1 / 133

Cystic Fibrosis - history

Cystic Fibrosis - history. Dorothy Anderson 1938 - documented as clinical and pathological entity all dying at 1 week+: pneumonia, purulent bronchitis, bronchiectasis & abscess Blackfan -main problem is inspissiated secretions

penn
Download Presentation

Cystic Fibrosis - history

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Cystic Fibrosis - history • Dorothy Anderson 1938 - documented as clinical and pathological entity all dying at 1 week+: pneumonia, purulent bronchitis, bronchiectasis & abscess • Blackfan -main problem is inspissiated secretions • Fanconi - lack of pancreatic enzymes lead to malabsorption; association with bronchiectasis

  2. CF - history • Faber 1943-45: the pathology of the pancreas is only one manifestation of the abnormality affecting all of the mucus glands • Harry Shwachman: diagnosis based on pancreatic enzyme analysis & clinical state • Anderson 1953 - abnormal sweat electrolytes

  3. CF - history • Harvey White 1958 - Children’s Memorial Hospital Chicago • “Extensive antibiotic therapy and surgery will undoubtedly prolong life, so that we will see these children reaching their teens and young adult years with chronic pulmonary disease” • We have now moved beyond this with increasing numbers of patients in middle age

  4. What is cystic fibrosis? • The most common genetic disease in caucasians • Gene frequency - carrier status 1 in 20-25 • Autosomal recessive inheritance • Live births in UK - approx 1 in 2000-2500 • A complex multisystem disease

  5. How common ?Delta F508, G551D, G542X, 621+1(G>T) and 1898(G>A)

  6. UK CF Survey • current population in UK 8000 to 9000 • About 250 children born per year with CF • About 150 patients with CF die each year • Incidence showing a fall from 1:2,500 (antenatal screening, cascade screening, increased ethnic mix) • Adult population > 50% total

  7. What is CF? • Affects respiration, digestion, hepatobiliary, reproductive, vascular, musculoskeletal, endocrine systems, and renal

  8. CF • Multisystem disease but respiratory problems account for most of morbidity and mortality

  9. Primary cause death 1999 CFF data

  10. What happens in CF? • The lungs are normal at birth • at post mortem - mucopurulent plugs, emphysema, collapse, pneumonia, haemorrhage • loss of cilia, bronchial epithelial metaplasia, massive neutrophil dominated inflammatory cell infiltrate

  11. What is CF? • Over 90% pancreatic insufficient • sticky secretions to blocked ducts • secondary damage to secretory gland tissue • digestive juices - enzymes and bicarbonate • malabsorption, steatorrhoea, malnutrition, stunting, delayed puberty, fat sol vits

  12. What is CF? • CF gene causes abnormal production of the CFTR protein • CFTR acts as a chloride channel in apical cell membrane and regulates sodium transport • CFTR found in lungs, salivary glands, sweat ducts, pancreas, liver, reproductive tract, kidney

  13. CFTR • 1480 amino acids • Localizes to the apical cell membrane • Over 1500 mutations documented • ΔF508 is the most common mutation in Caucasian population • Five mutation classes

  14. Normal I II III IV V Nosynthesis Block inprocessing Block inregulation Altered conductance Reduced synthesis Nonsense G542X MissenseG551D MissenseR117H MissenseA455E AA deletionDF508 Frameshift394delTT Alternativesplicing3849+10kbC→T Splice junction1717-1G→A Molecular Consequences of CFTR Mutations CFTR Vankeerberghen A, et al. J Cyst Fibros. 2002. http://www.genet.sickkids.on.ca/cftr/

  15. Pathophysiology • CFTR expressed on the luminal surface of epithelial cells • Impairment of function • Defective chloride transport • Increased sodium transport • Increased fluid reabsorption • Overall increased viscosity of epithelial surface secretions

  16. glycosylation Golgi apparatus mRNA Endoplasmic reticulum The airway cell- normal epithelial cell - Cl- wild type CFTR Cl- Cl- Cl- Cl- ATP Chromosome 7 800 different mutations

  17. Impairment of CFTR function causes reduced fluid production. Enhanced sodium absorption through epithelial Na+ channels (ENaC) and basolateral Na/K ATPase pumps results in increased fluid absorption leading to dryer airways and impaired ciliary clearance

  18. How does CF present to the doctor?

  19. Rare presenting features • Nasal polyps/sinus disease - 5% • rectal prolapse - 2% • oedema - 2% • other - male infertility, pancreatitis

  20. At time of diagnosis • CF is a serious disorder despite major advances in Rx and understanding • Health now and longterm depend on effective Rx • Outlook improves year by year • Complex illness needing specialist care • Sweat test sibs, “cascade screen”

