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cystic fibrosis (CF, mucoviscidosis)

Epidemiology: 1) Caucasians: a) 1 in 2000-3500 live births b) 1 in 20 (3-5%) are heterozygous carriers c) the most common lethal genetic disease in Caucasians 2) Blacks: 1 in 17,000 live births 3) Asians: 1 in 90,000 live births 4) no sex predominance 5) 10% of cases diagnosed in patients > 10 years of age Pathology: 1) clinical manifestations reflect alterations in exocrine secretions such that mucus becomes excessively thick & tenacious 2) impaired mucociliary clearance 3) bacterial colonization of airways 4) lysis of neutrophils releases DNA & actin filaments further reducing mucociliary clearance 5) the DNA in purulent sputum forms a viscous gel that that increases viscosity of sputum [9] 6) chronic inflammation leads to bronchiectasis, obstructive lung disease, pulmonary fibrosis & cor pumonale 7) all exocrine glands, except sweat glands are adversely affected; sweat becomes salty 8) 10% of patients & carriers develop hyper-responsive airways & asthma 9) 10% of patients develop bronchopulmonary aspergillosis 10) azoospermia is due to congenital absence of a vas deferens a) congenital bilateral absence of the vas deferens may represent a mild form of cystic fibrosis b) majority of men with cystic fibrosis lack the vas deferens Genetics: 1) autosomal recessive, with asymptomatic heterozygous carriers 2) mutations in the cystic fibrosis transmembrane regulator (CFTR) gene, which encodes an epithelial chloride channel 3) about 70% of patients carry the same mutation, a deletion of phenylalanine 508 in one of the two CFTR ATP-binding domains (F508del) a) this mutation results in a temperature-sensitive defect in protein processing (not in aberrant regulation by ATP) b) at 27 C, the mutant form of CFTR forms functionally active chloride channels, but at 37 C, it gets stuck in the maturation pathway & fails to reach plasma membrane, thus giving rise to a very severe disease state in which epithelial chloride channels are absent 4) about 400 different mutations are known 5) other implicated genes - PLCZ1 Clinical manifestations: 1) pulmonary (97% of adult CF patients) a) accounts for most of the morbidity & mortality b) chronic & progressive with acute exacerbations c) almost always begins in the upper lobes d) hyperinflation, bronchiectasis & microabscesses occur secondary to mucous plugging e) chest may be hyperresonant to percussion f) chronic productive cough with purulent sputum g) atelectasis h) hemoptysis (60-71% of adult CF patients) i) pneumothorax (16% of adult CF patients) j) recurrent or persistent lower respiratory tract infections (pneumonia) - Pseudomonas aeruginosa (most common) - Haemophilus influenzae - Staphylococcus aureus - Burkholderia cepacia - nontuberculous mycobacterial infection [4] k) allergic bronchopulmonary aspergillosis [4] 2) extrapulmonary manifestations include: a) upper respiratory tract (48% of adult CF patients) - chronic sinusitis - nasal polyps b) intestinal: - constipation - volvulus - intussusception - fecal impactation - rectal prolapse - chronic diarrhea, steatorrhea c) pancreatic: - malabsorption (95%), but seldom symptomatic - malnutrition - pancreatitis - diabetes mellitus d) hepatobiliary: - fatty liver - cholelithiasis - biliary cirrhosis - portal hypertension e) genitourinary - infertility & sterility: azoospermia (95% of males) - may rarely present in adulthood with isolated azoospermia as only symptom - epididymitis f) skeletal - hypertrophic osteoarthropathy - retardation of growth - retardation of bone maturation - demineralization of bone - clubbing Laboratory: 1) sweat chloride using pilocarpine iontophoresis is the gold standard for diagnosis of CF a) > 80 meq/L is abnormal in adults; > 60 meq/L in children b) abnormal results on at least 2 tests is necessary for diagnosis c) a negative sweat chloride in an adult does not rule out CF [4] d) confirm bronchiectasis prior to sweat chloride (see Radiology:) - immunoglobulins in serum if bronchiectasis confirmed prior to sweat chloride 2) respiratory/sputum culture & sensitivity using oropharyngeal swab a) at least quarterly [23] b) common organisms include: - Pseudomonas aeruginosa - dominant organism - impossible to eradicate - Pseudomonas cepacia (Burkholderia cepacia) - associated with rapid deterioration in lung function - Staphylococcus aureus - Haemophilus influenza 3) cystic fibrosis genotyping (PCR/southern blot) 4) sperm analysis a) azoospermia b) absence of fructose from the seminal vesicles 5) newborn screening may be of benefit [7] 6) screen for development of pancreatic insufficiency using