This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
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
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)
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
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*
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).
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.
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)
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).
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
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).
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
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.
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
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
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)
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).
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).
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
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.
References1 Bardana EJ Jr. The clinical spectrum of aspergillosis—part
1: epidemiology, pathogenicity, infection in animals andimmunology of Aspergillus. Crit Rev Clin Lab Sci 1981;13:21–83
2 Geiser DM, Klich MA, Frisvad JC, et al. The current statusof species recognition and identification in Aspergillus. StudMycol 2007; 59:1–10
3 Walsh TJ, Anaissie EJ, Denning DW, et al. Treatment ofaspergillosis: clinical practice guidelines of the infectiousdiseases society of America. Clin Infect Dis 2008; 46:327–360
6 Rosenberg M, Patterson R, Mintzer R, et al. Clinical andimmunologic criteria for the diagnosis of allergic broncho-pulmonary aspergillosis. Ann Intern Med 1977; 86:405–414
7 Greenberger PA, Patterson R, Ghory A, et al. Late sequelaeof allergic bronchopulmonary aspergillosis. J Allergy ClinImmunol 1980; 66:327–335
8 Patterson R, Greenberger PA, Radin RC, et al. Allergicbronchopulmonary aspergillosis: staging as an aid to man-agement. Ann Intern Med 1982; 96:286–291
9 Patterson R, Greenberger PA, Halwig JM, et al. Allergicbronchopulmonary aspergillosis: natural history and classifi-cation of early disease by serologic and roentgenographicstudies. Arch Intern Med 1986; 146:916–918
10 Patterson R, Greenberger PA, Lee TM, et al. Prolongedevaluation of patients with corticosteroid-dependent asthmastage of allergic bronchopulmonary aspergillosis. J AllergyClin Immunol 1987; 80:663–668
11 Greenberger PA, Patterson R. Allergic bronchopulmonaryaspergillosis and the evaluation of the patient with asthma.J Allergy Clin Immunol 1988; 81:646–650
12 Greenberger PA, Miller TP, Roberts M, et al. Allergicbronchopulmonary aspergillosis in patients with and withoutevidence of bronchiectasis. Ann Allergy 1993; 70:333–338
13 Greenberger PA. Clinical aspects of allergic bronchopulmo-nary aspergillosis. Front Biosci 2003; 8:S119–S127
14 Rajan TV. The Gell-Coombs classification of hypersensitivityreactions: a re-interpretation. Trends Immunol 2003; 24:376–379
15 Geha RS, Sampson HA, Askenase PW, et al. Allergy andhypersensitivity. In: Janeway CA, Travers P, Walport M, et al.eds. Immunobiology. New York, NY: Garland, 2001; 517–556
16 Hinson KFW, Moon AJ, Plummer NS. Broncho-pulmonaryaspergillosis; a review and a report of eight new cases.Thorax 1952; 7:317–333
17 Muscat I, Oxborrow S, Siddorn J. Allergic bronchopulmo-nary mycosis. Lancet 1988; 1:1341
18 Kirsten D, Nowak D, Rabe KF, et al. [Diagnosis of bron-chopulmonary aspergillosis is often made too late]. Med Klin(Munich) 1993; 88:353–356
19 Behera D, Guleria R, Jindal SK, et al. Allergic bronchopul-monary aspergillosis: a retrospective study of 35 cases.Indian J Chest Dis Allied Sci 1994; 36:173–179
20 Al-Mobeireek AF, El-Rab M, Al-Hedaithy SS, et al. Allergicbronchopulmonary mycosis in patients with asthma: periodprevalence at a university hospital in Saudi Arabia. RespirMed 2001; 95:341–347
21 Chakrabarti A, Sethi S, Raman DS, et al. Eight-year study ofallergic bronchopulmonary aspergillosis in an Indian teach-ing hospital. Mycoses 2002; 45:295–299
22 Agarwal R, Gupta D, Aggarwal AN, et al. Allergic broncho-pulmonary aspergillosis: lessons from 126 patients attendinga chest clinic in North India. Chest 2006; 130:442–448
23 Agarwal R, Gupta D, Aggarwal AN, et al. Clinical signifi-cance of hyperattenuating mucoid impaction in allergicbronchopulmonary aspergillosis: an analysis of 155 patients.Chest 2007; 132:1183–1190
24 Agarwal R, Chakrabarti A. Epidemiology of allergic bron-chopulmonary aspergillosis. In: Pasqualotto A, ed. As-pergillosis: from diagnosis to prevention. New York, NY:Springer, 2009 (in press)
25 Bateman ED. A new look at the natural history of Aspergil-lus hypersensitivity in asthmatics. Respir Med 1994; 88:325–327
27 Tillie-Leblond I, Tonnel AB. Allergic bronchopulmonaryaspergillosis. Allergy 2005; 60:1004–1013
