Allergic Bronchopulmonary Aspergillosis

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Allergic Bronchopulmonary Aspergillosis

  1. 1. Allergic Bronchopulmonaryaspergillosis<br />Boonthorn<br />9 June 2010<br />
  2. 2. Outline <br />Definition<br />Epidemiology<br />Pathogenesis<br />Pathology<br />Clinical feature<br />Laboratory finding<br />Diagnosis<br />Management <br />
  3. 3. Definition<br />allergic pulmonary disorder caused by hypersensitivity to Aspergillusfumigatus1<br />Occurs in asthma or cystic fibrosis2<br />result of immune response to Aspergillus colonization of airway and poor clearance of mucus secretions<br />subsequent bronchiectasis, pulmonary fibrosis, and compromise of pulmonary function<br />first described by Hinson et al in 1952 in UK<br />1.CHEST 2009; 135:805–826.<br />2. Middleton’s Allergy, Principle&Practice 7th edition.<br />
  4. 4. Epidemiology <br />1–2% of patients with chronic asthma 1<br />2–15% of patients with cystic fibrosis 2<br />Meta-analysis, prevalence of AH and ABPA in asthma of 28% and 12.9%,respectively3<br />Prevalence of AH<br />ID test(28.7%) VS SPT (24.8%) (p=0.002)3<br />prevalence of ABPA <br />in acute severe asthma admitted in ICU, AH (51%) and ABPA (39%)<br />in patients with acute asthma (39%) compared to outpatient bronchial asthma ( 21%)<br />Greenberger PA et al. J Allergy ClinImmunol1988;82:164–70.<br />Stevens D, et al. Clin Infect Dis 2003;37(suppl 3):S225–64.<br />Int J Tuberc Lung Dis 2009<br />
  5. 5. Studies Describing Prevalence of AH and/or ABPA in Patients with Bronchial Asthma Over the Last Two Decades<br />(43%)<br />(6%)<br />(18%)<br />(25%)<br />(23%)<br />(16%)<br />(22%)<br />(28%)<br />(7%)<br />(38%)<br />(20%)<br />(30%)<br />(7%)<br />CHEST 2009; 135:805–826<br />
  6. 6. Pathophysiology of ABPA. From Aspergillus adherence and penetration of the bronchial mucosa to the B and T cell response<br />Allergy 2005: 60: 1004–1013<br />
  7. 7. Genetic Factors Involved in Pathogenesis of ABPA<br />HLA associations: <br />HLA-DR molecules (DR2, DR5, and possibly, DR4 or DR7) associated with susceptibility <br />HLA-DQ2 molecules associated with resistance<br />Pulmonary surfactant protein A gene polymorphisms<br />CFTR (cystic fibrosis transmembrane conductor regulatorgene) mutation<br />Other<br />IL-4 receptor polymorphisms<br />IL-10 promoter polymorphisms <br />IL-13 polymorphisms<br />IL-15 polymorphisms<br />TNF-α polymorphisms<br />Toll-like receptor gene polymorphisms<br />CHEST 2009; 135:805–826.<br />
  8. 8. Animal model<br />GM-CSF, IL-4 and IL-5 positive cells was higher in ABPA murine models than in controls<br />Allergy 2005: 60: 1004–1013<br />
  9. 9. Human model<br />sIL-2R elevated in ABPA sera compared with sera from asthma without ABPA and nonatopicpatients<br />high numbers of CD3+ HLA DP, DQ, and DR+ T cells or CD19CD23+ B cells<br />levels of IgE and IgA-Aspergillus-specific Abwere higher in BAL than in blood<br />bronchiectasis formation occurs in ABPA as consequence of local influx of N& E<br />IL-8 gene expression and protein levels in sputum were higher in ABPA than controls<br />IL8 may be key mediator of tissue damage in ABPA<br />Allergy 2005: 60: 1004–1013<br />
