Allergic Bronchopulmonary Aspergillosis

Abstract

There remains lack of agreement on diagnostic criteria and approaches to treatment of patients with Allergic Bronchopulmonary Aspergillosis (ABPA). The results of a survey of AAAAI members regarding these 2 issues are presented and compared for concordance with published recommendations. The literature was reviewed for pertinent reports and an electronic survey was conducted of AAAAI members and fellows regarding diagnostic criteria, numbers of patients evaluated for ABPA, and treatment approaches. From 508 respondents to the survey sent to 5155 U. S. physicians in the AAAAI database of members and fellows, 245 (48%) health professionals had treated at least 1 patient with ABPA in the previous year. For the diagnosis of ABPA, there was a difference in the threshold concentration of total serum IgE as 44.9% used ≥ 417 kU/L whereas 42.0% used ≥ 1000 kU/L. These findings suggest that ABPA might be underdiagnosed. Regarding pharmacotherapy, oral steroids were recommended for 97.1% of patients and oral steroids + inhaled corticosteroids + anti-fungal agent were utilized in 41.2% of patients. The armamentarium for treatment of ABPA includes oral corticosteroids as the initial treatment with inhaled corticosteroids used for management of persistent asthma. Azoles remain adjunctive. Published experience with omalizumab has been limited.

The global prevalence of Allergic Bronchopulmonary Aspergillosis (ABPA) has been estimated to be as high as 2.5%¹, yet delays in diagnosis or undertreatment may lead to pulmonary fibrosis, bronchiectasis with chronic sputum production, and increasingly severe persistent asthma with loss of lung function. There are differences of opinion over the criteria for diagnosis, screening tests in patients with asthma, and how best to manage and treat the patient.² ABPA is almost always caused by Aspergillus fumigatus, which has intrinsic virulence, survival characteristics, pro-inflammatory actions, and enzymatic properties in susceptible hosts. The purpose of this review is to consider fungi implicated in Allergic Bronchopulmonary Mycoses, a brief discussion of the immunopathology, approaches to management and treatment, and report findings from a survey of allergist-immunologists in the AAAAI that explored the diagnostic criteria and treatments of ABPA.

Allergic Bronchopulmonary Mycosis

Since the original description of Allergic Bronchopulmonary Aspergillosis in 1952³, a number of other fungi or yeasts have been implicated as causing a similar clinical syndrome. Examples are listed in Table 1. Aspergillus fumigatus is by far responsible for the majority of these cases. But other fungi or yeasts have been identified when patients presented with features of ABPA (e.g., pulmonary infiltrates with peripheral blood eosinophils, +/− bronchiectasis, underlying asthma) but lacked evidence of sensitization or recovery of Aspergillus fumigatus. The culprit fungus was identified in sputum or airway samples along with evidence of sensitization to the fungus by skin test or in vitro measurement. The diagnosis of ABPM therefore is predicated on the identification of fungi, other than A. fumigatus, by appropriate culture or molecular biology techniques in patients with clinical features of ABPA. Often there is repeated recovery of the rare fungus or yeast that leads to the diagnosis. Since commercially available reagents for skin testing and for in vitro methods to detect specific IgE antibodies are lacking for many of these fungi involved in ABPM, investigators need to prepare their own reagents or refer patients/samples to specialized centers for evaluation. It is likely that additional case reports of ABPM will appear due to the spectrum of fungi in the environment and the increasing prevalence of asthma.

Table 1.

Fungi Associated with Allergic Bronchopulmonary Mycoses

Organism	Reference
Aspergillus fumigatus	Hinson et al, 19523
Aspergillus ochraceus	Greenberger, 19884
Aspergillus oryzae	Akiyama, at al. 19875
Aspergillus terreus	Elliott et al, 19976
Alternaria alternata	Chowdhary et al, 20127
Bipolaris (Dreschleria) hawaiiensis	McAleer et al, 19818
Candida albicans	Akiyama et al, 19849
Cryptococcus neoformans	Arora et al, 200510
Curvularia lunata	Halwig et al, 198511
Fusarium vasinfectum	Backman et al, 199512
Geotricum candidum	Elliott et al, 19976
Helminthosporium species	Hendrich DJ, et al 198213
Penicillium species	Elliott et al, 19976
Peudoallescheria boydii	Elliott et al, 19976
Sacchromycetes cerevisiae	Ogawa et al, 200414
Schizophyllum commune	Kamei K et al, 199415
Stemphyllium lanuginosum	Benatar et al, 198016
Torulopsus glabrata (now designated Candida glabrata)	Patterson et al, 198217

