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A. Backgroundnavigator

  1. Most common Caucasian lethal genetic disease
  2. Autosomal recessive genetic disease
    1. Most common type is classical CF with full spectrum of disease
    2. Nonclassical CF: symptoms and pathology in a subset of typically affected systems
  3. Gene frequency 1:27 in caucasians
  4. Likely that heterozygote confers resistance to dehydration by infectious diarrhea
  5. CF Disease Rate ~1:2500 caucasian live births
    1. About 1 in 14,000 in blacks
    2. About 1 in 90,000 in orientals
    3. Overall about 30,000 patients in USA
    4. Overall about 100,000 patients worldwide
  6. About 80% of CF patients die due to respiratory complications / failure
  7. Currently, median lifespan ~37 years for classical CF [7]

B. Cystic Fibrosis Chloride Channel [2] navigator

  1. CF Gene codes for CF Chloride Channel
    1. Gene on human chromosome 7
    2. Codes for 1480 amino acid protein, MW 167K (170-180K)
    3. Protein is called CF transmembrane conductance regulator (CFTR)
    4. CFTR is a chloride channel that mediates cAMP depedent chloride secretion
    5. CFTR found on a variety of epithelia
  2. CFTR Structure and Function
    1. Has 12 transmembrane regions, all alpha helical
    2. Two ATP binding domains; member of the ABC transporter family
    3. N-terminus is cytoplasmic, followed by initial transmembrane domain
    4. This followed by an initial nucleotide binding domain for binding ATP
    5. Large regulatory (R) domain follows this includes phosphorylation sites
    6. These sites are protein Kinase A (PK-A) and C phosphorylation sites (highly charged)
    7. Additional transmembrane domains, second nucleotide binding domains
    8. Followed by cytoplasmic C-terminus
    9. Structure very similar to proteins with transport functions
    10. This protein, CFTR, participates in transport of electrolytes across epithelia
    11. CFTR may also be involved in transport across intracellular membranes
  3. Ion Transport in CF
    1. Apical Cl- channel export dysfunction
    2. This leads to decreased Cl- excretion, water follows, and mucous is thicker
    3. CRTR Cl- channel also functions as a regulator of other Cl- and Na+ channels
    4. CFTR is the major chloride channel on apical surface of intestinal epithelium
    5. Cholera toxin increases cellular cAMP, PK-A, and intestinal chloride secretion
    6. Mutant CFTR in CF lead to hyperexpression of amiloride sensitive Na+ channels
    7. Mutant CFTR in CF also lead to reduced function of other chloride channels
  4. Tissue / Organ Expression of CFTR
    1. Bronchiolar epithelium
    2. Pancreatic exocrine cells
    3. Biliary duct cells
    4. Intestine
    5. Vas Deferens
    6. Sweat glands and ducts
  5. Classification of CFTR Mutations [1,3]
    1. Over 1500 distinct CFTR mutations have been identified in CF patients
    2. CFTR mutations into classes I through IV
    3. Class I mutations have stop codons and CFTR is not expressed
    4. Class II mutations have abnormal folding leading to defective processing and secretion
    5. Class III mutations have surface CFTR protein, but it is not regulated properly
    6. Class IV mutations have defective conduction
    7. Class V mutations have partially defective production or processing
    8. Class VI mutations have normal CFTR and defective regulation of other channels
    9. Class I-III mutations are most common
    10. Class II Delta F508 is most common single mutation
  6. Specific CFTR Mutations
    [Figure] "CF Ion Transport Defect"
    1. 70% of CF cases have a 3bp deletion of Phe508 codon (Delta F508 allele)
    2. This Delta F508 mutation is Class II, leading to abnormal folding and processing
    3. In addition, F508 in ATP binding domain normally permits ADP phosphorylation
    4. This mutation severely reduces levels of CFTR protein on surface of cells
    5. G551D and G1349D also cause severe CF and interfere with nucleotide binding domains
    6. G551D also inhibits CFTR interaction with ORCC chloride channel and Na+ channel
    7. Delta F508 heterozygotes with various other alleles have reduced mortality compared with Delta F508 homozygotes [4]
    8. Class I mutations may be overcome by application of gentamicin which causes suppression of stop codons by ribosomes and expression of CFTR protein [6]
  7. Genetic Modifiers in CF Lung Disease [8]
    1. Patients with Delta F508 mutations have a spectrum of mild to severe lung disease
    2. At least 10 genes have been reported to modify lung disease severity in CF
    3. Genetic variation in the 5' end of the transforming growth factor ß1 (TGF-ß1) gene modifies lung disease severity in CF patients with Delta F508 mutations
  8. Other Diseases associated with CFTR Mutations [3]
    1. Congenital absence of the vas deferens
    2. Chronic pancreatitis
    3. Allergic bronchopulmonary aspergillosis (ABPA)
    4. Chronic rhinosinusitis [5]
  9. Nonclassical CF [22]
    1. Spectrum of affected organs is narrower than typical CF
    2. Caused by mutations in genes other than CFTR
    3. Indicates that genes other than CFTR can cause CF like syndromes

