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Cystic FibrosisCystic Fibrosis
Richard H. SimonRichard H. Simon
Pulmonary and Critical Care MedicinePulmonary and Critical...
ObjectivesObjectives
Understand the basic facts about:Understand the basic facts about:
The genetic nature of cystic fibro...
What is Known About CFWhat is Known About CF
Autosomal recessive inherited diseaseAutosomal recessive inherited disease
Ge...
Cystic Fibrosis TransmembraneCystic Fibrosis Transmembrane
Conductance Regulator (CFTR)Conductance Regulator (CFTR)
Improved Survival in CFImproved Survival in CF
Current median survival: ~33 years of ageCurrent median survival: ~33 years...
Pathophysiology of CFPathophysiology of CF
Lung DiseaseLung Disease
Intrinsic inflammation in lung?Intrinsic inflammation ...
Bacterial Pathogens in CFBacterial Pathogens in CF
Common bacterial pathogensCommon bacterial pathogens
Haemophilus influe...
Natural History of CF Lung InfectionsNatural History of CF Lung Infections
Ps. aeruginosa or B. cepacia persistPs. aerugin...
Diagnostic criteria for cystic fibrosisDiagnostic criteria for cystic fibrosis
Part 1: Clinical Manifestation of DiseasePa...
Diagnostic criteria for cystic fibrosisDiagnostic criteria for cystic fibrosis
Part 2: Laboratory evidence of CFTR abnorma...
Acute Exacerbations ofAcute Exacerbations of
CF Lung DiseaseCF Lung Disease
SymptomsSymptoms
Increased cough with sputum p...
Acute Exacerbations ofAcute Exacerbations of
CF Lung DiseaseCF Lung Disease
Antibiotic treatmentAntibiotic treatment
Oral ...
IV Antibiotic TreatmentIV Antibiotic Treatment
For Pseudomonas, use 2 antibiotics forFor Pseudomonas, use 2 antibiotics fo...
Aerosolized AntibioticsAerosolized Antibiotics
High dose tobramycin proven for chronicHigh dose tobramycin proven for chro...
Mucolytic Therapy for CFMucolytic Therapy for CF
DNase (PulmozymeDNase (Pulmozyme ®®
))
Chronic use improves FEV1 and caus...
Asthma in Patients with CFAsthma in Patients with CF
Higher frequency than in generalHigher frequency than in general
popu...
Bronchodilators in CFBronchodilators in CF
No studies in acute exacerbationsNo studies in acute exacerbations
FEV1 improve...
Anti-Inflammatory TreatmentAnti-Inflammatory Treatment
in CFin CF
GlucocorticoidsGlucocorticoids
Oral (prednisone)Oral (pr...
Macrolide Therapy for CFMacrolide Therapy for CF
Susceptibility testing in the clinical microbiologySusceptibility testing...
Physiotherapy for CFPhysiotherapy for CF
No studies in acute exacerbationsNo studies in acute exacerbations
But “standard ...
Physiotherapy Options for CFPhysiotherapy Options for CF
Postural drainage and percussionPostural drainage and percussion
...
Supplemental OxygenSupplemental Oxygen
Use same guidelines as COPDUse same guidelines as COPD
Home Versus Hospital TherapyHome Versus Hospital Therapy
Home regimen must duplicate full hospitalHome regimen must duplic...
Assisted Ventilation in CFAssisted Ventilation in CF
Past studies show very poor outcomesPast studies show very poor outco...
Lung Transplantation CFLung Transplantation CF
Double lung transplantationDouble lung transplantation
Outcome similar to n...
Experimental Developments in CFExperimental Developments in CF
Gene therapyGene therapy
““Protein repair” therapyProtein r...
ReferencesReferences
Simon RH. Treatment of CF lung disease.Simon RH. Treatment of CF lung disease.
UpToDate, 2003.UpToDat...
