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ABPA

ABPA. Allergic Bronchopulmonary Aspergillosis. Münevver Erdinç Ege Üniversitesi Tıp Fakültesi Göğüs Hastalıkları Anabilim Dalı munevver.erdinc@ege.edu.tr. Pulmonary Diseases Caused by Aspergillus. I. Allergic Aspergillosis - Allergic bronchopulmonary aspergillosis (ABPA)

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ABPA

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  1. ABPA Allergic Bronchopulmonary Aspergillosis Münevver Erdinç Ege Üniversitesi Tıp Fakültesi Göğüs Hastalıkları Anabilim Dalı munevver.erdinc@ege.edu.tr

  2. Pulmonary Diseases Caused by Aspergillus I. Allergic Aspergillosis - Allergic bronchopulmonary aspergillosis (ABPA) - IgE related asthma - Hypersensitivity pneumonias - Allergic aspergillus sinusitis II. Saprophytic colonisation - Aspergilloma III. İnvazive disease - İnvazive pulmonary aspergillosis (IPA) - Airway invazive aspergillosis - Chronic necrotizing pneumonia (Semi-invaziv)

  3. Aspergillosis • Aspergillus fumigatus (~%90) • Aspergillus flavus(~%10) • Aspergillus niger (~%2) • Aspergillus clavatus (<%1) • ubiquitous molds found in organic matter • 1.5~6um sized spores • structure • Conidiospores • Aerial hyphae (conidiophore) • Vesicle • Phialides Soubani AO.Chest 2002;121:1988-1999

  4. Allergic Bronchopulmonary Aspergillosis • ABPA is caused by a complex hypersensitivity reaction to Aspergillus organisms. • Clinically; chronic asthma recurrent pulmonary infiltrates bronchiectasis • A immediate hypersensitivity reaction(type I) with IgE and IgG release occurs. • Immune complexes and inflammatory cells are then deposited in the bronchial mucosa (type III). • Production of necrosis and eosinophilic infiltrates (type IVb) with bronchial wall damage and bronchiectasis.

  5. ABPA Prevalence in Asthma

  6. Clinical Features • 3.-4.decade , no gender • HLA-DR2 and HLA-DR5 genotypes, mutations CFTR gene, polymorphisms of the collagen region of the surfactant protein A2 • Asthma • Low grade fever, wheezing ±, hemoptysis, bronchial hyperreactivity, malaise • Expectoration of brownish mucus plugs(31-69%) • Clubbing rare (16%) • Pulmonary hypertension, respiratory failure Zander S.Arch Pathol Lab Med 2005;129:924-928 Moss RB. Medical Mycology2005;43:S203-S206

  7. Genetik anormallik Epitelin preaktivasyonu (astım, kistik fibroz) Hücresel ve humoral yanıt CD4+Th2 lenfositler AF Proteolitik enzimler Gliotoxin IL-4, IL-13 GMCSF IL-5 Aktive olmuş epitel hücreleri Bronş lümeni CD23, CD68 Bronşiyal tutunma ve AF’nin penetrasyonu Eozinofiller B-hücreleri IgG, IgA, IgE / AF IL-6, IL-8, MMP-8 Nötrofillerce başlatılan bronşiyal hasar ABPA Pathogenesis Zander S.Arch Pathol Lab Med 2005;129:924-928

  8. ABPA Pathology ABPA Pathology • Mucoid impaction of bronchi, eosinophilic pneumonia, bronchocentric granulomatosis • Mucus, fibrin, Curschmann spirals, Charcot-Leyden crystals, inflammatory cells • Asthma • Septated hyphae with dichotomous branching may be seen in mucous, but do not invade the mucosa. • Culture + in 2/3 of patients

  9. Laboratory Findings • Aspergillus skin test: Immediate cutaneous hypersensitivity is a characteristic findings • Total serum IgE levels : 1000 ng/mL  or 417 IU/mL. Normal IgE levels excludes ABPA • Serum IgE and IgG Antibodies specific to Af: IgG/IgE more than twice the pooled serum (AH? ABPA?) • Peripheral eosinophilia: >1000 is major criteria, low eosinophil count not excludes • Sputum Cultures for a Af : Supportive but no diagnostic • Spesific Aspergillus Antigens: Frequently cross-react with other antigens

  10. ABPA PFTs • Airflow obstruction – reduced FEV1 • Air trapping – increased RV • Positive BD response in ½ • Mixed obst. and rest. if bronchiectasis and fibrosis present • Reduced DLCO if bronchiectasis present

  11. ABPA After bronchoscopy Before bronchoscopy

  12. ABPA Radiologic features • Upper lobe infiltrates • Atelectasis • “Tram lines” • “Parallel lines” • Ring shadows • “Toothpaste shadows” • “Gloved finger shadows” • Perihilar infiltrates may simulate adenopathy • Cylindrical bronchiectasis

  13. Consolidation • Finger like shadow • Mucoid impaction of central bronchiectasis. • Atelectasis

  14. .

