how important is aspergillus in cystic fibrosis? richard b moss md department of pediatrics stanford...
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How Important is Aspergillus in Cystic
Fibrosis?
How Important is Aspergillus in Cystic
Fibrosis?
Richard B Moss MD Richard B Moss MD Department of Pediatrics Department of Pediatrics
Stanford University Stanford University
Palo Alto CA, USAPalo Alto CA, USA
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Spores of Aspergillus can be inhaled into small airways, germinate and grow
•3-4 µM diameter--respirable•Optimal growth at body temperature
Branching filaments (hyphae) of A. fumigatus in sputum
Aspergillus Grows in Mucus Plugs (e.g. Asthma, CF)
Chronic sinus and lung diseaseChronic sinus and lung disease
Gastrointestinal abnormalitiesGastrointestinal abnormalities
Male Infertility (obstructive Male Infertility (obstructive azoospermia)azoospermia)
Typical Clinical Features Typical Clinical Features
Malnutrition Malnutrition
Vitamin deficienciesVitamin deficiencies
Salt-loss syndromesSalt-loss syndromes
Most common lethal genetic disease of Caucasians1 in 4000 births; 70,000+ CF patients worldwide
Single gene recessive inheritance; resulting from mutation in CFTR,
a salt and water channel in the membrane of cells lining certain organs
What is Cystic Fibrosis?
CF Lung Disease - Infected, Inflamed, Obstructed Airways
CF Lung Disease - Infected, Inflamed, Obstructed Airways
Normal Airway CF Airway
Filled with Mucus, Cells, and Microbes
Aspergillus Commonly Grows in CF Patient Sputum
Aspergillus Commonly Grows in CF Patient Sputum
Bakare et al. Bakare et al. Mycoses 2003;46:19Mycoses 2003;46:19
Factors Associated with Aspergillus Lung Infection in
Cystic Fibrosis
Factors Associated with Aspergillus Lung Infection in
Cystic Fibrosis
•Increasing over time: 2% in 1997, to 28% in 2007•Age - more common in adults than children •Treatment - more common during chronic oral antibiotic use - onset more likely with inhaled antibiotic use•Disease severity - more common as lung function declines•Surprise finding - less common while on inhaled corticosteroids
Sudfield CR et al, J Cyst Fibros 2009 Dec 30 Epub
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Chronic Airway Infection with Aspergillus Lowers Lung Function in CF
Amin R et al, Chest 2010;137:171-6
A Spectrum of Lung Disease Due to Aspergillus -Role of Host Immune Competence
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CF
How Do We Diagnose ABPA in CF?How Do We Diagnose ABPA in CF?
Clinical deteriorationClinical deterioration
— Cough, wheeze, exercise intolerance, bronchospasm, Cough, wheeze, exercise intolerance, bronchospasm, ↓↓lung lung function, function, ↑↑ sputum sputum
Blood allergy protein (IgE) >500 IU/mL
Allergy skin test reaction to Aspergillus or Aspergillus serum allergic (IgE) antibodies
Serum Aspergillus–specific anti-infection (IgG) antibodies
and/or
New or recent abnormalities on chest imaging (plain x-ray or CAT scan)— Infiltrates, mucus plugging, or change from previous film
Stevens et al. Clin Infect Dis 2003;37:S225-64
Problem: CF Often Has Some Features of ABPAProblem: CF Often Has Some Features of ABPA
Allergy to Aspergillus (≥50%)—Positive allergy skin test
—Serum allergic (IgE) Aspergillus antibodies
Episodic obstructive airways disease (“asthma”) 25-50%
Lung infiltrates
Bronchiectasis (enlargement of airways)
Atopy (general susceptibility to allergies; 50-70% of CF)
Antibodies to Aspergillus (25-50%)
Elevated IgE (25-33% of CF)
Environmental and Immunologic Risk Factors for ABPA
•Environmental exposure (e.g., compost, geographic, seasonal)
•Atopy
•CFTR mutations
•Variants of immune system genes and their products
Surfactant protein A
Mannose-binding lectin
IL-10
HLA-DR2
T cell receptor
•Infection with certain bacteria, e.g., S. maltophilia
Early Diagnosis - Screen for ABPA in CFEarly Diagnosis - Screen for ABPA in CF
Annual IgE from school age onweards
If total IgE >500 IU/mL: Aspergillus skin test or blood antibody test
If total IgE <500 IU/mL: repeat if increased suspicion for ABPA (such as flare up of lung disesae) and do skin test or serum antibody test