Criteria for Diagnosis of Allergic Bronchopulmonary Aspergillosis

In a 2012 review in the Journal of Allergy and Clinical Immunology, the criteria for diagnosis were presented as follows: “The minimal criteria required for the diagnosis of ABPA are as follows: (1) asthma or CF with deterioration of lung function, (2) immediate Aspergillus species skin test reactivity, (3) total serum IgE level of 1000 ng/mL (416 IU/mL) or greater, (4) increased Aspergillus species–specific IgE and IgG antibodies, and (5) chest radiographic infiltrates. (See Table 2) Additional criteria might include peripheral blood eosinophilia, Aspergillus species serum precipitating antibodies, central bronchiectasis, and Aspergillus species–containing mucus plugs.”¹⁸

Table 2.

Diagnostic Criteria for Allergic Bronchopulmonary Aspergillosis in Patients with Asthma or Cystic Fibrosis

Patients with Asthma or Cystic Fibrosis (2012 Criteria in JACI18)

Asthma or if Cystic Fibrosis, with deterioration of lung function

Immediate skin reactivity to Aspergillus species

Total serum IgE ≥ 1000 ng/mL (416 IU/mL)*

Increased Aspergillus species-specific IgE and IgG antibodies

Chest roentgenographic infiltrates

“Additional criteria might include peripheral blood eosinophilia, Aspergillus species serum precipitating antibodies, central bronchiectasis, and Aspergillus species-containing mucus plugs”

ABPA Consensus Conference of the Cystic Fibrosis Foundation (200319)

Acute or subacute clinical deterioration (increased cough, wheezing, exercise induced asthma, increased sputum, decrease in pulmonary function)

Total serum IgE concentration > 1000 kU/L unless the patient is receiving systemic corticosteroids

Immediate cutaneous reactivity (prick skin test) to Aspergillus or presence of serum IgE-A. fumigatus

Precipitating antibodies to A. fumigatus or serum IgG-A. fumigatus

If the total serum IgE concentration is >500 but ≤ 1000, then repeat it especially if the patient no longer requires oral corticosteroids. See text for criteria when the total IgE is 200–500 kU/L.

^*1 IU/mL = 1 kU/L = 2.4ng/mL

In 2003, the ABPA Consensus Conference of the Cystic Fibrosis Foundation¹⁹ proposed that ABPA be diagnosed for a classic case as follows: 1) acute or subacute clinical deterioration (increased cough, wheezing, exercise induced asthma, increased sputum, decrease in pulmonary function), 2) serum total IgE concentration >1000 kU/L unless the patient is receiving systemic corticosteroids, 3) immediate cutaneous reactivity (prick skin test) to Aspergillus or presence of serum IgE-A. fumigatus, and 4) precipitating antibodies to A. fumigatus or serum IgG-A fumigatus. The minimal diagnostic criteria are 1) acute or subacute clinical deterioration (increased cough, wheezing, exercise induced asthma, increased sputum, decrease in pulmonary function), 2) serum total IgE concentration > 500 kU/L, (If ABPA is suspected and the total serum IgE level is 200–500 kU/L, repeat the total serum IgE in 1–3 months. If the patient is using oral corticosteroids, repeat the total serum IgE when steroid treatment has been discontinued.¹⁹) 3) immediate cutaneous reactivity (prick skin test) or presence of serum IgE122 A. fumigatus, 4) One of the following: a) precipitins to A. fumigatus or demonstration of IgG-A. fumigatus or b) new or recent abnormalities on chest radiography (infiltrates or mucus plugging) or chest CT (bronchiectasis) that has not cleared with antibiotics and standard physiotherapy.¹⁹

