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Summary
Clinical Allergic bronchopulmonary aspergillosis (ABPA) is an immunological pulmonary disorder
& caused by hypersensitivity to Aspergillus fumigatus, manifesting with poorly controlled
asthma, recurrent pulmonary infiltrates and bronchiectasis. There are estimated to be in
Experimental excess of four million patients affected world-wide. The importance of recognizing ABPA
relates to the improvement of patient symptoms, and delay in development or prevention
Allergy of bronchiectasis, one manifestation of permanent lung damage in ABPA. Environmental
factors may not be the only pathogenetic factors because not all asthmatics develop ABPA
despite being exposed to the same environment. Allergic bronchopulmonary aspergillosis
is probably a polygenic disorder, which does not remit completely once expressed,
although long-term remissions do occur. In a genetically predisposed individual, inhaled
Correspondence: conidia of A. fumigatus germinate into hyphae with release of antigens that activate the
Ritesh Agarwal, Department of
innate and adaptive immune responses (Th2 CD4+ T cell responses) of the lung. The Inter-
Pulmonary Medicine, Postgraduate
Institute of Medical Education and
national Society for Human and Animal Mycology (ISHAM) has constituted a working
Research, Sector-12, Chandigarh group on ABPA complicating asthma (www.abpaworkinggroup.org), which convened an
160012, India. international conference to summarize the current state of knowledge, and formulate con-
E-mails: riteshpgi@gmail.com; sensus-based guidelines for diagnosis and therapy. New diagnosis and staging criteria for
agarwal.ritesh@pgimer.edu.in ABPA are proposed. Although a small number of randomized controlled trials have been
Cite this as: R. Agarwal, conducted, long-term management remains poorly studied. Primary therapy consists of
A. Chakrabarti, A. Shah, D. Gupta,
oral corticosteroids to control exacerbations, itraconazole as a steroid-sparing agent and
J. F. Meis, R. Guleria, R. Moss, D. W.
Denning and For the ABPA
optimized asthma therapy. Uncertainties surround the prevention and management of
complicating asthma ISHAM working bronchiectasis, chronic pulmonary aspergillosis and aspergilloma as complications, con-
group, Clinical & Experimental Allergy, current rhinosinusitis and environmental control. There is need for new oral antifungal
2013 (43) 850–873. agents and immunomodulatory therapy.
© 2013 John Wiley & Sons Ltd, Clinical & Experimental Allergy, 43 : 850–873
852 R. Agarwal et al
Table 1. Prevalence of Aspergillus sensitization (AS) and allergic bronchopulmonary aspergillosis (ABPA) complicating asthma in studies
conducted in this millennium
conidia of A. fumigatus (and occasionally other fungi) [83]. Other symptoms include low grade fever, weight
are able to persist and germinate, leading to hyphal loss, malaise and fatigue. Expectoration of brownish
growth. A. fumigatus releases a variety of proteins, black mucus plugs is seen in only 31–69% of patients
which promote release of pro-inflammatory cytokines [12, 30, 32]. Patients can also be asymptomatic (albeit
by the airway epithelium [65–67]. In addition, certain with asthma medications) and are diagnosed on routine
Aspergillus proteases are directly toxic to pulmonary investigations [25, 32, 84]. In a series of 155 cases of
epithelium causing cell detachment and death [65, 67, ABPA, 19% of ABPA patients had well-controlled
68]. All these events activate the innate immune system asthma [32]. Clubbing is uncommon, and is seen in
of the lung leading to production of several inflamma- those with long-standing bronchiectasis [32]. Physical
tory cytokines [65, 69–71]. Exposure of A. fumigatus examination can also detect complications of ABPA
antigens to pulmonary dendritic cells prime na€ıve Th such as pulmonary hypertension [85]. During ABPA
cells to Aspergillus specific T cells. The immune reac- exacerbations, patients are symptomatic with fever,
tion of the human host to Aspergillus is a Th1 CD4+ T wheezing, hemoptysis and productive cough. Examina-
cell response. However, the immune response in AS and tion may reveal localized findings of consolidation and
ABPA (quantitatively greater in ABPA than AS [72–75]) atelectasis, which need to be differentiated from other
is a Th2 CD4+ T cell response with IL-4, IL-5 and IL-13 pulmonary diseases.
