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Allergic bronchopulmonary aspergillosis

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Allergic bronchopulmonary aspergillosis
Presented by Yoavanit Srivaro, MD.
September19, 2014

Published in: Health & Medicine
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Allergic bronchopulmonary aspergillosis

  1. 1. Allergic Bronchopulmonary Aspergillosis Yoavanit Srivaro M.D.
  2. 2. OUTLINE • HISTORICAL PERSPECTIVE • EPIDEMIOLOGY • PATHOGENESIS AND ETIOLOGY • CLINICAL FEATURES • DIAGNOSIS • TREATMENT
  3. 3. HISTORICAL PERSPECTIVE • Asthma and “aspergillosis” were first associated by Renon in 1897 • 1st report of ABPA was published in 1952 by Hinson and colleagues described 3 pts with -recurrent episodes of “wheezy bronchitis” -serum eosinophilia -sputum production -fever -infiltrates on chest x-ray films. JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 2013:1000-13
  4. 4. HISTORICAL PERSPECTIVE Hinson KFW, Moon A Bronchopulmonary aspergillosis. Thorax 1952;7:317-33.
  5. 5. HISTORICAL PERSPECTIVE Hinson KFW, Moon A Bronchopulmonary aspergillosis. Thorax 1952;7:317-33
  6. 6. HISTORICAL PERSPECTIVE Hinson KFW, Moon A Bronchopulmonary aspergillosis. Thorax 1952;7:317-33
  7. 7. EPIDEMIOLOGY • Later, Agarwal and associates estimated overall prevalence of ABPA in asthmatic populations at 12.9% (95% confidence interval [CI] 7.9 to 18.9) • Most authors appear to agree that approximately 2% of asthmatic patients • And 1% to 15% of CF patients develop ABPA JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 2013:1000-13
  8. 8. EPIDEMIOLOGY • Usually manifesting between the third and fourth decades of life. • No gender predilection. JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 2013:1000-13
  9. 9. Pathogenesis And Etiology -Aspergillus is a ubiquitous fungus -Widely in nature -Decaying vegetable matter -An opportunistic pathogen JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 2013:1000-13
  10. 10. Pathogenesis And Etiology (above diagrams from MycoAlbum CD by George Barron)
  11. 11. Pathogenesis And Etiology Aspergillus species • Saprobic habitat -Soil -Plants -Water -Pepper -Air Dr. Patrick R. Murray et al Medical Microbiology;7 th edition 2012
  12. 12. Pathogenesis And Etiology Aspergillus species • Mode of infection -Inhalation of conidia -Transfer to wound via contaminate tape /bandages Dr. Patrick R. Murray et al Medical Microbiology;7 th edition 2012
  13. 13. Pathogenesis And Etiology • Aspergillus species • Growth at 37 C • Binding to fibrinogen and laminin • Secretion of elastase and proteases • Catalase • Gliotoxin(?) Dr. Patrick R. Murray et al Medical Microbiology;7 th edition 2012
  14. 14. Pathogenesis And Etiology • Aspergillus species • ABPA • Sinusitis • Aspergilloma • Invasive aspergillosis • Lung • Brain • Skin • GI • Heart Dr. Patrick R. Murray et al Medical Microbiology;7 th edition 2012
  15. 15. Oppotunistic mycosis Aspergillus fumigatus Aspergillus flavus Aspergillus niger Aspergillus terreus Dr. Patrick R. Murray et al Medical Microbiology;7 th edition 2012
  16. 16. Figure 3.1 Life cycle of Aspergillus (2013 Atsu)
  17. 17. the colonies of Aspergillus may be black, brown, green, yellow, white, or other colors, depending upon the species Original uploader was Jankaan at nl.wikipedia
  18. 18. Aspergillus fumigatus. Lactophenol cotton blue preparation show conidial head Dr. Patrick R. Murray et al Medical Microbiology;7 th edition 2012
  19. 19. Aspergillus terreus. Lactophenol cotton blue preparation show conidial head Dr. Patrick R. Murray et al Medical Microbiology;7 th edition 2012
  20. 20. Aspergillus niger.in lung lesion showing both hyphae and conidial head Dr. Patrick R. Murray et al Medical Microbiology;7 th edition 2012
  21. 21. Aspergillus in tissue showing acute angle branching septate hyphae Dr. Patrick R. Murray et al Medical Microbiology;7 th edition 2012
