Expert Review of Respiratory Medicine

ISSN: 1747-6348 (Print) 1747-6356 (Online) Journal homepage: http://www.tandfonline.com/loi/ierx20

Developments in the diagnosis and treatment of

allergic bronchopulmonary aspergillosis

Ritesh Agarwal, Inderpaul S Sehgal, Sahajal Dhooria & Ashutosh N Aggarwal

To cite this article: Ritesh Agarwal, Inderpaul S Sehgal, Sahajal Dhooria & Ashutosh N
Aggarwal (2016): Developments in the diagnosis and treatment of allergic bronchopulmonary
aspergillosis, Expert Review of Respiratory Medicine

To link to this article: http://dx.doi.org/10.1080/17476348.2016.1249853

Accepted author version posted online: 17

Oct 2016.

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Download by: [Cornell University Library] Date: 17 October 2016, At: 02:29
Publisher: Taylor & Francis

Journal: Expert Review of Respiratory Medicine

DOI: 10.1080/17476348.2016.1249853

Review

Developments in the diagnosis and treatment of allergic bronchopulmonary

aspergillosis
1
Ritesh Agarwal
2
Inderpaul S Sehgal
2
Sahajal Dhooria
3
Ashutosh N Aggarwal
2
Assistant Professor, 1Additional Professor and 3Professor
Department of Pulmonary Medicine
Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

Address for Correspondence

Dr. Ritesh Agarwal MD, DM
Additional Professor
Department of Pulmonary Medicine
Postgraduate Institute of Medical Education and Research
Chandigarh. India. 160012
Email: agarwal.ritesh@outlook.in; agarwal.ritesh@pgimer.edu.in

ABSTRACT

1
Introduction: Allergic bronchopulmonary aspergillosis (ABPA) is a complex pulmonary disorder

characterized by recurrent episodes of wheezing, fleeting pulmonary opacities and bronchiectasis. It is the

most prevalent of the Aspergillus disorders with an estimated five million cases worldwide. Despite six

decades of research, the pathogenesis, diagnosis and treatment of this condition remains controversial.

The International Society for Human and Animal Mycology has formed a working group to resolve the

controversies around this entity. In the year 2013, this group had proposed new criteria for diagnosis and

staging, and suggested a treatment protocol for the management of this disorder. Since then, several

pieces of new evidence have been published in the investigation and therapeutics of this condition.

Areas covered: A non-systematic review of the available literature was performed. We summarize the

current evidence in the evaluation and treatment of this enigmatic disorder. We suggest modifications to

the existing criteria and propose a new scoring system for the diagnosis of ABPA.

Expert commentary: All patients with asthma and cystic fibrosis should routinely be screened for ABPA

using A. fumigatus-specific IgE levels. Glucocorticoids should be used as the first-line of therapy in

ABPA, and itraconazole reserved in those with recurrent exacerbations and glucocorticoid-dependent

disease.

Keywords: allergic bronchopulmonary aspergillosis, allergic bronchopulmonary mycosis, Aspergillus,

ABPA, ABPM, fungal sensitization, allergy, asthma, cystic fibrosis

1. INTRODUCTION

Aspergillus fumigatus can lead to a variety of pulmonary disorders depending on the host

immunity and the burden of the organism.[1] The pulmonary disorders caused by Aspergillus can be

broadly classified as saprophytic (aspergilloma), allergic (A. fumigatus associated asthma, allergic
2
bronchopulmonary aspergillosis) and invasive (chronic pulmonary aspergillosis, invasive pulmonary

aspergillosis).[2] Far more prevalent than invasive aspergillosis, allergic bronchopulmonary aspergillosis

(ABPA) is a disease entity at the allergic spectrum of the Aspergillus disorders. Allergic aspergillosis is a

complex pulmonary disorder caused by immunological reactions mounted against A. fumigatus colonizing

the airways of patients with asthma and cystic fibrosis (CF).[3] The prevalence of ABPA in asthma in

referral centers and secondary care cohorts is believed to be about 13% and 0.7-3.5%, respectively;[4,5]

while the prevalence of ABPA in CF has been estimated at around 9%.[6] The global burden of ABPA

complicating asthma has been estimated to be about 5 million cases,[4] with about 1.4 million cases in

India alone.[7] A related disorder, allergic bronchopulmonary mycosis (ABPM) is an ABPA-like

syndrome caused by fungi other than A. fumigatus.[8] The prevalence of ABPM is far less when compared

to ABPA. The interest in allergic aspergillosis springs from the fact that the condition is exquisitely

sensitive to treatment with glucocorticoids. In fact, early diagnosis and treatment can prevent the

progression of bronchiectasis. However, if the condition is not recognized timely and/or treated

adequately, it progresses implacably resulting in end-stage lung disease. ABPA was first described by

Hinson et al. in three subjects in 1952.[9] Even after six decades, it is poorly recognized and inadequately

treated. In fact, there are reports of patients presenting very late in the course, with pulmonary

hypertension and respiratory failure.[10]

The International Society for Human and Animal Mycology (ISHAM) has formed an ABPA

working group to resolve the controversies related to the pathogenesis, diagnosis and treatment of this

disorder. In 2013, the working group had proposed new criteria for diagnosis and staging of ABPA

complicating asthma, and had also suggested a protocol for therapy.[11] Further, the group had made a call

to evaluate new diagnostic tests and validate the existing investigations (and their cutoff values) in the

diagnosis of ABPA. More than three years have elapsed since the working group report was published. In

this review, we summarize the current concepts in the diagnosis and management of this enigmatic

disorder.
3
2. PATHOGENESIS OF ABPA

The pathogenesis of ABPA largely remains speculative (Figure 1).[12] Although the conidia of

A.fumigatus are ubiquitous, they are immunologically inert due to the presence of surface hydrophobin

(Rod A hydrophobin).[13,14] In patients with asthma and CF, defective clearance of conidia in the airways

allows them to germinate into hyphae. In those destined to develop ABPA, there is persistence of

A.fumigatus probably due to several defects in innate and adaptive immunity.[15] During fungal growth

and metabolism, several proteins are released that can both activate and damage the airway epithelium.[16-

19] The innate immune cells (airway epithelium, dendritic cells, macrophages and others) recognize the

fungal products (pathogen-associated molecular patterns including β glucan, galactomannan,

glycosaminogalactan and others) through pattern recognition receptors (such as toll like receptors,

nucleotide-binding oligomerization domain [NOD]-like receptors, C-type lectin receptors, and others) or a

complement receptor 3 (CR-3) pathway.[20,21] Subsequently, there is release of chemokines and cytokines

that orchestrate adaptive immune response mediated by T-helper cells.[22] Normally, a Th1 CD4+ T cell

response against Aspergillus leads to clearance of Aspergillus secondary to macrophage and neutrophil-

mediated phagocytosis.[23] However, the immune response in ABPA is a Th2 CD4+ T cell response

mediated by the binding of chemokine [C-C motif] ligand 17 (CCL17) and CCL22 to the C-C chemokine

receptor type 4 (CCR4) located on Th2 cells.[24-26] The activation of pattern recognition receptors also

primes group 2 innate lymphoid cells towards Th2 differentiation.[27] The Th2 response triggers release of

Th2 chemokines and cytokines (CCL17, 1L-4, IL-5, IL-9, IL-13 and others). Instead of clearing the

fungi,[28] the aberrant immune response causes profound inflammatory reaction with mast cell

degranulation, influx of large number of inflammatory cells (neutrophils and eosinophils)[29] and IgE

(total and A.fumigatus specific) synthesis.[30] This causes the characteristic pathological findings of ABPA

namely eosinophilic pneumonia, bronchocentric granulomatosis, mucus plugging and bronchiectasis.

Exacerbations of ABPA are believed to result from a hyperactive immune response to transient

colonization of A. fumigatus in the tracheobronchial tree.