cytokine secretion [47, 72, 76–78]. The Th2 response
causes profound inflammatory reaction with influx of
Diagnostic test findings
various inflammatory cells (including neutrophils and
eosinophils) [67, 79] and IgE (total and A. fumigatus Aspergillus skin test. An immediate cutaneous hyper-
specific) synthesis (Fig. 2) [80]. There is evidence for a sensitivity to A. fumigatus antigens (either crude or
regulatory T cell defect in some patients with CF and recombinant) is hallmark of ABPA, and represents the
ABPA [81]; however, the role, if any, of Th17 and regu- presence of IgE antibodies specific to A. fumigatus. The
latory T cells in ABPA complicating asthma is yet to be test can be performed either using a skin prick test or
fully explored [82]. an intradermal injection [86, 87]. When both are avail-
able, a skin prick test should be performed first, and if
negative, some patients may only manifest hypersensi-
Clinical features
tivity with an intradermal test. The sensitivity of a posi-
Patients generally present with poorly controlled tive result in diagnosis of ABPA is about 90% [88],
asthma, wheezing, hemoptysis and productive cough although up to 40% of asthmatics without ABPA can
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Allergic bronchopulmonary aspergillosis 853
Table 2. Genetic susceptibility in allergic bronchopulmonary aspergillosis (ABPA) complicating asthma and cystic fibrosis (CF)
(continued)
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854 R. Agarwal et al
Table 2 (continued)
also demonstrate a type 1 response to Aspergillus without any clear explanation [91–94]. Thus some
antigen [29]. groups use the cut-off value of 417 IU/mL, while oth-
ers employ a value of 1000 IU/mL [95].
Total serum IgE levels. The serum total IgE level is a Unfortunately, there is a wide variation in IgE
useful test in both diagnosis and follow-up of ABPA. A concentrations in normal persons, atopic asthmatics
normal serum IgE (in the absence of systemic glucocor- and ABPA patients [90, 96]. Moreover, there has been
ticoid therapy) generally excludes active ABPA as the no receiver operating characteristic curve (ROC) analysis
cause of patient’s current symptoms. There is no con- on the IgE values between ABPA, SAFS and Aspergil-
sensus on the cut-off value of IgE level that should be lus-sensitized asthma; the cut-offs may be different in
used for diagnosis of ABPA, and the cut-off value ABPA complicating asthma or CF. In a series of 146 CF
remains speculative. Further, the IgE values are patients, ABPA-S and Aspergillus-sensitized CF patients
reported in different units that leads to erroneous inter- were separated from each other using total IgE [area
pretation (1 IU/mL equals 2.4 ng/mL; 1000 ng/mL under the curve (AUC), 0.91] and A. fumigatus-specific
equals 417 IU/mL). The first paper documenting raised IgE levels (AUC, 0.90). The sensitivity and specificity of
IgE values in patients with allergic aspergillosis was total IgE > 400 IU/mL and A. fumigatus-specific IgE
published in 1970; however, this study reported IgE > 8.5 kUA/L was 78% and 95%, and 78% and 79%
values only in a semi-quantitative fashion (> 0.8 lg/ respectively. Applying the CF consensus criteria, the IgE
mL) [89]. Thereafter in several studies, the Patterson value of > 500 IU/mL (minimum diagnostic criteria for
group suggested a cut-off value of > 2500 ng/mL ABPA) separated ABPA from all other patient groups
(> 1042 IU/mL) [5, 90]. Subsequently, they proposed including sensitization with a sensitivity of 70% and
cut-offs of < 1000 ng/mL for ‘ABPA probably specificity of 99%, whereas a level of > 1000 IU/mL
excluded’ and > 2000 ng/mL (833 IU/mL) for ‘Further (classic ABPA) gave a sensitivity of 39% and specificity
serological studies required’ [6]. However, over the of 100%. ROC curve analysis showed the optimum total
years, the IgE cut-off has been cited as > 1000 ng/mL IgE level of > 180 IU/mL to be 91% sensitive and 90%
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Allergic bronchopulmonary aspergillosis 855
Fig. 2. Current concepts in the pathogenesis of allergic bronchopulmonary aspergillosis (statistically significant genetic associations have been
indicated in bold font). CFTR, CF transmembrane conductance regulator; HLA, human leucocyte antigen; IL, interleukin; SP, surfactant protein;
TLR, toll-like receptor.
