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How Important is
Aspergillus in Cystic
Fibrosis?
Richard B Moss MD
Department of Pediatrics
Stanford University
Palo Alto CA, USA
Spores of Aspergillus
can be inhaled into
small airways,
germinate and grow
•3-4 µM diameter--respirable
•Optimal growth
at body temperature
Aspergillus Grows in Mucus Plugs (e.g. Asthma, CF)
Branching filaments (hyphae) of A. fumigatus in sputum
What is Cystic Fibrosis?
 Most common lethal genetic disease of Caucasians
1 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
Typical Clinical Features
Malnutrition
Chronic sinus and lung disease
Vitamin deficiencies
Gastrointestinal abnormalities
Salt-loss syndromes
Male Infertility (obstructive
azoospermia)
CF Lung Disease - Infected, Inflamed,
Obstructed Airways
Normal Airway
CF Airway
Filled with Mucus, Cells, and Microbes
Aspergillus Commonly Grows
in CF Patient Sputum
Bakare et al. Mycoses 2003;46:19
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
Chronic Airway Infection with
Aspergillus Lowers Lung Function in CF
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Amin R et al, Chest 2010;137:171-6
A Spectrum of Lung Disease Due to Aspergillus Role of Host Immune Competence
CF
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How Do We Diagnose ABPA in CF?
 Clinical deterioration
— Cough, wheeze, exercise intolerance, bronchospasm, ↓lung
function, ↑ 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 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
ABPA Hastens Loss of Lung Function in CF
Kraemer et al. AJRCCM 2006;174:1211-20
Early 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
IgE and Lung Function in an 8 Year Old with CF
and APBA
Skowronski E, Fitzgerald DA, Med J Aust 2005;182:482
ABPA - Central Bronchiectasis on CAT Scan
Large ABPA Mucus Plug on CAT Scan
Detail of airway
Exacerbation of ABPA
Acute
Remission
Same patient
APBA 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, Chest 1999; 115:364
Treatment 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
 Indications: Slow or poor response to steroids; relapse; steroiddependence; 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 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
Voriconazole for ABPA in CF
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IgE response for 11 episodes in 9 patients
Glackin et al, Irish Med J 2009;102:29
Amphotericin B Aerosol Therapy
•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
Kuper L & Ruijgrok EJ.J Aerosol Med Pulm Drug Deliv 2009;22:1-15
“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 prednisone
Equal responses, shorter duration
Cohen-Cymberknoh M et al.J Cyst Fibros 2009;8:253-7
Omalizumab (Anti-IgE):
Mechanism in Allergic Asthma
Reduces allergy chemicals release
B lymphocyte
-switch
Allergic
mediators
Allergic
Inflammation:
eosinophils and
lymphocytes
Plasma cell
Release
of IgE
Binds free IgE
Allergens
Clinical Exacerbation
Reduces asthma
attacks
Reduces IgE receptors on
allergy cells
Omalizumab in CF-ABPA
Zirbes & Milla, Ped Pulmonol 2008;43:607
Kanu & Patel, Ped Pulmonol 2008;43:1249
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