C. Symptoms and Signs [7]navigator

  1. Respiratory
    1. Recurrent Infectious Bronchitis
    2. Recurrent pneumonia, especially Pseudomonas, Staphylococci, and/or Burkholderia
    3. Pseudomonas plays the most significant role in lung destruction [9,15,22]
    4. Bronchiectasis (persistent endobronchial bacterial infections)
    5. Nasal polyps and/or (recurrent) sinusitis
    6. Hemoptysis
    7. Airway obstruction, hyperinflation, pneumothorax
    8. About 80% of CF patients die due to respiratory failure / complications
  2. Gastrointestinal
    1. Meconium Ileus (17% of newborns) and peritonitis
    2. Bowel Atresia, Rectal Prolapse
    3. Intussusception
    4. Pancreatic Insufficiency with malabsorption (>80% of persons) - greasy bowel movements
    5. Hepatic cirrhosis with neonatal jaundice and portal hypertension (15%)
    6. Gall Bladder Obstruction
    7. Edema due to hypoalbuminemia
  3. Miscellaneous
    1. Male sterility (azoospermia >90%), reduced female fertility
    2. Congenital absence of the vas deferens
    3. Elevated sweat electrolytes (chloride)
    4. Metabolic alkalosis - Cl- loss with HCO3- retention
    5. Heat Prostration
    6. Digital Clubbing
    7. Arthropathy
    8. Abnormal fatty acid metabolism [27]
    9. Malnutrition - increase caloric intake; goal body-mass index 22 for women, 23 for men
  4. Screening all infants for CF permits early detection and malnutrition prevention

D. Diagnostic Criterianavigator

  1. Persistently elevated sweat electrolyte (chloride) concentrates
    1. Sweat chloride determination is standard initial screening test
    2. Sweat chloride concentration >60mmol/L diagnostic of CF
    3. Sweat chloride test should be repeated (two tests required for definitive diagnosis)
    4. Sweat chloride concentrations in 40-60mmol/L range found in ~2% of CF
    5. Range 40-60 mmol/L results should prompt genotyping (two known mutations)
    6. Characteristic bioelectric abnormalities by direct CFTR measurement nasal epithelium
  2. Differential Diagnosis of Elevated Sweat Electrolytes
    1. Metabolic: CF, fucosidosis, glycogen storage diseases, mucopolysaccharidosis, hypothyroidism, adrenal insufficiency, peripheral diabetes insipidus
    2. Skin and sweat-gland disease - malnutirition, ectodermal dysplasia, atopic dermatitis
    3. Drugs - prostaglandin E1 infusion
  3. Characteristic Clinical Findings
    1. Pulmonary disease - progressive and recurrent pulmonary infections
    2. Gastrointestinal disease - pancreatic exocrine deficiency
    3. Possible obstructive azoospermia - usually absence of vas deferens
  4. Genotyping is improving in ability to establish diagnosis or rule it out
    1. Commercially available test kits detect 70 different mutations (~90% of CF cases)
    2. In about 18% of CF cases, more than one abnormality can be found
    3. Used for early diagnosis along with blood test trypsinogen levels
  5. Early Identification of CF and Pseudomonas Screening [22]
    1. Pseudomonas colonization occurs during first several years of life
    2. Perinatal CF genotyping can identify CF patients prior to development of malnutrition and end organ damage
    3. Early detection using ELISA-based serum screening for antibodies is now possible
    4. Chest radiograph changes and serum antibodies both predate lung symptoms
    5. Early identification of Pseudomonas colonization may permit early preventative therapy
    6. Chronic use of antibiotics which do not kill Pseudomonas may exacerbate colonization and hasten lung function decline