  15. CT showing central bronchiectasis

  16. ABPA Diagnostic Criteria • Primary criteria: • Asthma • Peripheral blood eosinophilia • Positive skin test for aspergillus • Precipitating antibodies(IgG) in serum • Serums Af spesific IgG and IgE • IgE elevation (>1000mL) • Pulmonary infiltrations • Central bronchiectasis • Secondary criteria: • Positive sputum culture for aspergillus • History of brown mucus plug expectoration • Positive type III(Arthus) reaction for aspergillosis Soubani AO.Chest 2002;121:1988-1999 Lazarus AA. Dis Mon 2008;54:547-564 Agarwal R. Chest 2009;135:805-826

  17. Rosenberg-Patterson criteria • ABPA-Central Bronchiectasis (ABPA-SB) • Asthma • Central bronchiectasis • Immediate cutaneous hyperreactivity to Af antigens • Elevated IgE ( >417 U/L or 1000ng/ml) • Raised A fumigatus specific IgE and IgG • ABPA-Serological (ABPA-S) • Asthma • Immediate cutaneous hyperreactivity to Af antigens • Elevated IgE ( >417 U/L or 1000ng/ml) • Raised Af specific IgE and IgG • Transient pulmonary infiltrates on chest radiograph Rosenberg M.Annals of Intern Med 1977;86:405-414 Greenberger PA. JACI 2002;110:685-692 Agarwal R. Chest 2009;135:805-826

  18. All patients with asthma Positive Aspergillus skin testi Negative IgE levels Follow-up with repeat skin test 500-1000 IU/mL >1000 IU/mL <500 IU/mL IgG/IgE spesific to Af IgE / yıl ile izlem Chest radiograph, HRCT IgG/IgE spesific to Af Eosinophil count Precipitins to Af Spirometry More than two-fold compared AH No Yes Follow-up with IgE levels every 6 wk ABPA Diagnostic Algoritm If increasing or >1000 IU/mL Treatment for ABPA Agarwal R. Chest 2009;135:805-826

  19. Allergic Bronchopulmonary Aspergillosis • Stage I Acute phase • Stage II Remission • Stage III Exacerbation • Stage IV Steroid dependent • Stage V  End-stage (Fibrotic) Patterson R. Ann Intern Med 1982;96,286-291 Greenberger PA. JACI 2002;110:685-692 Agarwal R. Chest 2009;135:805-826

  20. Stage I Acute Phase Clinical picture Usually symptomatic, fever, weight loss, wheeze Radiologic findings Normal or presence of radiologic opacities Immunologic Features and treatment IgE > 1.000 IU/mL, specific IgG/IgE , precipitins to As.f 0.5-1mg/kg prednisone for 1-2 wk for 6-8 wk taper by 5-10 mg every 2 wk and discontinue repeat total IgE and chest radiograph in 6-8 wk

  21. Stage II Remission Clinical picture Asymptomatic Radiologic findings Normal or significant resolution of radiologic opacities Immunologic Features and treatment Usually 35-50% decline in IgE levels by 6wk to 3 mo Complete remission  no ABPA exacerbations over the next 3 mo after stopping steroid therapy Follow-up serial IgE levels every 6 mo then annually

  22. Stage III Exacerbation Clinical picture Symptomatic as in acute phase Radiologic findings Transient or fixed pulmonary opacities Immunologic Features and treatment Doubling of IgE levels from baseline Treatment as in acute phase 25-50% of the patients have exacerbation

  23. Stage IV Glucocorticoid-dependent ABPA Clinical picture Symptomatic Radiologic findings Transient or fixed pulmonary opacities Immunologic Features and treatment • IgE levels not rise but require steroids for asthma control • Steroids are required to continually supress diseases • activity (glucocorticoid-dependent ABPA) • Should be alternate-day prednisone with the least possible dose