fecal elastase [23] 6) see ARUP consult [11] Special laboratory: Pulmonary function tests: 1) obstructive pattern with evidence of air trapping & bronchial hyper-reactivity in some patients 2) later in the course of the disease, hypoxemia & hypercapnia Radiology: 1) chest X-ray a) hyperinflation b) bronchiectasis & hilar adenopathy c) microabscesses d) increased interstitial reticular marking e) upper lobes are generally more involved than the lower lobes 2) chest computed tomography - high-resolution computed tomography (CT) of thorax to confirm bronchiectasis - no more frequently than every 2-3 years [23] - risk of radiation exposure may exceed benefit 2) abdominal imaging: dilated loops of small intestine Differential diagnosis: (in adults) 1) features favoring cystic fibrosis a) clinical features of cystic fibrosis b) positive family history c) sweat chloride > 80 meq/L d) pancreatic insufficiency 2) common variable immunodeficiency - complication of autoimmune disorder Management: 1) goals of therapy: a) control infections 1] exacerbations of pulmonary infections may present subacutely 2] treat any change in pulmonary function as infection 3] most patients are chronically infected with Pseudomonas aeruginosa 4] maintenance aerosolized tobramycin for control of chronic pulmonary infection [5,13] 5] maintenance azithromycin may be useful [6] b) provide bronchopulmonary hygiene 2) antibiotics: a) 3rd generation cephalosporin + aminoglycoside (dual IV coverage) b) empiric coverage for Pseudomonas aeruginosa c) because of increased clearance & volume of distribution, larger than usual doses of antibiotics may be needed d) inhaled antibiotics for new or chronic Pseudomonas aeruginosa infection [23] - direct aerosolized tobramycin - suppression of chronic pulmonary infections [4] - NOT useful for infectious exacerbations 3) chest physiotherapy & postural drainage - daily airway clearance therapy - more frequently during exacerbations [23] 4) nutrition - adequate hydration - high-salt diet, especially in summer or warm locations [23] - pancreatic enzyme replacement (pancrelipase) & fat soluble vitamin supplemention as indicated [4] 5) treat reactive airway disease (asthma) a) evidence is insufficient to recommend for or against use of bronchodilators, ibuprofen, leukotriene modifiers, azithromycin [23] b) avoid systemic or inhaled glucocorticoids [23] 7) recombinant human deoxyribonuclease I (rhDNAse) a) FDA-approved b) decreases viscoelasticity of sputum c) dornase alpha (Pulmozyme) 2.5 mg/day inhaled via jet nebulizer - adverse effects: - pharyngitis, laryngitis, rash, chest pain, conjunctivitis d) rhDNAse therapy associated with decreased mortality [9] 8) CFTR potentiator therapy - oral ivacaftor 150 mg PO every 12 hours improves pulmonary function in patients with CFTR mutation G551D [10] - ivacaftor/lumacaftor (Orkambi) FDA-approved for patients with 2 copies of the CFTR mutation F508del [16] - ivacaftor/tezacaftor for patients homozygous for CFTR mutation Phe508del [26] - one of two CFTR correctors VX-445 & VX-659 used in combination with ivacaftor/tezacaftor for patients homozygous for CFTR mutation Phe508del improved forced expiratory volume [27] - elexacaftor added to tezacaftor + ivacaftor improves lung function & quality of life in cystic fibrosis with F508del [30] 9) aerosolized hypertonic saline (7%) may be useful [8] 10) mannitol dry powder may be useful for patients with FEV1 decline > 2% annually who cannot tolerate rhDNAse (see NGC {NICE}) 11) oxygen therapy - CPAP for nocturnal hypoxemia or hypercarbia [4] 12) organ transplantation a) 10.3% of Canadians vs 6.5% of Americans may contribute to longer survival in Canadians [24] b) bilateral lung transplantation - 3 year survival is 50-55% c) liver transplantation for advanced liver disease [5] 13) gene therapy - not yet successful - nebulised nonviral CFTR gene-liposome complex every 4 weeks for 1 year [15] 14) preventive medicine a) pneumococcal vaccination PCV13 & PPSV23 8 weeks later b) annual flu vaccine c) patients with cystic fibrosis should wear masks during ambulatory care visits except in the exam room [25] d) patients should not wait with other patients in reception area e) clinicians should follow Contact Precautions 15) prognosis: a) mean age of survival significantly increased from 2000 - 2010 to 39 years [14] b) Canadians with cystic fibrosis live ~10 years longer than Americans [24] (50.9 years vs 40.6 years) c) poor prognostic indicators: 1] female sex 2] residence in a northern climate 3] pneumothorax 4] hemoptysis 5] recurrent bacterial infections 6] infection with Pseudomonas cepacia 7] systemic complications