specific (AUC 0.97) [97]. On the other hand, in a series IgE test available, not on that obtained in a referral
of 372 asthmatic patients (R. Agarwal, personal com- clinic after months, or years of therapy, recognizing
munication), ABPA (56 patients) was separated from that levels may fall spontaneously and with therapy.
asthma using the best cut-off values of total IgE of After treatment, serum IgE levels start declining [34,
2346.5 IU/mL (sensitivity 87.5%, specificity 66.9%) and 98], but in most patients do not reach normal value.
A. fumigatus IgE of 5.23 kUA/L (sensitivity 96.4%, Repeated measurements of IgE levels are required to
specificity 88%). These gave ROC values of AUC 87.7 determine the ‘new’ baseline value for an individual
(95% confidence interval [CI] 82.9–92.4) and AUC 93.5 patient during remission. The serum IgE also represents
(95% CI 91.0–96.1) respectively. Clearly, an occasional an important tool in follow-up of patients, and an
patient with ABPA would meet all criteria, but IgE increase in IgE levels may signify an impending exac-
would be < 1000 IU/mL. erbation.
The expert group felt that a cut-off of 500 IU/mL
may lead to over-diagnosis of ABPA as these levels Serum IgE antibodies specific to A. fumigatus. An
are often encountered in AS and SAFS, and hence a elevated level of IgE antibodies specific to A. fumigatus
cut-off value of 1000 IU/mL should be employed. is considered a characteristic finding of ABPA [84]. The
Additional validation cohorts examining the prevalence cut-off value of specific IgE against A. fumigatus in
of IgE values are required to arrive at a better consen- diagnosis of ABPA is not clear but a value more than
sus value. Diagnosis should be based on the earliest twice the pooled serum samples from patients with
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856 R. Agarwal et al
Fig. 4. High-resolution CT (HRCT) chest showing the presence of high-attenuation mucus (bold arrow) in the mediastinal windows with
corresponding lung window sections. The mucus is visually denser than the paraspinal skeletal muscle (asterisk).
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Allergic bronchopulmonary aspergillosis 857
(a) (b)
Fig. 5. Computed tomography (CT) scan of a patient with chronic pulmonary aspergillosis complicating allergic bronchopulmonary aspergillosis
(ABPA). There is extensive bilateral upper lobe cavitation, pleural fibrosis and left-sided bronchiectasis (2A) and marked right-sided circumferen-
tial pleural fibrosis with small cavitation within this fibrosis anteriorly, left lingual pleural fibrosis and right-sided proximal bronchiectasis.