E. Pulmonary Diseasenavigator

  1. Colonization and spread of bacteria in lung incites inflammation [9,15]
  2. Progression of Pathogens in CF Airways [15]
    1. Initially normal, sterile lungs
    2. Transient infections with Haemophilus influenzae (nontypeable), Staphylococcus aureus, then Pseudomonas aeruginosa
    3. Chronic non-mucoid Pseudomonas aeruginosa
    4. Then mucoid biofilm (highly resistant to antibiotics) P. aeruginosa
    5. P. aeruginosa is acquired in 30% of CF patients by age 6 months; increases thereafter
    6. Nonmucoid P. aeruginosa is aquired first by median age 1 year
    7. Mucoid P. aeruginosa acquired by median age 13 years
    8. Colonization and infections with Haemophilus influenzae, Staphylococcus aureus, Burkholderia cepacia and B. cenocepacia occur in addition to pseudomonas [7]
  3. Prolonged and over-exuberant inflammation drives lung destruction
    1. Inability to bind and destroy colonizing bacteria
    2. Excessively viscous mucous which not cleared properly
  4. Factors Contributing to Pulmonary Decline
    1. Altered transport of water with ions across epithelium due to Cl- channel dysfunction
    2. Alterations in inflammatory response
    3. Altered respiratory defenses - poor ciliary clearance
    4. Autonomic nervous system dysfunction
    5. Deterioration in lung function over time correlates with transition from non-mucoid to mucoid P. aeruginosa
  5. Progressive Inflammation and Dibrosis Occurs
    1. Bronchitis and Bronchiolitis
    2. Airway obstruction due to thick mucous
    3. Atelectasis and Bronchiectasis with air trapping
  6. Pulmonary Symptoms and Signs
    1. Hemoptysis (Bronchiectasis), Pneumothorax (trapping), Abscess (empyema)
    2. Pulmonary hypertension leads to cor pulmonale, heart failure
    3. Decline in FEV1 is ~3-4% per year in most patients
  7. Eradication of bacteria in early CF lung disease likely reduces respiratory decline
  8. Death from CF usually due to respiratory failure (~80%), cardiac failure, or infection