  22. 22. Pathogenesis And Etiology •Fungal spors(conidia) 2.5-3.5mm are inhale in to the lower airway & alveoli • Aspergillus grows through the product of hyphae from sprout conidiophores • Aspergillus secrete proteolytic enz. •Adherence of conidia to resp. epith. cells JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 2013:1000-13
  23. 23. Pathogenesis And Etiology Adherence of conidia to respiratory epithelial cells Cellular dysfunction Initially cilial disruption The fungal colony grows, Hyphae are produced invade between & through epithelial cells Leading to substantial tissue disruption • JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 2013:1000-13
  24. 24. Schematic representation of components of the host response to inhaled Aspergillus conidia. Park S J , and Mehrad B Clin. Microbiol. Rev. 2009;22:535-551
  25. 25. Pathogenesis And Etiology • Inhalation of fungal spores is ubiquitous • Aspergillus colonization and infection only occur in some patients • Predisposing factors must enable Aspergillus proliferation up to a high antigen burden. • First, the breakdown of local nonspecific immunity (e.g., mucociliary clearance mechanisms) will likely render an individual more susceptible to the adherence of spores to the airway epithelium. • Preexisting lung disease such as bronchiectasis, as occurs in CF • Other factors may include the viscous mucus layer present in the airways of these patients. JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 2013:1000-13
  26. 26. Figure 61-1 Pathogenesis of allergic bronchopulmonary aspergillosis JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 2013:1000-13
  27. 27. Figure 3 | Balancing protection and immunopathology in fungal infections: a cooperative effort of the innate and adaptive immune systems Luigina Romani,Nature Reviews Immunology 4, 11-24 (January) 2004)
  28. 28. Pathogenesis And Etiology Luigina Romani,Nature Reviews Immunology 4, 11-24 (January 2004)
  29. 29. Immune responses:Innate immune response • TLRs2, 4, and 9 are considered important for immunity to Aspergillus species • Chronic fungal sensitization model:mouse • Human studies comparing ABPA patients with healthy controls and asthma with fungal infection did not support a TLR2 allele • A single-nucleotide polymorphism (SNP) in TLR9, a receptor-binding nonmethylated CpG motif, was associated with an odds ratio of 2.5 for ABPA JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 2013:1000-13
  30. 30. Luigina Romani,Nature Reviews Immunology 4, 11-24 (January 2004)
  31. 31. Immune responses:Innate immune response • TLRs2, 4, and 9 are considered important for immunity to Aspergillus species • Chronic fungal sensitization model:mouse • Human studies comparing ABPA patients with healthy controls and asthma with fungal infection did not support a TLR2 allele • A single-nucleotide polymorphism (SNP) in TLR9, a receptor-binding nonmethylated CpG motif, was associated with an odds ratio of 2.5 for ABPA JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 2013:1000-13
  32. 32. Chronic fungal sensitization model Wild type TLR2-def delayed and attenuated bronchial hyperresponsiveness to Aspergillus airway colonization, with persistence of fungi longer than delayed and attenuated bronchial hyperresponsiveness to Aspergillus airway colonization, with persistence of fungi shorter than JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 2013:1000-13
  33. 33. Immune responses:Innate immune response • TLRs2, 4, and 9 are considered important for immunity to Aspergillus species • Chronic fungal sensitization model:mouse • Human studies comparing ABPA patients with healthy controls and asthma with fungal infection did not support a TLR2 allele • A single-nucleotide polymorphism (SNP) in TLR9, a receptor-binding nonmethylated CpG motif, was associated with an odds ratio of 2.5 for ABPA JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 2013:1000-13
  34. 34. SNP in TLR9, a receptor-binding nonmethylated CpG motif, was associated with an odds ratio of 2.5 for ABPA Abul K. Abbas et al.Cellular&Molecular immunology;9 edition2012:55-88
