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DOI 10.1378/chest.08-2586 2009;135;805-826 Chest Ritesh Agarwal Allergic Bronchopulmonary Aspergillosis http://chestjournal.chestpubs.org/content/135/3/805.full.html services can be found online on the World Wide Web at: The online version of this article, along with updated information and ISSN:0012-3692 ) http://chestjournal.chestpubs.org/site/misc/reprints.xhtml ( written permission of the copyright holder. this article or PDF may be reproduced or distributed without the prior Dundee Road, Northbrook, IL 60062. All rights reserved. No part of Copyright2009by the American College of Chest Physicians, 3300 Physicians. It has been published monthly since 1935. is the official journal of the American College of Chest Chest © 2009 American College of Chest Physicians by guest on September 27, 2011 chestjournal.chestpubs.org Downloaded from

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Page 1: Abpa Chest

DOI 10.1378/chest.08-2586 2009;135;805-826Chest

 Ritesh Agarwal Allergic Bronchopulmonary Aspergillosis

  http://chestjournal.chestpubs.org/content/135/3/805.full.html

services can be found online on the World Wide Web at: The online version of this article, along with updated information and 

ISSN:0012-3692)http://chestjournal.chestpubs.org/site/misc/reprints.xhtml(

written permission of the copyright holder.this article or PDF may be reproduced or distributed without the priorDundee Road, Northbrook, IL 60062. All rights reserved. No part of Copyright2009by the American College of Chest Physicians, 3300Physicians. It has been published monthly since 1935.

is the official journal of the American College of ChestChest

 © 2009 American College of Chest Physicians by guest on September 27, 2011chestjournal.chestpubs.orgDownloaded from

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Allergic BronchopulmonaryAspergillosis*Ritesh Agarwal, MD, DM, FCCP

Allergic bronchopulmonary aspergillosis (ABPA) is an immunologic pulmonary disorder causedby hypersensitivity to Aspergillus fumigatus. Clinically, a patient presents with chronic asthma,recurrent pulmonary infiltrates, and bronchiectasis. The population prevalence of ABPA is notclearly known, but the prevalence in asthma clinics is reported to be around 13%. The disorderneeds to be detected before bronchiectasis has developed because the occurrence of bronchiec-tasis is associated with poorer outcomes. Because many patients with ABPA may be minimallysymptomatic or asymptomatic, a high index of suspicion for ABPA should be maintained whilemanaging any patient with bronchial asthma whatever the severity or the level of control. Thisunderscores the need for routine screening of all patients with asthma with an Aspergillus skintest. Finally, there is a need to update and revise the criteria for the diagnosis of ABPA. Thisreview summarizes the advances in the diagnosis and management of ABPA using a systematicsearch methodology. (CHEST 2009; 135:805–826)

Key words: allergic bronchopulmonary aspergillosis; Aspergillus; bronchial asthma; cystic fibrosis; prevalence

Abbreviations: AAS � allergic Aspergillus sinusitis; ABPA � allergic bronchopulmonary aspergillosis; ABPA-CB � allergicbronchopulmonary aspergillosus with central bronchiectasis; ABPA-CB-ORF � allergic bronchopulmonary aspergillosus withcentral bronchiectasis and other radiological findings; ABPA-S � seropositive allergic bronchopulmonary aspergillosus;AH � Aspergillus hypersensitivity; CF � cystic fibrosis; HRCT � high-resolution CT; IL � interleukin

A spergillus is a ubiquitous mold representing be-tween 0.1% and 22% of the total air spores

sampled.1 There are approximately 250 species ofAspergillus, but only a few are human pathogens.2,3

Depending on the host immunity and the organismvirulence, the respiratory diseases caused by As-pergillus are classified as saprophytic (aspergilloma),allergic (allergic Aspergillus sinusitis, allergic bron-chopulmonary aspergillosis [ABPA], and hypersensitiv-ity pneumonias) and invasive (airway invasive aspergil-losis, chronic necrotizing pulmonary aspergillosis, andinvasive aspergillosis).4 ABPA is an allergic pulmonarydisorder caused by hypersensitivity to Aspergillus fu-

migatus clinically manifesting as chronic asthma, recur-rent pulmonary infiltrates, and bronchiectasis.5–13 Thecondition has immunologic features of immediate hy-persensitivity (type I), antigen-antibody complexes(type III), and eosinophil-rich inflammatory cellresponses (type IVb), based on the revised Gell andCoombs classification of immunologic hypersensitiv-ity.14,15 The disorder was first described by Hinson etal16 in 1952 in the United Kingdom. Occasionally,patients can develop a syndrome similar to ABPA,but it is caused by fungi other than A fumigatus andis called allergic bronchopulmonary mycosis.17 Theprevalence of ABPA is believed to be about 1 to 2%in patients with asthma and 2 to 15% in patients withcystic fibrosis (CF).13 The condition remains underdi-agnosed in many countries with reports of mean diag-nostic latency of even 10 years between the occurrenceof symptoms and the diagnosis.18 In the past twodecades, there has been an increase in the numberof cases of ABPA due to the heightened physicianawareness and the widespread availability of sero-logic assays.19–23 This review provides a summary ofthe advances in the field of ABPA. For the purpose ofthis review, a systematic search of PubMed and Em-

*From the Department of Pulmonary Medicine, PostgraduateInstitute of Medical Education and Research, Chandigarh, India.The author has no conflicts of interest to disclose.Manuscript submitted November 4, 2008; revision acceptedNovember 20, 2008.Reproduction of this article is prohibited without written permissionfrom the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).Correspondence to: Ritesh Agarwal, MD, DM, FCCP, AssistantProfessor, Department of Pulmonary Medicine, PostgraduateInstitute of Medical Education and Research, Sector-12, Chandi-garh 160012, India; e-mail: [email protected]: 10.1378/chest.08-2586

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Base was performed for relevant studies published from1952 to 2008. A total of 250 articles were reviewed for thepurpose of this article.