  21. CF - survival • 1938 - 70% died in the 1st year • 2000 - 50% survive to over 30 years • Median age death 1987 to 1999, 19 to 23 yrs • Median predicted survival 1999 = 29 yrs [25.5 in 1985] • Adult [>17 yrs] USA - 1989 & 1999 31% & 38% of all patients • 2007 average survival is 39 years

  22. MEDIAN SURVIVAL AGE FOR PATIENTS WITH CF AT VARIOUS TIMES SINCE FIRST DESCRIPTION OF CF

  23. Increasing survival • >50% patients now adults (UK data) • Median survival 38.6 years (USA data)

  24. 100 90 80 Percent predicted FEV1 70 60 1990 2001 50 40 6 8 10 12 14 16 18 24 26 28 30 20 22 Age (Years) Median Percent Predicted FEV1 vs Age: 1990 and 2001 Cystic Fibrosis Foundation. Patient Registry Annual Data Report. 2002.

  25. Pseudomonas aeruginosa • Wilmott 1985 • Chronic infection in 1st 5 years - 20% survival to 16 years • No infection - 95% survival to 16 years

  26. Survival with CF • Many reasons for improved prognosis BUT • survival better without chronic chest infection • USA data 1990s: average survival with chronic PA infection = 28 years BUT without chronic PA infection = 39 years

  27. Pseudomonas aeruginosa infection - Kerem 1990 • Life after pseudomonas in 895 patients attending Toronto clinic - At 7 years of age the mean percentage predicted FEV1 was 10% lower in children already infected compared with those who were not - p<0.01 • Throughout clinic population FEV1 in those with PA was about 10% less of predicted than those without PA

  28. Chronic Pa Endobronchitis Is Associated with Poor Survival in CF 1.0 Pa-negative(n = 12) 0.9 Nonmucoid Pa (n = 19) 0.8 Mucoid Pa (n = 50) 0.7 Fraction surviving 0.6 0.5 0.4 0.0 20 50 60 70 80 90 100 0 40 10 30 Time (months) Henry RL, et al. Pediatr Pulmonol. 1992.

  29. Symptoms of infection • Cough one of earliest and most important • lethargy • weight loss • fever • more sputum, white to yellow or green • dyspnoea

  30. Age-specific prevalence of infections in CF patients 2003 Cystic Fibrosis Patient Registry 2003 – Annual Data Report. October 2004.

  31. Disease begins in the small airways Bronchioles fill with chronic mucopurulent material Childhood and adolescence: progressive loss of small airway function Pathology of CF Lung Disease At birth: lungs are normal Tomashefski JF, et al. The pathology of cystic fibrosis. In: Cystic Fibrosis. 1993.

  32. Structural Changes Occur Even in Mild CF Lung Disease • 60 children with CF (6-12 years old) • Mean FEV1 = 102% predicted • 11/37 patients with normal lung function (all PFT values >85% predicted) had HRCT evidence of bronchiectasis • FEV1: 91% of predicted • FVC: 95% of predicted • FEF25-75: 89% of predicted Brody AS, et al. J Pediatr. 2004.

  33. CT Scans of Normal and CF Lungs Normal CF Tiddens HA. Pediatr Pulmonol. 2002. http://www.rrcc-online.com/paprogram/HISTHTML/RADNORM/CHCT02.HTM.

  34. The Vicious Cycle of CF Lung Disease • Ibuprofen • Corticosteroids Inflammation Obstruction • Airway clearance • Dornase alfa • Hypertonic saline • Bronchodilators Infection • Tobramycin • Azithromycin Chmiel JF, et al. Clin Rev Allergy Immunol. 2002.

  35. Treatment of the chest in children with CF - 1st principle • PREVENTION • PREVENTION • PREVENTION

  36. Recovered from toys, baths, soaps, nebulizers, sink drains, and hands of patients and staff Nonmucoid strains can survive for 24 hours, mucoid strains for ≥48 hours On dry surfaces, pathogens suspended in sputum can live for up to 8 days Pseudomonas aeruginosa: Sources in the Healthcare Environment Saiman L. et al. Clin Microbiol Rev. 2004.

  37. P aeruginosa: Patient-to-Patient Transmission • Shared strains found in Germany, United Kingdom, Australia, Denmark, and United States • Linked to antibiotic resistance • May involve transmission from Pa-positive to Pa-negative patients • Documented between siblings with CF • Linked to summer camps • Possibly via contaminated environment Saiman L. et al. Clin Microbiol Rev. 2004.

  38. Modes of Transmission • Direct: body-to-body surface transfer • Kissing • Touching • Patient care • Shaking hands • Indirect: contact with a contaminated object • Toys • Shared toothbrushes • Eating utensils • Gloves • Respiratory equipment Saiman L. Cystic Fibrosis Foundation [webcast]. 2004.

More Related