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Cystic Fibrosis Richard H. Simon

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  1. 1. Cystic FibrosisCystic Fibrosis Richard H. SimonRichard H. Simon Pulmonary and Critical Care MedicinePulmonary and Critical Care Medicine Department of Internal MedicineDepartment of Internal Medicine richsimo@umich.edurichsimo@umich.edu 764-4554764-4554
  2. 2. ObjectivesObjectives Understand the basic facts about:Understand the basic facts about: The genetic nature of cystic fibrosis (CF)The genetic nature of cystic fibrosis (CF) The pathophysiology of CF lung diseaseThe pathophysiology of CF lung disease Know how to diagnose CFKnow how to diagnose CF Learn the basic approach to treating CFLearn the basic approach to treating CF lung diseaselung disease
  3. 3. What is Known About CFWhat is Known About CF Autosomal recessive inherited diseaseAutosomal recessive inherited disease Gene cloned in 1989: “CFTR”Gene cloned in 1989: “CFTR” Cystic Fibrosis Transmembrane conductionCystic Fibrosis Transmembrane conduction RegulatorRegulator cAMP modulated chloride channelcAMP modulated chloride channel Over 1,000 mutations in CFTR cause CFOver 1,000 mutations in CFTR cause CF diseasedisease An extensive amount of information isAn extensive amount of information is known about CFTRknown about CFTR
  4. 4. Cystic Fibrosis TransmembraneCystic Fibrosis Transmembrane Conductance Regulator (CFTR)Conductance Regulator (CFTR)
  5. 5. Improved Survival in CFImproved Survival in CF Current median survival: ~33 years of ageCurrent median survival: ~33 years of age Reasons for improved prognosis:Reasons for improved prognosis: Milder cases being diagnosed (minor factor)Milder cases being diagnosed (minor factor) Improved nutritionImproved nutrition Improved antibioticsImproved antibiotics Other reasonsOther reasons
  6. 6. Pathophysiology of CFPathophysiology of CF Lung DiseaseLung Disease Intrinsic inflammation in lung?Intrinsic inflammation in lung? Abnormal respiratory tract secretions andAbnormal respiratory tract secretions and bacterial defensesbacterial defenses Chronic bacterial infection -- bronchitisChronic bacterial infection -- bronchitis Airway damage -- bronchiectasisAirway damage -- bronchiectasis Chronic airflow obstructionChronic airflow obstruction Respiratory failureRespiratory failure DeathDeath
  7. 7. Bacterial Pathogens in CFBacterial Pathogens in CF Common bacterial pathogensCommon bacterial pathogens Haemophilus influenzaHaemophilus influenza Staphylococcus aureusStaphylococcus aureus Pseudomonas aeruginosaPseudomonas aeruginosa ((mucoidmucoid) 85% of) 85% of adultsadults Less common bacterial pathogensLess common bacterial pathogens Burkholderia cepaciaBurkholderia cepacia Methicillin-resistant Staphylococcus aureusMethicillin-resistant Staphylococcus aureus Stenotrophomonas maltophiliaStenotrophomonas maltophilia Achromobacter xylosoxidansAchromobacter xylosoxidans
  8. 8. Natural History of CF Lung InfectionsNatural History of CF Lung Infections Ps. aeruginosa or B. cepacia persistPs. aeruginosa or B. cepacia persist True infection, not “colonization”True infection, not “colonization” Difficulty in eradicating infection:Difficulty in eradicating infection: Intrinsic antibiotic resistanceIntrinsic antibiotic resistance Acquired antibiotic resistanceAcquired antibiotic resistance Poor antibiotic penetration into secretionsPoor antibiotic penetration into secretions Alginate produced by mucoid Ps. (biofilms)Alginate produced by mucoid Ps. (biofilms) CF-related defects in mucosal (but notCF-related defects in mucosal (but not systemic) defensessystemic) defenses
  9. 9. Diagnostic criteria for cystic fibrosisDiagnostic criteria for cystic fibrosis Part 1: Clinical Manifestation of DiseasePart 1: Clinical Manifestation of Disease At least one of the following:At least one of the following: 1)1) One or more clinical manifestations of CFOne or more clinical manifestations of CF Meconium ileusMeconium ileus Chronic bronchitis / bronchiectasisChronic bronchitis / bronchiectasis Chronic infection of the paranasal sinusesChronic infection of the paranasal sinuses Pancreatic insufficiencyPancreatic insufficiency Salt loss syndromesSalt loss syndromes Male infertility due to congenital bilateral absence of theMale infertility due to congenital bilateral absence of the vas deferensvas deferens 2)2) Positive newborn screening testPositive newborn screening test 3)3) History of CF in a siblingHistory of CF in a sibling
  10. 10. Diagnostic criteria for cystic fibrosisDiagnostic criteria for cystic fibrosis Part 2: Laboratory evidence of CFTR abnormalityPart 2: Laboratory evidence of CFTR abnormality At least one of the following:At least one of the following: 1)1) Elevated sweat chloride test (98%Elevated sweat chloride test (98% sensitive)sensitive) 2)2) Identification of a mutation in each CFTRIdentification of a mutation in each CFTR gene known to cause CF (currently ~81%gene known to cause CF (currently ~81% sensitive)sensitive) 3)3) In vivo demonstration of characteristicIn vivo demonstration of characteristic abnormalities in ion transport across nasalabnormalities in ion transport across nasal epithelium (not widely available)epithelium (not widely available)
