1. Allergic Bronchopulmonaryaspergillosis Boonthorn 9 June 2010

2. Outline Definition Epidemiology Pathogenesis Pathology Clinical feature Laboratory finding Diagnosis Management

3. Definition allergic pulmonary disorder caused by hypersensitivity to Aspergillusfumigatus1 Occurs in asthma or cystic fibrosis2 result of immune response to Aspergillus colonization of airway and poor clearance of mucus secretions subsequent bronchiectasis, pulmonary fibrosis, and compromise of pulmonary function first described by Hinson et al in 1952 in UK 1.CHEST 2009; 135:805–826. 2. Middleton’s Allergy, Principle&Practice 7th edition.

4. Epidemiology 1–2% of patients with chronic asthma 1 2–15% of patients with cystic fibrosis 2 Meta-analysis, prevalence of AH and ABPA in asthma of 28% and 12.9%,respectively3 Prevalence of AH ID test(28.7%) VS SPT (24.8%) (p=0.002)3 prevalence of ABPA in acute severe asthma admitted in ICU, AH (51%) and ABPA (39%) in patients with acute asthma (39%) compared to outpatient bronchial asthma ( 21%) Greenberger PA et al. J Allergy ClinImmunol1988;82:164–70. Stevens D, et al. Clin Infect Dis 2003;37(suppl 3):S225–64. Int J Tuberc Lung Dis 2009

5. Studies Describing Prevalence of AH and/or ABPA in Patients with Bronchial Asthma Over the Last Two Decades (43%) (6%) (18%) (25%) (23%) (16%) (22%) (28%) (7%) (38%) (20%) (30%) (7%) CHEST 2009; 135:805–826

6. Pathophysiology of ABPA. From Aspergillus adherence and penetration of the bronchial mucosa to the B and T cell response Allergy 2005: 60: 1004–1013

7. Genetic Factors Involved in Pathogenesis of ABPA HLA associations: HLA-DR molecules (DR2, DR5, and possibly, DR4 or DR7) associated with susceptibility HLA-DQ2 molecules associated with resistance Pulmonary surfactant protein A gene polymorphisms CFTR (cystic fibrosis transmembrane conductor regulatorgene) mutation Other IL-4 receptor polymorphisms IL-10 promoter polymorphisms IL-13 polymorphisms IL-15 polymorphisms TNF-α polymorphisms Toll-like receptor gene polymorphisms CHEST 2009; 135:805–826.

8. Animal model GM-CSF, IL-4 and IL-5 positive cells was higher in ABPA murine models than in controls Allergy 2005: 60: 1004–1013

9. Human model sIL-2R elevated in ABPA sera compared with sera from asthma without ABPA and nonatopicpatients high numbers of CD3+ HLA DP, DQ, and DR+ T cells or CD19CD23+ B cells levels of IgE and IgA-Aspergillus-specific Abwere higher in BAL than in blood bronchiectasis formation occurs in ABPA as consequence of local influx of N& E IL-8 gene expression and protein levels in sputum were higher in ABPA than controls IL8 may be key mediator of tissue damage in ABPA Allergy 2005: 60: 1004–1013

10. Pathology not necessary for diagnosis bronchial tree was dilated and filled with mucus plugs containing macrophages, eosinophils, Charcot–Leyden crystals and sometimes hyphae or hyphal fragments Bronchial walls were infiltrated with inflammatory cells (E, Land plasma cells), and thickening of basement membrane and epithelial abrasion Allergy 2005: 60: 1004–1013

11. Pathology showed mucin containing numerous eosinophils & occasional Charcot leyden crystals silver stain : occasional fungal hyphae morphologically consistent with Aspergillus species Clin Infect Dis 2008;47:540–1

12. Clinical feature Symptom occasionally be asymptomatic low-grade fever, wheezing, bronchial hyperreactivity, hemoptysis, or productive cough Expectoration of brownish black mucus plugs (31 to 69%) Physical examination normal or polyphonic wheeze Clubbing (16% ) coarse crackles (15%) localized findings of consolidation and atelectasis during exacerbation Complications eg. pulmonary HT and/or respiratory failure CHEST 2009; 135:805–826.