  35. 35. Immune responses:Innate immune response -Responses to fungi may also be influenced by certain serum acute phase reactants, the pentraxins. -In particular in a mouse model of fungal asthma “ in vitro stimulation of macrophages by serum amyloid protein (SAP) & reinfusion” “improved pulmonary outcomes ” “modulation of macrophage function may be achieved by regulation through SAP” improved outcomes of Aspergillus infections. JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 2013:1000-13
  36. 36. Table 4-3 Pattern Recognition Molecules of the Innate Immune System Abul K. Abbas et al.Cellular&Molecular immunology;9 edition2012:55-88
  37. 37. Immune responses • Some results suggest this may translate to humans where specific SNPs in surfactant proteins and mannose-binding lectin (MBL) have been associated with both presence of and protection from ABPA • Depending on the distinct alleles and genotype combinations of surfactant protein A2 and MBL JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 2013:1000-13
  38. 38. Table 4-3 Pattern Recognition Molecules of the Innate Immune System Abul K. Abbas et al.Cellular&Molecular immunology;9 edition2012:55-88
  39. 39. Immune responses:Cellular immune response
  40. 40. Figure 3 | Balancing protection and immunopathology in fungal infections: a cooperative effort of the innate and adaptive immune systems Luigina Romani,Nature Reviews Immunology 4, 11-24 (January) 2004)
  41. 41. Figure 61-1 Pathogenesis of allergic bronchopulmonary aspergillosis
  42. 42. Immune responses:Cellular immune response Garcia and colleagues -Demonstrated different patterns of T cell chemokine receptor expression ABPA allergic asthmatic patients Non-ABPA allergic asthmatic patients After Aspergillus antigen exposure After Aspergillus antigen exposure Proliferating allergen-specific CD4+ T cells downregulated the expression of CCR4 and CXCR3 in vitro T cell chemokine receptor were upregulated in stimulated allergen-specific T cells JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 2013:1000-13
  43. 43. Immune responses: Specific antibody responses • Gautum and associates used proteomics to identify 16 allergens associated with Aspergillus infection • Another study demonstrated the relevance of the Aspergillus antigen Asp f 34, showing that #94% of the ABPA #46% of the A. fumigatus–sensitized individuals ***Asp f 34–specific serum IgE.*** JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 2013:1000-13
  44. 44. Genetic associations with ABPA Miller and coworkers #demonstrated a higher prevalence of cystic fibrosis transmembrane conductance regulator (CFTR) mutations in ABPA patients than healthy controls. • In transgenic mice models the HLA-DR2 genotype, particularly DRB1 1503, appears to convey enhanced susceptibility to the pulmonary eosinophilic inflammation associated with ABPA JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 2013:1000-13
  45. 45. Genetic associations with ABPA • Other specific associations with ABPA have been found in -IL-4 receptor polymorphisms -IL-13 polymorphisms -tumor necrosis factor-α polymorphisms -IL-10 polymorphisms JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 2013:1000-13
  46. 46. CLINICAL FEATURES • The first descriptions of the clinical presentation of ABPA were of patients with -severe asthma -radiographic findings of pulmonary consolidation or segmental lung collapse - fever, malaise, and cough productive of brown sputum. JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 2013:1000-13
  47. 47. CLINICAL FEATURES • Diagnosis of asthma is reported to occur in more than 90% of patients with ABPA, most with asthma for over a decade • Not all patients with ABPA will have asthma • ABPA being highly prevalent in CF patients. • Overall, ABPA occurs most often in patients with -difficult-to-control asthma -CF and atopy. • Patients with asthma or CF who develop ABPA will present with deterioration of the disease with worsening of wheezing. JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 2013:1000-13