Serum precipitins or specific IgG against A. fumiga- from 39 to 60% depending on the number of specimens
tus. Serum precipitins (IgG) against A. fumigatus are examined [12, 122]. Interestingly, a recent study sug-
present in 69–90% of patients with ABPA [32, 120– gested that routine processing procedures for isolating
123] but also in 10% of asthmatics with or without filamentous fungi from respiratory sputum samples
SAFS [1]. IgG antibodies (including precipitins) against may underestimate fungal prevalence [131]. The authors
A. fumigatus can be demonstrated either using double used a different sputum processing method, whereby
gel diffusion techniques [123], enzyme linked immuno- sputum plugs are separated from saliva and aliquots of
assay (ELISA), fluorescent enzyme immunoassay (FEIA) approximately 150 mg are inoculated directly onto
or other methods [16]. Two commercial assays potato dextrose agar [131]. It is interesting to note that
(ImmunoCap and Platelia Aspergillus IgG EIA) are sen- the vast majority of culture-negative ABPA patients
sitive measures of Aspergillus IgG antibodies compared have detectable A. fumigatus DNA in their sputum
with counterimmunoelectrophoresis [124]. ImmunoCap [132]. As azole resistance has been documented in
method has better reproducibility and thus may be A. fumigatus [132], it may be valuable obtaining
more apt for monitoring IgG levels following treatment cultures before starting antifungal therapy, and suscep-
[124]. However, Aspergillus IgG may not be specific for tibility testing and/or realtime molecular testing for
ABPA as high levels are encountered in other forms of resistance of any isolates obtained [133].
aspergillosis especially CPA. High titres in ABPA, with
evidence of pleural fibrosis or persistent cavitation, Pulmonary function tests. Bronchial provocation with
may represent the interval development of CPA Aspergillus antigens are not recommended as it can
[125–127]. cause fatal bronchospasm [134]. Routine pulmonary
function tests are helpful in categorizing the severity of
Peripheral eosinophilia. A peripheral blood eosinophil asthma and the underlying lung disease. However, lung
count > 1000 cells/lL has been considered a major function tests can be normal in ABPA and a normal
criterion for diagnosis of ABPA. However, a recent spirometry should not exclude the diagnosis of ABPA
study found that only 40% of patients with ABPA pre- [84].
sented with an eosinophil count > 1000 cells/lL at
diagnosis [128]. In ABPA, the pulmonary eosinophilia Role of recombinant Aspergillus antigens. Patients with
is far greater than peripheral blood with little correla- ABPA are mostly evaluated with crude extracts from
tion between the two; thus, a low eosinophil count does Aspergillus. These antigens lack reproducibility and
not exclude ABPA [129, 130]. Highly elevated eosino- consistency, and frequently cross react with other anti-
phil counts are common in many other disorders and so gens [135]. Recent advances in technology have
the specificity of this criterion is problematic. Also, enabled cloning of several proteins of A. fumigatus.
patients receiving oral steroids can have lower or The recombinant allergens Asp f1, Asp f2, Asp f3, Asp
normal eosinophil levels. f4 and Asp f6 have been evaluated for their diagnostic
performance in asthma and ABPA [136–140]. Crameri
Sputum cultures for A. fumigatus. Culture of A. fumig- et al. demonstrated excellent correlation between the
atus in sputum is supportive but not diagnostic of Immunocap FEIA and in-house ELISA [139]. Antibodies
ABPA because the fungus can also be grown in other against rAsp f1 and rAsp f3 are elevated in both AS
pulmonary diseases due to ubiquitous nature of the and ABPA while antibodies against rAsp f4 and rAsp f6
fungi. In ABPA, the rates of culture positivity range are elevated only in ABPA (Table 3) [137, 140].
© 2013 John Wiley & Sons Ltd, Clinical & Experimental Allergy, 43 : 850–873
858 R. Agarwal et al
Table 3. Recombinant Aspergillus fumigatus antigens evaluated in Table 4. Newly proposed diagnostic criteria for allergic bronchopul-
allergic bronchopulmonary aspergillosis (ABPA) complicating asthma monary aspergillosis
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Allergic bronchopulmonary aspergillosis 859
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860 R. Agarwal et al
(mild), ABPA-CB (moderate) to ABPA-CB-HAM (severe). (Table 6), namely serological ABPA (ABPA-S), ABPA
They also observed that the classification scheme of with bronchiectasis (ABPA-B), ABPA with high-attenu-
Greenberger et al. was associated with immunological ation mucus (ABPA-HAM), and ABPA with chronic
severity in some parameters only while in the Kumar pleuropulmonary fibrosis (ABPA-CPF).