28 Donnelly SC, McLaughlin H, Bredin CP. Period prevalenceof allergic bronchopulmonary mycosis in a regional hospitaloutpatient population in Ireland 1985–88. Ir J Med Sci1991; 160:288–290
29 Novey HS. Epidemiology of allergic bronchopulmonaryaspergillosis. Immunol Allergy Clin North Am 1998; 18:641–653
30 Agarwal R, Aggarwal AN, Gupta D, et al. Prevalence ofAspergillus hypersensitivity and allergic bronchopulmonaryaspergillosis in patients with bronchial asthma: a systematicreview and meta-analysis. Int J Tuberc Lung Dis 2009 (inpress)
32 Schwartz HJ, Greenberger PA. The prevalence of allergicbronchopulmonary aspergillosis in patients with asthma,determined by serologic and radiologic criteria in patients atrisk. J Lab Clin Med 1991; 117:138–142
33 Eaton T, Garrett J, Milne D, et al. Allergic bronchopulmo-nary aspergillosis in the asthma clinic: a prospective evalu-ation of CT in the diagnostic algorithm. Chest 2000; 118:66–72
34 Kumar R, Gaur SN. Prevalence of allergic bronchopulmo-nary aspergillosis in patients with bronchial asthma. AsianPac J Allergy Immunol 2000; 18:181–185
35 Maurya V, Gugnani HC, Sarma PU, et al. Sensitization toAspergillus antigens and occurrence of allergic bronchopul-monary aspergillosis in patients with asthma. Chest 2005;127:1252–1259
36 Prasad R, Garg R, Sanjay, et al. A study on prevalence ofallergic bronchopulmonary aspergillosis in patients of bron-chial asthma. Internet J Pulmonary Med 2008; 9
37 Agarwal R, Nath A, Aggarwal AN, et al. Aspergillus hyper-sensitivity and allergic bronchopulmonary aspergillosis inpatients with acute severe asthma in a respiratory ICU inNorth India. Mycoses 2009 (in press)
41 Allmers H, Huber H, Baur X. Two year follow-up of agarbage collector with allergic bronchopulmonary aspergil-losis (ABPA). Am J Ind Med 2000; 37:438–442
42 Chauhan B, Knutsen A, Hutcheson PS, et al. T cell subsets,epitope mapping, and HLA-restriction in patients withallergic bronchopulmonary aspergillosis. J Clin Invest 1996;97:2324–2331
43 Miller PW, Hamosh A, Macek M Jr, et al. Cystic fibrosistransmembrane conductance regulator (CFTR) gene muta-tions in allergic bronchopulmonary aspergillosis. Am J HumGenet 1996; 59:45–51
44 Aron Y, Bienvenu T, Hubert D, et al. HLA-DR polymor-phism in allergic bronchopulmonary aspergillosis. J AllergyClin Immunol 1999; 104:891–892
45 Chauhan B, Santiago L, Hutcheson PS, et al. Evidence forthe involvement of two different MHC class II regions insusceptibility or protection in allergic bronchopulmonaryaspergillosis. J Allergy Clin Immunol 2000; 106:723–729
46 Marchand E, Verellen-Dumoulin C, Mairesse M, et al. Fre-quency of cystic fibrosis transmembrane conductance regulator
gene mutations and 5T allele in patients with allergic broncho-pulmonary aspergillosis. Chest 2001; 119:762–767
47 Eaton TE, Weiner Miller P, Garrett JE, et al. Cystic fibrosistransmembrane conductance regulator gene mutations: dothey play a role in the aetiology of allergic bronchopulmo-nary aspergillosis? Clin Exp Allergy 2002; 32:756–761
48 Saxena S, Madan T, Shah A, et al. Association of polymor-phisms in the collagen region of SP-A2 with increased levelsof total IgE antibodies and eosinophilia in patients withallergic bronchopulmonary aspergillosis. J Allergy Clin Im-munol 2003; 111:1001–1007
49 Brouard J, Knauer N, Boelle PY, et al. Influence of inter-leukin-10 on Aspergillus fumigatus infection in patients withcystic fibrosis. J Infect Dis 2005; 191:1988–1991
50 Knutsen AP. Genetic and respiratory tract risk factors foraspergillosis: ABPA and asthma with fungal sensitization.Med Mycol 2006; 44(suppl 1):61–70
52 Sambatakou H, Pravica V, Hutchinson IV, et al. Cytokineprofiling of pulmonary aspergillosis. Int J Immunogenet2006; 33:297–302
53 Vaid M, Kaur S, Sambatakou H, et al. Distinct alleles ofmannose-binding lectin (MBL) and surfactant proteins A(SP-A) in patients with chronic cavitary pulmonary aspergil-losis and allergic bronchopulmonary aspergillosis. ClinChem Lab Med 2007; 45:183–186
54 Carvalho A, Pasqualotto AC, Pitzurra L, et al. Polymor-phisms in toll-like receptor genes and susceptibility topulmonary aspergillosis. J Infect Dis 2008; 197:618–621
55 Tomee JF, Wierenga AT, Hiemstra PS, et al. Proteases fromAspergillus fumigatus induce release of proinflammatorycytokines and cell detachment in airway epithelial cell lines.J Infect Dis 1997; 176:300–303
56 Tomee JF, Kauffman HF, Klimp AH, et al. Immunologicsignificance of a collagen-derived culture filtrate containingproteolytic activity in Aspergillus-related diseases. J AllergyClin Immunol 1994; 93:768–778
57 Hogaboam CM, Blease K, Schuh JM. Cytokines and che-mokines in allergic bronchopulmonary aspergillosis (ABPA)and experimental Aspergillus-induced allergic airway orasthmatic disease. Front Biosci 2003; 8:e147–e156
58 Kauffman HF. Immunopathogenesis of allergic bronchopul-monary aspergillosis and airway remodeling. Front Biosci2003; 8:e190–e196
