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Pathophysiology and Therapy of the Lung Disease of Cystic Fibrosis (CF) in 1996

Warren Regelmann, MD

Outline

• Major clinical presentations of CF
• Sweat test
• Molecular basis of the disease
• Current pharmacotherapy
• Future directions
• References
• University of Minnesota Cystic Fibrosis Center Web site

I.Major clinical presentations of CF

• Gut
  • obstruction
    • congenital strictures
    • meconium ileus
    • distal obstruction syndrome
  • pancreatic insufficiency
    • exocrine
      • fat malabsorption
        • malnutrition
        • at soluble vitamin deficiency
      • recurrent pancreatitis
    • progressive failure of endocrine pancreatic function
      • diabetes mellitus
  • liver
    • focal cirrhosis
    • pharmocologic treatment
    • generalized cirrhosis
    • portal hypertension
• salt loss in sweat
• sterility
• respiratory tract
  • sinus mucosal hypertrophy and retained secretions
  • distal airway obstruction with retained intraluminal secretion
  • microbial overgrowth in distal airway
  • inflammatory response
  • cystic bronchiectasis
  • chronic obstructive pulmonary disease
  • chronic respiratory failure

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II.Sweat test for chloride anion concentration >60 mM after pilocarpine iontophoresis is used to confirm diagnosis

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III.Molecular basis of the disease

• a large gene on chromosome 7
• Resulting protein is a transmembrane protein regulating chloride anion passage through outer cell membrane and is transcribed primarily in epithelial cells and in serous cells of the submucosal glands of the respiratory tract
• how this location and chloride channel function result in abnormal mucus clearance is currently speculative
• as this molecular pathogenic mechanism becomes known, newer and more effective therapies will be suggested

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IV.Current pharmacotherapy of the respiratory abnormalities associated with CF

• distal airway obstruction with retained intraluminal secretion
  • open alternative Cl channel with UTP
  • reduce Na resorption across epithelium with amiloride Phase III trial underway
  • combination in preclinical trial
  • mechanical drainage, directed coughing
• microbial overgrowth in distal airway
  • periodic systemic and aerosol treatment for S. aureus and P. aeruginosa especially, other microbes in individual cases
  • prophylactic cephalexin under controlled phase III 7 year trial ending this year showed no significant effect on FEV1.
  • aerosolized gentamicin and tobramycin appear to improve FVC and FEV1 and reduce need of hospitilization for IV anti-pseudomonal therapy in two small controlled crossover trials.
  • intravenous ticarcillin and tobramycin reduced P. aeruginosa and total bacterial density in CF sputum and improved FVC, FEV1 and FEF25-75 more than placebo in small study of patients with increased sputum production, cough and declining spirometric measures. Effect on spirometry lasted about 4 months after hospitilization
    • CF patients have abnormally large Vd and increased ke for aminoglycosides
    • CF patients have abnormally large ke for beta lactams
  • anti-pseudomonal mucoid exopolysaccharide immune globulin in clinical trial for prevention of airway infection with P. aeruginosa, mucoid strains
• inflammatory response
  • rhDNase, Pulmozyme® (Genentech), approved for use in CF patients over age 5 and with FVC > 40% predicted to reduce viscosity of airway secretions due to polymeric DNA released from dead neutrophils that entered the airway in response to microbial peptides and epithelial chemoattractants. Regular use reduced frequency of IV antibiotics, pulmonary exacerbations and improves FEV1 and subjective well being in parallel double blind placebo controlled phase III trial.
  • gelsolin, protein from serum, unlinks polymeric actin filaments also released from dead neutrophils and also reduces viscosity of CF lung secretions. Preclinical studies completed
  • oral steroid trial--2mg/kg qod in infants--some improvement initially but increased cataracts; 1 mg/kg qod improvement initially but spirometry was similar to placebo after 5-7 years. Cataract rate somewhat increased in prednisone group
  • oral ibuprofen trial completed and drug seems effective in small number of patients.
    • pharmocokinetics are important for control of airway inflammation induced by P. aeruginosa in agar beads in animal model
    • study varied dose to achieve peak concentration, sampled every 30 min for 3 hrs, of greater than 50 and less than 100 mcg/ml
    • safety when used in larger number of patients is question
  • inhaled steroids in short term trial no measurable effect on spirometry
• cystic bronchiectasis
  • no curative therapy available
  • chronic mechanical drainage, directed cough may reduce acute exacerbations
  • progress may be slowed by attention to therapy for infection and inflammation but no therapy yet shown to stop or reverse progression
• chronic obstructive pulmonary disease
  • oxygen therapy as appropriate during night, with exercise or constant may slow development of pulmonary arterial hypertension and cor pulmonale
  • bilateral single lung transplantation when hypoxemic, FEV1 chronically at or below about 40% predicted, and before progressive malnutrition from increasing work of breathing, diabetic complications, increased tumor necrosis factor secretion, etc supervenes
• chronic respiratory failure
  • optimize nutrition
  • bilateral single lung transplantation

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V.Future directions

• respiratory tract
  • use of adenoviral-CFTR vector system for somatic gene therapy of CF airway
    • gene expression in human CF respiratory epithelium achieved
    • Chloride channel abnormality rectified
    • no integration of cDNA into host genome so effect declines over about 1 month
    • with repeat administration an inflammatory response occurs that decreases gene transfer efficiency and potentially may damage lung
  • current research is directed at improved or alternative vector systems
• gut
  • development of cellular site directed vector for delivery of normal CFTR gene to biliary epithelium
• pancreas
  • improved diagnosis and control of diabetes and its complications

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VI References

• Collins FS. Cystic fibrosis: molecular biology and therapeutic implications. Science, 256:774-9, 1992
• Crystal RG, McElvaney NG, Rosenfeld MA, et. al. Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis. Nature Genetics, 8:42-51, 1994. .
• Fitzsimmons SC. The changing epidemiology of cystic fibrosis. J Pediatr, 122:1-9, 1993
• Fuchs, HJ, Borowitz, DS, Christiansen, DH, Morris, EM, Nash, ML, Rosenstein, BJ, Smith, AJ, Wohl, ME for the Pulmozyme (rhDNase) Study Group. Aerosolized recombinant human DNase reduces respiratory exacerbations and improves pulmonary function in patients with cytstic fibrosis. NEJM, 331:637-42, 1994
• Hudson VL, Wilenski C, Regelmann WE: Prognostic implications of initial oropharyngeal bacterial flora in patients diagnosed with cystic fibrosis before the age of two years. Journal of Pediatrics, 122(6):854-60, 1993.
• Konstan MW, Byard PJ, Hoppel CL, Davis PB. Effect of high-dose ibuprofen in patients with cystic fibrosis. NEJM, 332:848-854, 1995.
• Ramsey BW, Dorkin HL, Eisenberg JD, Gibson RL, Harwood IR, Kravitz RM, Schidlow DV, Wilmott RW, Astley SJ, McBurnie MA, Wentz K, Smith AL. Efficacy of aerosolized tobramycin in patients with cystic fibrosis. NEJM, 328:1740-1746, 1993.
• Regelmann WE, Elliott GR, Clawson CC and Warwick WJ: Reduction of sputum Ps. aeruginosa density by antibiotics improves lung function in cystic fibrosis more than bronchodilators and chest physiotherapy alone. Am. Rev. Resp. Dis., 141:914-921, 1990.

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