classification, the immunological markers were most
severe in the ABPA-CB group and not ABPA-CB-ORF
Management
suggesting that ORF does not relate directly to immu-
nological severity [148]. The management of ABPA consists of anti-inflamma-
The expert group laid down a new radiological classi- tory therapy (systemic glucocorticoids) to suppress the
fication that incorporates all the current evidence on immune activity, and use of antifungal agents to atten-
the radiological findings in ABPA. Radiologically, uate the fungal load in the airways [153]. The goals of
ABPA has been classified into four major categories therapy include control of asthma, prevention and
Table 6. Newly proposed radiological classification of ABPA based on computed tomographic (CT) chest findings
Classification Features
ABPA-S (Serological ABPA) All the diagnostic features of ABPA (Table 4) but no abnormality resulting from ABPA on HRCT chest*
ABPA-B (ABPA with bronchiectasis) All the diagnostic features of ABPA including bronchiectasis on HRCT chest
ABPA-HAM (ABPA with high- All the diagnostic features of ABPA including presence of high-attenuation mucus
attenuation mucus)
ABPA-CPF (ABPA with chronic ABPA with at least two to three other radiological features such as pulmonary fibrosis, parenchymal
pleuropulmonary fibrosis) scarring, fibro-cavitary lesions, aspergilloma and pleural thickening without presence of mucoid
impaction or high-attenuation mucus
*Findings resulting from co-existent disease, bullae from asthma, tracheomalacia, etc. should not be considered while labelling the patients as
ABPA-S.
HRCT, high-resolution CT; ABPA, allergic bronchopulmonary aspergillosis.
© 2013 John Wiley & Sons Ltd, Clinical & Experimental Allergy, 43 : 850–873
Allergic bronchopulmonary aspergillosis 861
treatment of acute exacerbations, and arresting the Table 7) without antifungal therapy is associated with
development of bronchiectasis and CPA. higher occurrence of recurrent relapses or glucocorti-
coid dependence (45%) [6]. A higher dosage of gluco-
corticoids (regime 2 in Table 7) was shown to be
Systemic glucocorticoid therapy
associated with higher remission rates and a lower
Oral corticosteroids are currently the treatment of prevalence of glucocorticoid-dependent ABPA (13.5%)
choice for ABPA although there are no well-designed [84]. Whether a higher dose or prolonged duration of
trials of steroids in ABPA. Glucocorticoids are anti- corticosteroids is associated with better outcomes
inflammatory and suppress immune hyperreactivity of remains unclear in the absence of direct comparisons
both asthma and ABPA. There is no data to guide the between the two regimens. A randomized controlled
dose and duration of glucocorticoids, and different trial on the efficacy and safety of two different gluco-
regimens of glucocorticoids have been used (Table 7). corticoid dose regimens in ABPA has been completed
The use of lower doses of glucocorticoids (regime 1 in (clinical trials.gov; NCT00974766). Hopefully, the
results of this trial will help in answering the question
regarding dose of glucocorticoids in ABPA.
Table 7. Treatment protocols for the management of ABPA
Oral glucocorticoids
Regimen 1 [93] Inhaled corticosteroids (ICS)
Prednisolone 0.5 mg/kg/day for one to two weeks, then on
Inhaled corticosteroids achieve high concentrations in
alternate days for six to eight weeks. Then taper by 5–10 mg
the tracheobronchial tree with minimal systemic side-
every 2 weeks and discontinue
Regimen 2 [84, 92]
effects. Numerous small case studies have reported the
Prednisolone, 0.75 mg/kg for 6 weeks, 0.5 mg/kg for 6 weeks, use of ICS in ABPA [154–160]. These studies utilized
then tapered by 5 mg every 6 weeks to continue for a total varying doses of ICS and many patients continued to
duration of at least 6–12 months receive oral steroids while receiving ICS. Also in many
Oral itraconazole studies, clinical or radiological and spirometric criteria
Dose: 200 mg twice a day, with therapeutic drug monitoring for were used to define response, and IgE levels were not
at least 16 weeks. Response often takes longer than 16 weeks measured. This makes it difficult to analyse whether the
Approaches: Recurrent short courses or long-term therapy beneficial effects were solely due to ICS.