59 Kauffman HK, Tomee JFC. Inflammatory cells and airwaydefense against Aspergillus fumigatus. Immunol Allergy ClinNorth Am 1998; 18:619–640
60 Kauffman HF, Tomee JF, van de Riet MA, et al. Protease-dependent activation of epithelial cells by fungal allergensleads to morphologic changes and cytokine production.J Allergy Clin Immunol 2000; 105:1185–1193
61 Chauhan B, Santiago L, Kirschmann DA, et al. Theassociation of HLA-DR alleles and T cell activation withallergic bronchopulmonary aspergillosis. J Immunol 1997;159:4072– 4076
62 Schuyler M. The Th1/Th2 paradigm in allergic bronchopul-monary aspergillosis. J Lab Clin Med 1998; 131:194–196
63 Knutsen AP, Bellone C, Kauffman H. Immunopathogenesisof allergic bronchopulmonary aspergillosis in cystic fibrosis.J Cyst Fibros 2002; 1:76–89
64 Slavin RG, Bedrossian CW, Hutcheson PS, et al. Apathologic study of allergic bronchopulmonary aspergil-losis. J Allergy Clin Immunol 1988; 81:718 –725
65 Chan-Yeung M, Chase WH, Trapp W, et al. Allergic bron-
chopulmonary aspergillosis. Clinical and pathologic study ofthree cases. Chest 1971; 59:33–39
66 Riley DJ, Mackenzie JW, Uhlman WE, et al. Allergicbronchopulmonary aspergillosis: evidence of limited tissueinvasion. Am Rev Respir Dis 1975; 111:232–236
67 Case records of the Massachusetts General Hospital.Weekly clinicopathological exercises. Case 24–2001. A 46-year-old woman with chronic sinusitis, pulmonary nodules,and hemoptysis. N Engl J Med 2001; 345:443–449
68 Hanson G, Flor N, Wells I, et al. Bronchocentric granulo-matosis: a complication of allergic bronchopulmonary as-pergillosis. J Allergy Clin Immunol 1977; 59:83–90
69 Kradin RL, Mark EJ. The pathology of pulmonary disordersdue to Aspergillus spp. Arch Pathol Lab Med 2008; 132:606–614
70 Starke ID, Keal EE. Cerebral aspergilloma in a patient withallergic bronchopulmonary aspergillosis. Br J Dis Chest1980; 74:301–305
71 Bodey GP, Glann AS. Central nervous system aspergillosisfollowing steroidal therapy for allergic bronchopulmonaryaspergillosis. Chest 1993; 103:299–301
72 Chung Y, Kraut JR, Stone AM, et al. Disseminated aspergil-losis in a patient with cystic fibrosis and allergic broncho-pulmonary aspergillosis. Pediatr Pulmonol 1994; 17:131–134
74 Ganassini A, Cazzadori A. Invasive pulmonary aspergillosiscomplicating allergic bronchopulmonary aspergillosis. Re-spir Med 1995; 89:143–145
75 Shah A, Kala J, Sahay S, et al. Frequency of familial occurrencein 164 patients with allergic bronchopulmonary aspergillosis.Ann Allergy Asthma Immunol 2008; 101:363–369
76 Agarwal R, Singh N, Gupta D. Pulmonary hypertension as apresenting manifestation of allergic bronchopulmonary as-pergillosis. Indian J Chest Dis Allied Sci 2009; 51:37–40
77 Ownby DR. Diagnostic tests in allergy. In: Lieberman P,Anderson JA, eds. Allergic diseases: diagnosis and treatment.Totowa, NJ: Humana Press, 2007; 27–38
78 Malo JL, Paquin R. Incidence of immediate sensitivity toAspergillus fumigatus in a North American asthmatic pop-ulation. Clin Allergy 1979; 9:377–384
79 Ricketti AJ, Greenberger PA, Patterson R. Serum IgE as animportant aid in management of allergic bronchopulmonaryaspergillosis. J Allergy Clin Immunol 1984; 74:68–71
80 Imbeau SA, Nichols D, Flaherty D, et al. Relationshipsbetween prednisone therapy, disease activity, and the totalserum IgE level in allergic bronchopulmonary aspergillosis.J Allergy Clin Immunol 1978; 62:91–95
81 Leser C, Kauffman HF, Virchow C Sr, et al. Specific serumimmunopatterns in clinical phases of allergic bronchopulmo-nary aspergillosis. J Allergy Clin Immunol 1992; 90:589–599
82 Wang JL, Patterson R, Rosenberg M, et al. Serum IgE andIgG antibody activity against Aspergillus fumigatus as adiagnostic aid in allergic bronchopulmonary aspergillosis.Am Rev Respir Dis 1978; 117:917–927
83 McCarthy DS, Simon G, Hargreave FE. The radiologicalappearances in allergic broncho-pulmonary aspergillosis.Clin Radiol 1970; 21:366–375
84 Mintzer RA, Rogers LF, Kruglik GD, et al. The spectrum ofradiologic findings in allergic bronchopulmonary aspergillo-sis. Radiology 1978; 127:301–307
85 Shah A, Panchal N, Agarwal AK. Allergic bronchopulmonaryaspergillosis: the spectrum of roentgenologic appearances.Indian J Radiol Imaging 1999; 9:107–112
86 Shah A. Allergic bronchopulmonary and sinus aspergillo-
sis: the roentgenologic spectrum. Front Biosci 2003; 8:e138 – e146
87 Phelan MS, Kerr IH. Allergic broncho-pulmonary aspergil-losis: the radiological appearance during long-term follow-up. Clin Radiol 1984; 35:385–392
88 Lynch DA. Imaging of asthma and allergic bronchopulmo-nary mycosis. Radiol Clin North Am 1998; 36:129–142
89 Panchal N, Bhagat R, Pant C, et al. Allergic bronchopulmo-nary aspergillosis: the spectrum of computed tomographyappearances. Respir Med 1997; 91:213–219
