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

Kraemer et al. AJRCCM 2006;174:1211-20

ABPA Hastens Loss of Lung Function in CF

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

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 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