Diagnosis of Allergic Bronchopulmonary Aspergillosis: A Case-Based Approach

Sahajal Dhooria; Ritesh Agarwal

Future Microbiol. 2014;9(10):1195-1208.

What Is the Next Investigation for an Asthma Patient Found to Be Sensitized to A. fumigatus?

The next best step in the algorithmic workup of ABPA is total serum IgE (Box 4).

Total Serum IgE Levels

The serum total IgE level is a valuable test both in the initial diagnosis, and during follow-up of ABPA. A patient's current symptoms cannot be attributed to ABPA in the face of a normal serum IgE (provided that the patient is not on systemic glucocorticoid therapy).^[2] As for specific IgE, the cutoff value of IgE level that should be used for diagnosis of ABPA remains uncertain. This is due to the fact that the levels of IgE overlap between normal individuals, atopic individuals (with or without fungal sensitization) and ABPA.^[34] In 1970, Heiner et al. reported raised IgE values in patients with allergic aspergillosis.^[35] The original paper published in 1977, describing the criteria proposed by the Patterson group did not provide a cutoff for total IgE.^[4] The same group suggested a cutoff of 1500 ng/ml in 1978,^[24] while it was stated as 2500 ng/ml (for the acute stage) in 1982.^[36] In 1986, they proposed that an IgE <1000 ng/ml along with an absence of Aspergillus precipitins probably excluded ABPA while in those with IgE >2000 ng/ml and presence of precipitins, determination of A. fumigatus specific IgE (and IgG levels) was required.^[37] The Northwestern Allergy Immunology series of ABPA used an IgE cutoff of 1000 ng/ml.^[38] Later series have used a cutoff of 1000 IU/ml for diagnosing ABPA in asthma too.^[9,30,39,40] In a latent-class analysis, a cutoff of 1000 IU/ml gave a sensitivity and specificity of 92 and 40%, respectively, whereas using a value of 417 IU/ml (1000 ng/ml) reduced the specificity to 24% with only a marginal increase in sensitivity to 96%.^[8] The latest expert guideline therefore recommends the use of a 1000 IU/ml cutoff for the diagnosis of ABPA.^[7]

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Next Section

Abstract and Introduction
How Does ABPA Manifest Clinically?
Should All Asthmatics Be Screened for ABPA?
What Investigations Are Used for Screening of ABPA?
What Is the Next Investigation for an Asthma Patient Found to Be Sensitized to A. fumigatus?
What Is the Next Step in the Protocol for the Diagnosis of ABPA?
What Criteria Should Be Used for the Diagnosis & Classification of Aspergillus-related Hypersensitivity phenomena in Asthma?
What Should Be the Basis for Staging ABPA?
Is There Any Role of Spirometry in the Diagnosis of ABPA?
Do Sputum Cultures for A. fumigatus Have Any Significance in Diagnosing ABPA?
What Vision Do We Have for 2020 in the Field of ABPA Diagnostics?
Conclusion & Future Perspective
References
Sidebar

Table 1. Clinical staging of allergic bronchopulmonary aspergillosis in patients with asthma.
Stage	Definition	Features
0	Asymptomatic	Never diagnosed to have ABPA in the past, presentation with controlled asthma (according to GINA guidelines) and meeting the diagnostic criteria of ABPA (Box 6)
1	Acute	Never diagnosed to have ABPA in the past, presentation with uncontrolled asthma/constitutional symptoms and meeting the diagnostic criteria of ABPA
1a	With mucoid impaction	Presence of mucoid impaction on thoracic imaging or bronchoscopy
1b	Without mucoid impaction	No mucoid impaction on thoracic imaging or bronchoscopy
2	Response	Clinical and/or radiological improvement^† and fall in IgE by ≥25% of baseline at 8 weeks
3	Exacerbation	Clinical and/or radiological worsening accompanied by an increase in IgE by ≥50% from the previous baseline
4	Remission	Sustained clinicoradiological improvement with IgE levels remaining at or below baseline (or increase by <50%) for ≥6 months off therapy with oral steroids
5a	Treatment-dependent ABPA	Two or more relapses within 6 months of stopping treatment or deterioration in clinical and/or radiological condition and/or immunological worsening on tapering oral steroids/azoles
5b	Glucocorticoid-dependent asthma	Systemic corticosteroids required for asthma control while the ABPA activity is controlled (as indicated by IgE levels and thoracic imaging)
6	Advanced ABPA	Presence of complications (cor pulmonale and/or chronic type II respiratory failure) along with presence of extensive bronchiectasis consistent with ABPA on thoracic radiology after excluding alternate causes

^†For example, resolution of mucoid impaction and consolidation. Permanent changes such as bronchiectasis may persist.
ABPA: Allergic bronchopulmonary aspergillosis; GINA: Global initiative for asthma.
Adapted with permission from [7].