4
3. DIAGNOSIS AND STAGING OF ABPA

The clinical presentation of ABPA is with recurrent episodes of wheezing (and poorly controlled

asthma), fleeting pulmonary opacities and bronchiectasis. Patients can also manifest fever, malaise,

fatigue, weight loss and hemoptysis.[31] Expectoration of brownish mucus plugs is another characteristic

complaint, although seen only in 31-69% of the patients.[32-34] However, patients can be surprisingly

asymptomatic, especially when ABPA develops on a background of asthma. In a study involving 155

patients with ABPA complicating asthma, almost 19% of the patients were categorized as having well

controlled asthma (with the use of inhaled corticosteroids and long-acting β2 agonists). The development

of ABPA in CF is associated with deterioration of lung function, higher rates of microbial colonization,

pneumothorax, hemoptysis and poor nutritional status.[35-37] The diagnosis of ABPA in CF may be

perplexing as CF-lung disease and ABPA share many clinical characteristics including wheezing, fleeting

pulmonary opacities, bronchiectasis and mucus plugging.[38] All the aforementioned points suggest that

symptoms and even radiology alone are poor guides to diagnosing ABPA, and it underscores the need for

routinely screening asthmatic (or CF) patients for ABPA.

The diagnosis of ABPA is based on a composite criteria incorporating clinical, radiological and

immunological findings.

3.1 Immunological investigations used in the evaluation of ABPA

Aspergillus skin test: Skin test against Aspergillus is a surrogate marker for the diagnosis of allergic

sensitization against Aspergillus fumigatus.[39,40] An immediate cutaneous hypersensitivity to A. fumigatus

antigens represent the presence of IgE antibodies specific to A. fumigatus.[39,40] The type 3 and type 4 skin

reactions do not offer any added information and are not recommended. Skin testing can be performed by

injecting the Aspergillus extract (commercial or in-house),[5] either intradermally,[2,11,41] or as a prick test

(injected in epidermis). Intradermal tests are more sensitive compared to skin prick tests.[5] The

Aspergillus skin test has several limitations including requirement of a standardized antigen and proper

performance by trained personnel, both of which are subject to tremendous variability.[5] Also, there is a
5
potential risk of anaphylactic reactions to the injected antigen and consequent requirement of the

availability of resuscitation facilities. Further, the patient needs to be observed for an hour to observe the

type 1 reaction.[3] Due to these reasons, the test may not be acceptable to several patients as well as

physicians. Moreover, in a recent study, intradermal skin test using an in-house antigen extract offered a

sensitivity ranging between 88 and 94%. Thus, Aspergillus skin test as screening tool can inherently miss

about one in ten patients with ABPA, and is not recommended.[41]

A. fumigatus-specific IgE: Elevated IgE antibodies against A.fumigatus are considered to be a hallmark of

ABPA.[41] There is however a controversy regarding the cutoff value in the diagnosis of ABPA. Patterson

et al. suggested a value more than twice the pooled serum samples from asthma controls.[42] However, this

proposed method would require generation of specific cutoffs for each geographical region, which may be

impractical on a larger scale. The ISHAM working group proposed a cutoff value >0.35 kUA/L

(performed using fluorescent enzyme immunoassay on the Phadia platform), for the diagnosis of

Aspergillus sensitization and ABPA, based on expert opinion and consensus.[11] Subsequently, in a study

involving 372 asthmatic patients, A.fumigatus-specific IgE >0.35 kUA/L was found to have a sensitivity

and specificity of 100% and 66.2%, respectively in the diagnosis of ABPA.[41] Thus, with a sensitivity of

100%, A. fumigatus IgE <0.35 kUA/L is a good ‘rule-out’ test and should be used as a screening test for

ABPA. Although a good screening test, A. fumigatus-specific IgE has limited utility during followup. In a

recent study, it was found that the trend of A.fumigatus-specific IgE following treatment was

unpredictable.[43] The serum total IgE declined by a median of 52% whereas A.fumigatus-specific IgE

increased (instead of an expected decline) in half the individuals after treatment. During exacerbation,

while the IgE levels increased in all patients, A.fumigatus-specific IgE increased in only 38%, making it

an unreliable investigation during followup.[43]

Total IgE: The serum total IgE is a useful investigation both in the initial diagnostic workup as well as

during followup. A normal IgE level excludes ABPA as the cause of the patient’s current symptoms. The

cut-off value for total IgE is controversial and ranges from 417-1000 IU/mL.[11,42,44,45] Currently, three
6
cut-offs for total IgE have been proposed, >417 IU/mL (1000 ng/mL) by the Patterson group,[42,44] >500

IU/mL (CF consensus criteria)[45] and a value >1000 IU/mL (2400 ng/mL) by the ISHAM group.[11]

Unfortunately, due to wide variation of IgE values in normal human subjects, in those with atopy and in

ABPA, it may be difficult to suggest a single value that reliably discriminates ABPA from those

without.[46] In a latent-class analysis, a cut-off value of 1000 IU/mL was shown to have a sensitivity and

specificity of 92% and 40%, respectively in the diagnosis of ABPA.[41] In the same study, a total IgE

value >417 IU/mL significantly reduced the specificity to 24%.[41] Thus, a cutoff >1000 IU/mL is

currently recommended for the diagnosis of ABPA. During followup, the serum IgE levels start declining

but do not reach the normal value.[47,48] The lowest value attained after treatment (corresponding to the

clinical and radiological improvement) is taken as the ‘new’ baseline for an individual. An increasing

level (>50% of the ‘new’ baseline) of total IgE along with worsening respiratory symptoms and

appearance of consistent radiological findings suggests an exacerbation of ABPA.[48]

Total eosinophil count: The eosinophil count is raised in ABPA and ABPA falls into the category of a

syndrome characterized by pulmonary infiltrates with eosinophilia. However, eosinophilia in the

peripheral blood is a non-specific finding observed in a myriad of disorders. Further, the magnitude of

pulmonary eosinophilia is far greater than peripheral blood eosinophilia in ABPA, with little correlation

between the two.[49,50] Thus, the total peripheral blood eosinophil count is a poor screening test for ABPA.

In one study, almost 60% of patients with ABPA presented with peripheral blood eosinophil count <1000

cells/µL, and almost 25% of the patients had counts <500 cells/ µL.[42,51] The ISHAM working group

suggests a peripheral blood eosinophil count of >500 cells/ µL as a cut-off in the diagnosis of ABPA.[11]

IgG antibodies against A. fumigatus: Detection of IgG antibodies against A. fumigatus is a useful

investigation in the diagnosis of ABPA.[52,53] The A. fumigatus-specific IgG antibodies have traditionally

been detected using the double diffusion technique of Ouchterlony (Aspergillus precipitins).[52-54] This

was replaced by counterimmunoelectrophoresis, but this method is also time consuming and is limited by

its qualitative results and poor sensitivity.[55] Direct detection of IgG using commercially available
7
enzyme immunoassays have been shown to be more sensitive than the traditional methods.[3,11,41,56] In a

recent study, the sensitivity of Aspergillus precipitins was only 27% compared to 89% for A. fumigatus-

specific IgG.[57] At a cutoff of 27 mgA/L, the sensitivity and specificity of A.fumigatus-specific IgG was

found to be 89% and 100%, respectively in the diagnosis of ABPA, making it a good ‘rule-in’ test.[57]

3.2 Imaging modalities in the evaluation of ABPA

Chest radiograph: Chest radiograph is normal in almost 50% of patients with ABPA,[58] and thus has

limited value as a screening tool. However, it is a useful investigation in diagnosis of ABPA.[59] For

example, the presence of fleeting opacities or finger-in-glove opacities in patient with asthma are highly

indicative of ABPA. It is also a useful investigation during followup as it obviates the need for repeated

CT scans.[60] Findings such as consolidation, lobar or segmental atelectasis, band-like or toothpaste

shadows, tramline shadows and gloved-finger shadows represent active disease, and these clear up

following treatment.[60] Tooth-paste and gloved-finger opacities represent mucus impaction.[61] Permanent

changes are reflected by ring-shadows and tram-lines, and these suggest the presence of bronchiectasis.

High resolution computed tomography (HRCT) of thorax: HRCT of thorax is the preferred radiologic

investigation in ABPA as it allows better assessment of the distribution of bronchiectasis and detects other

abnormalities such as centrilobular nodules that are not apparent on the chest radiograph,[15,58,61,62].

