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Cystic FibrosisCystic Fibrosis
Richard H. SimonRichard H. SimonPulmonary and Critical Care MedicinePulmonary and Critical Care MedicineDepartment of Internal MedicineDepartment of Internal Medicine
[email protected]@umich.edu
764-4554764-4554
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 CF Learn the basic approach to treating CF lung diseaselung disease
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 conduction Cystic Fibrosis Transmembrane conduction
RegulatorRegulator
cAMP modulated chloride channelcAMP modulated chloride channel
Over 1,000 mutations in CFTR cause CF Over 1,000 mutations in CFTR cause CF diseasedisease
An extensive amount of information is An extensive amount of information is known about CFTRknown about CFTR
Cystic Fibrosis Transmembrane Cystic 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 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
Pathophysiology of CFPathophysiology of CFLung DiseaseLung Disease
Intrinsic inflammation in lung?Intrinsic inflammation in lung?
Abnormal respiratory tract secretions and Abnormal 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
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
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 not CF-related defects in mucosal (but not systemic) defensessystemic) defenses
Diagnostic criteria for cystic fibrosisDiagnostic criteria for cystic fibrosisPart 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 CF One 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 the Male infertility due to congenital bilateral absence of the
vas deferensvas deferens
2)2) Positive newborn screening test Positive newborn screening test
3)3) History of CF in a sibling History of CF in a sibling
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 CFTR Identification 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 characteristic In vivo demonstration of characteristic abnormalities in ion transport across nasal abnormalities in ion transport across nasal epithelium (not widely available)epithelium (not widely available)
Acute Exacerbations ofAcute Exacerbations ofCF 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 (not Worsening infiltrates on chest x-ray (not required)required)
Acute Exacerbations ofAcute Exacerbations ofCF 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
IV Antibiotic TreatmentIV Antibiotic Treatment
For Pseudomonas, use 2 antibiotics for For Pseudomonas, use 2 antibiotics for synergysynergy
Higher doses of aminoglycosides are Higher doses of aminoglycosides are neededneeded
Duration usually >10 daysDuration usually >10 days
Continue until symptoms return to Continue until symptoms return to baseline statusbaseline status
Aerosolized AntibioticsAerosolized Antibiotics
High dose tobramycin proven for chronic High dose tobramycin proven for chronic infectioninfection TOBITOBI®® 300 mg in 5 ml bid every other month 300 mg in 5 ml bid every other month
Mucolytic Therapy for CFMucolytic Therapy for CF
DNase (Pulmozyme DNase (Pulmozyme ®®)) Chronic use improves FEV1 and causes fewer Chronic use improves FEV1 and causes fewer
exacerbationsexacerbations
Asthma in Patients with CFAsthma in Patients with CF
Higher frequency than in general Higher frequency than in general populationpopulation
Allergic bronchopulmonary aspergillosis Allergic bronchopulmonary aspergillosis occurs in CF occurs in CF
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 -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)
Anti-Inflammatory TreatmentAnti-Inflammatory Treatmentin 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
Macrolide Therapy for CFMacrolide Therapy for CF
Susceptibility testing in the clinical microbiology Susceptibility testing in the clinical microbiology lab shows no killing of Ps. aeruginosalab shows no killing of Ps. aeruginosa
But, macrolides beneficial in another disease that But, macrolides beneficial in another disease that has bronchiectasis and Ps. infection (diffuse has bronchiectasis and Ps. infection (diffuse panbronchiolitis)panbronchiolitis)
Recent Phase III study of azithromycin in CF Recent 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
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
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
Supplemental OxygenSupplemental Oxygen
Use same guidelines as COPDUse same guidelines as COPD
Home Versus Hospital TherapyHome Versus Hospital Therapy
Home regimen must duplicate full hospital Home regimen must duplicate full hospital programprogram IV drugsIV drugs
PhysiotherapyPhysiotherapy
NutritionNutrition
Et ceteraEt cetera
Results from small studies showed mixed Results from small studies showed mixed resultsresults
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
Lung Transplantation CFLung Transplantation CF
Double lung transplantationDouble lung transplantation
Outcome similar to non-CF Outcome similar to non-CF transplantationtransplantation
ProblemsProblems Long waiting listsLong waiting lists
Many exclusionsMany exclusions
Living donor transplants Living donor transplants
Experimental Developments in CFExperimental Developments in CF
Gene therapyGene therapy
““Protein repair” therapyProtein repair” therapy
Other ion channelsOther ion channels
Recognition that bacteria grow differently Recognition that bacteria grow differently in vivo and in laboratory culturesin vivo and in laboratory cultures
Drug development using combinatorial Drug development using combinatorial chemistry and high throughput screeningchemistry and high throughput screening
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. Lancet Ratjen F, Doring G. Cystic fibrosis. Lancet 2003;361:681-92003;361:681-9