Potential diagnostic tools related to detection of fungal infection or colonization include findings from studies of invasive aspergillosis²⁰ and cystic fibrosis²¹ consisting of enzyme assays for detection of antigenic side chains of Aspergillus galactomannan,²⁰ 1,3-β-D-glucan, which is the cell wall component of A fumigatus and other fungi,²⁰ and A fumigatus DNA by PCR.²⁰ The latter methodology detects viable and dead fungal organisms and inert spores.²¹

Genetic Risk Factors

Genetic studies may provide potential aids in diagnosis and pathogenesis. For example, HLA-DR restriction has been shown to be a risk factor for the development of ABPA. Chauhan et al^22–24 observed that patients with asthma and CF patients who expressed HLA-DR2 and/or DR5 but lacked HLA-DQ2 were at increased risk for ABPA after exposure to A. fumigatus. In particular, HLA-DR2 HLA-DRB1*1501 and HLA-DRB1*1503 genotypes were reported to provide high relative risk. Further studies indicated that the presence of HLA-DQ2, especially DQB1*0201, provided protection from the development of ABPA. Brouard et al²⁵ reported that the -1082GG genotype of the IL-10 promoter was associated with colonization of A. fumigatus and the development of ABPA in CF. The -1082GG polymorphism has been associated with increased IL-10 synthesis; whereas the -1082A allele has lower IL-10 synthesis. Saxena et al²⁶ reported that ABPA patients with polymorphisms (ala91pro, arg94arg) in the collagen region of pulmonary surfactant protein A2 (SP-A2) had elevated total IgE concentrations and higher percentages of eosinophilia than observed in those patients who lacked the SNPs. They also found that 80% of patients carrying both alleles had ABPA (P = 0.0079, OR = 10.4), while only 50% and 60% of patients carrying each allele, individually, were ABPA subjects, suggesting an additive effect.²⁶ It is theorized that changes in conformation or affinity of SP-A2 may decrease these interactions and compromise host defense.

Miller et al²⁷ examined mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) in asthmatic subjects who did not have a diagnosis of cystic fibrosis. Mutations were present at a higher frequency in asthmatic patients who developed ABPA, 6 of 21 (28.5%), versus control patients with asthma, 2 of 43 (4.6%). These ABPA patients were heterozygous for the mutations. It is unclear what effect heterozygous CFTR mutations may have on mucus quality in airways of patients with asthma. Carvalho et al²⁸ examined Toll-like receptor (TLR) polymorphisms of TLR2, TLR4 and TLR9 in cavitary pulmonary aspergillosis (CCPA), severe asthma associated with fungal sensitization (SAFS) and ABPA patients. ABPA patients had increased frequency of allele C for the TLR9 T-1237C polymorphism compared to control patients. TLR-9 is a receptor that recognizes CpG motifs prevalent in bacterial and viral DNA. Novak et al²⁹ reported that the TLR9 C allele of T-1237C decreases expression. Thus, decreased TLR-9 protective function may be an underlying susceptibility in the development of ABPA.

Diagnostic Criteria by Allergist-Immunologists

The results from a survey carried out by the AAAAI in 2012 are presented in Tables 3–5. Using the AAAAI’s database of 5155 U. S. physicians, members and fellows were contacted on multiple occasions. (see Appendix 1 for the questionnaire). The response rate was 9.8% (508 physicians). Of these, 245 allergist-immunologists answered affirmatively to question 1 (Appendix 1) that they had seen a patient with ABPA in the past year and provided demographic information about their practice locations and range of patients with ABPA seen in the past year (Table 3). The range of diagnostic criteria used are presented in Table 4. There is an evenly divided difference between using the total IgE concentration of ≥ 417 IU/mL (kU/L) by 44.9% and ≥ 1000 IU/mL (kU/L) by 42% respondents respectively. In retrospect, some results may be attributable to the order of questions in the survey (Appendix 1, question 3 comes after both 1 and 2 and should have come after 1 to focus on ABPA and the same question coming after question 2 to focus on cystic fibrosis). Alternatively, because 83.7% of respondents referred to patients with ABPA, it is suspected that some of the difference in concentration of total IgE as a criterion does apply to ABPA). Bronchiectasis was a diagnostic criteria by 49.8% of the respondents. These data emphasize the need to clarify diagnostic criteria in order to increase (enhance) uniform application.