Related

chloride (Cl-) in sweat cystic fibrosis (CFTR) genotyping cystic fibrosis carrier cystic fibrosis transmembrane conductance regulator; CFTR; cAMP-dependent chloride channel; ATP-binding cassette transporter sub-family C member 7 (CFTR ABCC7)

General

inborn error of metabolism obstructive lung disease pancreatic disease

Properties

DEFICIENCY: cystic fibrosis transmembrane conductance regulator

Database Correlations

OMIM 219700

References

  1. Mendelian Inheritance in Man (1990) MIM#219700
  2. Miller C. Cystic fibrosis. Sickly channels in mild disease. Nature 362:106 1993 PMID: 7680767
  3. Manual of Medical Therapeutics, 28th ed, Ewald & McKenzie (eds), Little, Brown & Co, Boston, 1995, pg 245-47
  4. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2015, 2018, 2022. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  5. Harrison's Principles of Internal Medicine, 13th ed. Isselbacher et al (eds), McGraw-Hill Inc. NY, 1994, pg 1038
  6. Journal Watch 22(23):175, 2002 Equi A, Balfour-Lynn IM, Bush A, Rosenthal M. Long term azithromycin in children with cystic fibrosis: a randomised, placebo-controlled crossover trial. Lancet 360:978, 2002 PMID: 12383667
  7. Sims EJ, McCormick J, Mehta G, Mehta A; UK CF Database Steering Committee. Newborn screening for cystic fibrosis is associated with reduced treatment intensity. J Pediatr. 2005 Sep;147(3):306-11. PMID: 16182666 - Schechter MS, Margolis P. Improving subspecialty healthcare: lessons from cystic fibrosis. J Pediatr. 2005 Sep;147(3):295-301. No abstract available. PMID: 16182664
  8. Elkins MR, Robinson M, Rose BR, Harbour C, Moriarty CP, Marks GB, Belousova EG, Xuan W, Bye PT; National Hypertonic Saline in Cystic Fibrosis (NHSCF) Study Group. A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. N Engl J Med. 2006 Jan 19;354(3):229-40. PMID: 16421364 - Ratjen F. Restoring airway surface liquid in cystic fibrosis. N Engl J Med. 2006 Jan 19;354(3):291-3. No abstract available. PMID: 16421371
  9. George PM et al. Improved survival at low lung function in cystic fibrosis: Cohort study from 1990 to 2007. BMJ 2011 Feb 28; 342:d1008 PMID: 21357627
  10. Ramsey BW et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011 Nov 3; 365:1663. PMID: 22047557 - Davis PB. Therapy for cystic fibrosis - The end of the beginning? N Engl J Med 2011 Nov 3; 365:1734. PMID: 22047565
  11. ARUP Consult: Cystic Fibrosis - CF The Physician's Guide to Laboratory Test Selection & Interpretation https://www.arupconsult.com/content/cystic-fibrosis
  12. ARUP Consult: Jewish Genetic Disease The Physician's Guide to Laboratory Test Selection & Interpretation - Ashkenazi Jewish Genetic Diseases Carrier Screening Algorithm https://arupconsult.com/algorithm/jewish-genetic-diseases-carrier-screening-algorithm - Ashkenazi Jewish Genetic Diseases Panel https://arupconsult.com/ati/ashkenazi-jewish-genetic-diseases-panel
  13. FDA News Release: March 22, 2013 FDA approves TOBI Podhaler to treat a type of bacterial lung infection in cystic fibrosis patients. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm345123.htm