Bronchiectasis and mucoid impaction are the classic findings in ABPA, however there are a plethora of

other findings that can manifest on CT in ABPA.[61,63,64] Patients of ABPA with no abnormality on HRCT

chest are labelled as serologic ABPA (ABPA-S). Central bronchiectasis has been considered a hallmark

of ABPA (Figure 2). However, central bronchiectasis has poor discriminatory value in the diagnosis of

ABPA,[65] probably because the bronchiectasis extends to the periphery in about 26-39% of the

cases.[58,60,61] Mucoid impaction of the airways is a common finding in ABPA. Although mucoid

impaction is generally hypodense, high-attenuation mucus (defined as mucus visually denser than

paraspinal skeletal muscle) is a pathognomonic feature of ABPA (Figure 2). Hyperattenuating mucoid

impaction has a specificity of 100% (sensitivity 19-32%), thus making it a good ‘rule-in’ test.[66,67] The
8
presence of high attenuation mucus has been shown to be associated with initial immunologic severity

and frequent exacerbations.[33,48,64,67] In advanced disease, findings of pleuroparenchymal fibrosis may be

observed. Some patients with ABPA develop progressive upper lobe fibrosis, which could suggest the

development of chronic pulmonary aspergillosis.[58,60,61]

Magnetic resonance imaging: Although HRCT of the thorax is the modality of choice for imaging in

ABPA, MRI may be used in situations where exposure to radiation may not be safe (pregnancy, children).

In a recent report, Garg et al. utilized MRI thorax to demonstrate hyperintense lesions in the lungs that

corresponded to bronchiectasis with impacted mucus.[68] On T2 turbo spin, nodules with hypointense foci

corresponding to areas of HAM on HRCT could be identified. Although more evidence is needed, it

seems possible that MRI can be used as a replacement for CT in the diagnosis of ABPA.

3.3 Other investigations

Lung function testing: Spirometry helps in the demonstration of airflow obstruction; however, a normal

spirometry does not exclude the diagnosis of either asthma or ABPA.[69] Hence, it should not be used in

the decision-making, either for screening or treatment.[70] However, spirometry helps in the assessment of

the severity of impairment of lung function, and is thus a useful tool during followup to monitor

improvement. Bronchial provocation testing with Aspergillus antigens can cause severe bronchospasm,

and should be avoided.[71]

Sputum cultures for A. fumigatus: The presence of A.fumigatus in sputum samples is not necessarily

diagnostic of ABPA because the fungus can also be encountered in other pulmonary disorders due to its

omnipresence.[72] The yield of sputum cultures for A.fumigatus is about 40-60%.[32,42,71] Recently, a better

technique for processing sputum samples has been described, which increases the yield of cultures.[73]

Interestingly, the vast majority of ABPA patients have been found to have detectable A.fumigatus in their

sputum by nucleic acid amplification despite negative cultures.[74] The role of sputum culture (if an isolate

can be obtained) mainly lies in testing the susceptibility (phenotypic and/or molecular testing) of the

organism to antifungal agents.[74]

9
Recombinant Aspergillus antigens: Detection of antibodies specific to A. fumigatus is an essential

component in making a diagnosis of ABPA.[11] However, most of the current methods utilize crude

antigens to detect these antibodies. These crude antigens are believed to lack reproducibility, may cross

react with other antigens and yield false positive results.[75,76] Recent technological advances have enabled

cloning of several proteins of A. fumigatus.[76] A number of recombinant proteins namely Asp f1, Asp f2,

Asp f3, Asp f4, Asp f6 have been evaluated in ABPA and are now available commercially for use in the

clinical setting. The results of some studies evaluating these recombinant antigens in the serodiagnosis of

ABPA indicate that IgE antibodies against Asp f1 and f3 are seen in both Aspergillus sensitization and

ABPA while Asp f4 and Asp f6 are seen specifically in ABPA.[75,77-79] However, other studies indicate

overlap of IgE responses against these recombinant proteins in patients with ABPA, patients with

Aspergillus-sensitized asthma and healthy controls.[80-82] Moreover, in a recent study the sensitivity of

A.fumigatus- specific IgE was 100% compared to only 36-68% for Asp f1, Asp f2, Asp f3, Asp f4, Asp

f6.[83] Thus, more data are required before recombinant antigens could be routinely used in differentiating

ABPA from Aspergillus sensitization.

Engineered allergens: Several fungal proteins are cross-reactive allergic proteins (so called pan-allergens).

These proteins belong to the same protein family and are highly conserved molecules with similar

functions present in widely different species.[84,85] They are also responsible for cross-reactivity between

crude fungal extracts. For instance, the Alternaria alternata manganese-dependent superoxide dismutase

cross reacts with Asp f6.[86] One way to alter this cross reactivity is by means of engineered allergens.

The immune reactivity of an antigen can be modified by either changing the conformation or

deleting the linear epitopes. Use of a specific allergen with enhanced IgE binding epitope may enhance

the diagnostic accuracy of a particular antigen. In an experimental study to delineate the structure-

function relationship of Asp f3, the authors demonstrated seven linear IgE binding regions. They further

demonstrated strong binding of IgE from patients with ABPA patients to Asp f3 and one mutant, Asp f31-

150. The authors concluded that a better understanding of primary and secondary structure of an allergen
10
may have implications in immunodiagnosis and immunotherapy.[87] In another study, two epitopes were

identified that are involved in T cell activation and are essential for the binding of IgE from patients with

ABPA.[88] The use of genetically engineered antigens seems promising but needs further testing in clinical

practice.

Galactomannan detection: Galactomannan is a polysaccharide component of the Aspergillus cell wall, and

is released during growth of the fungus. Measurement of serum galactomannan has been approved for the

diagnosis of invasive pulmonary aspergillosis, in combination with other clinical findings.[89,90] In a recent

study, 120 patients (70 ABPA, 50 asthma) were investigated for the utility of serum galactomannan in

differentiating asthma from ABPA.[91] The sensitivity of serum galactomannan in patients with ABPA

was 25.7%, while the specificity was 82%, making it a poor test in the diagnostic evaluation of ABPA.[91]

In another study comprised of five patients with ABPA, BAL galactomannan index at a cut-off of ≥1.0

was also found to have poor sensitivity.[92] Thus, serum and BAL galactomannan estimation has limited

utility in the evaluation of ABPA.

Thymus and activation regulated chemokine (TARC): ABPA is characterised by a profound Th2 immune

associated with overexpression of the chemokines TARC (CCL17), CCL22 and macrophage-derived

chemokine (MDC).[3,11,93] In one study, patients with ABPA were not only found to have significantly

higher levels of TARC at baseline but the TARC levels were also shown to increase during exacerbation

of ABPA.[94] In another study, the levels of TARC were shown to be significantly higher in CF-related

ABPA, and offered a diagnostic accuracy of 93%.[95] However, in a different study, the plasma TARC

levels did not differ between patients with CF, ABPA, fungal sensitization.[96] Also, no study has

evaluated the usefulness of TARC levels in ABPA complicating asthma. Thus, more data are required

before using TARC estimation in the diagnosis of ABPA.

Basophil activation test (BAT): Basophil activation test (BAT) measures the upregulation of CD203c on

the basophil surface after stimulation with the specific allergen to which a patient is sensitized.[96] CD203c

is a type II transmembrane ectoenzyme that is expressed on basophil surface and plays an important role
11
in type II immune responses.[96] CD203c can be rapidly measured by means of flow cytometry and has

been proposed as a diagnostic tool in patients with atopic disease, including peanut, drug, and wasp

venom allergy.[97,98] In a proof of concept study, blood basophils were demonstrated to elicit

hyperresponsiveness to A. fumigatus allergen stimulation in patients with CF-related ABPA and could

reliably differentiate patients with ABPA and those with fungal colonization or CF controls.[96] This was

confirmed in a subsequent long-term followup studies.[99,100] Also, in a recent study, serum CD203c levels

correlated inversely with lung functions and directly with serum Aspergillus-specific IgE levels.[101] Thus,

BAT seems promising in the diagnosis of CF-related ABPA. However, more data is needed in ABPA-

complicating asthma.

3.4. New diagnostic criteria for ABPA

The Patterson criteria (eight major, three minor) have been the most widely used benchmark for

the diagnosis of ABPA.[42] However, there were several limitations of these criteria. There was lack of

consensus on the number of major and minor criteria required for the diagnosis. Also, there was no

uniformity for the cutoff values of various immunological tests. Moreover, these criteria provided equal

weightage to the individual components. Over the years, several groups have proposed different criteria

for the diagnosis of ABPA in asthma and CF.[37,44,102-108] The ISHAM working group suggested more

practical criteria for ABPA (Table 1).[11] Based on these criteria, a diagnosis of ABPA can be made in the

presence of a predisposing condition, when both the obligatory criteria are met along with at least two of

the three additional criteria. After publication of these criteria, more evidence has surfaced from studies

on individual components of the criteria. Therefore, we propose some changes in these criteria (Table 1).