  10. 10. Pathology<br />not necessary for diagnosis<br />bronchial tree was dilated and filled with mucus plugs containing macrophages, eosinophils, Charcot–Leyden crystals and sometimes hyphae or hyphal fragments<br />Bronchial walls were infiltrated with inflammatory cells (E, Land plasma cells), and thickening of basement membrane and epithelial abrasion <br />Allergy 2005: 60: 1004–1013<br />
  11. 11. Pathology<br />showed mucin containing numerous eosinophils & occasional Charcot leyden crystals<br />silver stain : occasional fungal hyphae morphologically consistent with Aspergillus species <br />Clin Infect Dis 2008;47:540–1<br />
  12. 12. Clinical feature<br />Symptom <br />occasionally be asymptomatic <br />low-grade fever, wheezing, bronchial hyperreactivity,<br />hemoptysis, or productive cough<br />Expectoration of brownish black mucus plugs (31 to 69%)<br />Physical examination <br />normal or polyphonic wheeze<br />Clubbing (16% )<br />coarse crackles (15%)<br />localized findings of consolidation and atelectasis during exacerbation<br />Complications eg. pulmonary HT and/or respiratory failure<br />CHEST 2009; 135:805–826.<br />
  13. 13. Clinical Features<br />CHEST 2009; 135:805–826<br />
  14. 14. Laboratory Findings<br />Aspergillus Skin Test<br />Type I and III reaction<br />SPT and intradermal test (if SPT negative )<br />locally prepared or commercial Ag : no difference<br />Total Serum IgE Levels<br />most useful test for diagnosis and follow-up of ABPA<br />Exclude ABPA ( if not steroid used)<br />35 to 50% decrease : criteria for remission<br />Doubling of baseline IgE levels : relapse of ABPA<br />CHEST 2009; 135:805–826<br />
  15. 15. Laboratory Findings<br />Serum IgE and IgG Antibodies Specific to A. fumigatus<br />Hallmark of ABPA<br />cutoff value of IgG/IgE> twice pooled serum samples from AH can help in differentiation of ABPA from other conditions<br />Serum Precipitins Against A. fumigatus<br />Precipitating IgGAb using double gel diffusion technique<br />present in other pulmonary disorders <br />Peripheral Eosinophilia<br />AEC >1,000 cells/μL (major criteria)<br />low eosinophil count not exclude ABPA<br />CHEST 2009; 135:805–826<br />
  16. 16. Laboratory Findings<br />Sputum Cultures for A fumigatus<br />supportive ,but not diagnostic<br />grown in other pulmonary diseases<br />rarely perform for diagnosis of ABPA<br />Pulmonary Function Tests<br />Categorize severity, no diagnostic value<br />usual finding is obstructive defect<br />Role of Specific Aspergillus Antigens<br />Further studies are required<br />CHEST 2009; 135:805–826<br />
  17. 17. Radiologic Investigations<br />Chest radiographic findings<br />Transient changes<br />Patchy areas of consolidation<br />Radiologic infiltrates: toothpaste and gloved finger shadows due to mucoid impaction in dilated bronchi<br />Collapse: lobar or segmental<br />Permanent changes<br />Parallel-line shadows representing bronchial widening<br />Ring-shadows 1–2 cm in diameter representing dilated bronchi en face<br />Pulmonary fibrosis: fibrotic scarred upper lobes with cavitation<br />HRCT findings<br />Centralbronchiectasis<br />Mucus plugging with bronchoceles<br />Consolidation<br />Centrilobular nodules with tree-in-bud opacities<br />Bronchial wall thickening<br />Areas of atelectasis<br />Mosaic perfusion with air trapping on expiration<br />CHEST 2009; 135:805–826<br />
  18. 18.
