Cystic FibrosisCystic Fibrosis

Richard H. SimonRichard H. SimonPulmonary and Critical Care MedicinePulmonary and Critical Care MedicineDepartment of Internal MedicineDepartment of Internal Medicine

richsimo@umich.edurichsimo@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