Table 3.

Patients and practice settings of 508 allergist-immunologists who completed a survey about their allergic bronchopulmonary aspergillosis (ABPA) patients

	Results number (%)
PATIENTS
ABPA patients
No	263 (51.8 %)
Yes	245 (48.2 %)
Patients with asthma with ABPA	205 (83.7%)
1–5 patients	214(87.3%)
6–10 patients	23 (9.4%)
>11 patients	8 (3.3%)
Patients with Cystic Fibrosis with ABPA	40 (16.3%)
1–5 patients	36 (14.7%)
6–10 patients	3 (1.2%)
>11 patients	1 (0.4%)
PRACTICE SETTING OF PHYSICIANS WITH ABPA PATIENTS
Rural area	9 (3.7%)
Metropolitan area population
<100,000	33 (13.5%)
100–999,000	84 (34.3%)
>1,000,000	116 (47.3 %)
Missing	3 (1.2 %)

Table 5.

Medications/Testing by 245 allergist-immunologists for patients with allergic bronchopulmonary aspergillosis in the past year

Treatment or Test	Patients, number (%)
OCS	238 (97.1%)
OCS + ICS	124 (50.6%)
OCS, no ICS	26 (10.6%)
Anti-fungal alone	3 (1.2%)
OCS/ICS + anti-fungal	101 (41.2%)
Voriconazole and/or posiconazole	65 (26.5%)
Omalizumab	23 (9.4%)
ACTH stimulation test
1 month	13 (5.3%)
3–6 months	36 (14.7%)

OCS: oral corticosteroid

ICS: inhaled corticosteroid

Table 4.

Diagnostic criteria used by 245 allergist-immunologists who diagnosed allergic bronchopulmonary aspergillosis in the past year

Study	Patients or Number (%)
Asthmatic patients with ABPA	205 (83.7%)
Cystic Fibrosis patients with ABPA	40 (16.3%)
Aspergilus fumigatus prick skin test (PST)	188 (76.7%)
Aspergillus fumigatus intradermal skin test (IDST)	104 (42.4%)
Anti-Aspergillus fumigatus IgE	157 (64.1%)
PST/ IDST/anti-Aspergillus fumigatus IgE	231 (94.3%)
Aspergillus fumigatus precipitins	127 (51.8%)
Anti-Aspergillus fumigatus IgG	99 (40.4%)
Af precipitins/ Anti-Aspergillus fumigatus IgG	175 (71.4%)
Total IgE ≥417 IU/ml	110 (44.9%)
Total IgE ≥1000 IU/ml	103 (42.0%)
Peripheral Blood Eosinophils ≥400/µL	54 (22.0%)
Bronchiectasis	122 (49.8%)

Management of Allergic Bronchopulmonary Aspergillosis

Treatment Goals

The overall goals are four-fold: 1) control of symptoms of asthma or cystic fibrosis (CF); 2) prevent or treat pulmonary exacerbations of ABPA; 3) reduce or remit pulmonary inflammation; and 4) mitigate progression to end-stage fibrotic or cavitary disease (Table 6). Early and aggressive treatment of ABPA has the greatest likelihood of preventing progression to end-stage fibrotic lung disease (stage V).^30–34 Following therapy, many patients with stage I (acute stage) and stage III (exacerbation stage) can enter complete remission, stage II, represented by a 35–50% reduction in total serum IgE by 6 weeks, clearing of pulmonary infiltrates and symptomatic improvement. Unfortunately this may not be permanent, as some patients relapse and have additional pulmonary infiltrates.^33–34 Earlier diagnosis and treatment appears to lower the risk of advancement to stage IV (glucocorticosteroid dependent) or stage V (fibrocavitary disease).³⁴

Table 6.