  48. 48. CLINICAL FEATURES • Typically, cough occurs with thick,brown sputum or plugs of mucus with histologic evidence of eosinophilic debris and Aspergillus hyphae. • Although rarely severe, hemoptysis is also described. JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 2013:1000-13
  49. 49. CLINICAL FEATURES Hinson KFW, Moon A Bronchopulmonary aspergillosis. Thorax 1952;7:317-33
  50. 50. CLINICAL FEATURES • Fever, weight loss, and fatigue are common in individuals who develop ABPA • Fever, weight loss, and fatigue should raise suspicion of its presence when seen in patients with asthma and CF. JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 2013:1000-13
  51. 51. CLINICAL FEATURES • Clinical picture is often accompanied by typical radiologic findings ****central bronchiectasis**** • Not all patients develop permanent pulmonary lesions • Pulmonary parenchymal infiltrates on chest radiography may disappear with treatment JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 2013:1000-13
  52. 52. CLINICAL FEATURES • ABPA serologic (ABPA-S) #milder form of the disease #diagnosed in the absence of radiologic abnormalities • The range of lung features vary from the presence #clinical features with no pulmonary opacities #clinical features with classic, dominantly central bronchiectasis or end-stage fibrosis with associated respiratory failure JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 2013:1000-13
  53. 53. DIAGNOSIS
  54. 54. a.Rosenberg M, Patterson R, Mintzer R, et al 1977 b.Schwartz HJ, Greenberger PA 1991 c.Greenberger PA. 1994 d.Agarwal R, Khan A, Gupta D, et al 2010
  55. 55. BOX 61-1 DIAGNOSTIC CLASSIFICATIONS FOR ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS (ABPA) PRIMARY AND SECONDARY CRITERIA Primary Asthma Serum eosinophilia Immediate skin reactivity to Aspergillus Precipitins to Aspergillus Elevated IgE Pulmonary infiltrates (transient or fixed) Central bronchiectasis • Secondary Aspergillus fumigatus in sputum Expectoration of brown plugs Late skin reactivity to Aspergillus Rosenberg M, Patterson R, Mintzer R, et al. Clinical and immunologic criteria for the diagnosis of allergic bronchopulmonary aspergillosis. Ann Intern Med 1977;86:405-14;
  56. 56. BOX 61-1 DIAGNOSTIC CLASSIFICATIONS FOR ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS (ABPA) ABPA-CB/-S CLASSIFICATION ABPA-CB: Minimal Essential Criteria ABPA-S: Minimal Essential Criteria Asthma Asthma Immediate skin test reactivity to Aspergillus Immediate skin test reactivity to Aspergillus Elevated total IgE (1000 ng/mL) Elevated total IgE (1000 ng/mL) Proximal bronchiectasis Elevated Aspergillus-specific IgE and/or IgG Additional Criteria Current or previous pulmonary infiltrates Mucus plugs Presence of Aspergillus in sputum Precipitins to Aspergillus Delayed skin test positive Eosinophilia (>1000/μL) Schwartz HJ, Greenberger PA. The prevalence of allergic bronchopulmonary aspergillosis in patients with asthma, determined by serologic and radiologic criteria in patients at risk. J Lab Clin Med 1991;117:138-42; Greenberger PA. Diagnosis and management of allergic bronchopulmonary aspergillosis. Allergy Proc 1994;15:335-9;
  57. 57. BOX 61-1 DIAGNOSTIC CLASSIFICATIONS FOR ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS (ABPA) AGARWAL CLASSIFICATION Patients Diagnosed with ABPA if They Meet Both of the Following Criteria: 1. Total IgE levels >1000 ng/mL 2. Aspergillus fumigatus–specific IgE levels >0.35 kUA/L And Two of the Following Criteria: 1. Presence of serum precipitins against A. fumigatus 2. Radiographic pulmonary opacities (fixed/transient) 3. Absolute blood eosinophil count >1000 cells/μL 4. Central bronchiectasis on HRCT Agarwal R, Khan A, Gupta D, et al. An alternate method of classifying allergic bronchopulmonary aspergillosis based on high-attenuation mucus. PLoS One 2010;5
  58. 58. DIAGNOSIS -Fungal airways disease caused by Aspergillus may represent a continuum colonization of the airway severe fibrosis airway immunologic reactions to the fungus JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 013:1000-13