Stevens et al. Clin Infect Dis 2003;37:S225-64
Skowronski E, Fitzgerald DA, Med J Aust 2005;182:482
IgE and Lung Function in an 8 Year Old with CF and APBA
APBA in CF ExacerbationsAPBA in CF Exacerbations
Pulmonary Admissions to Lucile Packard
Stanford Children’s Hospital in 1995
•162 admissions, 92 patients
•IgE >500 IU/mL: 14% admits, 13% patients
•Acute ABPA: 6% admits, 10% patients
Nepomuceno et al, Nepomuceno et al, ChestChest 1999; 115:364 1999; 115:364
Treatment of ABPA - CorticosteroidsTreatment of ABPA - Corticosteroids
Indications: All except those with steroid toxicity
Initial dose: daily high oral prednisone for 1-2 weeks
Begin taper: change to alternate day dosing for 1-2 weeks
Taper off: Attempt to taper off within 2-3 months
Relapse: Increase dose, add anti-fungal (itraconazole); taper steroids when clinically improved
Stevens et al. Clin Infect Dis 2003;37:S225-64
Treatment of ABPA - antifungal agent Itraconazole
Treatment of ABPA - antifungal agent Itraconazole
Indications: Slow or poor response to steroids; relapse; steroid- dependence; steroid toxicity
Dosing: Daily– twice daily dosing for higher doses
Duration: 3-6 months or longer
Monitor: Liver function; itraconazole blood levels
CF Issue: Variable absorption and need for acidic stomach
Drug Interactions: Antacids and acid suppressor, any other drugs handled by same liver detoxification system
Stevens et al. Clin Infect Dis 2003;37:S225-64
Voriconazole for ABPA in CFVoriconazole for ABPA in CF
• 21 children with CF (5-16 yrs)
• 13 with ABPA; 8 with sputum Aspergillus but not ABPA
• Voriconazole for 1-50 weeks
• Improvements in ABPA patients
• Side effects in 7 (33%)
Hilliard T et al, J Cystic Fibrosis 2005;4:215-20
Interpatient variability is great (~100 fold)Pediatric doses are higher than adults
Pasqualotto AC et al, Arch Dis Child 2008;93:578-81
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Voriconazole for ABPA in CF
IgE response for 11 episodes in 9 patientsGlackin et al, Irish Med J 2009;102:29
Amphotericin B Aerosol TherapyAmphotericin B Aerosol Therapy
Kuper L & Ruijgrok EJ.J Aerosol Med Pulm Drug Deliv 2009;22:1-15
•Safer and less toxic than IV, so more appropriate for ABPA
•4 different forms available
•First clinical aerosol use in 1959
•Most experience in lung transplant and cancer
•Several forms and nebulizer systems shown to deliver adequate amount to airways to treat ABPA
•Generally well-tolerated
“Pulse” (Monthly High-Dose Intravenous) Steroids for ABPA in CF
“Pulse” (Monthly High-Dose Intravenous) Steroids for ABPA in CF
• 4 children with CF and ABPA (3.5-12 yrs)
• Relapses despite daily oral steroids and
itraconazole, toxicity
• Some improvements in ABPA with less toxicity
• Side effects in 2 (hypertension, lethargy/
malaise) led to stop; no improvement in 1
Thomson JM et al, Pediatr Pulmonol 2006;41:164-70
9 CF patients (7-36 yr)Better tolerated than prednisoneEqual responses, shorter duration
Cohen-Cymberknoh M et al.J Cyst Fibros 2009;8:253-7
Omalizumab (Anti-IgE): Mechanism in Allergic Asthma
Release of IgE
Plasma cell
B lymphocyte
-switch
Clinical Exacerbation
AllergicInflammation:
eosinophils and lymphocytes
Allergens
Allergic mediators
Binds free IgE
Reduces IgE receptors on allergy cells
Reduces allergy chemicals release
Reduces asthma attacks
Omalizumab in CF-ABPA
Kanu & Patel, Ped Pulmonol 2008;43:1249Kanu & Patel, Ped Pulmonol 2008;43:1249
Zirbes & Milla, Ped Pulmonol 2008;43:607
Conclusions Conclusions
•ABPA occurs principally in CF (~10%) and asthma (~5%)
•A high Index of suspicion and appropriate tests are vital to diagnose; annual IgE screening in CF is valuable
•Criteria for diagnosis are somewhat diferent in asthma and CF
•Aspergillus infection and ABPA are important contributors to CF lung disease
•Steroids remain the mainstay of ABPA treatment but have troubling side effects
•Antifungals such as itraconazole are effective steroid-sparing agents in ABPA
•Alternative agents (other oral and inhaled anti-fungals, pulse steroids, and omalizumab) are being explored
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