Stages of allergic bronchopulmonary aspergillosis in patients with asthma

Stage	Radiography on Chest Roentgenogram or CT Lungs (examples)	Total IgE Concentration
I
(Acute)	Homogeneous infiltrates, mucus plugging, Consolidation or lobar collapse, “tree-in-bud” findings, bronchiectasis	Elevated
II
(Remission)	No infiltrates	Normal or elevated but less than in Stage I
III
(Exacerbation)	As in stage 1	Elevated (double that of Stage 2)
IV
(Steroid dependent asthma)	No infiltrates, can have atelectasis or hyperinflation from asthma (if an exacerbation occurs, pulmonary infiltrates such as in stage 1 can be present)	Elevated or normal
V
(End Stage Fibrotic)	Scarring, hyperinflation, chronic infiltrates, fibrosis or cavities or fibrocavitary findings	Normal or elevated

Exposure

Bioaerosols of very large numbers of fungi (with bacteria and endotoxins) occur from disturbing organic waste and have been associated with ABPA in 2 of 28 garden waste collectors.³⁵ We were unable to find evidence to make a strong recommendation to minimize exposure to fungi through avoidance and mitigation such as from moldy basements, water damaged buildings, saunas, and indoor areas with improper home ventilation. While these are prime locations for growth of molds³⁶, and can be pertinent for patients with asthma and allergic rhinitis, there is a lack of evidence to make a strong recommendation regarding prevention of pulmonary infiltrates in ABPA.

Therapeutics

Oral Corticosteroids

Corticosteroids remain the mainstay in the management of ABPA, by targeting the inflammatory response triggered by A. fumigatus.³⁴ Most patients with ABPA require periods of oral steroid treatment, followed by tapering doses. Dosing of oral steroids for ABPA has not been well defined. Lower dose oral steroids have been associated with a higher rate of relapse, whereas higher doses for longer duration have a higher remission rate. A common strategy³⁴ is 2 weeks of daily prednisone 0.5mg/kg, followed by 6 to 8 weeks of alternate day therapy and then tapering by 5–10mg every 2 weeks. A more aggressive approach^32,33 is prednisolone 0.75mg/kg/day for 6 weeks, then 0.5mg/kg/day for 6 weeks, followed by a tapering dose of 5mg every 6 weeks to continue for a total duration of 6 to 12 months.

Oral steroids are important in the control of symptoms and reducing the likelihood of relapse. Patients are considered in remission when they remain without pulmonary infiltrates/eosinophilia for 6 months after oral steroid withdrawal.³⁴ A useful marker of disease activity and success of therapy is a total serum IgE concentration. Total serum IgE is monitored every 6 to 8 weeks after the initiation of oral steroids and continued for one year thereafter. The goal is to achieve a 35% to 50% reduction of total serum IgE, which leads to clinical and radiological improvement. Chest imaging, either by chest x219 ray or high resolution chest CT, after 4 to 8 weeks of initiation of oral steroid therapy, is important to assess resolution of infiltration. Spirometry is also a useful tool to objectively assess response to therapy.³⁰

Intravenous Corticosteroids

Pulse therapy with monthly intravenous methylprednisolone at a dose of 10–20mg/kg/day for three consecutive days, in conjunction with itraconazole, has been demonstrated effective in both reduction in subjective symptoms as well as objective measurements.^37,38 This may be a consideration in patients demonstrating resistance to oral therapy. A potent inhibitor of CYP3A4, itraconazole increases concentrations of methylprednisolone but not prednisolone and can cause suppression of cortisol secretion.³⁹

Inhaled Corticosteroids

Inhaled corticosteroids are a central component in the management of persistent asthma; however in the dosage equivalent of 400–800 μg of beclomethasone dipropionate, when combined with a long acting beta agonist, they have not been shown to be effective in preventing increasing concentrations of total IgE.⁴⁰ While symptoms of asthma were improved, they could not be controlled completely.⁴⁰ The authors concluded that “High doses of ICS alone have no role in the management of ABPA-S and should not be used as first-line therapy.”⁴⁰

Antifungals

Antifungals play an important, yet adjunctive role in the management of ABPA. Antifungals may reduce the requirement for prolonged high dose systemic corticosteroids by decreasing the burden of fungal colonization and attenuating inflammatory responses. The majority of the literature addressing antifungal therapy focuses on the use of Amphotericin and the azoles (ketoconazole, itraconazole, voriconazole and posaconazole). In recent years the use of Amphotericin B and ketoconazole has been replaced by antifungals with fewer potential side effects.