  24. Stage V End-Stage (Fibrotic ABPA) Clinical picture Symptomatic, fixed airway obstruction, severe pulmonary dysfunction, type II RF, cor pulmonale Radiologic findings Bronchiectasis, pulmonary fibrosis,pulmonary hypertension Immunologic Features and treatment • Serum IgE levels and spesific Igs do not become normal in most patients, and frequent exacerbations • Prednisolon (long term) • Itraconazole 200mg bid for 16 wk

  25. Treatment Protocols ABPA • Oral glucocorticoids - 0.5 mg/kg/d for 1-2 wk then on alternate days for 6-8 wk. Then taper by 5-10 mg/2wk - Repeat total IgE and radiography in 6 to 8 wk - 35% decline in IgE level signifies response • Oral Itraconazole - 200 mg bid for 16 wk then once a day for 16 wk - First relapse ABPA or glucocorticoid-dependent ABPA - Inhibits the metabolism methylprednisolone • Inhaled Corticosteroids No superiority over placebo. NEJM 2000;342:756-762.

  26. Itraconazole (ABPA) - 1991 BeforeAfter Prednisone (mg/d) 43 24* Total IgE 2462 525* FEV1 1.48 1.79* FVC 2.3 2.9 *p=0.04 Denning et al, Chest 1991; 35:1329

  27. Itraconazole (ABPA) - 2000 ItraconazolePlacebo Overall response 13/28 (46%) 5/27 (19%) p=0.04 Age >50 8/12 (67%) 3/14 (21%) p=0.045 RCT Prospective 55 Steroid-dependent ABPA Stage IV 28 patient 200mg X 2 /d 16 wks Stevens et al, New Engl J Med 2000; 342:756

  28. Itraconazole and ABPA 12 trials, but only three were RCT. 94 participants • Ketoconazole 400 mg/d 12 mo.No significant impr. in PFT. • Itraconazole for 16 wks. Sputum eos. by 35% compared to 19% with placebo (p < 0.01). • The numberof exacerbations requiring oral corticosteroids was 0.4 per patient with itraconazole compared with 1.3 per patient with placebo (p <0.03) Itraconazole more likely to have decline in IgEover 25% or Wark P.Cochrane Database Issue1,2009

  29. Omalizumab(ABPA) Treatment of Allergic Bronchopulmonary Aspergillosis (ABPA) in CF With Anti-IgE Antibody (Omalizumab) Adaobi Kanu. Pediatr Pulmonol. 2008; 43:1249–1251 Successful treatment of allergic bronchopulmonary aspergillosis with recombinant anti-IgE antibody Cornelis K van der Ent . Thorax 2007;62;276-277 Steroid-Sparing Effect of Omalizumab for Allergic Bronchopulmonary Aspergillosis and Cystic Fibrosis Jacquelyn M. Zirbes . Pediatr Pulmonol. 2008; 43:607–610

  30. Allergic Bronchopulmonary Aspergillosis in Patients with Moderate and Severe Asthma Gereç ve Yöntem: Orta ve ağır persistan astımlı olgular ABPA-Santral bronşektazi (ABPA-SB) tanısı; astım, santral bronşektazi, Aspergillus fumigatus deri testi veya serumda aspergillus sIgE pozitifliği; ABPA-Seropozitif (ABPA-S) tanısı; astım, yüksek total IgE düzeyi, Aspergillus fumigatus deri testi pozitifliği ve serumda aspergillus sIgE saptanması ile konmuştur. Bulgular: 64 olgunun %71.9’u orta, %28.2’si ağır persistan astım Aspergillus sIgE, 2(%3.1) olguda +. Deri testlerinde Af + 4 olguda (%7.8) HRCT 7(%14.6) olguda santral bronşektazi, 1(%2) olguda santral yerleşimli mukus tıkacı 2 (%3.1) olgu ABPA-SB , 2 (%3.1) olgu da ABPA-S Aydoğan Ö, Erdinç M. Aytemur ZA, Sin A, Savaş R. Tur Toraks Der 2008;9:151-6

  31. Prevalence of AH in patients with Cystic Fibrosis 34%(27-41)

  32. Prevalence of ABPA in patients with Cystic Fibrosis 7.8% (5.8-10)

  33. Eosinophilic Fungal Rhinosinusitis (Allergic Fungal Sinusitis) Patient with chronic symptoms of nasal obstruction, loss of smell and nasal polyps Ponikau et al, Mayo Clinic Proc 1999;74:877

  34. Teşekkürler…

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