  59. 59. DIAGNOSIS Differential Diagnosis • Severe asthma with fungal sensitization” (SAFS) • Pulmonary infiltrates from bacterial or viral pneumonia in the setting of SAFS • Impaired lung function in those with severe asthma who have coexistent fungal sensitization
  60. 60. DIAGNOSIS Differential Diagnosis • Serum total IgE is higher than 1000 ng/mL (417 IU/mL) in ABPA patients. • The levels between 500 and 1000 ng/mL should be closely monitored for development of ABPA, with follow-up IgE levels monitored every 6 weeks. JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 013:1000-13
  61. 61. DIAGNOSIS Cystic fibrosis -Recognition of ABPA is complicated by the usual concomitant bronchiectasis, with variable presence of asthma. -Frequent colonization of airways with Aspergillus species  elevation of serum total IgE and problems with coexistent fungal sensitization JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 013:1000-13
  62. 62. JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 013:1000-13
  63. 63. Skin Testing&Laboratory Investigations • Absence of sensitivity to Aspergillus effectively excludes ABPA, except in rare individuals • Absence of reactivity to Aspergillus antigens makes a diagnosis of ABPA extremely unlikely, • Prevalence of fungal sensitization has been reported as high as 66% in severely asthmatic patients, with sensitivity to Aspergillus of 45%. • Indicating that both blood and skin testing should be performed to ascertain fungal sensitization. JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 013:1000-13
  64. 64. Skin Testing&Laboratory Investigations Aspergillus Skin Test: • The Aspergillus skin test is performed using an A fumigatus antigen -Commercial (eg, Aspergillin; Hollister-Stier Laboratories; Spokane, WA) -Locally prepared. Ritesh Agarwal, CHEST / 135 / 3 / MARCH, 2009
  65. 65. Skin Testing&Laboratory Investigations Aspergillus Skin Test: The test is read every 15 min for 1 h, and then after 6 to 8 h. ** The reactions are classified as** Type I reaction if a wheal and erythema developed within 1 min, reaches a maximum after 10 to 20 min, and resolves within 1 to 2 h. Type III reaction read after 6 h, and any amount of subcutaneous edema is considered a positive result. Ritesh Agarwal, CHEST / 135 / 3 / MARCH, 2009
  66. 66. Skin Testing&Laboratory Investigations Aspergillus Skin Test: An immediate cutaneous hypersensitivity to A fumigatus antigens “ is a characteristic finding of ABPA and represents the presence A fumigatus specific IgE antibodies” A type III skin reaction “probably represents the immune complex hypersensitivity reaction, although its exact significance remains unclear. “ Ritesh Agarwal, CHEST / 135 / 3 / MARCH, 2009
  67. 67. Skin Testing&Laboratory Investigations • More than 80 allergens of Aspergillus have been identified in humans. • Asthma & CF, reactivity to the antigens Asp f 1, 3, 4 & 6 • Pts with asthma appear to recognize Asp f 1 and 3, • Both asthma & CF Pts, the presence of antibodies to either Asp f 4 or Asp f 6 has been associated with high sensitivity and specificity for ABPA. • The use of recombinant antigens for testing #not currently routine #but may improved diagnostic rigor. JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 013:1000-13
  68. 68. Skin Testing&Laboratory Investigations • ABPA is highly elevated serum total IgE level. • Agawal and coworkers proposed a threshold of 1000 IU/mL as a criterion for ABPA diagnosis. • Not all agree with such a high threshold • Total IgE may be even lower in some patients, (being treated with corticosteroids.) JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 013:1000-13
  69. 69. Skin Testing&Laboratory Investigations • Many patients have very high levels of total IgE, (>10,000 IU/mL). • The most sensitive indicator of disease progression is serial measurements of total IgE showing increasing levels of IgE. • A decline in serum total IgE of 35% is considered diagnostic of achieving remission of ABPA. • A doubling of serum total IgE is considered diagnostic of relapse of ABPA, especially in CF patients. • Oral corticosteroids will reduce blood IgE levels and also need consideration.