Which agent to use
Oral steroids
ABPA with mucoid impaction Oral azoles
ABPA with significant deterioration of lung function attributed
to worsening asthma or ABPA (and not intercurrent infection)
Although systemic steroids are highly efficacious in the
would require treatment with glucocorticoids. management of ABPA [32, 34, 84, 148, 151], almost
In those with mucoid impaction and proximal collapse, assessment 50% of patients relapse when they are tapered and 20–
should be made at 3 weeks and if the collapse has not resolved, 45% become glucocorticoid dependent [6, 84]. Many
therapeutic bronchoscopy should be performed patients also develop adverse effects related to chronic
Azoles (with or without concomitant steroids) steroid therapy [161, 162]. The use of specific antifun-
ABPA with recurrent exacerbations (to prevent exacerbations gal agents in ABPA can decrease the immune response
after controlling the exacerbation with glucocorticoids) by reducing the antigenic stimulus consequent to a
Glucocorticoid-dependent ABPA decreased fungal burden, and can thus obviate/reduce
Inhaled steroids
the need for glucocorticoids [163]. Ketoconazole has
Single agent ICS therapy should not be used as first-line in the
been used in ABPA [164, 165], but has been replaced
management of ABPA
Can be used for the control of asthma once the oral prednisolone
by the less toxic and more active agent, itraconazole
dose is < 10 mg/day [166–172]. Two randomized controlled studies (84
Follow-up and monitoring patients) have evaluated the role of itraconazole in
The patients are followed up with a history and physical ABPA [171, 172]. In one study, 55 patients with ‘gluco-
examination, chest radiograph, total IgE levels and quality of corticoid dependent’ ABPA were randomized to receive
life questionnaire every 8 weeks either itraconazole 200 mg twice daily or placebo. The
A ≥ 25% decline in IgE level along with clinicoradiological difference between the two groups was in favour of
improvement signifies satisfactory response to therapy itraconazole in terms of a composite end-point (reduc-
If the patient cannot be tapered off prednisolone/azole then the tion in steroid dose by ≥ 50%; and, decrease in total
disease has evolved into stage 4. Management should be
IgE by ≥ 25%; and, at least one of the following:
attempted with alternate-day prednisone/azole in the least
increase in exercise tolerance by ≥ 25%, improvement
possible dose
Monitor for adverse effects of treatment
of ≥ 25% in results of spirometry, resolution of
pulmonary opacities) but failed to reach statistical
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862 R. Agarwal et al
significance when each outcome was examined (4–6 months) or long-term therapy with azoles. A major
separately [171]. The other study included 29 ‘clinically limitation of long-term treatment with azoles is the
stable’ ABPA patients randomized to receive itraconaz- development of resistance in A. fumigatus [132, 184].
ole or placebo. There was significant decline in sputum Whatever the treatment approach used, it should pro-
inflammatory markers, serum IgE levels and the number vide maximum benefit to the patient with least propen-
of exacerbations [172]. A major limitation was that nei- sity for adverse reactions. High doses of ICS alone have
ther study reported outcomes longer than 8 months in no role in the management of ABPA. Inhaled corticos-
terms of relapses of ABPA. Itraconazole therapy should teroids can be used for the control of asthma once the
generally be monitored by drug levels to ensure ade- oral prednisolone dose is reduced to below 10 mg/day.
quate bioavailability [173]. Toxicity can be minimized Clinicians should also be aware of the profound interac-
if the blood levels are maintained in a therapeutic range tion between ICS and itraconazole in some patients
[174]. Recent data also suggest that lower blood levels leading to cushingoid effects and long-term adrenal
may be associated with clinical failure and possible failure, if dose of ICS is not significantly reduced.