Epidemiology of ABPA

Aspergillus hypersensitivity (AH) is defined by thepresence of an immediate-type cutaneous hypersen-sitivity to A fumigatus antigens, and it is the first stepin the development of ABPA.24 Only a minority ofpatients with AH develop the complete clinicalpicture of ABPA.25 The population prevalence ofABPA in asthma, generally referred to as 1 to2%,5,13,26,27 is based on the inference of only threestudies (one peer-reviewed and two non–peer-re-viewed studies).28,29 In the only peer-reviewedstudy,28 14 patients with allergic bronchopulmonarymycosis were identified from a total of 1,390 newreferrals in a catchment area population of half amillion, estimating a period prevalence of just above1%. The other two non–peer-reviewed question-naire-based studies suggested a maximum preva-lence of ABPA of 1% in the United States.29 In arecent metaanalysis,30 we demonstrated a prevalenceof AH and ABPA in asthma of 28% and 12.9%,respectively. The limitation noted in this review wasthat all the studies were performed in specializedclinics and may not be representative of the generalpopulation. Thus the exact population prevalence ofABPA remains speculative but is likely to be fairly

high in patients attending asthma clinics. Table 1summarizes the prevalence of ABPA in patients withasthma reported in various studies20,23,31–36 over thelast two decades. The prevalence of ABPA in pa-tients admitted with acute severe asthma is evenhigher. In a recent study of 57 patients with acutesevere asthma admitted in the respiratory ICUs, wedemonstrated the prevalence of AH and ABPA to bearound 51% and 39%, respectively.37 The occurrenceof AH and ABPA was significantly higher in patientswith acute asthma compared to the outpatient bron-chial asthma (around 39% and 21%, respectively).23

Pathogenesis of ABPA

The susceptibility of asthmatic patients to developABPA is not fully understood (Fig 1). Some authorshave reported that exposure to large concentrationsof spores of A fumigatus may cause ABPA.16,38–41

Environmental factors are not considered the mainpathogenetic factors because not all asthmatics de-velop ABPA despite being exposed to the sameenvironment. In a genetically predisposed individu-al42–54 (Table 2), inhaled conidia of A fumigatuspersist and germinate into hyphae with release ofantigens that compromise the mucociliary clearance,stimulate and breach the airway epithelial barrier,and activate the innate immunity of the lung.55–58

This leads to inflammatory cell influx and a resultantearly- and late-phase inflammatory reaction.59,60 The

Table 1—Studies Describing the Prevalence of AH and/or ABPA in Patients with Bronchial Asthma Over the LastTwo Decades*

Study/Year Type of StudyType of Skin

Test Type of AntigenCriteria Used for

Diagnosis of ABPAPrevalence of AHin Asthma (n/N)

Prevalence of ABPAin Asthma (n/N)

Attapattu31/1991 Prospective Intradermal Commercial (BencardAllergie; Munich,Germany)

Major (A/R/T/E/P)Minor (C)

58/134 8/134

Eaton et al33/2000 Prospective Prick Commercial (Hollister-Stier Laboratories)

Major (A/R/T/E/P/I/C/S)

47/255 9/35

Kumar and Gaur34/2000

Prospective Intradermal Locally prepared Major (A/R/T/E/P/I/C/S)

47/200 32/200

Minor (C/S/B)Al-Mobeireek et al20/

2001Prospective Prick Commercial (Soluprick;

ALK Laboratories;Wallingford, CT)

12/53

Maurya et al35/2005 Prospective Intradermal Locally prepared Major (A/R/T/E/P/I/C/S)

30/105 8/105

Minor (C/S)Agarwal et al23/2007 Prospective Intradermal Commercial (Hollister-

Stier Laboratories)Major (A/R/T/E/P/

I/C/S)291/755 155/755

Minor (S/B)Prasad et al36/2008 Prospective Intradermal Not available Major (A/R/T/E/P/

I/C/S)74/244 18/244

Minor (C/S/B)

* Criteria for ABPA: Major (A � asthma, R � radiologic opacities, T � immediate positive skin test, E � eosinophilia, P � precipitins to Afumigatus, I � IgE elevated, C � central bronchiectasis, S � specific IgG/IgE to A fumigatus); Minor (C � sputum cultures of A fumigatus,S � type III skin test positivity, B � brownish black mucus plugs).

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antigens are also processed presented to T-cells withactivation of Th2 CD4� T-cell responses.42,61–63 The Th2cytokines (interleukin [IL]-4, IL-5, and IL-13) lead to totaland A fumigatus-specific IgE synthesis, mast cell degran-ulation, and promotion of a strong eosinophilic response.This causes the characteristic pathology of ABPA.

Pathology of ABPA

The pathology of ABPA varies from patient topatient, and in different areas of the lung in the samepatient (Fig 2).64,65 Histologic examination revealsthe presence of mucus, fibrin, Curschmann spirals,

Charcot-Leyden crystals, and inflammatory cells.Scanty hyphae can often be demonstrated in thebronchiectatic cavities. The bronchial wall in ABPAis usually infiltrated by inflammatory cells, primarilythe eosinophils.65 The peribronchial parenchymashows an inflammatory response with conspicuouseosinophilia. Occasionally, fungal growth in the lungparenchyma can occur in some patients with ABPA.66

Patients can also demonstrate a pattern similar to thatof bronchiolitis obliterans with organizing pneumo-nia.67 Bronchocentric granulomatosis, the presence ofnoncaseating granulomas containing eosinophils and

Figure 1. A line diagram depicting the pathogenesis of allergic bronchopulmonary aspergillosis. Th � T-helper.

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multinucleated giant cells centered on the airway, arealso seen.68,69 Rarely, invasive aspergillosis complicat-ing the course of ABPA has also been described.70–74

Clinical Features

There is no gender predilection and majority of thecases present in the third to fourth decade. A familyhistory of ABPA may be elicited occasionally.75 Table 3summarizes the clinical features of ABPA encoun-tered in three large series from our institute.19,21,23

Most present with low-grade fever, wheezing, bron-chial hyperreactivity, hemoptysis, or productivecough. Expectoration of brownish black mucus plugs

is seen in 31 to 69% of patients.21,23,34 The symptomsof hemoptysis, expectoration of brownish black mu-cus plugs, and history of pulmonary opacities in anasthmatic patient suggests ABPA. Patients can oc-casionally be asymptomatic, and the disorder isdiagnosed on routine screening of asthmatic pa-tients.22,23,33 Physical examination can be normal ormay reveal polyphonic wheeze. Clubbing is rare,seen in only 16% of patients. On auscultation, coarsecrackles can be heard in 15% of patients.23 Physicalexamination can also detect complications such aspulmonary hypertension and/or respiratory failure.76

During exacerbations of ABPA, localized findings ofconsolidation and atelectasis can occur that needs tobe differentiated from other conditions.

