Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis

32
Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis Paul A. Greenberger, M.D. 6 December 2011 Workshop 12

description

Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis. Paul A. Greenberger, M.D. 6 December 2011 Workshop 12. Objectives. To review the differential diagnosis of pulmonary eosinophilia in patients with asthma - PowerPoint PPT Presentation

Transcript of Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis

Page 1: Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis

Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis

Paul A. Greenberger, M.D.6 December 2011

Workshop 12

Page 2: Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis

Objectives

• To review the differential diagnosis of pulmonary eosinophilia in patients with asthma

• To discuss classification of Allergic Bronchopulmonary Aspergillosis (ABPA)

• To consider treatment options for ABPA-corticosteroids, anti-fungals, and immunomodulators

Page 3: Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis

Minimal Diagnostic Criteria for ABPA-Central Bronchiectasis (ABPA-CB)

• Asthma• Central bronchiectasis• Immediate cutaneous reactivity to Aspergillus

species or A. fumigatus• Elevated total serum IgE (>417 kU/L)• Elevated serum IgE-A.fumigatus and or IgG-

A.fumigatus compared to sera from prick positive patients with asthma

Page 4: Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis

Populations at Risk of ABPA

• Asthma, mild intermittent to persistent severe asthma-about 1% of persistent asthma patients – diagnosed before age 20 but can be found in children and even geriatric patients. (Dx may be overlooked for decades)

• Cystic Fibrosis- from 1-14% in literature; ABPA may worsen the course of CF (air trapping, airway narrowing, unequal ventilation)

Page 5: Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis

The Genus Aspergillus Has Over 180 Species

• There are 22 recognized recombinant Aspergillus allergens by the IUIS designated Asp f 1 to Asp f 29. Molecular weights 11-90 kD.

• Four of the 22 include 2 from A. niger and 1 from A. oryzae and 1 from A. flavus.

• Approximately 40 components of A. fumigatus bind to IgE antibodies.

Page 6: Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis

A. fumigatus- Characteristics

• Ubiquitous-outdoor recoveries even in winter• Thermotolerant• High numbers of spores occur after exposure

to moldy hay, compost piles, potting soil, moldy wood chips, decaying vegetation, crawl spaces and basements, etc

Page 7: Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis
Page 8: Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis

Question: What fungi grow in bird droppings?

• ___________________• ___________________• ___________________• ___________________

Page 9: Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis

In The Indoor Environment, Aspergillus fumigatus Can Be Recovered In/From

• Bedrooms Yes No ?• Hallways Yes No ?• Bathrooms Yes No ?• Water supply Yes No ?

Page 10: Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis

Normal Defenses Against Inhaled A. fumigatus Spores

• Alveolar macrophages-ingest and kill spores• PMNs-kill by an oxidative burst• Pulmonary epithelium-as a barrier• Alternative pathway of Complement-C3 and

C5• Platelets

Page 11: Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis

Presentation of ABPA

• Asymptomatic pulmonary infiltrate• Pulmonary infiltrate(s) with eosinophilia• Worsening asthma• Peripheral blood eosinophilia• Inspisated mucus difficult to remove during

bronchoscopy..• Minimal cough or wheeze (or no asthma)

Page 12: Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis

Complications of ABPA

• End Stage fibro-cavitary lung disease-Pseudomonas pneumonias, chronic sputum production, home O2

• Deaths, lung transplants• Worsening of asthma from mild to prednisone

dependent

Page 13: Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis

Obejctive 1: Differential Diagnosis• Asthma with middle lobe

syndrome• Severe asthma with fungal sensitization (SAFS)• Asthma with community

acquired pneumonia• Chronic eosinophilic

pneumonia• Churg-Strauss Syndrome• Mucoid impaction syndrome• ABPMycosis

• Bronchocentric granulomatosis

• Hyper IgE Syndrome• Chronic Granulomatous

Disease• Parasitism (Ascaris,

Strongyloides etc) • Cystic Fibrosis• Idiopathic Bronchiectasis

Page 14: Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis

Randomized Controlled Trial of Oral AntifungalTreatment for Severe Asthma with Fungal Sensitization

The Fungal Asthma Sensitization Trial (FAST) Study• AJRCCM 2009;179:11-18• Patients with SAFS do not fulfill criteria for ABPA

• Criteria for SAFS….• 1. severe (poorly controlled) asthma, 2. total IgE concentration < 1000 IU/mL (< 1000 kU/L) 3. skin test + or elevated in vitro IgE to ANY fungus

Page 15: Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis

Objective 2. Classification of ABPA

Page 16: Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis
Page 17: Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis

Stages---- Radiographic Findings----Total IgE

1. Acute Upper or middle Sharply elevated

2. Remission No infiltrate and no pred > 6 mon

Elevated or normal

3. Exacerbation Upper or middle Sharply elevated

4. Corticosteroid dependent asthma

Often without infiltrates, but can have PIE

Elevated or normal

5. End Stage Fibrotic, bullous or cavitary

Might be normal

Page 18: Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis

Two Categories of ABPA

• ABPA-Central Bronchiectasis (ABPA-CB) with bronchiectasis present on inner 2/3 of CT field

• ABPA-Seropositive (ABPA-S)-which is a less aggressive form (Ann Allergy 1993;70:333-338)

• ABPA-S can convert to ABPA-CB

Page 19: Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis

Classification of ABPA

• ABPA with central bronchiectasis …..ABPA-CB• ABPA without bronchiectasis………….ABPA-S• ABPA with “other radiologic findings”..ABPA-ORF

• ABPA is classified into 5 stages for ABPA-CB and 4 stages for ABPA-Seropositive

• Patients can change stages over time in either direction except if stage 5 (end stage- fibrocavitary)

Page 20: Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis

Objective 3. Treatment Options

• Oral Corticosteroids• Anti-fungals • Immunomodulators

• TREAT the ASTHMA and CO-MORBIDITIES• CONSIDER ENVIRONMENTAL SOURCES

Page 21: Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis

Prednisone as Monotherapy

• 0.5mg/kg/each am for 2 weeks then on alterate mornings for 2 months….then

• Taper prednisone• Repeat HRCT examination• Repeat total IgE (should decline at least by

33%)• Environmental exposures to molds-inquire re

home and workplace for obvious sources

Page 22: Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis

Antifungals

• Oral (itraconazole, voriconazole, posaconazole)• Adverse effects of itraconazole…Gastrointestinal

intolerance, LFTs, headache, peripheral neuropathy, sleep disturbance….and inhibition of CYP 3A4 dependent hepatic metabolism (increases concentration of prednisolone (not prednisone) and inhaled budesonide and fluticasone causing HPA suppression)

Page 23: Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis

Itraconazole is a POTENT INHIBITOR of medications metabolized via CYP3A4

• Potentiation of budesonide 400 ug/day in 2 weeks leading to adrenal suppression (J Cyst Fibrosis 2003;2: 73-5)

• Methylprednisolone• Statins• Cyclosporine

Page 24: Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis

Anti-inflammatory effect of itraconazole in stable allergic bronchopulmonary aspergillosis: A

randomized controlled trialJACI 2003;111:952-7

• Itraconazole 400 mg daily for 16 weeks• Primary outcome was induced sputum eos• Secondary outcome measures: TEC, total IgE

concentration, IgE-A fumigatus by CAP• No pt had a change in LFTs• Baseline FEV1 % = 55 (itraconazole) and 52

(placebo)

Page 25: Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis

Outcomes

• Induced sputum eos: 3.8% decreased to 0.4% vs 3.0 to about 2% in controls

• Sputum ECP 4900 ng/ml decreased to 3000 in 4 weeks vs 3400 increased to 3600 in controls

• Thus, sputum eos are reduced with itraconazole; sputum ECP follows suit

Page 26: Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis

Clinical Markers

• Asthma exacerbations: 0 if itraconazole vs 1.5 for controls over 16 weeks

• No improvement in FEV1• Conclusions: There are reductions in AIRWAY

INFLAMMATION (induced sputum eos and sputum ECP) with itraconazole

Page 27: Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis

Voriconazole

• Improved oral bioavailability than itraconazole• Peripheral blood concentrations

have……….100 fold interpatient variability vs 15 fold with itraconazole!

• Adverse effects of hepatic, ophthalmologic, photosensitivity

• Dosage in adults <65 yrs is 200mg bid

Page 28: Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis

VORICONAZOLE THERAPY IN CHILDREN WITH CYSTIC FIBROSIS

J Cyst Fibrosis 2005;4:215-20

• 21 CF children (ages 5-16 yrs)• Monotherapy in 2 children, sustained improvement

for 13 months• Combined with steroids in 11 children with

improvement• Monotherapy in Af colonized, non-ABPA pts-no

change in symptoms• Adverse effects: 7 (33%) including photosensitivity,

nausea, LFTs, alopecia

Page 29: Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis

Question: The T ½ of Serum IgE is

• 6 days• 5 days• 23 days• 2.3 days• 14-21 days

Page 30: Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis

Omalizumab

• Case reports (some +, some -)• Controlled trial for CF-ABPA initiated

Page 31: Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis

Omalizumab (Thorax 2007;62:276-7)

Page 32: Eosinophilic Respiratory Problems: Allergic Bronchopulmonary Aspergillosis

Steroid dependency despite omalizumab treatment of ABPA in cystic fibrosis

AllergyVolume 65, Issue 1, pages 134-135, 5 OCT 2009 DOI: 10.1111/j.1398-9995.2009.02147.xhttp://onlinelibrary.wiley.com/doi/10.1111/j.1398-9995.2009.02147.x/full#f1