F. Treatment of Pulmonary Disease [7] navigator

  1. Genetic Counseling
    1. Genetic counseling should strongly be considered
    2. Disease is uniformly fatal and abortion of affected fetus should be considered
  2. Prevent / Control Infection
    1. Cycle antibiotic therapy - inhaled tobramycin preferred [24]
    2. Prophylactic Antibiotics - inhaled anti-pseudomonal agents (± oral agents)
    3. Prompt initiation of antibiotics for colonization with staphylococcus and pseudomonas is generally recommended [1]
    4. Inhaled DNAse - decreased need for antibiotics
    5. Hypertonic saline (preceded by bronchodilator) - reduces exacerbation, improves lung function, improves mucus clearance [16,17]
    6. Hypertonic saline (7% NaCl) should be considered 2-4X per day
  3. Prophylactic Antibiotics
    1. Eradication of P. aeruginosa reduces decline in lung function [15]
    2. Aerosolized tobramycin (600mg tid) is generally effective and safe
    3. Aerosolized tobramycin (300mg tid x 2 weeks on, then 2 weeks off) very effective [18]
    4. Aerosolized tobramycin reduced hospitalizations and improved pulmonary function [18]
    5. Inhaled tobramycin 80mg bid every other month eradicates colonized Pseudomonas aeruginosa and prevents recolonization in CF patients [24]
    6. Inhaled colistin also effective at eradication alone or in combinations
    7. Oral ciprofloxacin (Cipro®) + inhaled colistin is effective against pseudomonas
    8. Oral TMP/SMX (Bactrim®, Septra®) is not advised as it may lead to increased colonization and lung destruction by Pseudomonas [22]
    9. Oral azithromycin for 4-6 months improves lung function and reduces exacerbations in many patients [28]
    10. In CF patients chronically infected with Pseudomonas aeruginosa, intermittent oral azithromycin for 5 months improves FEV1, reduces exacerbations, increases weight [29]
    11. Oral antistaphylococcal penicillins (such as flucloxacillin) reduce staphylococcus but increase colonization with pseudomonas
  4. Inhaled DNAse (dornase alpha; Pulmozyme®) [25,26]
    1. Reduced viscosity of secretions
    2. Typical dose is 2.5mg daily by inhalation
    3. Increase in FEV1 ~15% and significant reduction in infection
    4. Daily 2.5mg recombinant DNAse more effective than inhaled hypertonic (3%) saline [25]
    5. Alternating day DNAse was as effective in increasing FEV1 as daily DNAse [25]
  5. Treatment of Exacerbation of Pulmonary Infection
    1. Obtain sputum and blood cultures and perform sensitivity testing
    2. Bronchoscopy may be required for obtaining adequate sample
    3. Double antibiotic coverage for 14-21 days
    4. Typically initiate therapy with aminoglycoside and anti-pseudomonal ß-lactam antibiotic
    5. When given with ceftazidime, intravenous tobramycin given once daily has equal efficacy to three-times daily and probably has less nephrotoxicity [10]
    6. Combination antibiotic testing did not improve outcomes in CF patients with exacerbations associated with multiresistant bacteria [12]
    7. Intensify physiotherapy for airway clearance: perform airway clearance 3-4X per day
    8. Strongly consider bronchodilator therapy
    9. Nebulized hypertonic saline preceded by bronchodilator reduces exacerbation rates [16,17]
  6. Anti-Inflammatory Agents
    1. Glucocorticoids - especially for bronchospasm (but not given chronically)
    2. Side effects of chronic glucocorticoids outway benefits in CF [1]
    3. Ibuprofen (dose levels 50-100µg/mL) reduced decline in FEV1 but toxicity develops
  7. Improve Water Transport
    [Figure] "CF Ion Transport Defect"
    1. Increase Cl- intercellular transport
    2. Na+ lumen channel blocker amiloride may improve pulmonary function
    3. Inhaled Uridine Triphosphate increases CF patient's chloride secretion
    4. Amiloride or inhaled UTP alone do not cause clinically significant improvements [11]
    5. Combination therapy trials are underway
    6. Class I mutations may be overcome by application of gentamicin which causes suppression of stop codons by ribosomes and expression of CFTR protein [6]
    7. Topical application of gentamicin to airway epithelium may increase CFTR expression
  8. Bronchodilator Therapy
    1. ß-adrenergic agonists may improve obstructive symptoms
    2. Use on patients whose FEV1 improves >10% with ß-agonist trial
    3. Theophylline should be used only in patients with poor responses to ß-agonists
    4. Caution with theophylline in patients receiving erythromycin or ciprofloxacin
  9. Gene Transfer
    1. Slow progress is being made for pulmonary epithelia gene transfer
    2. Gene transfer vectors in development including Adenovirus and Adeno-Associated Virus
    3. Liposomal mediated gene transfer can alter nasal and pulmonary chloride transport [20]
  10. Lung Transplantation [13,19,21,23]
    1. About 150 lung transplants per CF per year [7]
    2. Some patients will also require heart transplantation due to right heart failure
    3. In one analysis, lung transplant reduced risk of death for the entire cohort ~70% [23]
    4. In another analysis, lung transplantation did not improve mortality due to CF [19]
    5. Lung transplant related deaths are second most common cause of CF related deaths
    6. Lung transplantation improves survival in CF patients with life expectancy <30% at 5 years based on new prediction measure [23]
    7. One year survival is ~74%; five year survival is ~33%
  11. Indications for Lung Transplantation [19,21]
    1. FEV1<30% of predicted value OR
    2. Rapidly declining lung functions OR
    3. Frequent severe exacerbations OR
    4. Progressive weight loss
    5. Female sex and age of <18 years with FEV1 >30%
    6. Newer outcomes prediction module may be more accurate for indicating transplant [23]
  12. Protein replacement therapy is also being evaluated