Though asthma and CF are the most common conditions predisposing to the development of

ABPA, the disease can also manifest, though uncommonly in patients with COPD and post-tuberculosis

fibrocavitary disease.[106,109] Thus, these two conditions can be included as the predisposing conditions. In

a recent study, we have observed that A.fumigatus-specific IgG is far more sensitive than Aspergillus

precipitins (89% vs. 27%) measured by double-diffusion method, in patients with ABPA.[57] Therefore,
12
we propose that the presence of precipitating antibodies may be removed from the criteria in diagnosis of

ABPA, and can be replaced by A. fumigatus-specific IgG (>27 mgA/L) as one of the additional criteria for

diagnosis. Demonstration of hyperattenuating mucoid impaction on HRCT has a specificity of 100%

(sensitivity 19-32%) and thus should be considered as a radiological criteria separate from other findings.

The ISHAM criteria requires the presence of either positive type 1 Aspergillus skin test or elevated

serum IgE levels against A. fumigatus (>0.35 kUA/L) as one of the obligatory criteria for the diagnosis of

ABPA. Apart from the limitations of Aspergillus skin testing mentioned above, the sensitivity of

Aspergillus skin test is 88-94% while that of A. fumigatus-specific IgE is 100%.[41] Further, good

automated and standardized systems for the measurement of serum A. fumigatus specific IgE are now

widely available. Therefore, we propose that A. fumigatus-specific IgE should replace Aspergillus skin

test, and the latter test be used only if the former is not available.

3.5. New scoring system for the diagnosis of ABPA

There is no single reference standard in the diagnosis of ABPA and a combination of several

investigations are required for its diagnosis. Although the ISHAM criteria are evidence-based and can be

easily applied, a diagnostic score can further capture the results of all the investigations in a single value

making it even more objective. Thus, we propose a new scoring system for the diagnosis of ABPA (Table

2), based on the results of our previous studies,[33,41,43,48,57,67,70,110] with appropriate weightage given to the

individual diagnostic tests. For calculating the total score, the immunologic and radiologic scores need to

be calculated. HRCT of the chest is preferred over chest radiograph as it is less observer-dependent than

the chest radiograph. In this scheme, no radiologic abnormality is assigned a score of 0, and in the

presence of a total score ≥9, a diagnosis of ABPA-S can be made. With radiologic scores of 2, 3 (or 4),

and 5, the ABPA can be radiologically classified as ABPA with chronic pleuropulmonary fibrosis

(ABPA-CPF), ABPA with bronchiectasis (ABPA-B), and ABPA with high attenuation mucus (ABPA-

HAM), respectively.[11,67]

3.6. Staging of ABPA

13
 ABPA has been classified into five stages by Patterson et al.[111] However, there were no objective

definitions for each stage. The ISHAM ABPA working group now classifies ABPA into seven stages

objectively (Table 3). The sequentially numbered stages do not imply that the disease progresses serially

from one stage to the other. Most patients are diagnosed when they present for the first time in the acute

stage (stage 1), where the patient is symptomatic either with symptoms of ABPA or has uncontrolled

asthma. The thoracic imaging may (stage 1a) or may not (stage 1b) reveal mucoid impaction. It would be

ideal, if patients are diagnosed in the asymptomatic stage (stage 0), by appropriate screening in all

asthmatic patients, so that the damage to the lungs may be either be prevented or curbed with treatment.

Stages 2-5 are defined in patients undergoing treatment. Response is defined by a fall in the serum total

IgE by at least 25% (generally assessed after eight weeks of treatment), associated with an improvement

in clinical and/or radiological manifestations (stage 2). With successful treatment, IgE falls progressively,

and the nadir is established as a ‘new’ baseline. Exacerbation is defined by clinical and/or radiologic

worsening along with an increase in the total IgE levels by at least 50% from the established ‘new’

baseline (stage 3). Remission (stage 4) is defined only in patients who are off treatment with oral steroids

(or azoles) and continue to maintain clinical, immunologic (IgE at or below baseline or <50% increase

from baseline), and radiologic stability for at least six months. In patients who need prolonged

glucocorticoid treatment to maintain clinical stability, differentiation is needed between patients requiring

glucocorticoids for controlling asthma (stage 5b, glucocorticoid-dependent asthma) or activity of ABPA

(stage 5a, treatment-dependent ABPA), as discerned from IgE levels and thoracic imaging. A small

proportion of patients with ABPA may also manifest advanced disease with extensive bronchiectasis with

evidence of either pulmonary hypertension or respiratory failure (stage 6).

3.7. Practical approach to diagnosis

A practical approach to the diagnosis of ABPA is shown in Figure 3. All asthmatic patients should

undergo screening for ABPA with A.fumigatus-specific IgE.[112] If the value is <0.35 kUA/L, then the

patient does not have ABPA. Investigations for sensitization to other fungi are required only if there are
14
unexplained pulmonary opacities or if the asthma is uncontrolled despite standard therapy. In those with

A. fumigatus-specific IgE >0.35 kUA/L, the next step is to obtain a total IgE. If the total IgE level is <500

IU/mL, then ABPA is excluded in the vast majority. However, if the total IgE is >500 IU/mL, then other

investigations including A.fumigatus-specific IgG, peripheral blood eosinophil count and HRCT of the

thorax are required both to confirm the diagnosis and to determine the radiological stage and extent of the

disease (Table 2).[113]

No single test for ABPA provides the optimal combination of sensitivity and specificity, however

a combination of A. fumigatus-specific IgE, total IgE and total eosinophil count of >1.91 kUA/L, >2347

IU/mL and >507 cells/µL, respectively had a sensitivity and specificity of 70% and 100%,

respectively.[110] Further, in the presence of A. fumigatus-specific IgG >27 mgA/L or in those with high-

attenuation mucus, ABPA may be diagnosed even if the total serum IgE levels is <1000 IU/mL, due to the

high specificity of these tests.

4. TREATMENT OF ABPA

The principles in the treatment of ABPA include the use of anti-inflammatory agents (principally

glucocorticoids) to suppress the immune hyperreactivity and the use of anti-fungal agents to attenuate (or

eliminate) the fungal burden in the airways thereby limiting the stimulus responsible for the immune

hyperresponsiveness (Figure 1).[114,115] The natural history of ABPA is characterized by repeated episodes

of exacerbations. Hence, most patients require prolonged therapy. The goals of treatment include: (a)

reduction of pulmonary inflammation; (b) control of asthma; (c) treatment of acute stage of ABPA; (d)

prevent exacerbations of ABPA; and, (e) mitigate the onset or progression to bronchiectasis (a marker of

end-stage lung disease) and chronic pulmonary aspergillosis. Importantly, all the treatment goals should

be met with minimal or no adverse reactions related to treatment. Finally, it is of utmost importance to

identify and exclude any potential environmental source responsible for exposure to A. fumigatus as this

can trigger exacerbations of ABPA

4.1 Glucocorticoids
15
Oral glucocorticoids: Oral glucocorticoids are the most effective agents in the management of ABPA

(Table 4). They suppress all inflammatory responses triggered by antigens of A. fumigatus in the airways

(Figure 1). Glucocorticoids mediate their effects through intracellular glucocorticoid receptor; the binding

of glucocorticoids to glucocorticoid receptor leads to a conformational change in the receptor with

subsequent translocation into the cell nucleus. Thereafter, most of the anti-inflammatory effects of

glucocorticoids occur through a mechanism known as transrepression,[116] wherein the glucocorticoid

receptor binds to the nuclear chromatin by interacting with DNA-bound transcription factors, particularly

nuclear factor (NF)-κB and activator protein-1. Glucocorticoids have been shown to regulate up to 20% of

the human genome in different cell types.[117]

Several observational studies over the last three decades have conclusively proven the efficacy of

glucocorticoids in ABPA.[3,111] However, there is no clear agreement on the dosing protocols of oral

glucocorticoids in ABPA.[70,118] The most widely used regime is the low-dose regime in which

prednisolone is administered at a dose of 0.5 mg/kg/day for two weeks followed by 0.5 mg/kg/day on

alternate days for eight weeks, then taper by 5 mg every two weeks to complete a total steroid duration of

3-5 months.[118] At our center, we had been using the high-dose (medium dose according to the

standardized nomenclature for glucocorticoid dosages[119]) where prednisolone is given at a dose of 0.75

mg/kg/day for six weeks followed by 0.5 mg/kg/day for six weeks, then taper by 5 mg every six weeks

and discontinue by 8-10 months.[33,70] There was some indication that the use of high-dose glucocorticoids

is associated with lower propensity of progressing to glucocorticoid-dependent ABPA.[120]

Recently, we have reported the results of a large randomized trial evaluating the two

aforementioned glucocorticoid protocols in ABPA.[121] Ninety-two patients with ABPA complicating

asthma were randomized to receive either high-dose (n=44) or low-dose (n=48) glucocorticoids. Almost,

three-fourths of the patients had bronchiectasis on CT chest. Overall, 42 (45.7%) patients experienced an

exacerbation and 12 of the 42 patients were classified as glucocorticoid-dependent ABPA. The number of

subjects with exacerbation after one year of treatment and glucocorticoid-dependent ABPA after two
16
years of treatment were similar in the two groups. The improvement in lung function and the time to first

exacerbation after stopping treatment was similar in the two groups. The occurrence of adverse reactions

to glucocorticoids was significantly higher in the high-dose arm. The results of this study suggest that

low-dose glucocorticoids are as effective as high-dose and are associated with lesser side effects.