13. Clinical Features CHEST 2009; 135:805–826

14. Laboratory Findings Aspergillus Skin Test Type I and III reaction SPT and intradermal test (if SPT negative ) locally prepared or commercial Ag : no difference Total Serum IgE Levels most useful test for diagnosis and follow-up of ABPA Exclude ABPA ( if not steroid used) 35 to 50% decrease : criteria for remission Doubling of baseline IgE levels : relapse of ABPA CHEST 2009; 135:805–826

15. Laboratory Findings Serum IgE and IgG Antibodies Specific to A. fumigatus Hallmark of ABPA cutoff value of IgG/IgE> twice pooled serum samples from AH can help in differentiation of ABPA from other conditions Serum Precipitins Against A. fumigatus Precipitating IgGAb using double gel diffusion technique present in other pulmonary disorders Peripheral Eosinophilia AEC >1,000 cells/μL (major criteria) low eosinophil count not exclude ABPA CHEST 2009; 135:805–826

16. Laboratory Findings Sputum Cultures for A fumigatus supportive ,but not diagnostic grown in other pulmonary diseases rarely perform for diagnosis of ABPA Pulmonary Function Tests Categorize severity, no diagnostic value usual finding is obstructive defect Role of Specific Aspergillus Antigens Further studies are required CHEST 2009; 135:805–826

17. Radiologic Investigations Chest radiographic findings Transient changes Patchy areas of consolidation Radiologic infiltrates: toothpaste and gloved finger shadows due to mucoid impaction in dilated bronchi Collapse: lobar or segmental Permanent changes Parallel-line shadows representing bronchial widening Ring-shadows 1–2 cm in diameter representing dilated bronchi en face Pulmonary fibrosis: fibrotic scarred upper lobes with cavitation HRCT findings Centralbronchiectasis Mucus plugging with bronchoceles Consolidation Centrilobular nodules with tree-in-bud opacities Bronchial wall thickening Areas of atelectasis Mosaic perfusion with air trapping on expiration CHEST 2009; 135:805–826

19. Chest x-ray in a patient with ABPA: ring shadows (long arrows) represent bronchiectatic airways seen in cross-section; tram lines (short arrow) seen longitudinally

20. Radiologic Investigations CHEST 2009; 135:805–826

21. Radiologic Investigations ( pathognomonic finding with ABPA ) CHEST 2009; 135:805–826

22. Bronchiectasis: cylindrical when bronchus taper and is 1.5 to >3 times caliberof diameter of adjacent artery J Allergy ClinImmunol2002;110:685-92.

23. J Allergy ClinImmunol2002;110:685-92.

24. Diagnosis and Diagnostic Criteria Rosenberg-Patterson criteria Major criteria ( ARTEPICS ) A = Asthma R = Roentgenographic fleeting pulmonary opacities T = Skin test positive for Aspergillus(type I) E = Eosinophilia P = Precipitating Abs (IgG) in serum I = IgE in serum elevated ( > 1,000 IU/mL) C = Central bronchiectasis S = Serums A fumigatus-specific IgG and IgE (more than twice the value of pooled serum samples from patients with asthma who have Aspergillus hypersensitivity) Minor criteria Presence of Aspergillus in sputum Expectoration of brownish black mucus plugs Delayed skin reaction to AspergillusAg (type III ) presence of 6 of 8 major criteria makes diagnosis almost certain; disease is further classified as ABPA-S or ABPA-CB CHEST 2009; 135:805–826

25. Diagnosis and Diagnostic Criteria(Minimal diagnostic criteria for ABPA) Minimal ABPA-CB Asthma Immediate cutaneoushyperreactivity to Aspergillus antigens Elevated IgE Raised A fumigatus-specific IgG and IgE Central bronchiectasis Minimal ABPA-S Asthma Immediate cutaneoushyperreactivity to Aspergillus antigens Elevated IgE Raised A fumigatus-specific IgG and IgE Transient pulmonary infiltrates on chest radiograph CHEST 2009; 135:805–826

27. Clinical staging of ABPA CHEST 2009; 135:805–826

28. Radiologic Classification of ABPA CHEST 2009; 135:805–826

29. Differential Diagnosis Aspergillus hypersensitive bronchial asthma pulmonary tuberculosis in endemic areas community-acquired pneumonia (especially acute presentations) other inflammatory pulmonary disorders eg. eosinophilic pneumonia, bronchocentricgranulomatosis, and Churg- Strauss syndrome CHEST 2009; 135:805–826

30. Complication recurrent asthma exacerbations development of bronchiectasis subsequent pulmonary hypertension Respiratory failure CHEST 2009; 135:805–826

31. Management 2 important aspects: glucocorticoids to control immunologic activity and close monitoring for detection of relapses antifungal agents to attenuate fungal burden secondary to fungal colonization in airways CHEST 2009; 135:805–826

32. Management Systemic Glucocorticoid Therapy treatment of choice for ABPA Suppress immune hyperfunction & antiinflammatory Long term therapy not recommended Regimen 1 (relapse /steroid dependence 45%) Prednisolone, 0.5 mg/kg/d, for 1–2 wk, then on AD for 6–8 wk. Then taper by 5–10 mg every 2 wk and discontinue Repeat total serum IgE and chest radiograph in 6 to 8 wk Regimen 2 (steroid dependence 13.5%) Prednisolone, 0.75 mg/kg/d, for 6 wk, 0.5 mg/kg for 6 wk, then tapered by 5 mg every 6 wk to continue for total duration of at least 6 to 12 mo. total IgE levels are repeated every 6 to 8 wk for 1 yr to determine baseline IgE CHEST 2009; 135:805–826