Itraconazole

Among the antifungals used to treat ABPA, itraconazole is the most commonly recommended. Itraconazole has been demonstrated to significantly reduce total serum IgE, sputum eosinophils and most importantly decrease symptoms and the oral steroid requirement.^41,42 Itraconazole is recommended for those patients who are steroid dependent and for those that have relapse following course of steroids. The recommended adult dose for itraconazole is 200mg twice daily for 4 to 6 months and then tapered over the following 4 to 6 months. As noted earlier, it is important to note that itraconazole can inhibit the metabolism of methylprednisolone. Renal function and concurrent medication usage should also be monitored. As with most azoles, adverse drug reactions are not uncommon and include nausea and vomiting, diarrhea, flatulence, hyperlipidemia, hypokalemia and elevated liver enzymes. Phototoxicity and photosensitivity (UVA) have been reported.⁴³ An alternative approach is for courses of 4–6 months.^44,45 As with any antimicrobial agent, resistance to azoles is well known, and fungal sensitivities may need to be obtained in some patients.^*

Other Azoles

Voriconazole and posaconazole are reported to be an effective adjunct therapy in the management of ABPA with clinical improvement in 68% of patients with ABPA treated with voriconazole and 78% of ABPA patients treated with posaconazole.⁴⁶ Side effect profiles were similar to itraconozole 40% of those treated with voriconazole and 22% of those with posaconazole.⁴⁶ Dosing of voriconazole adult patients is 300–600mg/day and posaconazole 880mg/day; adjusted by plasma monitoring. The target pre-dose voriconazole plasma level was 1.3–5.7 mg/mL. The target posaconazole random plasma level was >0.7 mg/L.⁴⁶ In patients who had failed to improve with itraconazole, at least 70% of patients, who tolerated either voriconazole or posaconazole, responded favorably.⁴⁷

Monoclonal Antibody Therapy

There have been a few case reports demonstrating benefit of omalizumab in the management of ABPA, where some patients had concurrent cystic fibrosis.^48–50 A trial of omalizumab in 16 patients with asthma and ABPA, demonstrated significant reductions in exacerbations and steroid requirement, although did not demonstrate improvement in spirometry.⁵¹ Reduction in exacerbations of asthma and oral steroid requirements have been reported by others.⁵² This potential adjunct in ABPA management, with a low side effect profile, warrants double blind, randomized, controlled trials. The role of treatment with antibodies to IL-4Rα (dupilumab), IL-5 (mepolizumab), IL-13 (lebrikizumab) or other targets in ABPA remains speculative.

Treatments and Tests by Allergist-Immunologists

The AAAAI survey results regarding treatment and testing approaches are presented in Table 5. Oral corticosteroids with or without inhaled corticosteroids were administered by 97% of the respondents. Antifungals plus corticosteroids were utilized by 41% of respondents. The distribution of medications or their combinations could reflect varying stages of ABPA (pulmonary infiltrates or none), repetitive expectoration of sputum plugs or none, ease or difficulty of treatment of concomitant asthma or ABPA, and physician and patient preferences among other explanations.

Summary

As the worldwide prevalence of asthma has increased, it appears that the prevalence of ABPA also has increased. Thus, ABPA is no longer a rare condition and has been recognized as specific subtype (endotype) of asthma.⁵³ The results of the study of allergist-immunologists in the AAAAI suggest that uniform criteria for diagnosis are needed, especially as to the cut-off of total IgE concentration (and the appropriate units (eg kU/L, IU/mL in which it is expressed), and that controlled trials would be informative to understand the place in therapy of all of the therapies that are employed. Establishing separate registries of patients with ABPA with asthma and with cystic fibrosis in terms of risk factors, exposures, and diagnostic criteria and treatment, would provide valuable information in better understanding and treating ABPA.

Abbreviations

ABPA

Allergic Bronchopulmonary Aspergillosis

ABPM

Allergic Bronchopulmonary Mycosis

CCPA

Chronic cavitary Pulmonary Aspergillosis

CF

Cystic Fibrosis

CFTR

Cystic Fibrosis transmembrane conductance regulator

SAFS

Severe asthma associated with fungal sensitization

SP-A2

Surfactant protein A2

TLR

Toll-like receptor