90 Goyal R, White CS, Templeton PA, et al. High attenuationmucous plugs in allergic bronchopulmonary aspergillosis:CT appearance. J Comput Assist Tomogr 1992; 16:649–650
92 Karunaratne N, Baraket M, Lim S, et al. Case quiz: thoracicCT illustrating hyperdense bronchial mucous plugging; al-lergic bronchopulmonary aspergillosis. Australas Radiol2003; 47:336–338
93 Molinari M, Ruiu A, Biondi M, et al. Hyperdense mucoidimpaction in allergic bronchopulmonary aspergillosis: CTappearance. Monaldi Arch Chest Dis 2004; 61:62–64
94 Agarwal R, Aggarwal AN, Gupta D. High-attenuation mucusin allergic bronchopulmonary aspergillosis: another cause ofdiffuse high-attenuation pulmonary abnormality. AJR Am JRoentgenol 2006; 186:904
95 Morozov A, Applegate KE, Brown S, et al. High-attenuationmucus plugs on MDCT in a child with cystic fibrosis:potential cause and differential diagnosis. Pediatr Radiol2007; 37:592–595
96 Scadding JG. The bronchi in allergic aspergillosis. Scand JRespir Dis 1967; 48:372–377
97 Neeld DA, Goodman LR, Gurney JW, et al. Computer-ized tomography in the evaluation of allergic bronchopul-monary aspergillosis. Am Rev Respir Dis 1990; 142:1200 –1205
98 Angus RM, Davies ML, Cowan MD, et al. Computedtomographic scanning of the lung in patients with allergicbronchopulmonary aspergillosis and in asthmatic patientswith a positive skin test to Aspergillus fumigatus. Thorax1994; 49:586–589
99 Ward S, Heyneman L, Lee MJ, et al. Accuracy of CT in thediagnosis of allergic bronchopulmonary aspergillosis in asth-matic patients. AJR Am J Roentgenol 1999; 173:937–942
100 Agarwal R, Aggarwal AN, Gupta D, et al. A rare cause ofmiliary nodules: allergic bronchopulmonary aspergillosis.BJR 2009 (in press)
101 Agarwal R, Reddy C, Gupta D. An unusual cause of hilarlymphadenopathy. Lung India 2006; 23:90–92
102 Shah A, Kala J, Sahay S. Allergic bronchopulmonary as-pergillosis with hilar adenopathy in a 42-month-old boy.Pediatr Pulmonol 2007; 42:747–748
103 Murphy D, Lane DJ. Pleural effusion in allergic broncho-pulmonary aspergillosis: two case reports. Br J Dis Chest1981; 75:91–95
104 O’Connor TM, O’Donnell A, Hurley M, et al. Allergicbronchopulmonary aspergillosis: a rare cause of pleuraleffusion. Respirology 2001; 6:361–363
105 Ogasawara T, Iesato K, Okabe H, et al. A case of pleuraleffusion associated with allergic bronchopulmonary aspergil-losis during a relapse of the disease. Nihon Kokyuki GakkaiZasshi 2003; 41:905–910
106 Cote CG, Cicchelli R, Hassoun PM. Hemoptysis and a lungmass in a 51-year-old patient with asthma. Chest 1998;114:1465–1468
107 Ko WK, Choi SW, Park JM, et al. A case of allergic
110 Coop C, England RW, Quinn JM. Allergic bronchopulmo-nary aspergillosis masquerading as invasive pulmonary as-pergillosis. Allergy Asthma Proc 2004; 25:263–266
111 Agarwal R, Srinivas R, Aggarwal AN, et al. Pulmonarymasses in allergic bronchopulmonary aspergillosis: mecha-nistic explanations. Respir Care 2008; 53:1744–1748
112 Longbottom JL, Pepys J. Pulmonary aspergillosis: diag-nostic and immunological significance of antigens andC-substance in Aspergillus fumigatus. J Pathol Bacteriol1964; 88:141–151
113 Vlahakis NE, Aksamit TR. Diagnosis and treatment ofallergic bronchopulmonary aspergillosis. Mayo Clin Proc2001; 76:930–938
115 Malo JL, Hawkins R, Pepys J. Studies in chronic allergicbronchopulmonary aspergillosis: 1. Clinical and physiologi-cal findings. Thorax 1977; 32:254–261
117 Nichols D, Dopico GA, Braun S, et al. Acute and chronicpulmonary function changes in allergic bronchopulmonaryaspergillosis. Am J Med 1979; 67:631–637
118 Kurup VP. Aspergillus antigens: which are important? MedMycol 2005; 43(suppl):S189–S196
120 Crameri R, Hemmann S, Ismail C, et al. Disease-specificrecombinant allergens for the diagnosis of allergic broncho-pulmonary aspergillosis. Int Immunol 1998; 10:1211–1216
121 Crameri R. Recombinant Aspergillus fumigatus allergens:from the nucleotide sequences to clinical applications. IntArch Allergy Immunol 1998; 115:99–114
122 Crameri R, Lidholm J, Gronlund H, et al. Automated specificIgE assay with recombinant allergens: evaluation of the recom-binant Aspergillus fumigatus allergen I in the Pharmacia CapSystem. Clin Exp Allergy 1996; 26:1411–1419
123 Nikolaizik WH, Moser M, Crameri R, et al. Identification ofallergic bronchopulmonary aspergillosis in cystic fibrosispatients by recombinant Aspergillus fumigatus I/a-specificserology. Am J Respir Crit Care Med 1995; 152:634–639
124 Hemmann S, Nikolaizik WH, Schoni MH, et al. DifferentialIgE recognition of recombinant Aspergillus fumigatus aller-gens by cystic fibrosis patients with allergic bronchopulmo-nary aspergillosis or Aspergillus allergy. Eur J Immunol1998; 28:1155–1160
125 Nikolaizik WH, Weichel M, Blaser K, et al. Intracutaneoustests with recombinant allergens in cystic fibrosis patientswith allergic bronchopulmonary aspergillosis and Aspergillusallergy. Am J Respir Crit Care Med 2002; 165:916–921