Laboratory Findings

Aspergillus Skin Test: The Aspergillus skin test isperformed using an A fumigatus antigen, eithercommercial (eg, Aspergillin; Hollister-Stier Labora-tories; Spokane, WA) or locally prepared. The test isread every 15 min for 1 h, and then after 6 to 8 h.The reactions are classified as type I if a wheal anderythema developed within 1 min, reaches a maxi-mum after 10 to 20 min, and resolves within 1 to 2 h.A type III reaction is read after 6 h, and any amountof subcutaneous edema is considered a positiveresult. An immediate cutaneous hypersensitivity to Afumigatus antigens is a characteristic finding ofABPA and represents the presence A fumigatus-specific IgE antibodies, whereas a type III skinreaction probably represents the immune complexhypersensitivity reaction, although its exact signifi-cance remains unclear. The test can be performedusing either a skin-prick test or intradermal injectionwith the latter being more sensitive.30,77,78 A skin-prick test should be performed for Aspergillus skintesting, and if the results are negative should beconfirmed by an intradermal test.30 There is nodifference on the outcome of the test and the type ofantigen (locally prepared or commercial) used forperformance of the test.30

Total Serum IgE Levels: The total IgE level is themost useful test for diagnosis and follow-up of ABPA. Anormal serum IgE level excludes ABPA as the cause ofthe patient’s current symptoms. The only situationwhere IgE levels can be normal in active ABPA is whenthe patient is already on glucocorticoid therapy for anyreason and investigation for IgE levels has been con-ducted. After treatment with glucocorticoids, the se-rum IgE levels decline, and a 35 to 50% decrease istaken as a criteria for remission.79 The serum IgEdetermination is also used for follow-up, and a doublingof the patient’s baseline IgE levels indicates relapse ofABPA.80,81

Table 2—Genetic Factors Involved in the Pathogenesisof ABPA*

HLA associations: presence of HLA DR-2 and absence ofHLA-DQ2 sequences42,44,45

IL-10 promoter polymorphisms49

Polymorphism at position 1,082 produces higher levels of IL-10if 1082G allele is present and lower levels of IL-10 if the1082A allele is present

In patients with CF there is a relationship between the 1082GGgenotype with both Aspergillus colonization and ABPA

Surfactant protein A gene polymorphisms48,53

A significantly higher frequency of the AGA allele (A1660G) ofSP-A2 found in patients with ABPA vs control subjects.Coexistence of A1660G polymorphism with SP-A2 G1649C(Ala91Pro) found with 10-fold higher odds in patients withABPA. Patients with ABPA with GCT and AGG allelesshowed significantly higher levels of total IgE and percentageeosinophilia vs patients with ABPA with CCT and AGAalleles48

The T allele at T1492C and G allele at G1649C of SP-A2observed at higher frequencies in ABPA patients than incontrols. Also there is a higher frequency of the TT genotypeat position1492 of SP-A2 than controls53

There were no polymorphisms found in SP-A1 gene53

CFTR gene mutation:43,46,47 increased frequency of CFTRmutations in patients with ABPA vs skin-prick test positive ornegative patients with bronchial asthma

IL-15 polymorphisms:52 higher frequency of IL-15 � 13689*Aallele and A/A genotype

TNF-� polymorphisms:52 lower frequency of the TNF-� 308 * A/Agenotype

Mannose-binding lectins:53 the intronic single nucleotidepolymorphism G1011A of mannose-binding lection seen withincreased frequency in patients with ABPA

IL-4 receptor polymorphisms:51 single nucleotide polymorphism ofthe extracellular IL-4R� ile75val observed in 80% of ABPApatients

IL-13 polymorphisms:50 the arg110gln polymorphism found withincreased frequency in ABPA and the combination of IL-4R�ile75val/IL-13 arg110gln polymorphism found with an evenhigher frequency

Toll-like receptor gene polymorphisms:54 susceptibility to ABPAwas associated with allele C on T1237C (TLR9)

*HLA � human leukocyte antigen; TNF � tumor necrosis factor;CFTR � CF transmembrane conductance regulator.

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Serum IgE and IgG Antibodies Specific to Afumigatus: An elevated level of A fumigatus-specificantibodies measured by fluorescent enzyme immuno-assay is considered the hallmark of ABPA.22 A

cutoff value of IgG/IgE more than twice the pooledserum samples from patients with AH can greatlyhelp in the differentiation of ABPA from otherconditions.82

Table 3—Clinical Features Encountered in Three Large Case Series of ABPA Published From the Author’sInstitute*

Clinical Features Behera et al19/1994 Chakrabarti et al21/2002 Agarwal et al23/2007

Patients, No. 35 89 155Male/female gender, No. 14/21 53/35 79/76Mean age, yr 34.3 36.4 33.4Mean duration of asthma, yr 11.1 12.1 8.9History of asthma 94% 90% 100%Expectoration of sputum plugs Not available 69% 46.5%Mean eosinophil count, per �L 1,264AEC � 500/�L, % 12/28 (43%) 100% 76.1%Fleeting shadows 77% 74% 40%History of intake of antituberculous drugs 34% 29% 44.5%Skin test against Aspergillus

Type I 51% 85% 100%Type III 25.7% 16.9% 83.2%

Mean IgE levels Not done Not done 6,434Elevated IgE levels, % 100%Aspergillus-specific IgE/IgG Not done Not done 100%Serum precipitins against Aspergillus 77% 71.9% 86.5%Central bronchiectasis 71% 69% 76.1%

*AEC � absolute blood eosinophil count.

Figure 2. Histopathologic findings in a patient with allergic bronchopulmonary aspergillosis. Top left, A:photomicrograph showing bronchial lumen containing allergic mucin (hematoxylin-eosin, original �100). Topright, B: high-magnification photomicrograph of allergic mucin having variegated appearance, necrotic eosino-phils, Charcot-Leyden crystals (thin arrow), and an occasional septate fungal hyphae indicated by a thick arrow(hematoxylin-eosin, original �200). Bottom left, C: photomicrograph showing eosinophilic pneumonia. There isfilling of the alveolar spaces by eosinophils admixed with variable number of macrophages (hematoxylin-eosin,original �200). Bottom right, D: photomicrograph showing bronchocentric granulomatosis. There is partialreplacement of bronchial epithelium by palisading histiocytes (hematoxylin-eosin, original �100).