However, the proportion of subjects with a response after six weeks was higher in the high-dose

group.[121] Thus, a small proportion of patients treated with low-dose glucocorticoids may not have an

adequate response during initial treatment. Hence, the initial treatment needs to be closely monitored and

failure to respond to low doses of glucocorticoids should necessitate institution of higher doses.

Importantly, this study evaluated only patients with ABPA complicating asthma and the results may not

be extrapolated to patients with CF.

The use of glucocorticoids is associated with a plethora of side effects including weight gain,

osteopenia, acne, skin atrophy, diabetes mellitus, glaucoma, cataracts, avascular necrosis of bone,

infection, hypertension and growth retardation in children. Thus glucocorticoids should be judiciously

used in the management of ABPA.

Inhaled glucocorticoids: Inhaled corticosteroids (ICS) achieve high concentrations in the tracheobronchial

tree and are associated with significantly fewer side-effects compared to oral glucocorticoids. ICS have

been investigated as a treatment modality in ABPA. A double-blind multicenter placebo controlled trial in

32 patients of ABPA found no benefit of using low doses of ICS (400 µg of beclomethasone per day) over

placebo.[122] Subsequently, several case-reports and small case series have evaluated the efficiency of ICS

in ABPA.[123-126] Unfortunately, these studies have several limitations apart from the small sample size.

These studies utilized different doses of ICS, and most patients were also continued on oral

glucocorticoids while receiving ICS. Further, patients received oral steroids during clinical and/or

radiological worsening. This makes it difficult to interpret whether the beneficial effects were solely due

to ICS. In another study involving 21 patients with ABPA-S, patients were initially treated with a

combination of ICS and long-acting beta2 agonists (formoterol/budesonide, [24/1600 micrograms/day]).

17
There was subjective improvement in all patients treated with ICS but none had complete control of

asthma. In fact, after six months of treatment with ICS, the median IgE levels increased by 99%. Patients

then received treatment with oral glucocorticoids following which there was complete resolution of

asthma symptoms and IgE levels fell by a median of 53% after six weeks of treatment.[127] Thus, it seems

that high doses of ICS alone have little role in the management of ABPA. Inhaled steroids alone should

not be used for controlling the immunological activity of ABPA but they can be used for the control of

asthma symptoms in ABPA.

Intravenous pulse doses of glucocorticoids: Intravenous pulse doses of glucocorticoids (15 mg/kg of

methylprednisolone, maximum 1 gm) have been used in pediatric patients with ABPA as a steroid-sparing

modality to abrogate the side-effects of daily therapy with glucocorticoids.[128] Whether pulse therapy is

superior to daily therapy with glucocorticoids in adults, requires more research. The other situation where

pulse doses of methylprednisolone are employed is refractory ABPA exacerbations. Although most

patients with ABPA respond to standard doses (0.5 mg/kg of prednisolone) of glucocorticoids during

exacerbations, occasional patients do not respond to oral glucocorticoid therapy.[129] This is usually seen

in patients on long-term steroid use, which may be associated with downregulation of steroid receptors

thus leading to a steroid resistance state.[130] The use of pulse doses of methylprednisolone may

potentially overcome the steroid-resistant effect by its non-genomic effects that are independent of the

glucocorticoid receptor.[131]

4.2. Antifungal agents

Although glucocorticoids are highly efficacious in the management of ABPA, the therapeutic

benefits of glucocorticoids are partly offset by their side effects. Antifungal agents by decreasing the

fungal burden reduce the antigenic stimulus for the ongoing inflammatory activity. Thus, antifungal drugs

can act as steroid-sparing agents. The use of antifungal agents in ABPA dates back to 1967 when nystatin

inhalation was shown to be useful in its treatment.[132] Subsequently, ketoconazole was tried however due

to its limited efficacy and significant toxicity, its use did not gain acceptance.[133,134] Later, a randomized
18
trial evaluating the use of nebulized natamycin also found the drug ineffective in the management of

ABPA.[135] The currently available triazoles have far lesser side-effects and seem to be an attractive option

in the management of ABPA.

Itraconazole: The most widely used triazole in the management of ABPA is itraconazole. Azoles act by

inhibiting the enzyme 14-α-sterol-demethylase, which impairs the biosynthesis of ergosterol, an essential

component of the fungal cytoplasmic membrane. Further, it leads to the accumulation of 14-α-

methylsterols, which disrupt the close packing of acyl chains of phospholipids, thereby impairing the

functions of certain membrane-bound enzyme systems, and inhibiting the fungal growth. In general,

triazoles are considered to be fungistatic. In ABPA, the fungal burden in the airways is far lower

compared to that in invasive disorders, thus itraconazole seems to have the desired effect. Several

observational studies have reported the beneficial effects of itraconazole in patients with ABPA both in

asthma and CF.[35,136-141] However, these studies are limited by their small sample size, and long-term

outcomes especially the occurrence of exacerbations has not been evaluated.

Two randomized trials have evaluated the effectiveness of itraconazole in ABPA complicating

asthma.[142,143] In one study, 55 patients with ‘glucocorticoid-dependent’ ABPA were randomized to

receive either oral itraconazole (400 mg/day) or placebo for 16 weeks (followed by 200 mg/day for 16

weeks in all patients during the open phase). While the difference between the two groups was significant

in terms of the overall composite response criteria (reduction in glucocorticoid dose by ≥50%; and,

decrease in serum total IgE value by ≥25%; and, at least one of the following [increase in exercise

capacity by ≥25%, improvement in pulmonary function test values by ≥25%, resolution of pulmonary

infiltrates]), the study failed to reach statistical significance when each outcome was examined

separately.[142] The other study included 29 ‘clinically stable’ ABPA patients randomized to receive

itraconazole (400 mg/day orally) or placebo. There was significant decline in sputum inflammatory

markers and serum IgE levels. Although the study was not designed to evaluate exacerbations, the authors

noted a decrease in the number of exacerbations warranting glucocorticoid usage.[143] Pooled analysis
19
showed that itraconazole could significantly decrease IgE levels by ≥25% compared to placebo but did

not significantly improve the lung function.[144] Neither study reported outcomes more than eight months

with regards to ABPA exacerbation, thus the long-term benefits of azole therapy remain unknown.

Itraconazole has poor bioavailability and interactions with several drugs hence therapeutic drug

monitoring is generally advised. However, there is no robust evidence on direct correlation between drug

levels and efficacy. In fact, the dose of itraconazole has never been standardized in the treatment of

ABPA, and lower doses (200 mg/day) have also been found to be clinically efficacious.[138,139,141,142]

Clinicians managing ABPA should be aware of the interaction between glucocorticoids and itraconazole.

Itraconazole by inhibiting cytochrome P450 dependent CYP3A4, inhibits the metabolism of several

glucocorticoids most notably oral methylprednisolone and inhaled budesonide. This inhibition can lead to

iatrogenic hypercortisolism and long-term suppression of the hypothalamo-pituitary axis.[145,146]

Newer azoles: Few studies have evaluated the newer azoles (voriconazole, posaconazole) for their

efficacy in ABPA.[147-149] In the largest of these studies, Chishimba et al. retrospectively analyzed the

efficacy and safety of voriconazole (300-600 mg/day) or posaconazole (800 mg/day) in 20 patients with

ABPA.[149] Overall, clinical improvement with voriconazole or posaconazole therapy was seen in about

70-75%. There was reduction in the requirement of oral glucocorticoids, improvement in asthma control

and decline in IgE levels.