126 Campbell MJ, Clayton YM. Bronchopulmonary aspergillo-sis. A correlation of the clinical and laboratory findings in272 patients investigated for bronchopulmonary aspergillo-sis. Am Rev Respir Dis 1964; 89:186–196
127 McCarthy DS, Pepys J. Allergic broncho-pulmonary as-pergillosis: clinical immunology; 2. Skin, nasal and bronchialtests. Clin Allergy 1971; 1:415–432
128 Wang JL, Patterson R, Roberts M, et al. The management ofallergic bronchopulmonary aspergillosis. Am Rev Respir Dis1979; 120:87–92
129 Denning DW, O’Driscoll BR, Hogaboam CM, et al. Thelink between fungi and severe asthma: a summary of theevidence. Eur Respir J 2006; 27:615–626
130 Wark PA, Hensley MJ, Saltos N, et al. Anti-inflammatoryeffect of itraconazole in stable allergic bronchopulmonaryaspergillosis: a randomized controlled trial. J Allergy ClinImmunol 2003; 111:952–957
131 Agarwal R, Chakrabarti A. Clinical features and naturalhistory of allergic bronchopulmonary aspergillosis. In: Pas-qualotto A, ed. Aspergillosis: from diagnosis to prevention.New York, NY: Springer, 2009 (in press)
132 Greenberger PA, Patterson R. Application of enzyme-linkedimmunosorbent assay (ELISA) in diagnosis of allergic broncho-pulmonary aspergillosis. J Lab Clin Med 1982; 99:288–293
133 Rosenberg M, Patterson R, Roberts M, et al. The assess-ment of immunologic and clinical changes occurring duringcorticosteroid therapy for allergic bronchopulmonary as-pergillosis. Am J Med 1978; 64:599–606
134 Ricketti AJ, Greenberger PA, Patterson R. Varying presen-tations of allergic bronchopulmonary aspergillosis. Int ArchAllergy Appl Immunol 1984; 73:283–285
135 Halwig JM, Greenberger PA, Levine M, et al. Recurrence ofallergic bronchopulmonary aspergillosis after seven years ofremission. J Allergy Clin Immunol 1984; 74:738–740
136 Lee TM, Greenberger PA, Patterson R, et al. Stage V(fibrotic) allergic bronchopulmonary aspergillosis: a reviewof 17 cases followed from diagnosis. Arch Intern Med 1987;147:319–323
137 Patterson R. Allergic bronchopulmonary aspergillosis andhypersensitivity reactions to fungi. In: Fishman AP, Elias JA,Fishman JA, et al, eds. Fishman’s pulmonary diseases anddisorders. New York, NY: McGraw-Hill, 1998; 777–782
139 Kumar R, Chopra D. Evaluation of allergic bronchopulmo-nary aspergillosis in patients with and without central bron-chiectasis. J Asthma 2002; 39:473–477
140 Kumar R. Mild, moderate, and severe forms of allergicbronchopulmonary aspergillosis: a clinical and serologicevaluation. Chest 2003; 124:890–892
141 Denning DW, Van Wye JE, Lewiston NJ, et al. Adjunctivetherapy of allergic bronchopulmonary aspergillosis withitraconazole. Chest 1991; 100:813–819
142 Heinig JH, Weeke ER, Groth S, et al. High-dose localsteroid treatment in bronchopulmonary aspergillosis: a pilotstudy. Allergy 1988; 43:24–31
143 Balter MS, Rebuck AS. Treatment of allergic bronchopul-monary aspergillosis with inhaled corticosteroids. RespirMed 1992; 86:441–442
144 Imbeault B, Cormier Y. Usefulness of inhaled high-dosecorticosteroids in allergic bronchopulmonary aspergillosis.Chest 1993; 103:1614–1617
145 Seaton A, Seaton RA, Wightman AJ. Management of allergicbronchopulmonary aspergillosis without maintenance oralcorticosteroids: a fifteen-year follow-up. QJM 1994; 87:529–537
146 Inhaled beclomethasone dipropionate in allergic broncho-pulmonary aspergillosis: report to the Research Committeeof the British Thoracic Association. Br J Dis Chest 1979;73:349–356
147 Shale DJ, Faux JA, Lane DJ. Trial of ketoconazole innon-invasive pulmonary aspergillosis. Thorax 1987;42:26–31
148 De Beule K, De Doncker P, Cauwenbergh G, et al. Thetreatment of aspergillosis and aspergilloma with itracon-azole, clinical results of an open international study (1982–1987). Mycoses 1988; 31:476–485
149 Mannes GP, van der Heide S, van Aalderen WM, et al.Itraconazole and allergic bronchopulmonary aspergillosis intwin brothers with cystic fibrosis. Lancet 1993; 341:492
150 Pacheco A, Martin JA, Cuevas M. Serologic response toitraconazole in allergic bronchopulmonary aspergillosis.Chest 1993; 103:980–981
151 Germaud P, Tuchais E. Allergic bronchopulmonary as-pergillosis treated with itraconazole. Chest 1995; 107:883
152 Nikaido Y, Nagata N, Yamamoto T, et al. A case of allergicbronchopulmonary aspergillosis successfully treated withitraconazole. Respir Med 1998; 92:118–119
153 Nepomuceno IB, Esrig S, Moss RB. Allergic bronchopul-monary aspergillosis in cystic fibrosis: role of atopy andresponse to itraconazole. Chest 1999; 115:364–370
154 Salez F, Brichet A, Desurmont S, et al. Effects of itracon-azole therapy in allergic bronchopulmonary aspergillosis.Chest 1999; 116:1665–1668
155 Suzuki M, Sugiyama Y, Kitamura S. A case of allergicbronchopulmonary aspergillosis refractory to the corticoste-roid therapy and successfully treated by itraconazole. Japa-nese J Chest Dis 1999; 58:770–775