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Radiologic Investigations: A wide spectrum ofradiographic appearances can occur in ABPA (Table4). The chest radiographic findings of ABPA includetransient or fixed pulmonary opacities (Fig 3), tram-line shadows, finger-in-glove opacities, and tooth-paste shadows.83–87 Findings noted on high-resolutionCT (HRCT) include central bronchiectasis, mucoidimpaction, mosaic attenuation, presence of centri-lobular nodules, and tree-in-bud opacities (Fig4).88,89 High-attenuation mucoid impaction (mucusvisually denser than the paraspinal muscle) is apathognomonic finding encountered in patients withABPA.23,90–95 Central bronchiectasis with peripheraltapering of bronchi on HRCT is believed to be a sinequa non for the diagnosis of ABPA. Bronchiectasismay not be present in all patients with ABPA, may bepresent in patients with CF without ABPA, andalmost 40% of the bronchiectatic segments can also

have associated peripheral bronchiectasis.22,96 Mini-mal bronchiectasis can also be seen in asthma,97,98

but the findings of bronchiectasis affecting three ormore lobes, centrilobular nodules, and mucoid im-paction are highly suggestive of ABPA.99 The un-common radiologic manifestations of ABPA includemiliary nodular opacities,100 perihilar opacitiessimulating hilar lymphadenopathy,84,101,102 pleuraleffusions,103–105 and pulmonary masses.106–111

Serum Precipitins Against A fumigatus: The pre-cipitating IgG antibodies are elicited from crudeextracts of A fumigatus and can be demonstratedusing the double gel diffusion technique.112,113 Theycan also be present in other pulmonary disorders andthus represent supportive not diagnostic evidence forABPA.112–114

Peripheral Eosinophilia: A blood absolute eosino-phil count � 1,000 cells/�L is also a major criterionfor the diagnosis of ABPA. However, 53% of patientsin our series22 had an absolute eosinophil count� 1,000 cells/�L, and thus a low eosinophil countdoes not exclude the diagnosis of ABPA.

Sputum Cultures for A fumigatus: Culture of Afumigatus in the sputum is supportive but not diag-nostic of ABPA. The fungus can also be grown inpatients with other pulmonary diseases due to theubiquitous nature of the fungi. We rarely performsputum cultures for the diagnosis of ABPA.

Pulmonary Function Tests: These tests help cate-gorize the severity of the lung disease but have nodiagnostic value in ABPA and need not constitutethe basis for screening.22 The usual finding is anobstructive defect of varying severity.115–117

Role of Specific Aspergillus Antigens: Patients withABPA are evaluated with crude extracts from As-pergillus, which lack reproducibility and consistency,and they frequently cross-react with other anti-gens.118 The advances in molecular techniques haveenabled detection and cloning of specific Aspergillusantigens. The recombinant allergens Asp f1, Asp f2,Asp f3, Asp f4, and Asp f6 have been evaluated fortheir diagnostic performance in serologic studies inasthmatic patients119–122 and in patients withCF121,123–125 Preliminary data suggest a promisingrole of these antigens in the diagnosis of ABPA.Further studies are required before they can beimplemented in routine clinical practice.

Diagnosis and Diagnostic Criteria

The Rosenberg-Patterson criteria6,9 are most oftenused for the diagnosis (Table 5). There are also a set

Table 4—Radiologic Findings Encountered in PatientsWith ABPA

1. Chest radiographic findingsTransient changes

CommonPatchy areas of consolidationRadiologic infiltrates: toothpaste and gloved finger shadows

due to mucoid impaction in dilated bronchiCollapse: lobar or segmental

UncommonBronchial wall thickening: tramline shadowsAir-fluid levels from dilated central bronchi filled with fluidPerihilar infiltrates simulating adenopathyMassive consolidation: unilateral or bilateralSmall nodulesPleural effusions

Permanent changesCommon

Parallel-line shadows representing bronchial wideningRing-shadows 1–2 cm in diameter representing dilated

bronchi en facePulmonary fibrosis: fibrotic scarred upper lobes with

cavitationUncommon

Pleural thickeningMycetoma formationLinear scars

2. HRCT findingsCommon

Central bronchiectasisMucus plugging with bronchocelesConsolidationCentrilobular nodules with tree-in-bud opacitiesBronchial wall thickeningAreas of atelectasisMosaic perfusion with air trapping on expiration

UncommonHigh-attenuation mucus (finding most helpful in differential

diagnosis)Pleural involvementRandomly scattered nodular opacities

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of minimal diagnostic criteria for ABPA (Table5).32,33 These criteria continue to be challenged andmodified because there is lack of evidence on thenumber of criteria that should be present to makethe diagnosis. The differentiation of patients withABPA from patients with AH can also be problem-atic. Serum precipitins to A fumigatus is present in69 to 90% of patients with ABPA23,112,116,126,127 butalso in 9% of asthmatics.112 Central bronchiectasiscan be seen in patients with asthma without

ABPA.97–99 There are no cutoffs for total IgE levelswith many using 1,000 IU/mL,8,9,22,23,82,128–130 andothers using 1,000 ng/mL (equivalent to 417 IU/mL).5,27,33,34 The total IgE levels may also be ele-vated in patients with AH without ABPA. As theunderstanding of ABPA has evolved, it is clear thatpatients with AH may present with less than the fullcomplement of diagnostic criteria.131 Thus, a cutoffvalue of 1,000 ng/mL IgE will probably lead to anoverdiagnosis of ABPA.131 The use of A fumigatus-

Figure 4. HRCT images of different patients with allergic bronchopulmonary aspergillosis. Top right:bilateral central bronchiectasis with centrilobular nodules and tree-in-bud opacities in the left lung. Topleft: bilateral central bronchiectasis with many mucus-filled bronchi. Bottom, left and right: images fromthe same patient show high-attenuation mucoid impaction. Bottom right: the mucoid impaction in theright lung is visually denser than the paraspinal skeletal muscle.

Figure 3. Chest radiograph showing transient pulmonary opacities in the right lower lobe (left) in apatient with allergic bronchopulmonary aspergillosis that have spontaneously disappeared (right).

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specific IgE and IgG levels can help in confirmingthe diagnosis of ABPA because values of IgG/IgEmore than twice the pooled serum samples frompatients with asthma are raised only in ABPA.113,132

We currently use a cutoff value of 1,000 IU/mL forthe diagnosis of ABPA.22,23 While investigating apatient with asthma, we first perform an Aspergillusskin test. Once it is positive, the total serum IgElevels are done.131 If the value is � 1,000 IU/mL, weperform the other tests (Fig 5). If the value isbetween 500 and 1,000 IU/mL, the next step is analysisof A fumigatus-specific IgE and IgG antibodies. If thelevels are raised, the patient is followed up every 6 weekswith total IgE levels. If the absolute value rises � 1,000IU/mL or there is a rising trend with clinical deterioration,the treatment is started. If the value is between 500 and1,000 IU/mL and IgE and IgG specific to A fumigatus arenot raised, the patient is followed up with a yearly totalIgE levels (Fig 5).