  19. 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<br />
  20. 20. Radiologic Investigations<br />CHEST 2009; 135:805–826<br />
  21. 21. Radiologic Investigations<br />( pathognomonic finding with ABPA )<br />CHEST 2009; 135:805–826<br />
  22. 22. Bronchiectasis: cylindrical when bronchus taper and is 1.5 to >3 times caliberof diameter of adjacent artery<br />J Allergy ClinImmunol2002;110:685-92.<br />
  23. 23. J Allergy ClinImmunol2002;110:685-92.<br />
  24. 24. Diagnosis and Diagnostic Criteria<br />Rosenberg-Patterson criteria<br />Major criteria ( ARTEPICS )<br />A = Asthma<br />R = Roentgenographic fleeting pulmonary opacities<br />T = Skin test positive for Aspergillus(type I)<br />E = Eosinophilia<br />P = Precipitating Abs (IgG) in serum<br />I = IgE in serum elevated ( > 1,000 IU/mL)<br />C = Central bronchiectasis<br />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)<br />Minor criteria<br />Presence of Aspergillus in sputum<br />Expectoration of brownish black mucus plugs<br />Delayed skin reaction to AspergillusAg (type III )<br />presence of 6 of 8 major criteria makes diagnosis almost certain; disease is further classified as ABPA-S or ABPA-CB <br />CHEST 2009; 135:805–826<br />
  25. 25. Diagnosis and Diagnostic Criteria(Minimal diagnostic criteria for ABPA)<br />Minimal ABPA-CB<br />Asthma<br />Immediate cutaneoushyperreactivity to Aspergillus antigens<br />Elevated IgE<br />Raised A fumigatus-specific IgG and IgE<br />Central bronchiectasis<br />Minimal ABPA-S<br />Asthma<br />Immediate cutaneoushyperreactivity to Aspergillus antigens<br />Elevated IgE<br />Raised A fumigatus-specific IgG and IgE<br />Transient pulmonary infiltrates on chest radiograph<br />CHEST 2009; 135:805–826 <br />
  26. 26.
  27. 27. Clinical staging of ABPA<br />CHEST 2009; 135:805–826 <br />
  28. 28. Radiologic Classification of ABPA<br />CHEST 2009; 135:805–826 <br />
  29. 29. Differential Diagnosis <br />Aspergillus hypersensitive bronchial asthma<br />pulmonary tuberculosis in endemic areas<br />community-acquired pneumonia (especially acute presentations)<br />other inflammatory pulmonary disorders eg. eosinophilic pneumonia, bronchocentricgranulomatosis, and Churg- Strauss syndrome<br />CHEST 2009; 135:805–826 <br />
  30. 30. Complication<br />recurrent asthma exacerbations<br />development of bronchiectasis<br />subsequent pulmonary hypertension <br />Respiratory failure<br />CHEST 2009; 135:805–826 <br />
  31. 31. Management<br />2 important aspects: <br />glucocorticoids to control immunologic activity and close monitoring for detection of relapses<br />antifungal agents to attenuate fungal burden secondary to fungal colonization in airways<br />CHEST 2009; 135:805–826 <br />
  32. 32. Management<br />Systemic Glucocorticoid Therapy<br />treatment of choice for ABPA<br />Suppress immune hyperfunction & antiinflammatory<br />Long term therapy not recommended<br />Regimen 1 (relapse /steroid dependence 45%)<br />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<br />Repeat total serum IgE and chest radiograph in 6 to 8 wk<br />Regimen 2 (steroid dependence 13.5%)<br />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. <br />total IgE levels are repeated every 6 to 8 wk for 1 yr to determine baseline IgE<br />CHEST 2009; 135:805–826 <br />
  33. 33. Management<br />Follow-up and monitoring<br />Hx and PE , chest radiograph, and total IgE every 6 wk to demonstrate decline in IgE levels and clearing of chest radiograph<br />35% decline in IgE level signifies satisfactory response to therapy<br />Doubling of baseline IgE : silent ABPA exacerbation<br />If cannot be tapered off prednisolone, disease has evolved into stage IV. Management should be attempted with alternate-day prednisone with least possible dose<br />Monitor for adverse effects (eg, HT, secondary DM)<br />Prophylaxis for osteoporosis: oral calcium and bisphosphonates<br />CHEST 2009; 135:805–826 <br />
  34. 34. Management<br />Oral itraconazole<br />Dose: 200 mg bid for 16 wk then once a day for 16 wk<br />Indication: First relapse of ABPA or glucocorticoid-dependent ABPA<br />Follow-up and monitoring<br />Monitor for adverse effects (eg, nausea, vomiting, diarrhea,and elevated liver enzymes)<br />Monitor for drug–drug interactions<br />Monitor clinical response based on clinical course,radiography, and total IgE levels<br />CHEST 2009; 135:805–826 <br />
