risk Behaviors • H/O sexually activity 28.3% vs. 46.4% • No difference in risky sexual behaviors: condom use, no contraception, and pregnancy • Tendency for improved health promoting behaviors • Seat belt use, bicycle helmets

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