Natural History

The natural history of ABPA is not well character-ized.9,128,133–136 An early diagnosis and initiation of

systemic corticosteroids are essential to prevent irre-versible damage.137 The natural course of ABPA canbe best understood if we recognize the two impor-tant classification schemes (Tables 6 and 7) of ABPA:(1) classification of ABPA into five stages as de-scribed by Patterson et al8, and (2) classification ofABPA into ABPA-S (seropositive ABPA) and ABPA-CB(ABPA with central bronchiectasis) described byGreenberger et al.12

Staging of ABPA: ABPA has been classified intofive stages, but a patient does not necessarilyprogress from one stage to the other sequentially(Table 6). Patients in stage I or III (depending onwhether or not the disorder has been previouslydiagnosed) are generally symptomatic with radio-graphic infiltrates, raised IgE levels, and elevated Afumigatus-specific IgG/IgE.23 With glucocorticoidtherapy, there is clearing of radiographic opacitieswith a 35 to 50% decline in IgE levels by 6 weeksthat defines remission or stage II. The aim ofglucocorticoid therapy is not normalization of totalIgE levels because the immunologic process goes inremission with just 35 to 50% decline in IgE levels,and in many patients the IgE levels do not come todown to normal values. The test needs to be oftenrepeated during therapy to determine the lowestlevel for an individual patient that serves as thebaseline for that particular patient. Treatment iscontinued for 6 to 9 months, and if there are noexacerbations over the next 3 months after stoppingtherapy, we label it as “complete remission.” Patientsin complete remission are followed up by serial IgElevels every 6 months for the first year and thenannually. Even in patients with complete remission,the IgE levels decline to normal in only a minority ofpatients,128,133 and the aim of glucocorticoid therapyis not achievement of normal IgE levels.79 A com-plete remission does not imply a permanent remis-sion because exacerbations can occur several yearsafter remission.135 Almost 25 to 50% of the patientshave relapse/exacerbation of the disease, defined bydoubling of the baseline IgE levels (stage III).8,9,22

Patients in stage IV require oral glucocorticoids forcontrol of asthma (glucocorticoid-dependent asthma)or ABPA (glucocorticoid-dependent ABPA).10,22 Pa-tients in stage V are those with widespread bronchi-ectasis and varying degrees of pulmonary dysfunc-tion. We define patients in stage V if they havehypercapnic respiratory failure (Pao2 � 60 mm Hgand Paco2 � 45 mm Hg) and/or cor pulmonale.Even in stage V ABPA, the disease can be clinicallyas well as immunologically active requiring long-term glucocorticoid therapy.136,138

Table 5—Criteria Used for the Diagnosis of ABPA

Rosenberg-Patterson criteria6,9

Major criteria (mnemonic ARTEPICS)A � AsthmaR � Roentgenographic fleeting pulmonary opacitiesT � Skin test positive for Aspergillus (type I reaction,

immediate cutaneous hyperreactivity)E � EosinophiliaP � Precipitating antibodies (IgG) in serumI � IgE in serum elevated (� 1,000 IU/mL)C � Central bronchiectasisS � Serums A fumigatus-specific IgG and IgE (more than

twice the value of pooled serum samples from patients withasthma who have Aspergillus hypersensitivity)

Minor criteriaPresence of Aspergillus in sputumExpectoration of brownish black mucus plugsDelayed skin reaction to Aspergillus antigen (type III

reaction)The presence of six of eight major criteria makes the diagnosis

almost certain; the disease is further classified as ABPA-S orABPA-CB on the absence or presence of centralbronchiectasis, respectively

Minimal diagnostic criteria for ABPA32

Minimal ABPA-CBAsthmaImmediate cutaneous hyperreactivity to Aspergillus antigensCentral bronchiectasisElevated IgERaised A fumigatus-specific IgG and IgE

Minimal ABPA-SAsthmaImmediate cutaneous hyperreactivity to Aspergillus antigensTransient pulmonary infiltrates on chest radiographElevated IgERaised A fumigatus-specific IgG and IgE

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Radiologic Classification of ABPA: ABPA is clas-sified as ABPA-S or ABPA-CB, respectively, de-pending on the absence or presence of bronchiec-tasis or as ABPA-S (mild), ABPA-CB (moderate),

and ABPA-CB-ORF (other radiologic findings)(Table 7). Patients with ABPA-S probably repre-sent the earliest stage of the disorder. It is be-lieved that patients with ABPA-S have a milder

Figure 5. Algorithm followed in the diagnostic workup for allergic bronchopulmonary aspergillosis in the author’s chest clinic.

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clinical course and less severe immunologic find-ings when compared to ABPA-CB based on theinference of three studies (total of 124 pa-tients).12,139,140 In the largest of these three studies(76 patients), only the A fumigatus-specific IgGlevels were higher in patients with ABPA-CBcompared to ABPA-S. Other immunologic param-eters were not significantly different between thetwo groups.12 In our study of 126 patients, theclinical, spirometric, and immunologic findingswere not significantly different when classifyingABPA into ABPA-S and ABPA-CB or as ABPA-S,ABPA-CB, and ABPA-CB-ORF.22

However, the course of patients with ABPA-S islikely to be less severe when compared to those withABPA-CB. In a multivariate analysis of 155 patientswith ABPA, we demonstrated that the severity ofbronchiectasis and presence of hyperattenuatingmucoid impaction on HRCT-predicted relapses ofABPA and the severity of bronchiectasis was anindependent predictor of failure to achieve long-term remission.23 Thus it may not be important tostage the severity of ABPA based on the presenceor absence of CB, but it remains prudent todiagnose and treat ABPA early to prevent thedevelopment of bronchiectasis because it in-

creases the probability of a smoother course of thisrelapsing-remitting disorder.

Management

The management of ABPA includes two importantaspects: institution of glucocorticoids to control theimmunologic activity and close monitoring for detec-tion of relapses. Another possible target is the use ofantifungal agents to attenuate the fungal burdensecondary to the fungal colonization in the airways.