  11. 11. Acute Exacerbations ofAcute Exacerbations of CF Lung DiseaseCF Lung Disease SymptomsSymptoms Increased cough with sputum productionIncreased cough with sputum production HemoptysisHemoptysis Increased shortness of breathIncreased shortness of breath Fever (not required)Fever (not required) Reduction in FEV1Reduction in FEV1 Worsening infiltrates on chest x-ray (notWorsening infiltrates on chest x-ray (not required)required)
  12. 12. Acute Exacerbations ofAcute Exacerbations of CF Lung DiseaseCF Lung Disease Antibiotic treatmentAntibiotic treatment Oral antibioticsOral antibiotics If symptoms are mild, andIf symptoms are mild, and Bacteria are susceptibleBacteria are susceptible Intravenous antibiotics otherwiseIntravenous antibiotics otherwise
  13. 13. IV Antibiotic TreatmentIV Antibiotic Treatment For Pseudomonas, use 2 antibiotics forFor Pseudomonas, use 2 antibiotics for synergysynergy Higher doses of aminoglycosides areHigher doses of aminoglycosides are neededneeded Duration usually >10 daysDuration usually >10 days Continue until symptoms return toContinue until symptoms return to baseline statusbaseline status
  14. 14. Aerosolized AntibioticsAerosolized Antibiotics High dose tobramycin proven for chronicHigh dose tobramycin proven for chronic infectioninfection TOBITOBI®® 300 mg in 5 ml bid every other month300 mg in 5 ml bid every other month
  15. 15. Mucolytic Therapy for CFMucolytic Therapy for CF DNase (PulmozymeDNase (Pulmozyme ®® )) Chronic use improves FEV1 and causes fewerChronic use improves FEV1 and causes fewer exacerbationsexacerbations
  16. 16. Asthma in Patients with CFAsthma in Patients with CF Higher frequency than in generalHigher frequency than in general populationpopulation Allergic bronchopulmonary aspergillosisAllergic bronchopulmonary aspergillosis occurs in CFoccurs in CF
  17. 17. Bronchodilators in CFBronchodilators in CF No studies in acute exacerbationsNo studies in acute exacerbations FEV1 improves acutely in some patientsFEV1 improves acutely in some patients ββ-adrenergic agonists (e.g. albuterol)-adrenergic agonists (e.g. albuterol) Anticholinergic agents (ipratroprium bromide)Anticholinergic agents (ipratroprium bromide) Theophylline (used less frequently)Theophylline (used less frequently)
  18. 18. Anti-Inflammatory TreatmentAnti-Inflammatory Treatment in CFin CF GlucocorticoidsGlucocorticoids Oral (prednisone)Oral (prednisone) InhaledInhaled IbuprofenIbuprofen Beneficial for young patientsBeneficial for young patients No evidence for improvement in adultsNo evidence for improvement in adults
  19. 19. Macrolide Therapy for CFMacrolide Therapy for CF Susceptibility testing in the clinical microbiologySusceptibility testing in the clinical microbiology lab shows no killing of Ps. aeruginosalab shows no killing of Ps. aeruginosa But, macrolides beneficial in another disease thatBut, macrolides beneficial in another disease that has bronchiectasis and Ps. infection (diffusehas bronchiectasis and Ps. infection (diffuse panbronchiolitis)panbronchiolitis) Recent Phase III study of azithromycin in CFRecent Phase III study of azithromycin in CF showed benefit:showed benefit: Improved FEV1Improved FEV1 Fewer exacerbations of CF lung diseaseFewer exacerbations of CF lung disease
  20. 20. Physiotherapy for CFPhysiotherapy for CF No studies in acute exacerbationsNo studies in acute exacerbations But “standard of care” treatmentBut “standard of care” treatment Beneficial for chronic managementBeneficial for chronic management
  21. 21. Physiotherapy Options for CFPhysiotherapy Options for CF Postural drainage and percussionPostural drainage and percussion ExerciseExercise Flutter deviseFlutter devise PEP maskPEP mask Percussive vestPercussive vest Others gadgetsOthers gadgets
  22. 22. Supplemental OxygenSupplemental Oxygen Use same guidelines as COPDUse same guidelines as COPD
  23. 23. Home Versus Hospital TherapyHome Versus Hospital Therapy Home regimen must duplicate full hospitalHome regimen must duplicate full hospital programprogram IV drugsIV drugs PhysiotherapyPhysiotherapy NutritionNutrition Et ceteraEt cetera Results from small studies showed mixedResults from small studies showed mixed resultsresults
  24. 24. Assisted Ventilation in CFAssisted Ventilation in CF Past studies show very poor outcomesPast studies show very poor outcomes Non-invasive ventilation being triedNon-invasive ventilation being tried
  25. 25. Lung Transplantation CFLung Transplantation CF Double lung transplantationDouble lung transplantation Outcome similar to non-CFOutcome similar to non-CF transplantationtransplantation ProblemsProblems Long waiting listsLong waiting lists Many exclusionsMany exclusions Living donor transplantsLiving donor transplants
  26. 26. Experimental Developments in CFExperimental Developments in CF Gene therapyGene therapy ““Protein repair” therapyProtein repair” therapy Other ion channelsOther ion channels Recognition that bacteria grow differentlyRecognition that bacteria grow differently in vivo and in laboratory culturesin vivo and in laboratory cultures Drug development using combinatorialDrug development using combinatorial chemistry and high throughput screeningchemistry and high throughput screening
  27. 27. ReferencesReferences Simon RH. Treatment of CF lung disease.Simon RH. Treatment of CF lung disease. UpToDate, 2003.UpToDate, 2003. Ratjen F, Doring G. Cystic fibrosis. LancetRatjen F, Doring G. Cystic fibrosis. Lancet 2003;361:681-92003;361:681-9
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