Allergic Bronchopulmonary aspergillosis

Boonthorn9 June 2010

Outline DefinitionEpidemiologyPathogenesisPathologyClinical featureLaboratory findingDiagnosisManagement

Definitionallergic pulmonary disorder caused by

hypersensitivity to Aspergillus fumigatus 1

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.

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%) 1. Greenberger PA et al. J Allergy Clin Immunol

1988;82:164–70.2. Stevens D, et al. Clin Infect Dis 2003;37(suppl

3):S225–64.3. Int J Tuberc Lung Dis 2009

Studies Describing Prevalence of AH and/or ABPA in Patients with Bronchial Asthma Over the Last Two Decades

CHEST 2009; 135:805–826

(43%)

(18%)

(23%)

(22%)

(28%)

(38%)

(30%)

(6%)

(25%)

(16%)

(7%)

(20%)

(7%)

Pathophysiology of ABPA. From Aspergillus adherence and penetration of the bronchial mucosa to the B and T cell response

Allergy 2005: 60: 1004–1013

Genetic Factors Involved in Pathogenesis of ABPAHLA associations:

◦ HLA-DR molecules (DR2, DR5, and possibly, DR4 or DR7) associated with susceptibility

◦ HLA-DQ2 molecules associated with resistancePulmonary surfactant protein A gene

polymorphismsCFTR (cystic fibrosis transmembrane conductor regulatorgene) mutationOther

◦ 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.

Animal modelGM-CSF, IL-4 and IL-5 positive

cells was higher in ABPA murine models than in controls

Allergy 2005: 60: 1004–1013

Human modelsIL-2R elevated in ABPA sera compared with

sera from asthma without ABPA and nonatopic patients

high numbers of CD3+ HLA DP, DQ, and DR+ T cells or CD19CD23+ B cells

levels of IgE and IgA-Aspergillus-specific Ab were 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

Pathologynot necessary for diagnosisbronchial 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

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

Clinical featureSymptom

◦ 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.

Clinical Features

CHEST 2009; 135:805–826

Laboratory FindingsAspergillus 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

ABPACHEST 2009; 135:805–826

Laboratory FindingsSerum 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 IgG Ab using double gel diffusion

technique◦ present in other pulmonary disorders

Peripheral Eosinophilia◦ AEC >1,000 cells/μL (major criteria)◦ low eosinophil count not exclude ABPACHEST 2009; 135:805–826

Laboratory FindingsSputum 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

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◦ Central bronchiectasis◦ 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

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

Radiologic Investigations

CHEST 2009; 135:805–826

Radiologic Investigations

CHEST 2009; 135:805–826( pathognomonic finding with ABPA )

Bronchiectasis : cylindrical when bronchus taper and is 1.5 to >3 times caliberof diameter of adjacent artery

J Allergy Clin Immunol 2002;110:685-92.

J Allergy Clin Immunol 2002;110:685-92.

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 Aspergillus Ag (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

Diagnosis and Diagnostic Criteria(Minimal diagnostic criteria for ABPA)

Minimal ABPA-CB

Asthma Immediate cutaneous

hyperreactivity to Aspergillus antigens

Elevated IgERaised A fumigatus-

specific IgG and IgECentral

bronchiectasis

Minimal ABPA-SAsthmaImmediate cutaneous

hyperreactivity to Aspergillus antigens

Elevated IgERaised A fumigatus-

specific IgG and IgETransient pulmonary

infiltrates on chest radiograph

CHEST 2009; 135:805–826

Clinical staging of ABPA

CHEST 2009; 135:805–826

Radiologic Classification of ABPA

CHEST 2009; 135:805–826

Differential Diagnosis Aspergillus hypersensitive bronchial

asthmapulmonary tuberculosis in endemic

areascommunity-acquired pneumonia

(especially acute presentations)other inflammatory pulmonary

disorders eg. eosinophilic pneumonia, bronchocentric granulomatosis, and Churg- Strauss syndrome

CHEST 2009; 135:805–826

Complicationrecurrent asthma exacerbationsdevelopment of bronchiectasissubsequent pulmonary

hypertension Respiratory failure

CHEST 2009; 135:805–826

Management2 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

ManagementSystemic 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 wkRegimen 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

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

ManagementOral 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 levelsCHEST 2009; 135:805–826

Itraconozole in ABPA

Respiratory Medicine (2004) 98, 915–923

Fall in total serum IgE by 25% or more after treatment with itraconazole

Respiratory Medicine (2004) 98, 915–923

Improvement in lung function tests by 25% or more after treatment with itraconazole

Respiratory Medicine (2004) 98, 915–923

Treatment with itraconazole

reduces immune activation in ABPAimproves short-term symptomsReduces 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

ManagementInhaled 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

ABPA in Special SituationsABPA 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

ABPA in Special SituationsABPA 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 ABPACHEST 2009; 135:805–826

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 Ab to A fumigatus or serum IgG to 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 IgE 200–500 IU/mL, repeat testing in 1–3 mo is recommended

Immediate cutaneous reactivity to Aspergillus or presence of serum IgE to A fumigatus

One of following: (1) precipitins to A fumigatus or

demonstration of IgG to A fumigatus; or

(2) new or recent abnormalities on chest radiography or chest CT scan that not cleared with ATB and standard physiotherapyCHEST 2009; 135:805–826

ABPA in Special SituationsABPA 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

Conclusion ABPA is common manifestation in chronic

allergic asthma and cystic fibrosisTh2 cytokine mediatedDiagnostic 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

Conclusion Treatment

◦Corticosteroid : drug of choice ◦Itraconazole : adjunctive therapy