  70. 70. Skin Testing&Laboratory Investigations • Precipitating antibodies to Aspergillus by gel diffusion #Predominantly of the IgG class #Occasionally IgE and IgA • Precipitating antibodies may also be detectable in several fungal pulmonary dis.:Aspergilloma
  71. 71. Skin Testing&Laboratory Investigations Eosinophilia • Not a specific test • Asthma & allergic disease • Suppressed in pts taking oral corticosteroids
  72. 72. Skin Testing&Laboratory Investigations • The presence of Aspergillus, particularly hyphae in the sputum, also suggests ABPA. • Aspergillus colonization of the airways may occur without sufficient criteria to diagnose ABPA and is also present in invasive fungal infections in the lung. • Curschmann spirals and eosinophilic debris (e.g., Charcot- Leyden crystals) may be found in the sputum of ABPA patients, indicating inflammatory airway response • These findings can be seen in asthmatic patients without ABPA as well. JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 013:1000-13
  73. 73. Curschmann spirals Wikipedia,the free encyclopedia
  74. 74. Charcot- Leyden crystals Wikipedia,the free encyclopedia
  75. 75. Radiologic Findings **Fleeting parenchymal pulmonary opacities** *Pulmonary opacities frequently manifest in those with ABPA-S but without overt evidence of symptoms* *May be confused with persistent pneumonia* JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 013:1000-13
  76. 76. Radiologic Findings •Once large airways are involved • Transitory opacities •Thickened airway walls •Central bronchiectasis •Mucus plugging atelectasis •More significant pulmonary collapse JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 013:1000-13
  77. 77. Ritesh Agarwal, CHEST / 135 / 3 / MARCH, 2009
  78. 78. Radiologic Findings HRCT:Lung Parenchymal Changes lung opacity Lung collapse Parenchymal Transient parenchymal scaring JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 2013:1000-13
  79. 79. Radiologic Findings HRCT:Airways Changes Bronchiectasis involving large central airways with a predilection for the upper lobes are diagnostic of ABPA. JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 013:1000-13
  80. 80. Radiologic Findings -Bronchiectasis at lobar & segmental levels and involving the majority of airways is characteristic. -Severe asthma can also be associated with bronchiectasis on CT ( not exceed two lobes, as typically occurs in ABPA) -Mucoid impaction leading to airway collapse -“Tree-in-bud” opacities is also described. -Severe central bronchectasis will also give rise to more peripheral bronchiectasis & the fibrosis associated with end-stage disease. JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 2013:1000-13
  81. 81. JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 2013:1000-13
  82. 82. Histopathologic Findings • Inflammatory infiltration of the airways by eosinophils and lymphocytes • Globlet cell hyperplasia • Granulomas with distal exudative bronchiolitis • Mucoid impaction • End-stage disease:fibrosis JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 2013:1000-13
  83. 83. Histopathologic Findings • Pathologic samples are not required for the diagnosis of ABPA • The detection of Aspergillus in lung tissue when lung biopsy is performed is useful because it supports the diagnosis. JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 2013:1000-13
  84. 84. The bronchi of this resected lobe are markedly distended with mucous. This is a manifestation of allergic bronchopulmonary aspergillosis
  85. 85. Mucin admixed with degenerating eosinophiles (allergic mucin) with multiple Charcot-Leyden crystals. This is a manifestation of allergic bronchopulmonary aspergillosis
  86. 86. The bronchi are markedly distended with mucous. This is a manifestation of allergic bronchopulmonary aspergillosis
  87. 87. This bronchus is markedly distended with mucous. This is a manifestation of allergic bronchopulmonary aspergillosis
  88. 88. Fig. 6. Protocol for investigating allergic bronchopulmonary aspergillosis(ABPA) in patients with asthma. Ritesh Agarwal et al, Clinical & Experimental Allergy,2013; 43 : 850–873
  89. 89. Ritesh Agarwal et al, Clinical & Experimental Allergy, 43 : 850–873
  90. 90. Ritesh Agarwal, CHEST / 135 / 3 / MARCH, 2009
  91. 91. TREATMENT
  92. 92. TREATMENT • Corticosteroid • Antifungal Agents • Anti-IgE Biologics JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 013:1000-13
  93. 93. AIM • Improve clinical symptoms of disease • Reduce exacerbations • Prevent progression of disease to central bronchiectasis. JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 013:1000-13
  94. 94. CORTICOSTEROID • Oral corticosteroids are the basis of therapy for patients with ABPA. • Serum total IgE is used to monitor disease activity. • Initial recommended treatments for ABPA were at least 3 months. JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 013:1000-13
  95. 95. CORTICOSTEROID Prednisone 0.5 mg/kg every day for 2 weeks Prednisone 0.5 mg/kg alternate days for 3 months Staging of disease & Repeat level of serum total IgE for monitor disease activity JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 013:1000-13
