2. How Important is Aspergillus in Cystic Fibrosis? Richard B Moss MD Department of Pediatrics Stanford University Palo Alto CA, USA

3. Spores of Aspergillus can be inhaled into small airways, germinate and grow 3-4 µM diameter--respirable Optimal growth at body temperature

4. Branching filaments (hyphae) of A. fumigatus in sputum Aspergillus Grows in Mucus Plugs (e.g. Asthma, CF)

5. Chronic sinus and lung disease Gastrointestinal abnormalities Male Infertility (obstructive azoospermia) Typical Clinical Features Malnutrition Vitamin deficiencies Salt-loss syndromes  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 What is Cystic Fibrosis?

6. CF Lung Disease - Infected, Inflamed, Obstructed Airways Normal AirwayCF Airway Filled with Mucus, Cells, and Microbes

7. Aspergillus Commonly Grows in CF Patient Sputum Bakare et al. Mycoses 2003;46:19

8. 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

9. Chronic Airway Infection with Aspergillus Lowers Lung Function in CF Amin R et al, Chest 2010;137:171-6

10. A Spectrum of Lung Disease Due to Aspergillus - Role of Host Immune Competence CF

11. 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

12. 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)

13. 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

14. Kraemer et al. AJRCCM 2006;174:1211-20 ABPA Hastens Loss of Lung Function in CF

15. 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

16. Skowronski E, Fitzgerald DA, Med J Aust 2005;182:482 IgE and Lung Function in an 8 Year Old with CF and APBA

17. ABPA - Central Bronchiectasis on CAT Scan

18. Large ABPA Mucus Plug on CAT Scan Detail of airway

19. Exacerbation of ABPA Acute Remission Same patient

20. 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 Nepomuceno et al, Chest 1999; 115:364

21. 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

22. 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

23. 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

24. Voriconazole for ABPA in CF IgE response for 11 episodes in 9 patients Glackin et al, Irish Med J 2009;102:29

25. Amphotericin 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

26. “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

27. Omalizumab (Anti-IgE): Mechanism in Allergic Asthma Release of IgE Plasma cell B lymphocyte  -switch Clinical Exacerbation Allergic Inflammation: eosinophils and lymphocytes Allergens Allergic mediators Binds free IgE Reduces IgE receptors on allergy cells Reduces allergy chemicals release Reduces asthma attacks

28. Omalizumab in CF-ABPA Kanu & Patel, Ped Pulmonol 2008;43:1249 Zirbes & Milla, Ped Pulmonol 2008;43:607

29. 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