Nebulized amphotericin B: Amphotericin B acts by binding to ergosterol in fungal cell membrane, which

leads to formation of pores that increase membrane permeability and cell death. Inhalation of

amphotericin achieves concentrations in the bronchoalveolar lavage fluid well above the minimal

inhibitory concentration of A. fumigatus (0.5 mg/L) while the serum concentration of amphotericin is

negligible.[150] Thus, there is clinical efficacy without the occurrence of adverse events with nebulized

therapy, in contrast to systemic treatment with amphotericin B. Several case reports and small case studies

have reported on the efficacy of nebulized amphotericin B in ABPA both in asthma and CF.[151-160]

Chishimba et al. evaluated the use of nebulized amphotericin B in 10 ABPA patients either failing azole
20
therapy or those experiencing side-effects with the use of azoles. The study found that nebulized

amphotericin B was effective in only two patients.[159] Thus, the efficacy of nebulized amphotericin B in

the management of ABPA exacerbations seems to be limited. However, they may be considered when

other alternative options have been exhausted. The dosing schedule of different preparations of

amphotericin is shown in Table 4.

Another approach in using nebulized amphotericin B could be to induce response with

glucocorticoids and then maintain the response/remission with nebulized amphotericin. In a recent pilot

study, we tested this approach in 21 patients with recurrent exacerbations (≥2) of asthmatic ABPA and in

the response stage (stage 2). Patients were randomized to receive either nebulized amphotericin B

(deoxycholate preparation; 10 mg b.i.d. thrice a week) plus nebulized budesonide (n=12) or nebulized

budesonide alone (n=9). While the time to first exacerbation was similar in the two groups, the number of

patients experiencing ABPA exacerbations were significantly lower in the amphotericin arm compare to

the control arm (1/12 [8.3%] vs. 6/9 [66.7%]; p=0.016). Thus, nebulized amphotericin B seems to be an

attractive option in the prevention of ABPA exacerbations. However, larger trials are required to confirm

these findings. The use of conventional preparation of amphotericin B has been associated with the

occurrence of bronchospasm due to alteration in the pulmonary surfactant activity by the deoxycholate

component. The lipid formulations of amphotericin have longer pulmonary retention and no effects on

lung surfactant. Hence, future trials should preferably use lipid preparations rather than conventional

amphotericin B.

4.3. Other therapies

Anti-IgE therapy: Omalizumab is a humanized monoclonal antibody against IgE. It binds to free serum

IgE and prevents the binding of IgE to high-affinity FcεRI receptor on the surface of mast cells and

basophils. Omalizumab is a preferred therapy for moderate or severe allergic asthma that is uncontrolled

on step 4 treatment according to the Global Initiative against Asthma guidelines.[161] The use of

21
omalizumab has been shown to be associated with reduction in the frequency of exacerbations and the

likelihood of withdrawing ICS completely in patients with moderate to severe asthma.[162]

The goal of treatment with omalizumab is to decrease the serum total IgE to less than 21 IU/mL.

In order to achieve this goal, a dose of 0.016 mg/kg/IU [IgE/mL] of omalizumab is required.[163] An upper

limit of IgE of 700 IU/mL and a maximum dose of omalizumab 750 mg monthly has been specified by

the manufacturer. In ABPA, the total IgE is significantly elevated (in tens of thousands) and the dose

requirement according to the standard calculation would be impossible to administer. In fact, in an

industry-sponsored study, a 600 mg daily dose of subcutaneous omalizumab was used, in addition to

itraconazole and glucocorticoids. The study was prematurely terminated due to significant dropout rate of

the patients (clinical trials.gov; NCT00787917).

On the other hand, several case reports and case series suggest that the routine doses of

omalizumab used in asthma may be sufficient in the treatment of ABPA despite the high IgE.[164-172]

Recently, Voskamp et al. have reported the results of a randomized, placebo-controlled cross-over trial of

omalizumab in ABPA complicating asthma.[173] Thirteen patients with chronic ABPA were randomized to

four-month treatment with subcutaneous omalizumab (750 mg monthly) or placebo followed by a three-

month washout period. The use of omalizumab was associated with a significant reduction in

exacerbations during the active treatment phase. Moreover, omalizumab treatment was associated with

reduction in exhaled nitric oxide levels, reduction in basophil sensitivity to A. fumigatus and decrease in

basophil FcεRI and surface-bound IgE levels.[173] The results of this study suggest that omalizumab may

be an effective treatment option in patients with ABPA.

Therapeutic bronchoscopy: One recent study employed therapeutic bronchial lavage to clear mucus plugs

in all patients with ABPA who had either bronchiectasis or HAM.[174] The authors noted significant

decline in IgE in the therapeutic bronchoscopy group however there was no difference in the exacerbation

rate.[174] We do not advocate therapeutic bronchoscopy routinely however it can be considered in patients

who have large airway collapse (up to segmental bronchi) that persists despite 3-4 weeks of oral
22
glucocorticoid therapy. The removal of mucus plugs not only causes significant improvement in

symptoms and lung function but also prevents damage of lung segments distal to the collapse.[175]

4.4. Supportive therapies

Supportive therapies include nebulized hypertonic saline (7%, 3-5 mL) to reduce the viscosity of

the sputum.[176] The use of hypertonic saline may lead to bronchospasm and the first dose should be given

under supervision and preceded by inhaled salbutamol. Its use is not recommended in patients with FEV1

<1L; this precludes its use in patients where it is needed most. Long-term azithromycin has been

advocated in patients with bronchiectasis.[11] Two recent trials evaluating long-term azithromycin found

that its use reduced the rate of pulmonary exacerbations requiring antibiotics in adults with non-CF

bronchiectasis over 6-12 months.[177,178] However, the improvement in exacerbations must be balanced

against the risk of experiencing drug-related side effects and the potential risk of acquiring antibiotic

resistance. Pneumococcal and influenza vaccination are generally recommended although there are no

studies specifically in ABPA patients. A recent study noted poor response to 23-valent polysaccharide

pneumococcal vaccine in ABPA patients compared to healthy adults.[179] Thus, an alternative vaccination

strategy (both polysaccharide and 13-valent conjugate vaccine) or delay of vaccination until the ABPA

activity is better controlled (and the patient is off glucocorticoids), may result in a superior response.

Domiciliary oxygen therapy is required in patients with chronic type 2 respiratory failure with PaO2 <55

mm Hg or with PaO2 <60 mm Hg if there is associated polycythemia or pulmonary hypertension.[180] Lung

transplantation is the only option for patients with end-stage lung disease. Interestingly, ABPA can recur

in the donor lungs,[181] and there is a report of successful treatment of ABPA in post-transplant setting

with nebulized amphotericin B.[151]

4.5. Practical approach to treatment

The treatment protocol followed at our Chest Clinic for the management of ABPA is shown in

Figure 4. Patients without bronchiectasis may be followed up without initiating any specific therapy for

ABPA provided the asthma is well controlled with inhaled medications. However, patients with
23
bronchiectasis or fleeting pulmonary opacities (suggesting end-organ damage), even if asymptomatic,

generally require treatment. Patients in stage 1 (acute stage) should receive treatment with low doses of

glucocorticoids. An attractive proposition would to be use azole monotherapy as this would altogether

avoid the adverse effects related to glucocorticoids. Two randomized trials are evaluating the role of

itraconazole and voriconazole monotherapy in acute stage ABPA (clinical trials.gov: NCT01321827,

NCT01621321). Hopefully, the results of these trials should clarify the role of triazole monotherapy in

ABPA. In the clinic, we have observed that ABPA patients with extensive mucoid impaction, widespread

bronchiectasis and uncontrolled asthma generally require treatment with oral glucocorticoids. Whether

antifungal agents in combination with glucocorticoids are superior to glucocorticoids alone in acute stage

ABPA (stage 1) is also not known, and is the focus of another ongoing randomized trial (clinical

trials.gov: NCT02440009). Thus, more studies are required to define the patient characteristics of ABPA

who are likely to benefit from the action of azoles.

