ABPA

Allergic BronchoPulmonary Aspergillosis

1. Allergic BronchoPulmonary Aspergillosis DR SANDEEP NAIN ,MD Respiratory Medicine

2. INTRODUCTION Allergic bronchopulmonary aspergillosis (ABPA) is an idiopathic inflammatory disease of the lung, characterized by an allergic inflammatory response to colonization of the airways by Aspergillus fumigatus or other fungi. Mostly in third to fifth decade of life Estimates :ABPA complicates 1.approximately 7%to 14% of cases of chronic steroid–dependent asthma 2.approximately 7% to 15% of cases of cystic fibrosis (CF). No gender predisposition

3. Spectrum of Pulmonary Aspergillosis Allergic Aspergillus sensitized asthma Allergic Aspergillus sinusitis Allergic Bronchopulmonary aspergillosis Hypersensitivity pneumonitis Saprophytic 1. Aspergilloma Invasive 1. Chronic necrotising pulmonary aspergillosis 2. Airway-invasive Aspergillosis 3. Angio-invasive Aspergillosis

4. Aspergillus Fumigatus Ubiquitous fungus Thermotolerant Reside in decaying organic matter and colonize most domestic environments, including carpets and air ducts An opportunistic pathogen Size of conidia spores 2-5 micron equal to pores of alveoli Growth at 37 degree C Aspergillus spp. - Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger , etc

5. Genetic factors in the pathogenesis of ABPA Defects in innate immunity Surfactant protein A2 gene polymorphisms Mannose-binding lectin gene polymorphisms Toll-like receptor 3,9 gene polymorphisms Adaptive immunity HLA associations Interleukin 4,10,13,15 polymorphisms Tumour necrosis factor‑ α polymorphisms Transforming growth factor‑ β polymorphisms Others CFTR gene mutation CHIT1 gene mutations Chitotriosidase 1

6. CFTR Gene Mutation Decrease chloride secretion and increase sodium absorption at the apical membrane of airway epithelial cells. Decreased airway surface liquid (ASL) height and altered mucociliary clearance Chronic bacterial infection, airways inflammation, and damage to lung tissue. Activation of both innate and adaptive immune responses against these antigens. Development of lung injury and bronchiectasis over time. Increases morbidity and mortality

7. Hypersensitivity reactions in ABPA Type I response (atopic, formation of IgE) The reaction of IgE with  Aspergillus  antigens results in mast cell degranulation with bronchoconstriction and increased capillary permeability. Type III Hypersensitivity reactions-  Immune complexes and inflammatory cells are deposited within the mucous membranes of the airways, leading to necrosis (tissue death) and  eosinophilic infiltration. Type IV hypersensitivity reactions- injury is caused by activated macrophages.

8. Hypersensitivity reactions in ABPA

9. Conidia immunologically inert because of the presence of surface hydrophobin that prevents immune recognition of fungal spores . The immune response is a Th2 CD4+ T cell response with IL-4, IL-5 and IL-13 cytokine secretion. profound inflammatory reaction with influx of various inflammatory cells (including neutrophils and eosinophils) and IgE (total and A. fumigatus specific) synthesis Airway macrophages recognize fungi through pattern recognition receptors (PRRs) such as toll-like receptors (TLRs) and mannose-binding lectin (MBL), which trigger secretion of pro-inflammatory cytokines hyphae forms are killed by neutrophils. defective clearance of conidia which allows them to germinate into hyphae which lead to the release of antigens which are presented by APCs Exposures to high concentrations of spores Inhalation of conidia spore Normal person Asthma or cystic fibrosis patient PATHOGENESIS

10. Greenberg and Schwartz Diagnostic Criteria ,1991

11. Predisposing Conditions (1) Asthma, (2) Cystic Fibrosis Obligatory Criteria (both need to be present) Type 1 Aspergillus skin test positive (immediate cutaneous hypersensitivity reaction ) or elevated IgE levels against Aspergillus fumigatus. Elevated total IgE levels more than 1,000 IU/mL (unless all other criteria is met, then total IgE levels can be less than 1,000 IU/mL) Other criteria (two out of three at least) Presence of IgG antibodies against Aspergillus fumigatus or precipitating antibodies. Presence of fleeting or radiograph pulmonary opacities consistent with ABPA. Eosinophil count more than 500 cells/ μL in steroid naive patient (may be a historical value)   International society for Human and Animal Mycology (ISHAM) Diagnostic criteria,2013

12. Patterson and Rosenberg Diagnostic Criteria ,1977 Bronchial asthma Immediate cutaneous hypersensitivity to  A fumigatus  antigen Serum total IgE levels (>1000 IU/mL) Serum  A fumigatus  specific IgG and/or IgE levels more than twice the mean plus two standard deviation values in patients with Aspergillus hypersensitive asthma Central bronchiectasis on HRCT chest Serum precipitins against  A fumigatus Fleeting or fixed pulmonary opacities on chest radiograph Peripheral blood eosinophil count >1000 cells/µL Major Criteria Minor Criteria • Sputum cultures demonstrating growth of  A fumigatus • Expectoration of brownish-black mucus plugs • Type III skin reactions to  A fumigatus  antigen The presence of 6 out of 8 major criteria makes the diagnosis almost certain.