Table 2. Revised radiologic classification of allergic bronchopulmonary aspergillosis based on findings on a high-resolution computed tomography of the chest.
Classification	Features
ABPA-S	Fulfils the diagnostic criteria of ABPA (Box 6) with absence of any radiological finding of ABPA on HRCT of the thorax
ABPA-B	Satisfies the diagnostic requirements of ABPA along with presence of bronchiectasis
ABPA-HAM	ABPA along with presence of high attenuation mucus on HRCT of the thorax
ABPA-CPF	Fulfils the diagnostic criteria of ABPA with at least two radiological features suggestive of fibrosis^† without presence of mucoid impaction (or HAM)

^†Includes fibrocavitary lesions, pulmonary fibrosis, pleural thickening and others.
ABPA: Allergic bronchopulmonary aspergillosis; ABPA-S: Serological ABPA; B: Bronchiectasis; CPF: Chronic pleuropulmonary fibrosis; HAM: High attenuation mucus; HRCT: High-resolution computed tomography.
Adapted with permission from [7].

Box 1. Initial case information.
Case 1: A 51-year-old patient with asthma diagnosed 9 years ago presents with fever, expectoration of mucus plugs and increasing breathlessness. She has been treated for 'pneumonia' thrice over the past 2 years Case 2: A 32-year-old asthmatic patient of 8 years duration maintains good asthma control with moderate doses of inhaled corticosteroids and has had two exacerbations over the past 3 years requiring oral steroids Case 3: A 26-year-old man presents to our chest clinic with history of well-controlled asthma for 6 years. He is being treated with low doses of inhaled steroids Case 4: A 44-year-old lady with history of asthma for 10 years requires high doses of inhaled corticosteroids for control of asthma and has had frequent exacerbations requiring short courses of oral steroids Case 5: A 43-year-old woman presents with history of asthma of 2 years duration. The asthma is well controlled with low doses of inhaled steroids. She has had one exacerbation requiring oral steroid therapy in the last 2 years

Box 2. Case commentary.
All our patients have asthma of several years duration. Cases 1 and 4 have poorly controlled asthma while cases 2, 3 and 5 have well-controlled asthma. Case 1 provides history of recurrent episodes of 'pneumonia' and now has fever and expectoration of mucus plugs which may be a pointer toward allergic bronchopulmonary aspergillosis. It is, however, difficult to predict allergic bronchopulmonary aspergillosis in the other cases

Box 3. Case update: initial workup.
Case 1: The patient is further investigated. She is found to have positive Aspergillus skin test, and a serum A. fumigatus- specific IgE level of 3.15 kUA/l Case 2: The patient is screened with an Aspergillus skin test which turns out to be negative. He seeks advice of another physician and is found to have serum A. fumigatus- specific IgE level of 1.89 kUA/ml Case 3: On investigating, serum A. fumigatus- specific IgE level is 0.53 kUA/l and Aspergillus skin test is positive Case 4: Further workup reveals a positive Aspergillus skin test and serum A. fumigatus- specific IgE level of 1.21 kUA/l Case 5: She is screened for allergic bronchopulmonary aspergillosis with serum A. fumigatus- specific IgE level, which is 0.04 kUA/l Case commentary Cases 1, 2, 3 and 4 have A. fumigatus -specific IgE levels above the presently accepted cutoff of 0.35 kUA/l. Thus, all of them are sensitized to A. fumigatus. Case 5 does not have sensitization to A. fumigatus, and further workup for allergic bronchopulmonary aspergillosis is not indicated in this patient. It is noteworthy that case 2 had a negative Aspergillus skin test, however was found to have a positive A. fumigatus- specific IgE. This highlights the point that allergic bronchopulmonary aspergillosis can be potentially overlooked if Aspergillus skin test is used as the screening test for ruling out allergic bronchopulmonary aspergillosis