Patients should be closely monitored, initially every eight weeks with serum IgE levels, chest

radiograph and lung function test (Table 4). The aim of therapy in ABPA is not normalization of IgE

levels but a decline in IgE of about 25%, that is generally associated with clinical, spirometric and

radiological improvement (stage 2).[48,182] As mentioned before, serial measurements of total IgE need to

be performed for every individual patient during therapy to determine the ‘new’ baseline value. About 45-

50% of patients experience an exacerbation (stage 3),[33,48,70,121] and in these patients, a combination of

glucocorticoids and itraconazole is recommended. The duration of azole therapy remains unclear, and

currently they are generally administered as recurrent 16-24 week courses or as long-term therapy. There

is a potential risk of induction of triazole resistance with long-term therapy.[74] Importantly, resistance to

one azole can lead to cross-resistance to other azoles and this point should also be kept in mind during

long-term therapy.[183]

In those with recurrent exacerbations or treatment-dependent ABPA (stage 5), one should consider

prolonged therapy with any of the following namely oral itraconazole, low-dose glucocorticoids, monthly
24
pulses of methyl prednisolone, nebulized amphotericin B or omalizumab. A large number of patients with

ABPA require long-term therapy, and they should be advised about side-effects of therapy especially that

of glucocorticoids. High doses of inhaled steroids should not be used as a single agent in the management

of ABPA. The combination of inhaled steroids, especially budesonide and itraconazole in some patients

can lead to cushingoid effects (lesser with fluticasone in the authors’ experience) and long-term failure of

hypothalamo-pituitary axis, if the dose of inhaled steroids is not significantly reduced.[184-188] Newer

azoles (voriconazole or posaconazole) should be used only in those patients who experience poor

response with itraconazole or encounter adverse effects with the use of itraconazole.

The treatment protocol of ABPA in CF is not very different from that of ABPA in asthma. As

patients with CF often have coexisting malabsorption, treatment is more complex as oral medications

especially itraconazole capsules are poorly absorbed. Although, voriconazole has better bioavailability, its

use is often associated with photosensitivity, especially in the Caucasian population, with risk of skin

cancer. Use of glucocorticoids often induces or worsens CF related diabetes.

4.6. Treatment in special situations

Children: The treatment protocol in children is similar to that in adults. However, due to concerns

regarding growth retardation with the use of glucocorticoids, it is advisable that glucocorticoid treatment

be given at the lowest possible dose for the shortest possible duration. Thereafter, remission is maintained

with use of either antifungal azoles, nebulized amphotericin or omalizumab. In those patients where

glucocorticoids are required, monthly pulse doses of methylprednisolone along with daily itraconazole

can be considered.

Pregnancy and lactation: The treatment of choice in pregnancy is glucocorticoids. In two separate studies,

the use of itraconazole during first trimester was not associated with increased risk of major congenital

anomalies,[189,190] however the rates of miscarriage were higher in the itraconazole-exposed group.[190]

Newer azoles are contraindicated in pregnancy except in life-threatening maternal disease without any

therapeutic alternative. Nebulized amphotericin B can be safely used during pregnancy.[191] Similarly, the
25
use of omalizumab has not been associated with any congenital abnormalities, prematurity or low birth

weight.[192] We generally avoid the use of itraconazole or omalizumab during the entire period of

pregnancy and lactation. We prefer the use of glucocorticoids and in those with contraindications to

glucocorticoids, we use nebulized amphotericin B.

5. CONCLUSIONS

In conclusion, the pathogenesis of ABPA, despite being one of the most prevalent of the

Aspergillus disorders, remains unclear. It is known that ABPA is an exaggerated Th2 response against

products of A. fumigatus colonizing the airways of patients with asthma and cystic fibrosis. Currently, the

best modality for screening susceptible patients for ABPA is the A. fumigatus-specific IgE. The ISHAM

working group criteria are the most cost-effective and practical method for the diagnosis of ABPA.

Further refinements in the criteria, as suggested by our group would improve the sensitivity and

specificity of these criteria. A practical scoring system suggested in this article could further aid in quick

diagnosis and differential diagnosis of the allergic Aspergillus disorders. Glucocorticoids are the

cornerstone of therapy. Unfortunately, a large number of patients experience recurrent exacerbations due

to intense pulmonary inflammation associated with this disorder. Thus, treatment should judiciously

include the use of anti-inflammatory agents to suppress the immune hyperresponsiveness and anti-fungal

agents to attenuate the fungal burden in the airways. There is a dire need for newer, less toxic and more

effective therapies in the management of this complex disorder.

6. EXPERT COMMENTARY

Despite six decades of research, the understanding of ABPA remains vague. In the developing

countries, patients are still misdiagnosed as pulmonary tuberculosis.[43] The proposed modifications to the

diagnostic criteria laid down by the International Society for Human and Animal Mycology ABPA

working group will ensure accurate diagnosis of patients with ABPA. However, ABPA can remain

surprisingly silent and this underscores the need for routinely screening asthmatic patients for ABPA.

Unfortunately, there is no single confirmatory test for the diagnosis of ABPA. Thus, a stepwise
26
algorithmic approach is the most cost effective method in its diagnosis. The most sensitive investigation

in the diagnosis of ABPA is A. fumigatus specific IgE while the most specific investigations are A.

fumigatus specific IgG and demonstration of high-attenuation mucus on computed tomography of the

chest. Thus, the best tool for screening asthmatic patients for allergic fungal airway disease is fungal

specific IgE. Although total IgE is also raised in all patients with allergic aspergillosis, it is a non-specific

marker of allergy and will be raised in several other disorders. Thus, screening with total IgE would lead

to a higher false-positive results (‘more noise, less signal’). Antifungal agents are widely used in the

treatment of ABPA, and have even been recommended as the first line treatment by several authorities.

However, glucocorticoids are the treatment of choice and antifungal agents are indicated for the

maintenance of remission is those with recurrent exacerbations. Unfortunately, ABPA can be a lifelong

illness in a large number of patients, and thus any therapy should be carefully chosen weighing the risk-

benefit ratio.[193]

7. FIVE-YEAR VIEW

Although there is some recent data on the pathogenesis of this entity,[194,195] there is a dire need

more studies evaluating this aspect. The occurrence of ABPA in only a proportion of patients with asthma

suggests strong host susceptibility, and there is an urgent need for whole-genome sequencing studies from

different centers. Although several advances have been made in the diagnosis of ABPA, there is a

necessity for evaluating TARC and BAT in ABPA, especially in ABPA complicating asthma. Also, more

data from different centers is required to confirm the utility of recombinant proteins in the diagnosis.

There are several unmet needs in the treatment of ABPA. Newer approaches are required to improve the

treatment outcomes of these patients. Recently, vitamin D deficiency has been shown to be more

prevalent in CF patients with ABPA than those without ABPA,[196] Also, vitamin D supplementation at a

dose of 4000 IU/day for six months in patients with CF and ABPA was associated with reduced

A.fumigatus induced IL-13 responses from peripheral CD4+ T cells.[197] Similar data, both on the

prevalence of vitamin D deficiency and that of vitamin D supplementation, are also required in patients
27
with ABPA complicating asthma. Lately, trials of monoclonal antibodies against IL-5 (mepolizumab,

reslizumab) have been shown to be beneficial in patients with asthma and evidence of eosinophilic

inflammation (raised blood or sputum eosinophil count).[198-201] These biological agents should also be

evaluated in patients with ABPA (Figure 1).

8. KEY ISSUES

• ABPA should be suspected in all patients with asthma and CF regardless of the severity or the

level of control.

• All patients with asthma should routinely be screened for ABPA using A. fumigatus-specific IgE

levels.

• Glucocorticoids should be used as the first-line of therapy in ABPA, and itraconazole reserved in

those with exacerbations and glucocorticoid-dependent disease.

• Newer therapies may be tried in those with recurrent exacerbations, glucocorticoid-dependent

ABPA or in patients who develop treatment-related adverse reactions.

Funding

This paper was not funded.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a
financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.
This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants
or patents received or pending, or royalties.

28
Figure 1: Pathogenesis of allergic bronchopulmonary aspergillosis (ABPA). The conidia of Aspergillus

fumigatus are immunologically inert, however in patients with asthma and cystic fibrosis, they germinate

into hyphae. The innate immune cells (airway epithelium, dendritic cells, macrophages and others)

recognize the fungal pathogen-associated molecular patterns (β glucan, galactomannan and

glycosaminogalactan) through pattern recognition receptors (such as toll like receptors, nucleotide-

binding oligomerization domain [NOD]-like receptors and C-type lectin receptors). In normal individuals,

the response against Aspergillus is a Th1 CD4+ T cell response leading to macrophage and neutrophil-

mediated phagocytosis. However, the immune response in ABPA is a Th2 CD4+ T cell response due to

release of chemokines and cytokines (binding of CCL17, CCL22 to CCR4 located on Th2 cells) by innate

immune cells. In those destined to develop ABPA, there is persistence of A. fumigatus with profound Th2

response leading to release of Th2 chemokines and cytokines (CCL17, IL-4, IL-5, IL-9, IL-13 and others).