  35. 35. Itraconozole in ABPA<br />Respiratory Medicine (2004) 98, 915–923<br />
  36. 36. Fall in total serum IgE by 25% or more after treatment with itraconazole<br />Respiratory Medicine (2004) 98, 915–923<br />
  37. 37. Improvement in lung function tests by 25% or more after treatment with itraconazole<br />Respiratory Medicine (2004) 98, 915–923<br />
  38. 38. Treatment with itraconazole<br />reduces immune activation in ABPA<br />improves short-term symptoms<br />Reduces frequency of exacerbations that require use of oral corticosteroids<br />Not shown improvement in lung function<br />may exacerbate adrenal suppression seen with regular corticosteroid use<br />Respiratory Medicine (2004) 98, 915–923<br />
  39. 39. Management<br />Inhaled Corticosteroids<br />DBPC multicenter (32 pts.) no superiority over placebo<br />Use only for control of asthma once oral prednisolone dose is reduced to 10 mg/d<br />Other Therapies<br />other antifungal agents (e.g. amphotericin B, ketoconazole, clitromazole, nystatin and natamycin) severe adverse effects and no significant beneficial effects <br />Omalizumab (case report) <br />CHEST 2009; 135:805–826 <br />
  40. 40. ABPA in Special Situations<br />ABPA Complicating CF<br />first reported in 1965<br />associated with deterioration of lung function, higher rates of microbial colonization, pneumothorax, massive hemoptysis, and poorer nutritional status<br />immunopathogenesis may be exposure to high levels of allergens due to abnormal mucus properties <br />Recognition can be difficult because ABPA shares many clinical characteristics with CF <br />CHEST 2009; 135:805–826 <br />
  41. 41. ABPA in Special Situations<br />ABPA Complicating CF<br />prevalence of AH in CF 29- 53% and ABPA 1-15%<br />Atopy : important risk factor <br />Atopic (22%) nonatopic (2%)<br />treatment of ABPA in CF is not very different from ABPA in bronchial asthma<br />recommendation :CF should be screened for ABPA age >6 yrs. , yearly or clinical suggestions of ABPA<br />CHEST 2009; 135:805–826 <br />
  42. 42. Consensus Conference Proposed Diagnostic Criteria for ABPA in CF<br />Classic diagnostic criteria<br />Acute or subacute clinical deterioration not explained by another etiology<br />total IgE > 1,000 IU/mL<br />Immediate cutaneous reactivity to Aspergillus or presence of serum IgE to A fumigatus<br />Precipitating Abto A fumigatus or serum IgGto A fumigatus<br />New or recent abnormalities on chest radiograph or chest CT scan that not cleared with ATB and standard physiotherapy<br />Minimal diagnostic criteria<br />Acute or subacute clinical deterioration not explained by another etiology<br />Total IgE> 500 IU/mL. If total IgE200–500 IU/mL, repeat testing in 1–3 mo is recommended<br />Immediate cutaneous reactivity to Aspergillus or presence of serum IgEto A fumigatus<br />One of following: <br />(1) precipitins to A fumigatus or demonstration of IgGto A fumigatus; or<br />(2) new or recent abnormalities on chest radiography or chest CT scan that not cleared with ATB and standard physiotherapy<br />CHEST 2009; 135:805–826 <br />
  43. 43. ABPA in Special Situations<br />ABPA Without Bronchial Asthma:<br />36 cases reported across the globe<br />mistaken initially for TB or CA<br />ABPA Complicating Other Conditions (case report): <br />idiopathic bronchiectasis, post-tubercular bronchiectasis, bronchiectasis secondary to Kartagener syndrome, COPD, and in patients with CGD and hyper IgE syndrome<br />CHEST 2009; 135:805–826 <br />
  44. 44. Conclusion <br />ABPA is common manifestation in chronic allergic asthma and cystic fibrosis<br />Th2 cytokine mediated<br />Diagnostic criteria<br />Asthma<br />pulmonary opacities<br />Skin test positive for Aspergillus<br />Eosinophilia<br />Precipitating Abs (IgG) in serum<br />IgE> 1,000 IU/mL<br />Central bronchiectasis<br />Serums A fumigatus-specific IgG and IgE<br />
  45. 45. Conclusion <br />Treatment<br />Corticosteroid : drug of choice <br />Itraconazole : adjunctive therapy<br />

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