156 Stevens DA, Schwartz HJ, Lee JY, et al. A randomized trialof itraconazole in allergic bronchopulmonary aspergillosis.N Engl J Med 2000; 342:756–762
157 Skov M, Hoiby N, Koch C. Itraconazole treatment ofallergic bronchopulmonary aspergillosis in patients withcystic fibrosis. Allergy 2002; 57:723–728
158 Kumar R, Singh P, Arora R, et al. Effect of itraconazoletherapy in allergic bronchopulmonary aspergillosis. SaudiMed J 2003; 24:546–547
159 Morimoto T, Ohnishi H, Fujiyama R, et al. Allergic bron-chopulmonary aspergillosis successfully treated with itracon-azole and fluticasone. Japanese J Chest Dis 2003; 62:55–60
160 Ferrari M, Bodini I, Lo Cascio V. Rhabdomyolysis after theadministration of itraconazole to an asthmatic patient withbronchopulmonary aspergillosis. Respiration 2004; 71:289–291
161 Wark PA, Gibson PG, Wilson AJ. Azoles for allergic bron-chopulmonary aspergillosis associated with asthma. Co-chrane Database Syst Rev (database online). Issue 3, 2004
162 Tucker RM, Haq Y, Denning DW, et al. Adverse eventsassociated with itraconazole in 189 patients on chronictherapy. J Antimicrob Chemother 1990; 26:561–566
163 Lebrun-Vignes B, Archer VC, Diquet B, et al. Effect ofitraconazole on the pharmacokinetics of prednisolone andmethylprednisolone and cortisol secretion in healthy sub-jects. Br J Clin Pharmacol 2001; 51:443–450
164 Main KM, Skov M, Sillesen IB, et al. Cushing’s syndromedue to pharmacological interaction in a cystic fibrosis pa-tient. Acta Paediatr 2002; 91:1008–1011
165 Skov M, Main KM, Sillesen IB, et al. Iatrogenic adrenalinsufficiency as a side-effect of combined treatment ofitraconazole and budesonide. Eur Respir J 2002; 20:127–133
166 Laoudi Y, Paolini JB, Grimfed A, et al. Nebulised cortico-steroid and amphotericin B: an alternative treatment forABPA? Eur Respir J 2008; 31:908–909
167 van der Ent CK, Hoekstra H, Rijkers GT. Successfultreatment of allergic bronchopulmonary aspergillosis withrecombinant anti-IgE antibody. Thorax 2007; 62:276–277
168 Thomson JM, Wesley A, Byrnes CA, et al. Pulse intravenousmethylprednisolone for resistant allergic bronchopulmonaryaspergillosis in cystic fibrosis. Pediatr Pulmonol 2006; 41:164–170
169 Mulliez P, Croxo C, Roy-Saint Georges F, et al. Allergic
broncho-pulmonary aspergillosis treated with voriconazole.Rev Mal Respir 2006; 23:93–94
170 Bandres Gimeno R, Munoz Martinez MJ. Prolonged thera-peutic response to voriconazole in a case of allergic bron-chopulmonary aspergillosis. Arch Bronconeumol 2007; 43:49–51
171 Erwin GE, Fitzgerald JE. Case report: allergic bronchopul-monary aspergillosis and allergic fungal sinusitis successfullytreated with voriconazole. J Asthma 2007; 44:891–895
172 Mearns M, Young W, Batten J. Transient pulmonary infil-trations in cystic fibrosis due to allergic aspergillosis. Thorax1965; 20:385–392
173 Kraemer R, Delosea N, Ballinari P, et al. Effect of allergicbronchopulmonary aspergillosis on lung function in childrenwith cystic fibrosis. Am J Respir Crit Care Med 2006;174:1211–1220
174 Mastella G, Rainisio M, Harms HK, et al. Allergic broncho-pulmonary aspergillosis in cystic fibrosis: a European epide-miological study; Epidemiologic Registry of Cystic Fibrosis.Eur Respir J 2000; 16:464–471
175 de Almeida MB, Bussamra MH, Rodrigues JC. Allergicbronchopulmonary aspergillosis in paediatric cystic fibrosispatients. Paediatr Respir Rev 2006; 7:67–72
176 Knutsen AP, Hutcheson PS, Mueller KR, et al. Serumimmunoglobulins E and G anti-Aspergillus fumigatus anti-body in patients with cystic fibrosis who have allergicbronchopulmonary aspergillosis. J Lab Clin Med 1990;116:724–727
178 Mroueh S, Spock A. Allergic bronchopulmonary aspergillo-sis in patients with cystic fibrosis. Chest 1994; 105:32–36
179 Nicolai T, Arleth S, Spaeth A, et al. Correlation of IgEantibody titer to Aspergillus fumigatus with decreased lungfunction in cystic fibrosis. Pediatr Pulmonol 1990; 8:12–15
180 Ritz N, Ammann RA, Casaulta Aebischer C, et al. Riskfactors for allergic bronchopulmonary aspergillosis and sen-sitization to Aspergillus fumigatus in patients with cysticfibrosis. Eur J Pediatr 2005; 164:577–582
181 Becker JW, Burke W, McDonald G, et al. Prevalence ofallergic bronchopulmonary aspergillosis and atopy in adultpatients with cystic fibrosis. Chest 1996; 109:1536–1540
182 Geller DE, Kaplowitz H, Light MJ, et al. Allergic broncho-pulmonary aspergillosis in cystic fibrosis: reported preva-lence, regional distribution, and patient characteristics; Sci-entific Advisory Group, Investigators, and Coordinators ofthe Epidemiologic Study of Cystic Fibrosis. Chest 1999;116:639–646
183 Skov M, McKay K, Koch C, et al. Prevalence of allergicbronchopulmonary aspergillosis in cystic fibrosis in an areawith a high frequency of atopy. Respir Med 2005; 99:887–893
184 Mearns M, Longbottom J, Batten J. Precipitating antibodiesto Aspergillus fumigatus in cystic fibrosis. Lancet 1967;1:538–539