G. Pancreatic Insufficiency navigator

  1. Common with F508 mutant CF
  2. Upregulation of phospholipase C isoform (NYD-SP27) may suppresses CFTR translocation to pancreatic cells and exacerbates pancreatic exocrine dysfunction
  3. Effects of Pancreatic Insufficiency
    1. Mainly exocrine deficiency with highly reduced pancreatic fluid bicarbonate (HCO3-) levels
    2. Major role in malnutrition, growth retardation, failure to thrive
    3. Early CF screening can detect disease prior to development of malnutrition
    4. Diabetes mellitus is rare in CF
  4. ~90% of CF patients require pancreatic enzyme supplementation
    1. Pancreatic enzyme replacements effective for malabsorption
    2. High potency, microencapsulated pancreatic enzyme replacements have been developed
    3. Diabetes - treated with Insulin
  5. Colonic fibrosis has been reported increasing numbers of patients with CF
  6. Strong correlation between high potency preparations and fibrosing colonopathy [14]

H. Liver Diseasenavigator

  1. ~20% of adolescents with CF develop chronic liver disease, mainly biliary
    1. Progressive fibrosis leads to portal hypertension
    2. Extra- and intrahepatic ductal anomalies
  2. Ursodiol may show some benefit
    1. High dose is used: 20mg/kg/d
    2. Improvement in pruritis and lab parameters reported
  3. Extra amounts of fat soluble vitamins A, D, E, K also required

References navigator

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  2. Rose SM, Miller S, Sorscher EJ. 2005. NEJM. 352(19):1992 abstract
  3. Super M. 2000. Lancet. 355(9218):1840 abstract
  4. McKone EF, Emerson SS, Edwards KL, Altken ML. 2003. Lancet. 361(9370):1671 abstract
  5. Wang XJ, Moylan B, Leopold DA, et al. 2000. JAMA. 284(14):1814 abstract
  6. Wilschanski M, Yahav Y, Yaacov Y, et al. 2003. NEJM. 349(15):1433 abstract
  7. Boyle MP. 2007. JAMA. 298(15):1787 abstract
  8. Drumm ML, Konstan MW, Schluchter MD, et al. 2005. NEJM. 353(14):1443 abstract
  9. Li Z, Kosorok MR, Farrell PM, et al. 2005. JAMA. 293(5):581 abstract
  10. Smyth A, Tan KHV, Hyman-Taylor P, et al. 2005. Lancet. 365(9459):573 abstract
  11. Stern RC. 1997. NEJM. 336(7):487 abstract
  12. Aaron SD, Vandemheen KL, Ferris W, et al. 2005. Lancet. 366(9484):463 abstract
  13. Hosenpud JD, Bennett LE, Keck BM, et al. 1998. Lancet. 351(9095):24 abstract
  14. FitzSimmons SC, Burkhart GA, Borowitz D, et al. 1997. NEJM. 336(18):1283 abstract
  15. Starner TD and McCray PB Jr. 2005. Ann Intern Med. 121(3):207
  16. Elkins MR, Robinson M, Rose BR, et al. 2006. NEJM. 354(3):229 abstract
  17. Donaldson SH, Bennett WD, Zeman KL, et al. 2006. NEJM. 354(3):241 abstract
  18. Ramsey BW, Pepe MS, Quan JM, et al. 1999. NEJM. 340(1):23 abstract
  19. Liou TG, Adler FR, Cox DR, Cahill BC. 2007. NEJM. 357(21):2143 abstract
  20. Alton EWFW, Stern M, Farley R, et al. 1999. Lancet. 353:947 abstract
  21. Aurora P, Whitehead B, Wade A, et al. 1999. Lancet. 354(9190):1591 abstract
  22. Groman JD, Meyer ME, Wilmott RW, et al. 2002. NEJM. 347(6):401 abstract
  23. Liou TG, Adler FR, Cahill BC, et al. 2001. JAMA. 286(21):2683 abstract
  24. Ratjen F, Doring G, Nikolaizik WH. 2001. Lancet. 358(9286):983 abstract
  25. Suri R, Metcalfe C, Lees B, et al. 2001. Lancet. 358(9290):1316 abstract
  26. Inhaled DNase. 1994. Med Let. 36(920):34
  27. Freedman SD, Blanco PG, Zaman MM, et al. 2004. NEJM. 350(6):560 abstract
  28. Equi A, Balfour-Lynn IM, Bush A, Rosenthal M. 2002. 360(9338):978 abstract
  29. Saiman L, Marshall BC, Mayer-Hamblett N, et al. 2003. JAMA. 290(13):1749 abstract