Systemic Glucocorticoid Therapy: Oral corticoste-roids are the treatment of choice for ABPA. They notonly suppress the immune hyperfunction but are alsoantiinflammatory. There are no data to guide thedose and duration of glucocorticoids, and differentregimens of glucocorticoids have been used (Table8). The use of lower doses of glucocorticoids wasassociated with frequent relapses or corticosteroiddependence (45%).9 We use a higher dosage ofglucocorticoids for a longer duration and observedhigher remission rates and a lower prevalence ofglucocorticoid-dependent ABPA (13.5%).22 Thisraises the possibility of a higher dose and prolongedduration of corticosteroid therapy being associated

Table 6—Stages of ABPA8,22

Stage Description Clinical Picture Radiologic Findings Immunologic Features

I Acute phase Usually symptomatic,fever, weight loss,wheeze

Normal or presence ofradiologic opacities

IgE � 1,000 IU/mL, raisedspecific IgG/IgE andprecipitins to A fumigatus

II Remission Asymptomatic Generally normal or significantresolution of radiologicopacities from the acutephase

Usually 35–50% decline in IgElevels by 6 wk to 3 mo; wegive additional label of“complete remission” if thepatient did not have anyadditional ABPA exacerbationsover the next 3 mo afterstopping steroid therapy

III Exacerbation Symptomatic as in acutephase

Transient or fixed pulmonaryopacities

Doubling of IgE levels frombaseline

IV Glucocorticoid-dependentABPA

Symptomatic Transient or fixed pulmonaryopacities

Two groups can be identified:one in whom IgE levels do notrise but require steroids forasthma control (glucocorticoid-dependent asthma); the otherin whom steroids are requiredto continually suppress thedisease activity (glucocorticoid-dependent ABPA)

V End-stage (fibrotic)ABPA

Symptomatic, findings offixed airwayobstruction, severepulmonarydysfunction, type IIrespiratory failure, corpulmonale

Evidence of bronchiectasis,pulmonary fibrosis,pulmonary hypertension

Serum IgE levels and specificimmunoglobulins do notbecome normal in mostpatients, and even thesepatients can have frequentexacerbations

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with better outcomes. However, there are no directcomparisons between the two regimens, and theselection is a matter of personal preference. Theclinical effectiveness of steroid therapy is reflectedby marked decreases in the patient’s total serum IgElevels (there seems to be no correlation betweenserum levels of A fumigatus-specific IgE levels anddisease activity141) along with symptom and radio-graphic improvements. The goal of therapy is not toattempt normalization of IgE levels but to decreasethe IgE levels by 35 to 50%, which leads to clinicaland radiographic improvement. One should alsoestablish a stable serum level of total IgE to serve asa guide to future detection of relapse.

Inhaled Corticosteroids: Although small case stud-ies suggest some benefit of inhaled corticosteroids inthe management of ABPA,142–145 a double-blind mul-ticenter placebo-controlled trial in 32 patients sug-gested no superiority over placebo.146 We use inhaledcorticosteroids only for the control of asthma once theoral prednisolone dose is reduced to � 10 mg/day.

Oral Itraconazole: Ketoconazole has been tried inthe past147 and has been replaced by the less toxic

agent, itraconazole.130,141,148–160 Only two random-ized controlled studies (84 patients) have evaluatedthe role of itraconazole in ABPA.130,156 Pooled anal-ysis showed that itraconazole could significantly de-crease the IgE levels by � 25% when compared toplacebo but did not cause significant improvement inlung function.161 A major limitation was that neitherof the studies reported long-term outcomes inABPA. Thus longer term trials are required before afirm recommendation can be made for the use ofitraconazole in ABPA. We currently use itraconazoleonly after the first relapse of ABPA despite glucocor-ticoid therapy or in patients with glucocorticoid-dependent ABPA (Table 8). In the limited numbersof patients in whom we have used the drug, therewas no observable advantage.22 Itraconazole not onlyhas numerous adverse effects,162 but it also inhibitsthe metabolism of methylprednisolone (but notprednisolone) with resultant increased frequency of

Table 7—Radiologic Classification of ABPA*

Classification Features

Greenberger et al12

classificationABPA-S All the diagnostic features of ABPA

but no evidence of centralbronchiectasis on HRCT.Patients with ABPA-S may beclassified as Patterson stages I toIV. These patients may haverecurrent exacerbations and mayalso be classified as stage III

(ABPA-CB) All findings of ABPA including CBon HRCT. Patients with ABPA-CB may belong to any of thePatterson stages

Kumar140 classificationABPA-S ABPA without CBABPA-CB ABPA with CBABPA-CB-ORF ABPA with CB other radiologic

features such as pulmonaryfibrosis, bleb, bullae,pneumothorax, parenchymalscarring, emphysematous change,multiple cyst, fibrocavitarylesions, aspergilloma, ground-glass appearance, collapse,mediastinal lymph node, pleuraleffusion, and pleural thickening

*Both the classification schemes believe that patients without CB andORF have serologically milder disease, but it has been shown thatthere is no difference in clinical, spirometric, and serologicalseverity between patients with and without bronchiectasis (see textfor details).

Table 8—Treatment Protocols for the Management ofABPA

Oral glucocorticoidsRegime 15

Prednisolone, 0.5 mg/kg/d, for 1–2 wk, then on alternate daysfor 6–8 wk. Then taper by 5–10 mg every 2 wk anddiscontinue

Repeat the total serum IgE concentration and chestradiograph in 6 to 8 wk

Regime 222,113

Prednisolone, 0.75 mg/kg, for 6 wk, 0.5 mg/kg for 6 wk, thentapered by 5 mg every 6 wk to continue for a total durationof at least 6 to 12 mo. The total IgE levels are repeatedevery 6 to 8 wk for 1 yr to determine the baseline IgEconcentrations

Follow-up and monitoringThe patients are followed up with a medical history and

physical examination, chest radiograph, and measurement oftotal IgE levels every 6 wk to demonstrate decline in IgElevels and clearing of the chest radiograph

A 35% decline in IgE level signifies satisfactory response totherapy. Doubling of the baseline IgE value can signify asilent ABPA exacerbation

If the patient cannot be tapered off prednisolone, the diseasehas evolved into stage IV. Management should beattempted with alternate-day prednisone with the leastpossible dose

Monitor for adverse effects (eg, hypertension, secondarydiabetes)

Prophylaxis for osteoporosis: oral calcium and bisphosphonatesOral itraconazole

Dose: 200 mg bid for 16 wk then once a day for 16 wkIndication: First relapse of ABPA or glucocorticoid-dependent

ABPAFollow-up and monitoring

Monitor for adverse effects (eg, nausea, vomiting, diarrhea,and elevated liver enzymes)

Monitor for drug–drug interactionsMonitor clinical response based on clinical course,

radiography, and total IgE levels

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steroid side effects including adrenal insufficiency.163

Adrenal suppression has also been reported with theconcomitant use of itraconazole and inhaled budes-onide.164,165

Other Therapies: There is a single patient casereport of ABPA treated with inhaled amphotericinand budesonide.166 Similarly, there is another caserecord on the use of omalizumab for the manage-ment of ABPA.167 One author has also used pulsedoses of IV methylprednisolone for the treatment ofsevere ABPA.168 Recently, voriconazole has alsobeen tried in the treatment of ABPA.169–171

Differential Diagnosis and Complications

The disorder needs to be differentiated from thefollowing conditions: Aspergillus hypersensitivebronchial asthma, pulmonary tuberculosis in en-demic areas, community-acquired pneumonia (espe-cially acute presentations), and other inflammatorypulmonary disorders such as eosinophilic pneumo-nia, bronchocentric granulomatosis, and Churg-Strauss syndrome. The complications of ABPA in-

clude recurrent asthma exacerbations and, ifuntreated, the development of bronchiectasis withsubsequent pulmonary hypertension and respiratoryfailure. In fact, this is the reason why routine screen-ing is recommended in bronchial asthma to preventthe complications just described.