185 Allan JD, Moss AD, Wallwork JC, et al. Immediate hyper-sensitivity in patients with cystic fibrosis. Clin Allergy 1975;5:255–261
186 Silverman M, Hobbs FD, Gordon IR, et al. Cystic fibrosis,atopy, and airways lability. Arch Dis Child 1978; 53:873–877
187 Nelson LA, Callerame ML, Schwartz RH. Aspergillosis andatopy in cystic fibrosis. Am Rev Respir Dis 1979; 120:863–873
188 Feanny S, Forsyth S, Corey M, et al. Allergic bronchopulmo-nary aspergillosis in cystic fibrosis: a secretory immune re-sponse to a colonizing organism. Ann Allergy 1988; 60:64–68
189 Schonheyder H, Jensen T, Hoiby N, et al. Clinical and
193 el-Dahr JM, Fink R, Selden R, et al. Development ofimmune responses to Aspergillus at an early age in childrenwith cystic fibrosis. Am J Respir Crit Care Med 1994;150:1513–1518
194 Marchant JL, Warner JO, Bush A. Rise in total IgE as anindicator of allergic bronchopulmonary aspergillosis in cysticfibrosis. Thorax 1994; 49:1002–1005
195 Hutcheson PS, Knutsen AP, Rejent AJ, et al. A 12-yearlongitudinal study of Aspergillus sensitivity in patients withcystic fibrosis. Chest 1996; 110:363–366
196 Cimon B, Carrere J, Chazalette JP, et al. Bronchopulmonarymycoses in cystic fibrosis: results of a five-year longitudinalstudy. J Mycol Med 2000; 10:128–135
197 Taccetti G, Procopio E, Marianelli L, et al. Allergic bron-chopulmonary aspergillosis in Italian cystic fibrosis patients:prevalence and percentage of positive tests in the employeddiagnostic criteria. Eur J Epidemiol 2000; 16:837–842
198 Almeida MB, Bussamra MH, Rodrigues JC. ABPA diagnosisin cystic fibrosis patients: the clinical utility of IgE specific torecombinant Aspergillus fumigatus allergens. J Pediatr (Rio J)2006; 82:215–220
199 Chotirmall SH, Branagan P, Gunaratnam C, et al. Aspergil-lus/allergic bronchopulmonary aspergillosis in an Irish cysticfibrosis population: a diagnostically challenging entity. Re-spir Care 2008; 53:1035–1041
200 Rapaka RR, Kolls JK. Pathogenesis of allergic bronchopul-monary aspergillosis in cystic fibrosis: current understandingand future directions. Med Mycol 2008; 1–7
201 Cunningham S, Madge SL, Dinwiddie R. Survey of criteriaused to diagnose allergic bronchopulmonary aspergillosis incystic fibrosis. Arch Dis Child 2001; 84:89
202 Stevens DA, Moss RB, Kurup VP, et al. Allergic broncho-pulmonary aspergillosis in cystic fibrosis: state of the art;Cystic Fibrosis Foundation Consensus Conference. ClinInfect Dis 2003; 37(suppl):S225–S264
203 Glancy JJ, Elder JL, McAleer R. Allergic bronchopulmonaryfungal disease without clinical asthma. Thorax 1981; 36:345–349
204 Yoshida N, Suguro H, Kohara F, et al. A case of allergicbronchopulmonary aspergillosis with no history of bronchialasthma. Nihon Kyobu Shikkan Gakkai Zasshi 1992; 30:2123–2127
205 Hoshino H, Tagaki S, Kon H, et al. Allergic bronchopulmo-nary aspergillosis due to Aspergillus niger without bronchialasthma. Respiration 1999; 66:369–372
206 Shah A, Maurya V, Panjabi C, et al. Allergic bronchopulmo-nary aspergillosis without clinical asthma caused by Aspergil-lus niger. Allergy 2004; 59:236–237
207 Berkin KE, Vernon DR, Kerr JW. Lung collapse caused byallergic bronchopulmonary aspergillosis in non-asthmaticpatients. BMJ (Clin Res Ed) 1982; 285:552–553
208 Bondue B, Remmelink M, Gevenois PA, et al. A pulmonarycavitated mass complicating long-standing allergic broncho-pulmonary aspergillosis. Respir Med Extra 2005; 1:39–42
209 Bahous J, Malo JL, Paquin R, et al. Allergic bronchopulmo-
nary aspergillosis and sensitization to Aspergillus fumigatusin chronic bronchiectasis in adults. Clin Allergy 1985;15:571–579
210 Agarwal R, Singh N, Aggarwal AN. An unusual associationbetween Mycobacterium tuberculosis and Aspergillus fu-migatus. Monaldi Arch Chest Dis 2008; 69:32–34
211 Sharma B, Sharma M, Bondi E. Kartagener’s syndromeassociated with allergic bronchopulmonary aspergillosis.MedGenMed 2005; 7:25
213 Eppinger TM, Greenberger PA, White DA, et al. Sensitiza-tion to Aspergillus species in the congenital neutrophildisorders chronic granulomatous disease and hyper-IgEsyndrome. J Allergy Clin Immunol 1999; 104:1265–1272
214 Safirstein BH. Aspergilloma consequent to allergic bronchopul-monary aspergillosis. Am Rev Respir Dis 1973; 108:940–943
215 Ein ME, Wallace RJ Jr, Williams TW Jr. Allergic broncho-pulmonary aspergillosis-like syndrome consequent to as-pergilloma. Am Rev Respir Dis 1979; 119:811–820
216 Israel RH, Poe RH, Bomba PA, et al. The rapid develop-ment of an aspergilloma secondary to allergic bronchopul-monary aspergillosis. Am J Med Sci 1980; 280:41–44
217 Rosenberg IL, Greenberger PA. Allergic bronchopulmonaryaspergillosis and aspergilloma: long-term follow-up withoutenlargement of a large multiloculated cavity. Chest 1984;85:123–125
218 Sharma TN, Gupta PR, Mehrotra AK, et al. Aspergillomawith ABPA due to Aspergillus niger. J Assoc Physicians India1985; 33:748