  96. 96. CORTICOSTEROID • Larger cohorts indicated use of higher doses of corticosteroids for longer duration to prevent disease relapse. • No controlled data compare dosage regimens. • More recent studies -higher-dose regimens -with duration of treatment determined by serologic and clinical response -in particular aiming for a 35% reduction in serum total IgE to reduce the risk of relapse JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 013:1000-13
  97. 97. CORTICOSTEROID 0.75 mg/kg/day for 6 weeks 0.5 mg/kg/day for 6 weeks then reduction of 5 mg/day every 6 weeks, with 6 to 12 mnth of tx JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 013:1000-13
  98. 98. CORTICOSTEROID • Lung damage can occur even in the absence of symptoms.Monitor serum total IgE levels every 1 to 2 months • Increase corticosteroid dosing if IgE levels double from the baseline values obtained after stability on the maintenance dose. • Alternate-day regimens may be an option for subjects who cannot be tapered off corticosteroids completely. JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 2013:1000-13
  99. 99. CORTICOSTEROID • Acute exacerbations should be treated with Prednisone 0.5 to 1.0 mg/kg/day for 1 to 2 weeks Prednisolone 0.5 mg/kg/day for 6 to 12 weeks on clinical remission JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 013:1000-13
  100. 100. CORTICOSTEROID *Monthly pulsed methylprednisolone regimen* 3 days of 10 to 15 mg/kg/day repeated every month JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 013:1000-13
  101. 101. CORTICOSTEROID • Methyl prednisolone with itraconazole demonstrated effective reduction of serum total IgE and improvement in symptoms. • Methylprednisolone with itraconazole has been used in patients with CF as well. • High-dose intravenous corticosteroid treatments have also been used in life-threatening situations involving ABPA JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 013:1000-13
  102. 102. CORTICOSTEROID • A study of budesonide and formoterol inhalation therapy in 21 patients with ABPA-S ABPA-s with Progressive elevation of serum IgE Responded to oral corticosteroids, with reduction in total IgE levels budesonide &formoterol 6 months no pt used antifungal therapy JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 2013:1000-13
  103. 103. Antifungal Agents
  104. 104. 19% 46% Stevens and associates showed symptomatic improvement decreased corticosteroid requirement in 46% of those receiving 200 mg of itraconazole twice daily versus 19% in the placebo group. Steven DA,et al N Engl J Med 2000;342:756-62
  105. 105. Placebo Itraconazole Wark and colleagues showed reduced sputum eosinophil counts in both patients with ABPA-S and patients with ABPA-CB in remission, using daily itraconazole(400 mg/day for 16 wks) Wark PAB et al, J Allergy Clin Immunol 2003;111:952-7
  106. 106. Limper AH et al .An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med 2011;183:96-12 Limper AH et al .An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary Limper AH et al .An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med 2011;183:96-128
  107. 107. Limper AH et al .An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med 2011;183:96-12 The apparent consensus is that itraconazole, 200 mg twice daily for 6 months, should be offered for these patients Limper AH et al .An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary Limper AH et al .An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med 2011;183:96-128
  108. 108. Antifungal Agents • Voriconazole has been used as an alternative antifungal agent and was effective in a case series. JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 013:1000-13
  109. 109. Antifungal Agents • Azoles are strong inhibitors of the cytochrome P450–dependent CYP3A4 enzyme involved in the metabolism of budesonide and other corticosteroids. • Adrenal suppression has been demonstrated by the ACTH stimulation test in pts receiving inhaled corticosteroids and itraconazole. • Some of the benefit of adjunctive azole therapy in ABPA might be caused by the relatively higher dose of bioavailable corticosteroid. JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 013:1000-13
  110. 110. Anti-IgE Biologics • Key role of IgE in the pathology of ABPA • Effectiveness of anti-IgE treatments in asthma • Anti-IgE therapy has been tried in ABPA. • Recommended dose range of IgE for which omalizumab has proved effective is frequently exceeded in patients with ABPA JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 013:1000-13
  111. 111. Anti-IgE Biologics • Uncontrolled case series report effective use of omalizumab in #ABPA patients #Corticosteroid-dependent CF patients • Others report the effective use of omalizumab with corticosteroids in life-threatening respiratory failure caused by ABPA. • Second-line option for ABPA in patients with and without CF. JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 013:1000-13
  112. 112. Take home message • Patients with well-treated but uncontrolled asthma should be screened for allergic bronchopulmonary aspergillosis. • Diagnostic criteria for ABPA include asthma, increased total IgE levels, positive skin testing to Aspergillus fumigatus, increased specific IgE to Aspergillus, and central bronchiectasis (may be absent in ABPA serologic). • First-line therapy for ABPA is systemic corticosteroids; the antifungal itraconazole or voriconazole may be considered as an alternative, corticosteroid-sparing agent.
  113. 113. THANK YOU

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