ABPA in Special Situations

ABPA Complicating CF: The association of ABPAand CF was first reported in 1965.172 The occur-rence of ABPA in CF is associated with deteriorationof lung function, higher rates of microbial coloniza-tion, pneumothorax, massive hemoptysis, and poorernutritional status.153,173,174 A key element in theimmunopathogenesis may be exposure to high levelsof Aspergillus allergens due to abnormal mucusproperties.175 The recognition of ABPA in CF can bedifficult because ABPA shares many clinical charac-teristics with poorly controlled CF lung disease.Presence of wheezing, pulmonary infiltrates, bron-chiectasis, and mucus plugging are common mani-festations of CF-related pulmonary disease withoutABPA. The prevalence of AH in patients with CF

Table 9—Studies Describing Prevalence of AH and/or ABPA in Patients With CF

Study Year Nature of Study Patients, No. AH in CF ABPA* in CF Diagnosis of AH†

Mearns et al184 1967 Prospective 86 28/86 Skin testAllan et al185 1975 Prospective 30 11/30 Skin testSilverman et al186 1978 Prospective 48 17 Skin testNelson et al187 1979 Prospective 46 18/46 5/46 Skin testLaufer et al177 1984 Prospective 100 53/100 10/100 Skin testFeanny et al188 1988 Prospective 117 18/117 12/117 Skin testSchonheyder et al189 1988 Prospective 200 10/200Zeaske et al190 1988 Prospective 75 44/75 10/75 Skin testKnutsen et al176 1990 Prospective 73 18/73 9/73 Skin testNicolai et al179 1990 Prospective 148 58/148 SerologySimmonds et al191 1990 Prospective 137 8/137Hutcheson et al192 1991 Prospective 79 24/79 Skin testel-Dahr et al193 1994 Prospective 147 30/147 22/147 SerologyMarchant et al194 1994 Retrospective 160 16/160 Skin testMroueh and Spock178 1994 Retrospective 236 38/87 15/236 Skin testBecker et al181 1996 Prospective 53 15/51 1/53 Skin testHutcheson et al195 1996 Prospective 118 47/112 6/118 Skin testGeller et al182 1999 Prospective 14,210 281/14,210Nepomuceno et al153 1999 Retrospective 172 16/172Cimon et al196 2000 Prospective 128 5/128Mastella et al174 2000 Prospective 12,447 967/12,447Taccetti et al197 2000 Prospective 3,089 191/3,089Ritz et al180 2005 Prospective 160 20/160 11/160 SerologySkov et al183 2005 Retrospective 277 13/277Almeida et al198 2006 Prospective 32 11/32 2/32 Skin testKraemer et al173 2006 Prospective 122 16/122Chotirmall et al199 2008 Prospective 50 6/50Rapaka and Kolls200 2008 Retrospective 440 31/440

* ABPA: Studies have used different inclusion criteria for diagnosing ABPA. See text for further details.† AH: Defined as immediate cutaneous hypersensitivity to Aspergillus antigen or a positive specific IgE in serum against A fumigatus

(radioallergosorbent test class � 2) and/or increased specific IgE in serum against rAsp f1 � 9.6 EU/mL, with normal values for rAsp f4 (� 8.4EU/mL) and rAsp f6 (� 7.2 EU/mL)

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has been reported between 29% and 53%,176–180 andthe prevalence of ABPA as 1 to 15%. Atopy seems tobe an important risk factor for ABPA in CF, withABPA observed in 22% of atopic patients but only2% of nonatopic patients.153,181–183

To determine the prevalence of AH/ABPA in CF,a systematic search was performed. The searchyielded 28 studies (16 studies [1,391 patients] de-scribing the prevalence of AH in CF and 23studies [32,589 patients] describing the prevalenceof ABPA in CF) that have described the preva-lence of AH and/or ABPA in patients with CF(Table 9).153,173,174,176–200 A proportion metaanalysis ofthese studies suggested the prevalence of AH in CFof 34% (95% confidence interval, 27 to 41) and the

prevalence of ABPA of 7.8% (95% confidence inter-val, 5.8 to 10) using a random effects model [Figs 6and 7]. There was no uniformity in the diagnosticcriteria between different studies with varying crite-ria used for diagnosis of AH and ABPA. This fact hasalso been previously reported in a questionnaire-based study, which revealed a considerable variabil-ity in the criteria used for the diagnosis of ABPA inCF.201 Therefore, prospective reporting of cases withuniform criteria would be the only way to reliablyidentify the true prevalence of ABPA in CF.

Although a high proportion of CF patients developsensitization to A fumigatus, many demonstrate aspontaneous decline in many immunologic parame-ters, including IgE levels.192 The diagnosis of ABPA

Figure 6. Proportion metaanalysis showing the prevalence of Aspergillus hypersensitivity in patients with cystic fibrosis (random effectsmodel).

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in CF should not be based solely on serology andskin test results, and prolonged testing might berequired to make a definite diagnosis (Table 10). Thetreatment of ABPA in CF is not very different fromthat of ABPA in bronchial asthma, except minimal

data are available to formulate conclusive treatmentrecommendations for ABPA in CF. The treatmentissues are further complicated because pulmonaryexacerbations in a patient with ABPA and CF couldbe related to ABPA or pulmonary infection, and

Figure 7. Proportion metaanalysis showing the prevalence of allergic bronchopulmonary aspergillosis in patients with CF (randomeffects model).