Box 4. Case update: IgE levels.
Case 1: Serum total IgE level of 10,900 IU/ml Case 2: Serum total IgE level of 8900 IU/ml Case 3: Serum total IgE level of 300 IU/ml Case 4: Serum total IgE level of 612 IU/ml Case commentary Cases 1 and 2 have raised serum total IgE levels. Thus, they may potentially have active allergic bronchopulmonary aspergillosis (ABPA). Case 3 has well-controlled asthma on low doses of inhaled steroids, is sensitized to A. fumigatus but has a normal total IgE (below any cutoff, either 417 or 1000 IU/ml for ABPA). Thus, the patient has Aspergillus -sensitized asthma but no ABPA. Case 4 is also sensitized to A. fumigatu s and has a normal total IgE, but her asthma is severe. Her diagnosis is severe asthma with fungal sensitization. Rarely, patients with untreated ABPA might have IgE levels between 417 and 1000 IU/ml, especially if they have received a course of oral corticosteroids for the control of their asthma. Therefore, we should go ahead with further workup of ABPA for case 4 as well

Box 5. Case update: other investigations.
Case 1: The patient has positive precipitins against A. fumigatus and eosinophil count of 1789 cells/µl. High-resolution computed tomography (HRCT) of the chest shows mucoid impaction in bilateral upper lobes (with presence of high attenuation mucus in the right lower lobe) and bronchiectasis in both upper lobes and right lower lobe. A review of the chest radiographs during her 'pneumonia' episodes reveals that those were fleeting opacities in the same areas as the mucoid impaction in the present CT scan Case 2: The laboratory findings in this patient are positive precipitins against A. fumigatus, peripheral blood eosinophil count of 975 cells/µl and normal HRCT of the chest Case 3: Workup reveals positive precipitins against A. fumigatus and total eosinophil count of 432 cells/µl. HRCT of thorax reveals minimal bronchiectasis in the right upper lobe Case 4: She has positive precipitins against A. fumigatus, total eosinophil count of 389 cells/µl and normal HRCT of the chest

Box 6. New diagnostic criteria for the diagnosis of allergic bronchopulmonary aspergillosis.
Predisposing conditions Bronchial asthma, cystic fibrosis Obligatory criteria (both must be present) Elevated serum IgE levels against A. fumigatus (>0.35 kUA/l) or immediate cutaneous hypersensitivity to A. fumigatus antigen (positive Type I Aspergillus skin test) Raised serum total IgE levels (>1000 IU/ml) ^† Other criteria (at least two of three) Presence of precipitating (or IgG) antibodies against A. fumigatus in serum Thoracic imaging findings consistent with allergic bronchopulmonary aspergillosis ^‡ Peripheral blood eosinophil count >500 cells/µl (may be historical)
^†An IgE value <1000 IU/ml may be acceptable, if all other criteria are met. ^‡The features on thoracic imaging consistent with allergic bronchopulmonary aspergillosis may be transient (i.e., fleeting opacities, toothpaste/gloved finger opacities, tram-track opacities, consolidation, nodules) or permanent (i.e., bronchiectasis, parallel lines, ring shadows and pleuropulmonary fibrosis).

Box 7. Case commentary: final diagnosis.
Case 1: The patient has Aspergillus sensitization, positive precipitins, high IgE levels and raised eosinophil count. She also has bronchiectasis and high attenuation mucus (HAM) on high-resolution computed tomography. According to the algorithm shown in Figure 3, and the radiological classification listed in Table 2, she fits into the classical picture of allergic bronchopulmonary aspergillosis (ABPA)-HAM. If there were only bronchiectasis without HAM, then this patient would be classified as ABPA with bronchiectasis. Case 2: This patient had a negative Aspergillus skin test but had all other features of ABPA on further investigation. In view of no abnormality on a chest high-resolution computed tomography, he is diagnosed as serological ABPA. Cases 3 and 4 reveal positive precipitins and normal peripheral blood eosinophil counts. Now, it is further confirmed that they have Aspergillus -sensitized asthma and severe asthma with fungal sensitization, respectively.