13. RADIOLOGICAL FINDINGS Chest Xray findings- Transient Fleeting opacities Band-like shadows -toothpaste opacities, appearance of a “V”, inverted “V” or a “Y” shaped shadow. -finger-in-glove opacities (ovoid perihilar shadows with an expanded rounded distal end Consolidation Pseudo hilar adenopathy Atelectasis Fixed Parallel line and ring shadows Cystic bronchiectasis HRCT Findings- Signet ring String of pearls

14. PA chest X-ray shows hyperinflated lungs, bronchial dilatation, and right lower lobe opacity consistent with mucoid impaction. Transient pulmonary infiltrates or fleeting shadows that are characteristic of allergic bronchopulmonary asperillosis

15. Chest radiograph shows mucoid impaction with the classic finger-in-glove pattern Tram- line shadow parallel linear shadows

16. Y shaped opacities- wine glass shadow

17. Dilated central bronchus consistent with cylindrical/central bronchiectasis. Toothpaste shadows - mucoid impaction of the bronchi

18. Tram- line shadow parallel linear shadows extending from the hilum in bronchial distribution and reflecting longitudinal views of inflamed, edematous bronchi Ring Shadows - dilated bronchi with inflamed bronchial walls seen on end

19. Radiological staging by Kumar CATEGORY ABPA-S ABPA-CB ABPA-CB-ORF FEATURES Patients meet the clinical, laboratory, and serologic diagnostic criteria except central bronchiectasis. Patients meet diagnostic criteria along with central bronchiectasis. Patients meet diagnostic criteria and, in addition to central bronchiectasis, they also have other radiographic features such as pulmonary fibrosis, scarring, emphysematous changes, fibrocavitary changes, and pleural changes. SEVERITY MILD Mild to moderate airflow obstruction Aspergillus IgG precipitins positive in 50% MODERATE Moderate to severe airflow obstruction. High IgE. Aspergillus IgG precipitins positive in 66% SEVERE Severe airflow obstruction. Very high eosinophil count and IgE. Aspergillus IgG precipitins positive in 100%

20. International Society for Human and Animal Mycology(ISHAM) radiologic classification FEATURES ABPA-S All the diagnostic features of ABPA but no evidence of bronchiectasis on CT All findings of ABPA including bronchiectasis on CT of the chest All features of ABPA including HAM on CT of the chest ABPA with other radiologic features such as pulmonary fibrosis, bleb, bullae, pneumothorax, parenchymal scarring, emphysematous change, multiple cyst, fibrocavitary lesions, aspergilloma , pleural thickening CLASSIFICATION ABPA-S (Serological) ABPA-B (Bronchiectasis) ABPA-HAM (high attenuation mucus) ABPA-CPF (chronic pleuropulmonary fibrosis ).

21. Clinical Staging in patients with asthma by ISHAM Stage Definition Features Asymptomatic No previous diagnosis of ABPA Controlled asthma .Fulfilling the diagnostic criteria of ABPA. 1 Acute No previous diagnosis of ABPA Symptoms consistent with ABPA Satisfying the diagnostic criteria of ABPA 1a With mucoid impaction Mucoid impaction observed on thoracic imaging 1b Without mucoid impaction Absence of mucoid impaction on thoracic imaging 2 Response Clinical and/or radiological improvement and decline in serum total IgE by ≥25% of baseline at 8 wk 3 Exacerbation Clinical and/or radiological worsening and increase in serum total IgE by at least 50% from the new baseline established during response/remission

22. Continued… Stage Definition Features 4 Remission Sustained clinical and radiological improvement and serum total IgE levels persisting at or below baseline for > 6 months off treatment. 5a Treatment-dependent ABPA Two or more exacerbations within six months of stopping therapy or clinical and/or radiological worsening, along with increase in serum total IgE levels, on tapering oral steroids/azoles 5b Glucocorticoid dependent asthma Systemic glucocorticoids required for control of asthma while the ABPA activity is controlled (as indicated by serum total IgE and thoracic imaging) 6 Advanced ABPA Extensive bronchiectasis due to ABPA on chest imaging along with either cor pulmonale and/or chronic Type II respiratory failure

23. Allergic Aspergillus Sinusitis A chronic indolent disease, characterized by the presence of 'allergic mucin' in the sinuses . Patients having rhinosinusitis with a positive skin allergy test to Aspergillus or other fungal antigens. Release of antigenic material from fungi cause chain of immunologic reactions culminating in the development of AAS. Computed tomography of the paranasal sinuses showing hyperdense lesions in the ethmoid and maxillary sinuses, suggestive of inspissated secretions.

24. DIAGNOSTIC ALGORITHM

25. MANAGEMENT

26. Treatment protocols Oral Glucocorticoids Indications - First-line treatment of ABPA, both in acute-stage and during exacerbation.

27. 2. Oral azoles Itraconazole: 200 mg twice a day for 24 weeks Indication: Second exacerbation of ABPA; glucocorticoid‑dependent ABPA; alternative to glucocorticoids as first‑line treatment of ABPA, especially in those with increased propensity for glucocorticoid‑related side effects. decrease the immune response by reducing the antigenic stimulus , Thus reduce the need for glucocorticoids. RCT comparing monotherapy of itraconazole vs. prednisolone in ABPA (MIPA study) is underway

28. 3. Other Therapies ABPA complicating CF - nebulized amphotericin and inhaled steroids. Omalizumab, a humanized monoclonal antibody against IgE, is a potential approach Pulse doses of IV methylprednisolone – for severe exacerbations Voriconazole and posaconazole are also efficacious.

29. Follow up and monitoring History and physical examination, chest radiograph, spirometry and measurement of total IgE levels every 8 wk (to determine the new baseline IgE) A 25% decline in serum total IgE along with clinical and/or radiological improvement, indicates a satisfactory response to therapy A clinical or radiological worsening along with a ≥50% increase in the new baseline IgE points to an ABPA exacerbation Worsening of symptoms in the absence of radiological or immunological worsening (serum total IgE) suggests an asthma exacerbation

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