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hence continuous assessment may be required overmonths with repeat performance of all the serologicinvestigations for ABPA before a decision to treat anindividual case is made.202

ABPA Without Bronchial Asthma: ABPA mayoccasionally develop in an individual without preex-isting asthma. We have performed a systematicMEDLINE search for the occurrence of ABPAwithout bronchial asthma.100 In total they included36 cases reported across the globe; two cases dem-onstrated bronchodilator reversibility,203 and oneshowed airway hyperresponsiveness to methacholinechallenge.204 Most of the cases demonstrated hy-persensitivity to A fumigatus, but three casesshowed hypersensitivity to Helminthosporium,203

and one case each to Aspergillus niger.205,206 Be-cause of the absence of bronchial asthma, thesecases are often mistaken initially for other pulmo-nary disorders like bronchogenic carcinoma206 –208

or pulmonary tuberculosis.100

ABPA Complicating Other Conditions: Occasion-ally ABPA has been reported to complicate other

lung diseases like idiopathic bronchiectasis,209

post-tubercular bronchiectasis,210 bronchiectasissecondary to Kartagener syndrome,211 COPD,212

and in patients with chronic granulomatous dis-ease and hyper IgE syndrome.213 However, theseare case reports or small case studies, and largerobservations are required to definitely establish anassociation.

Coexistence of ABPA and Aspergilloma: The sero-logic findings of ABPA have also been reported inpatients with aspergilloma214–224 and chronic necro-tizing pulmonary aspergillosis.225 This ABPA-likesyndrome probably represents a true hypersensitivityreaction consequent to the colonization of Aspergil-lus in long-standing pulmonary cavities and thecontinuous release of Aspergillus antigens that leadsto immunologic activation.214,215 Most patients showa brisk response to glucocorticoids.214–217,224

Allergic Bronchopulmonary Mycosis: Allergicbronchopulmonary mycosis is the occurrence of anABPA-like syndrome due to non-A fumigatus fungalorganisms. A variety of fungal agents (Table 11) havebeen reported to cause this syndrome, but the fre-quency is far less when compared to ABPA.218,226–240

ABPA and Allergic Aspergillus Sinusitis: AllergicAspergillus sinusitis (AAS) is a clinical entity in whichmucoid impaction akin to that of ABPA occurs in theparanasal sinuses.241 The pathogenesis is also similarto ABPA and represents an allergic hypersensitivityresponse to the presence of fungi within the sinuscavity.242 The patient is often asymptomatic or canmanifest with symptoms of nasal obstruction, rhinor-

Table 10—Consensus Conference Proposed Diagnosticand Screening Criteria for ABPA in CF202

Classic diagnostic criteria1. Acute or subacute clinical deterioration (cough, wheeze, and

other pulmonary symptoms) not explained by another etiology2. Serum total IgE levels � 1,000 IU/mL3. Immediate cutaneous reactivity to Aspergillus or presence of

serum IgE antibody to A fumigatus4. Precipitating antibodies to A fumigatus or serum IgG antibody

to A fumigatus5. New or recent abnormalities on chest radiograph or chest CT

scan that have not cleared with antibiotics and standardphysiotherapy

Minimal diagnostic criteria1. Acute or subacute clinical deterioration (cough, wheeze, and

other pulmonary symptoms) not explained by another etiology2. Total serum IgE levels � 500 IU/mL. If total IgE level is 200–

500 IU/mL, repeat testing in 1–3 mo is recommended3. Immediate cutaneous reactivity to Aspergillus or presence of

serum IgE antibody to A fumigatus4. One of the following: (1) precipitins to A fumigatus or

demonstration of IgG antibody to A fumigatus; or (2) new orrecent abnormalities on chest radiography (on chest radiographyor chest CT scan that have not cleared with antibiotics andstandard physiotherapy)

Screening for ABPA in CF1. Maintain a high level of suspicion for ABPA in patients with CF2. Determine the total serum IgE levels annually. If the total

serum IgE levels is � 500 IU/mL, perform A fumigatus skin testor use an IgE antibody to A fumigatus. If results are positive,consider diagnosis on the basis of minimal criteria

3. If the total serum IgE levels is 200–500 IU/mL, repeat themeasurement if there is increased suspicion for ABPA and performfurther diagnostic tests (immediate skin test reactivity to Afumigatus, IgE antibody to A fumigatus, A fumigatus precipitins, orserum IgG antibody to A fumigatus, and chest radiography)

Table 11—Fungi Implicated in the Causation ofAllergic Bronchopulmonary Mycosis

Fungi Study/Year

A niger Sharma et al218/1985Helminthosporium spp Dolan et al226/1970Penicillium spp Sahn and Lakshminarayan227/1973Aspergillus ochraceus Novey and Wells228/1978Stemphylium spp Benatar et al229/1980Aspergillus terreus Laham et al230/1981Drechslera spp McAleer et al231/1981Torulopsis spp Patterson et al232/1982Mucor-like spp Patterson et al232/1982Candida spp Akiyama et al234/1984Pseudallescheria spp Lake et al235/1990Bipolaris spp Lake et al236/1991Curvularia spp Lake et al236/1991Schizophyllum spp Kamei et al237/1994Fusarium spp Backman et al238/1995Cladosporium spp Moreno-Ancillo et al239/1996Saccharomyces spp Ogawa et al240/2004

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rhea, headache, and epistaxis. Occasionally, theallergic fungal sinusitis may extend into adjacentspaces such as the orbit and manifest as propto-sis.243 Although in many patients with ABPA,sinusitis can often be radiologically demonstrated,it may not be possible to confirm the diagnosis ofAAS because many patients decline to undergo thediagnostic procedures required to establish thediagnosis. We currently label the patients withABPA as having concomitant AAS if there iscombination of hyperattenuating mucus and/orbony erosion on a paranasal CT scan. Treatment isinitiated for ABPA with patients receiving addi-tional intranasal glucocorticoids. If the symptomspersist or are troublesome, surgical managementmay be required for the management of AAS.

Conclusions

A high index of suspicion for ABPA should bemaintained while managing any patient with bron-chial asthma whatever the severity or the level ofcontrol. Host immunologic responses are central tothe pathogenesis, and they are the primary determi-nants of the clinical, biologic, pathologic, and radio-logic features of this disorder. ABPA may precedethe clinical recognition of the disorder for manyyears or even decades, and it is often misdiagnosed asa variety of pulmonary diseases. Because a patientwith ABPA can be minimally symptomatic or asymp-tomatic, all patients with bronchial asthma should beroutinely screened with an Aspergillus skin test. Inpatients with Aspergillus hypersensitivity, furtherimmunologic studies are warranted to diagnoseABPA before the development of bronchiectasisbecause bronchiectasis is a poor prognostic markerin the natural history of this disease.

ACKNOWLEDGMENT: The author wishes to thank Dr. Aman-jit Bal, Assistant Professor, Department of Histopathology,PGIMER, Chandigarh for providing the histopathology photo-graphs.

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