development of azole resistance in A. fumigatus [173,
175]. Itraconazole has also used been used as mono-
Follow-up of patients on treatment
therapy in acute stages of ABPA [169, 172]. However,
more trials are required to confirm the efficacy of Patients on treatment should initially be followed every
itraconazole monotherapy. A randomized controlled 6–8 weeks with serum IgE levels, chest radiograph, lung
trial comparing monotherapy of itraconazole vs. pred- function test and quality of life questionnaire (Table 7).
nisolone in ABPA (MIPA study; clinical trials.gov; Chest radiographs need not be performed once there is
NCT01321827) is underway, which aims to answer this normalization (or return to baseline) of the radiographic
question. opacities. The clinical effectiveness of therapy is
reflected by decrease in the patient’s total serum IgE
levels along with symptomatic and radiological
Which therapy to use? Glucocorticoids or itraconazole
improvements. The goal of therapy is not to attempt
or both
normalization of IgE levels but to decrease the IgE lev-
Many patients with ABPA require long-term treatment, els by 25–50% which in most cases leads to clinical
and both steroids and itraconazole are associated with and radiographic improvement [34]. One should also
numerous adverse effects. The side-effects of glucocorti- aim to establish a stable serum level of total IgE which
coid therapy are well known, and azole therapy also has serves as a baseline to future detection of exacerbation
numerous side-effects including skin cancer with long- and helps in follow-up of the patient.
term voriconazole therapy [161, 162, 176–183]. It is also
not known whether treatment with steroids or itraconaz-
Other therapies
ole will improve long-term outcomes, in particular
prevent or reverse bronchiectasis and CPA. Moreover, it There are reports of ABPA complicating CF treated with
is not clear whether ABPA patients in stage 0 should be nebulized amphotericin and inhaled steroids [185–188].
treated or can be followed without any treatment. How- Omalizumab, a humanized monoclonal antibody against
ever, all experts agreed that if a decision is made not to IgE, could be a potential therapeutic approach since
treat the patient, then he/she should be closely followed. ABPA is associated with elevated IgE levels. The use of
Any significant deterioration in clinical, radiological or omalizumab in ABPA has been associated with
immunological status should prompt treatment. All improvement in symptoms, reduction in exacerbations
experts also agreed that ABPA with mucoid impaction and asthma hospitalizations, improvement in lung func-
and/or significant deterioration of lung function attrib- tion and reduction in dose of oral steroids [189–205].
uted to worsening asthma or ABPA (and not intercurrent However, most of these studies are either single patient
infection) would benefit from treatment with glucocor- case-reports or small case-series. Also, the dose required
ticoids (Table 7). In those with mucoid impaction and in ABPA may be very high and prohibitively expensive.
proximal collapse, assessment should be made at More data are required before any recommendation
3 weeks and if the collapse has not resolved despite regarding the use of omalizumab can be made. Cur-
adequate therapy, therapeutic bronchoscopy should be rently, it may be tried in those with steroid-dependent
performed. In those with recurrent exacerbations, one ABPA or in patients who develop treatment-related
should consider itraconazole therapy. Azoles are adverse reactions. Pulse doses of intravenous methyl-
effective in preventing ABPA exacerbations but more prednisolone have also been used for treatment of
trials are required for the role of azoles in managing severe exacerbations of ABPA [198, 206–210]. Newer
acute exacerbations of ABPA. There are two approaches antifungal agents including voriconazole [202, 211–
to the use of azole therapy: recurrent short courses 218], and posaconazole [183, 210] are also efficacious
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© 2013 John Wiley & Sons Ltd, Clinical & Experimental Allergy, 43 : 850–873
Allergic bronchopulmonary aspergillosis 865
serology and skin test results, as patients with CF may benefit in patients with severe asthma and sputum
demonstrate variable responses to A. fumigatus and eosinophilia [259], while a monoclonal antibody
prolonged testing might be required to make a definite against IL-13 has been found effective in asthma
diagnosis [254]. To overcome these difficulties, an patients with a high Th2 endotype [260]. These
international consensus conference has made recom- ‘anti-Th2’ therapies may also be investigated for their
mendations for diagnosis and management of ABPA in efficacy in patients with ABPA.