The exuberant immune response causes profound inflammatory reaction with mast cell degranulation,

influx of large number of inflammatory cells (neutrophils and eosinophils) and IgE (total and A. fumigatus

specific) synthesis. The targets of various therapeutic agents used in the management of ABPA is also

shown.

29
Figure 2: Computed tomography of the chest in a patient with allergic bronchopulmonary aspergillosis.

Mediastinal sections reveal high attenuation mucus i.e. mucus visually denser than skeletal muscle (bold

arrows, panel A). Lung window sections also shows bronchiectasis (arrow heads, panel B)

30
Figure 3: Protocol for the diagnosis of ABPA (ABPA) followed at the authors’ institute (ABPA-B: ABPA

with bronchiectasis; ABPA-HAM: ABPA with high attenuation mucus: ABPA-S: serologic ABPA; kUA-

kilounit of antibody, mgA-milligrams of antibody

31
Figure 4: Algorithm for the management of allergic bronchopulmonary aspergillosis (ABPA)

32
 Table 1. Comparison of the ABPA Working Group criteria (2013) and the newly proposed criteria
ABPA working group criteria Newly proposed criteria
A. Predisposing conditions A. Predisposing conditions
Bronchial asthma, cystic fibrosis Bronchial asthma, cystic fibrosis, chronic obstructive
pulmonary disease, post-tuberculous fibrocavitary
disease
B. Essential criteria (both must be met) B. Essential criteria (both must be met)
i. Serum Aspergillus fumigatus-specific IgE i. Serum Aspergillus fumigatus-specific IgE levels
levels >0.35 kUA/L or positive type I >0.35 kUA/L‡
Aspergillus skin test
ii. Elevated serum total IgE levels >1000 IU/mL* ii. Elevated serum total IgE levels >1000 IU/mL*
Additional criteria (at least two of three) Additional criteria (at least two of three)
i. Presence of precipitating (or IgG) antibodies i. Serum Aspergillus fumigatus-specific IgG levels
against A.fumigatus in serum >27 mgA/L
ii. Thoracic imaging findings consistent with ii. Thoracic imaging findings consistent with
ABPA† ABPA†
iii. Peripheral blood eosinophil count >500 iii. Peripheral blood eosinophil count >500 cells/µL
cells/µL (may be historical) (may be historical)
kUA: kilounit of antibody; mgA: milligram of antibody
*An IgE value <1000 IU/mL may be acceptable, if all other criteria are met (especially if the serum
Aspergillus fumigatus-specific IgG levels >27 mgA/L)
†Features on HRCT chest and/or chest radiograph consistent with ABPA include transient abnormalities
(i.e. nodules, consolidation, mucoid impaction, hyperattenuating mucus, fleeting opacities,
toothpaste/gloved finger opacities, tram-track opacities) or permanent (i.e. parallel lines, ring shadows,
bronchiectasis and pleuropulmonary fibrosis).
‡A positive type I Aspergillus skin test may be considered as a criterion in the place of serum Aspergillus
fumigatus-specific IgE levels only if the latter test is not available

33
Table 2. Proposed scoring system for the diagnosis of allergic bronchopulmonary aspergillosis (ABPA)
Immunological score Value/findings Score
A. fumigatus-specific IgE <0.35 kUA/L -7
0.35-1.9 kUA/L +1
>1.9 kUA/L +3
Total IgE <417 IU/mL -3
417-1000 IU/mL +1
1000-2300 IU/mL +2
>2300 IU/mL +3
Peripheral blood eosinophil count <500 cells/µL 0
500-1000 cells/µL +3
>1000 cells/µL +4
A. fumigatus-specific IgG <27 mgA/L 0
>27 mgA/L +4
Radiological score
HRCT chest* Normal 0
≥2 features of fibrosis +2
Bronchiectasis involving <3 lobes +3
Bronchiectasis involving ≥3 lobes +4
Extensive mucoid impaction +4
Hyperattenuating mucus +5
Scoring
Total score 8 with radiologic score 0 ABPA at risk
Total score ≥9 with radiologic score of 0 ABPA-S (serological ABPA)
Total score ≥9 with radiologic score of 2 ABPA-CPF (ABPA with chronic
pleuropulmonary fibrosis)
Total score ≥9 with radiologic score of 3 or 4 ABPA-B (ABPA with bronchiectasis)
Total score ≥9 with radiologic score of 5 ABPA-HAM (ABPA with high attenuation
mucus)
*The maximum score is taken.
HRCT-high resolution computed tomography, kUA-kilounit of antibody, mgA-milligrams of antibody

34
Table 3. Clinical staging of allergic bronchopulmonary aspergillosis (ABPA) in patients with asthma
Stage Definition Features
0 Asymptomatic • No previous diagnosis of ABPA
• Controlled asthma (according to GINA/EPR-3 guidelines)
• Fulfilling the diagnostic criteria of ABPA (Table 1)
1 Acute • No previous diagnosis of ABPA
• Uncontrolled asthma/symptoms consistent with ABPA
• Meeting the diagnostic criteria of ABPA
1a With mucoid Mucoid impaction observed on chest imaging or bronchoscopy
impaction
1b Without mucoid Absence of mucoid impaction on chest imaging or bronchoscopy
impaction
2 Response • Clinical and/or radiological improvement AND
• Decline in IgE by ≥25% of baseline at 8 weeks
3 Exacerbation • Clinical and/or radiological worsening AND
• Increase in IgE by ≥50% from the baseline established during
response/remission
4 Remission • Sustained clinico-radiological improvement AND
• IgE levels persisting at or below baseline (or increase by <50%) for
≥6 months off treatment
5a Treatment-dependent • ≥2 exacerbations within 6 months of stopping therapy OR
ABPA • Worsening of clinical and/or radiological condition, along with
immunological worsening (rise in IgE levels) on tapering oral
steroids/azoles
5b Glucocorticoid- Systemic glucocorticoids required for control of asthma while the
dependent asthma ABPA activity is controlled (as indicated by IgE levels and thoracic
imaging)
6 Advanced ABPA • Extensive bronchiectasis due to ABPA on chest imaging AND
• Complications (cor pulmonale and/or chronic type II respiratory
failure)
EPR-3: third expert panel report; GINA: global initiative against asthma

35
Table 4. Doses of various drugs used in the management of allergic bronchopulmonary aspergillosis
Oral glucocorticoids
Prednisolone (or equivalent) 0.5 mg/kg/day for two weeks, then on alternate days for eight
weeks. Then taper by 5 mg every two weeks and discontinue
Patients need to be closely followed as 13% of patients may not respond and may require
escalation of steroid dose
Oral azoles
Oral itraconazole 200 mg twice a day, for at least 24 weeks.
Oral voriconazole 200 mg twice a day, for at least 24 weeks.
Nebulized amphotericin B
Amphotericin B deoxycholate
Daily: 5-40 mg twice daily
Intermittent: 20 mg (10 mg twice daily) thrice weekly
Liposomal amphotericin B
Intermittent: 25 mg twice weekly
Amphotericin B lipid complex
Intermittent: 50 mg twice weekly
Pulse methylprednisolone
15 mg/kg/day (maximum 1 gm) intravenous infusion for three consecutive days
Omalizumab
375 mg subcutaneous injection every two weeks for 4-6 months
Inhaled corticosteroids
Single agent inhaled corticosteroid therapy should not be used for controlling immunological
activity of ABPA. However, they are useful agents in the management of asthma
Follow-up and monitoring
• Patients are followed up with monitoring of clinical symptoms (cough, dyspnea), chest
radiograph and total IgE levels, every eight weeks
• Monitor for adverse effects of treatment
• Satisfactory response to therapy is suggested when there is clinical and/or radiological
improvement with at least 25% decline in IgE levels
• Monitor IgE frequently to establish the ‘new’ baseline level for an individual patient
• Clinical and/or radiological worsening along with 50% increase in IgE levels suggests an
exacerbation

36
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