33. Management Follow-up and monitoring Hx and PE , chest radiograph, and total IgE every 6 wk to demonstrate decline in IgE levels and clearing of chest radiograph 35% decline in IgE level signifies satisfactory response to therapy Doubling of baseline IgE : silent ABPA exacerbation If cannot be tapered off prednisolone, disease has evolved into stage IV. Management should be attempted with alternate-day prednisone with least possible dose Monitor for adverse effects (eg, HT, secondary DM) Prophylaxis for osteoporosis: oral calcium and bisphosphonates CHEST 2009; 135:805–826

34. Management Oral itraconazole Dose: 200 mg bid for 16 wk then once a day for 16 wk Indication: First relapse of ABPA or glucocorticoid-dependent ABPA Follow-up and monitoring Monitor for adverse effects (eg, nausea, vomiting, diarrhea,and elevated liver enzymes) Monitor for drug–drug interactions Monitor clinical response based on clinical course,radiography, and total IgE levels CHEST 2009; 135:805–826

35. Itraconozole in ABPA Respiratory Medicine (2004) 98, 915–923

36. Fall in total serum IgE by 25% or more after treatment with itraconazole Respiratory Medicine (2004) 98, 915–923

37. Improvement in lung function tests by 25% or more after treatment with itraconazole Respiratory Medicine (2004) 98, 915–923

38. Treatment with itraconazole reduces immune activation in ABPA improves short-term symptoms Reduces frequency of exacerbations that require use of oral corticosteroids Not shown improvement in lung function may exacerbate adrenal suppression seen with regular corticosteroid use Respiratory Medicine (2004) 98, 915–923

39. Management Inhaled Corticosteroids DBPC multicenter (32 pts.) no superiority over placebo Use only for control of asthma once oral prednisolone dose is reduced to 10 mg/d Other Therapies other antifungal agents (e.g. amphotericin B, ketoconazole, clitromazole, nystatin and natamycin) severe adverse effects and no significant beneficial effects Omalizumab (case report) CHEST 2009; 135:805–826

40. ABPA in Special Situations ABPA Complicating CF first reported in 1965 associated with deterioration of lung function, higher rates of microbial colonization, pneumothorax, massive hemoptysis, and poorer nutritional status immunopathogenesis may be exposure to high levels of allergens due to abnormal mucus properties Recognition can be difficult because ABPA shares many clinical characteristics with CF CHEST 2009; 135:805–826

41. ABPA in Special Situations ABPA Complicating CF prevalence of AH in CF 29- 53% and ABPA 1-15% Atopy : important risk factor Atopic (22%) nonatopic (2%) treatment of ABPA in CF is not very different from ABPA in bronchial asthma recommendation :CF should be screened for ABPA age >6 yrs. , yearly or clinical suggestions of ABPA CHEST 2009; 135:805–826

42. Consensus Conference Proposed Diagnostic Criteria for ABPA in CF Classic diagnostic criteria Acute or subacute clinical deterioration not explained by another etiology total IgE > 1,000 IU/mL Immediate cutaneous reactivity to Aspergillus or presence of serum IgE to A fumigatus Precipitating Abto A fumigatus or serum IgGto A fumigatus New or recent abnormalities on chest radiograph or chest CT scan that not cleared with ATB and standard physiotherapy Minimal diagnostic criteria Acute or subacute clinical deterioration not explained by another etiology Total IgE> 500 IU/mL. If total IgE200–500 IU/mL, repeat testing in 1–3 mo is recommended Immediate cutaneous reactivity to Aspergillus or presence of serum IgEto A fumigatus One of following: (1) precipitins to A fumigatus or demonstration of IgGto A fumigatus; or (2) new or recent abnormalities on chest radiography or chest CT scan that not cleared with ATB and standard physiotherapy CHEST 2009; 135:805–826

43. ABPA in Special Situations ABPA Without Bronchial Asthma: 36 cases reported across the globe mistaken initially for TB or CA ABPA Complicating Other Conditions (case report): idiopathic bronchiectasis, post-tubercular bronchiectasis, bronchiectasis secondary to Kartagener syndrome, COPD, and in patients with CGD and hyper IgE syndrome CHEST 2009; 135:805–826

44. Conclusion ABPA is common manifestation in chronic allergic asthma and cystic fibrosis Th2 cytokine mediated Diagnostic criteria Asthma pulmonary opacities Skin test positive for Aspergillus Eosinophilia Precipitating Abs (IgG) in serum IgE> 1,000 IU/mL Central bronchiectasis Serums A fumigatus-specific IgG and IgE

45. Conclusion Treatment Corticosteroid : drug of choice Itraconazole : adjunctive therapy