CF [143]. The treatment of ABPA in CF is not very
different from that of ABPA in asthma. The treatment
Conclusions
issues are further complicated by the fact that
pulmonary exacerbations in a patient with ABPA and In conclusion, the expert group emphasized that a high
CF could be related to ABPA or pulmonary infection, index of suspicion for ABPA should be maintained
and hence continuous assessment may be required while managing any patient with bronchial asthma
before a decision to treat an individual case is made whatever the severity or the level of control. As patients
[143]. Treatment is more complex as itraconazole with ABPA can be minimally symptomatic or asymp-
capsules are poorly absorbed. Itraconazole solution tomatic, all asthmatic patients should be routinely
may be absorbed, but often requires a dose of investigated for ABPA in secondary care. Host immuno-
500–600 mg daily. Voriconazole may be more success- logical responses are central to the pathogenesis and
ful but often leads to photosensitivity in Caucasians are the primary determinants of the clinical, biological,
with the risk of skin cancer, and corticosteroids often pathological and radiological features of this disorder.
induce diabetes mellitus, with its serious consequences Finally, there is an urgent need for standardization of
in CF. oral antifungal therapy and immunomodulatory drugs
for efficient management of this chronic and debilitat-
ing condition.
Future directions
The cut-off values of various investigations such as
Conflicts of interest
IgE levels and A. fumigatus specific IgE levels could
vary by ethnicity or underlying disease (asthma or CF), JFM has acted as a paid consultant/speaker to Astellas,
and these need to be defined by a ROC analysis. The Basilea and Merck and has received funding from
role of novel assays such as recombinant Aspergillus Astellas, Basilea, Merck and Schering-Plough. No fund-
antigens, thymus-and activation-regulated cytokine ing was received related to this work. RA is current
(TARC) and the FACS basophil CD203c assay also recipient of grant support from Cipla, India on research
requires to be clarified [255–257]. The formation of on allergic bronchopulmonary aspergillosis. No funding
new diagnostic and staging criteria with precise defini- was received related to this work. DWD holds founder
tions would go a long way in not only strengthening shares in F2G Ltd a University of Manchester spin-out
the diagnosis and management of this chronic pulmo- company and has current grant support from the
nary disorder but would also allow better stratification National Institute of Allergy and Infectious Diseases,
of disease for genome-wide association studies and National Institute of Health Research, the European
drug trials. Newer treatment modalities need to be for- Union and AstraZeneca. He acts as an advisor/consul-
malized preferably by a multi-institutional collabora- tant to F2G and Myconostica (now part of Lab21 group)
tion [258]. For example, vitamin D has recently been and T2Biosystems as well as other companies over the
shown to down-regulate the Th2 pathway via an OX40 last 5 years including Pfizer, Schering Plough (now
ligand-dependent process in ABPA complicating CF Merck), Nektar, Astellas and Gilead. He has been paid
[81]. Vitamin D supplementation may prove beneficial for talks on behalf of Merck, Astellas, GSK, Novartis,
in treatment of ABPA, and is the focus of a recent trial Merck, Dainippon and Pfizer. RBM is current recipient
in patients with CF and ABPA (clinicaltrials.gov; of grant support from Genentech for research on immu-
NCT01222273). Trials of monoclonal antibodies direc- nopathogenesis on ABPA. All other authors declare no
ted against the Th2 cytokine IL-5 have shown clinical conflict of interest.
© 2013 John Wiley & Sons Ltd, Clinical & Experimental Allergy, 43 : 850–873
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