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  15. Alton EW, Armstrong DK, Ashby D et al Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet. July 3, 2015 PMID: 26149841 http://www.thelancet.com/pdfs/journals/lanres/PIIS2213-2600%2815%2900245-3.pdf
  16. FDA News Release. July 2, 2015 FDA approves new treatment for cystic fibrosis http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm453565.htm
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  23. Lahiri T, Hempstead SE, Brady C et al. Clinical practice guidelines from the Cystic Fibrosis. Foundation for preschoolers with cystic fibrosis. Pediatrics 2016 Apr; 137:e20151784 PMID: 27009033
  24. Stephenson AL, Sykes J, Stanojevic S et al Survival Comparison of Patients With Cystic Fibrosis in Canada and the United States: A Population-Based Cohort Study. Ann Intern Med. March 14, 2017. PMID: 28288488 http://annals.org/aim/article/2609289/survival-comparison-patients-cystic-fibrosis-canada-united-states-population-based
  25. Young K, Sadoughi S, Sofair A New Guidance Posted on Infection Control in Pediatric Ambulatory Settings. Physician's First Watch, Oct 23, 2017 David G. Fairchild, MD, MPH, Editor-in-Chief Massachusetts Medical Society http://www.jwatch.org - Rathore MH, Jackson MA, COMMITTEE ON INFECTIOUS DISEASES Infection Prevention and Control in Pediatric Ambulatory Settings Pediatrics Oct 2017, e20172857 PMID: 29061869
  26. Taylor-Cousar JL, Munck A, McKone EF et al Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del. N Engl J Med 2017; 377:2013-2023. Nov 23, 2017 PMID: 29099344 Free full text http://www.nejm.org/doi/full/10.1056/NEJMoa1709846 - Rowe SM, Daines C, Ringshausen FC et al Tezacaftor-Ivacaftor in Residual-Function Heterozygotes with Cystic Fibrosis. N Engl J Med 2017; 377:2024-2035. Nov 23, 2017 PMID: 29099333 Free full text http://www.nejm.org/doi/full/10.1056/NEJMoa1709847
  27. Davies JC, Moskowitz SM, Brown C et al. VX-659-Tezacaftor-ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles. N Engl J Med 2018 Oct 25; 379:1599. PMID: 30334693 https://www.nejm.org/doi/10.1056/NEJMoa1807119 - Keating D, Marigowda G, Burr L et al. VX-445-Tezacaftor-ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles. N Engl J Med 2018 Oct 25; 379:1612. PMID: 30334692 https://www.nejm.org/doi/10.1056/NEJMoa1807120 - Holguin F. Triple CFTR modulator therapy for cystic fibrosis. N Engl J Med 2018 Oct 25; 379:1671. PMID: 30334694 https://www.nejm.org/doi/10.1056/NEJMe1811996
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  30. Middleton PG, Mall MA, Drevinek P et al. Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J Med 2019 Nov 7; PMID: 31697873 https://www.nejm.org/doi/10.1056/NEJMoa1908639 - Heijerman HGM, McKone EF, Downey EG et al. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: A double-blind, randomised, phase 3 trial. Lancet 2019 Oct 30 PMID: 31679946 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)32597-8/fulltext
  31. Elborn SJ Cystic fibrosis. Lancet. 2016 Nov 19;388(10059):2519-2531. PMID: 27140670
  32. NIDDK: Cystic Fibrosis Research Directions http://www.niddk.nih.gov/health/endo/pubs/cystic/cystic.htm - National Heart, Lung, and Blood Institute (NHLBI) Cystic Fibrosis https://www.nhlbi.nih.gov/health-topics/cystic-fibrosis