219 Shah A, Khan ZU, Chaturvedi S, et al. Allergic bronchopul-monary aspergillosis with coexistent aspergilloma: a long-term followup. J Asthma 1989; 26:109–115
220 Bhagat R, Shah A, Jaggi OP, et al. Concomitant allergicbronchopulmonary aspergillosis and allergic Aspergillus si-nusitis with an operated aspergilloma. J Allergy Clin Immu-nol 1993; 91:1094–1096
221 Shah A, Bhagat R, Pant K, et al. Allergic bronchopulmonaryaspergillosis with aspergilloma: exacerbation after prolongedremission. Indian J Tuberc 1993; 40:39–41
222 Jaques D, Bonzon M, Polla BS. Serological evidence ofAspergillus type I hypersensitivity in a subgroup of pulmo-nary aspergilloma patients. Int Arch Allergy Immunol 1995;106:263–270
223 Sharma P, Agarwal AK, Shah A. Formation of an aspergil-loma in a patient with allergic bronchopulmonary aspergil-losis on corticosteroid therapy. Indian J Chest Dis Allied Sci1998; 40:269–273
224 Shah A, Panjabi C. Contemporaneous occurrence of allergicbronchopulmonary aspergillosis, allergic Aspergillus sinus-itis, and aspergilloma. Ann Allergy Asthma Immunol 2006;96:874–878
225 Denning DW, Riniotis K, Dobrashian R, et al. Chroniccavitary and fibrosing pulmonary and pleural aspergillosis:case series, proposed nomenclature change, and review.Clin Infect Dis 2003; 37(suppl):S265–S280
226 Dolan CT, Weed LA, Dines DE. Bronchopulmonary hel-minthosporiosis. Am J Clin Pathol 1970; 53:235–242
227 Sahn SA, Lakshminarayan S. Allergic bronchopulmonarypenicilliosis. Chest 1973; 63:286–288
228 Novey HS, Wells ID. Allergic bronchopulmonary aspergil-losis caused by Aspergillus ochraceus. Am J Clin Pathol1978; 70:840–843
229 Benatar SR, Allan B, Hewitson RP, et al. Allergic broncho-pulmonary stemphyliosis. Thorax 1980; 35:515–518
230 Laham MN, Allen RC, Greene JC. Allergic bronchopulmo-
nary aspergillosis (ABPA) caused by Aspergillus terreus:specific lymphocyte sensitization and antigen-directed se-rum opsonic activity. Ann Allergy 1981; 46:74–80
231 McAleer R, Kroenert DB, Elder JL, et al. Allergic broncho-pulmonary disease caused by Curvularia lunata and Drech-slera hawaiiensis. Thorax 1981; 36:338–344
232 Patterson R, Samuels BS, Phair JJ, et al. Bronchopulmonarytorulopsosis. Int Arch Allergy Appl Immunol 1982; 69:30–33
233 Kino T, Yamada Y, Honda K, et al. Diagnosis and treatmentof a case of allergic bronchopulmonary mycosis caused byMucor-like fungus. Nihon Kyobu Shikkan Gakkai Zasshi1983; 21:896–903
234 Akiyama K, Mathison DA, Riker JB, et al. Allergic broncho-pulmonary candidiasis. Chest 1984; 85:699–701
235 Lake FR, Tribe AE, McAleer R, et al. Mixed allergicbronchopulmonary fungal disease due to Pseudallescheriaboydii and Aspergillus. Thorax 1990; 45:489–491
236 Lake FR, Froudist JH, McAleer R, et al. Allergic broncho-pulmonary fungal disease caused by Bipolaris and Curvu-laria. Aust N Z J Med 1991; 21:871–874
nary mycosis caused by the basidiomycetous fungus Schizo-phyllum commune. Clin Infect Dis 1994; 18:305–309
238 Backman KS, Roberts M, Patterson R. Allergic bronchopul-monary mycosis caused by Fusarium vasinfectum. Am JRespir Crit Care Med 1995; 152:1379–1381
239 Moreno-Ancillo A, Diaz-Pena JM, Ferrer A, et al. Allergicbronchopulmonary cladosporiosis in a child. J Allergy ClinImmunol 1996; 97:714–715
240 Ogawa H, Fujimura M, Tofuku Y. Allergic bronchopulmo-nary fungal disease caused by Saccharomyces cerevisiae. JAsthma 2004; 41:223–228
241 Shah A, Panchal N, Agarwal AK. Concomitant allergicbronchopulmonary aspergillosis and allergic Aspergillus si-nusitis: a review of an uncommon association. Clin ExpAllergy 2001; 31:1896–1905
242 Saravanan K, Panda NK, Chakrabarti A, et al. Allergicfungal rhinosinusitis: an attempt to resolve the diagnosticdilemma. Arch Otolaryngol Head Neck Surg 2006; 132:173–178
243 Shah TS, Sundaram P, Rege JD, et al. Proptosis in anasthmatic patient. Postgrad Med J 2003; 79:710
http://chestjournal.chestpubs.org/content/135/3/805.full.htmlUpdated Information and services can be found at:
Updated Information & Services
http://chestjournal.chestpubs.org/content/135/3/805.full.html#ref-list-1This article cites 232 articles, 65 of which can be accessed free at:
References
http://chestjournal.chestpubs.org/content/135/3/805.full.html#related-urlsThis article has been cited by 18 HighWire-hosted articles:
Cited Bys
http://www.chestpubs.org/site/misc/reprints.xhtmlfound online at: Information about reproducing this article in parts (figures, tables) or in its entirety can bePermissions & Licensing
http://www.chestpubs.org/site/misc/reprints.xhtmlInformation about ordering reprints can be found online:
Reprints
"Services" link to the right of the online article.Receive free e-mail alerts when new articles cite this article. To sign up, select the
Citation Alerts
PowerPoint slide format. See any online figure for directions. articles can be downloaded for teaching purposes inCHESTFigures that appear in Images in PowerPoint format