Allergic bronchopulmonary aspergillosis (ABPA) in an atopic patient with difficult-to-expectorate airway secretions

In the workup of a 55-year-old atopic patient with cough and viscous secretions, we diagnosed an allergic bronchopulmonary aspergillosis (ABPA) on the basis of common diagnostic criteria for adult asthma patients (Rosenberg-Patterson and ISHAM), supported by the use of IgE antibodies against the Aspergillus components Asp f 2, f 4, and f 6. Initial treatment with prednisolone and itraconazole led to remission. In the long-term follow-up, there were few relapses until 2015, which responded well to standard treatment with oral steroids, and since 2016 the patient is in stable remission. The case highlights the valuable contribution of Aspergillus IgE measurements, including the specific IgEs against the components Asp f 1, f 2, f 4, and f 6 in the diagnosis of ABPA.

A 55-year-old male patient in good general condition presented for the first time in July 2010. He described rhinitis that had been present for 2 months and cough symptoms with viscous secretions that were difficult to expectorate and were yellowish in color. In the previous few days, he had occasionally coughed up a "worm-like plug of secretion". Occasionally, there was also discrete shortness of breath associated with the cough, so the family physician prescribed salbutamol DA as needed, but the patient used it very rarely.
For many years, the patient had been known to have tree pollen allergy with seasonal rhinoconjunctivitis in March and April and oral allergy syndrome to pome fruits.

Case report
However, the hay fever had improved in recent years. Otherwise, there were no relevant previous illnesses.
The patient was a journalist, there was no obvious exposure to dust or molds in his professional or private life and no pets.

Findings
Clinical examination on July 15, 2010, revealed a somewhat attenuated breath sound apically over both lungs with otherwise unremarkable findings.
Skin tests revealed immediate reactions to the two molds Aspergillus fumigatus and Alternaria alternata as well as sensitization to birch, ash, and grass pollen and house dust mites ( Table 1).
The laboratory values (Table 2) showed a massively increased total IgE with significantly increased specific IgE antibodies against Aspergillus fumigatus (including its components) and Alternaria alternata. In addition, there was an elevated IgG against Aspergillus fumigatus in the sense of a type-3 reaction, as well as an eosinophilia.
Chest X-ray on August 18, 2020 ( Figure  1), showed focal patchy compressions in the right upper lobe and at the cardiac apex, no effusion. The hilar region was unremarkable.

Evaluation
The strongly elevated total IgE as well as the elevated specific IgE antibodies against Aspergillus fumigatus and its components Asp 2, Asp f 4, and Asp f 6 raised the suspicion of the presence of allergic bronchopulmonary aspergillosis (ABPA), although the bronchial symptoms were mild except for the coughing up of secretory granules at initial presentation, and the pulmonary function showed only borderline obstruction with, however, a marked increase in FeNO, consistent with Th-2 bronchial asthma.
Based on the subsequent diagnostic workup (differential blood count, specific Aspergillus IgG, chest X-ray), a diagnosis of ABPA was finally made. Five major and two minor criteria of the Rosenberg-Patterson diagnostic criteria were present (Table 3) [1]. The 2021 International Society for Human and Animal Mycology (ISHAM) criteria, last revised, were also met (Table 4) The high-level sensitization to the mold Alternaria could also still direct suspicion to allergic bronchopulmonary mycosis (ABPM) caused by this fungus. Despite its ubiquitous occurrence, Alternaria triggers ABPM much less frequently than Aspergillus fumigatus and is also treated with systemic steroids in the same way as ABPA so that in the further course only the Aspergillus parameters were controlled.

Therapy
Under systemic steroid therapy with initially 40 mg prednisolone daily, which could be phased out over 5 months, as well as itraconazole 200 mg daily during the first 4 weeks, the symptoms subsided rapidly, the radiograph normalized, and the serological parameters decreased (Table 5).

Course
After a long stable course under asthma therapy using an inhaled steroid, relapses with clinical deterioration and significant increases in total IgE and specific Aspergillus IgE antibodies occurred again in October 2014 and August 2015 (Table 6).  The relapses were ameliorated by several weeks of systemic steroid administration, and no further relapses occurred in the last 4 years with inhaled asthma therapy only. No bronchiectasis was found on a chest CT carried out in May 2016.

Context (literature review)
ABPA is a complex clinical entity that usually develops on the background of allergic asthma or cystic fibrosis. The clinical picture can vary widely from severe disease to only mild symptoms, as in the case described, in which ABPA-S, i.e. ABPA without bronchiectasis and without permanent radiographic changes of the lungs, is present. If left untreated, irreversible changes such as bronchiectasis, fixed obstruction, pulmonary fibrosis, and respiratory failure may result.
Serology plays a central role in ABPA diagnosis. Rosenberg and Patterson's diagnostic criteria (Table 3), used since 1977, include an elevated total IgE of at least 1,000 ng/mL (equivalent to 418 kU/L today). In more recent literature, threshold values for total IgE of 500 kU/L or 1,000 kU/L are frequently used [2,3,16], although the value of 500 kU/L is to be preferred in screening due to its higher sensitivity. In addition, type 1 sensitization to Aspergillus fumigatus must be present, which can be detected by a positive skin test and a specific IgE > 0.35 kU/L, although much higher IgE concentrations are usually present.
In the 1990s, the Davos working group first described the importance of IgE antibodies against specific Aspergillus epitopes, in particular Asp f 2, f 4, and f 6, for the diagnosis of ABPA in both asthma and cystic fibrosis patients [4,5,6,7,8]. Subsequently, other research groups have also confirmed that these  Table 4. Modified ISHAM criteria 2021 [3].
A recent work from India has now shown that the combination of IgE antibodies against Asp f 1 (at a cutoff of 4.4 kU/L) and Asp f 2 (at a cutoff of 1.3 kU/L) have a sensitivity of 100% and a specificity of 81% in differentiating between Aspergillussensitized asthma patients and patients with ABPA in asthma [15].
For follow-up during therapy and for the detection of a relapse, the determination of total IgE is usually sufficient; here, antibodies against the Aspergillus components have only a limited additional benefit [16]. However, they are helpful for follow-up when other causes besides ABPA might have an influence on total IgE, such as atopic dermatitis, parasitosis, infection, or additional seasonal pollen allergy.
For ABPA screening in asthma patients, in the future, based on the current data from India, the excellent combined sensitivity of Asp f 1 and Asp f 2 may allow these two parameters to be used in combination with total IgE instead of specific IgE against total Aspergillus extract. The determination of sIgE against Asp f 4 and f 6 can then be performed for confirmation due to the very good specificity of these two parameters. It would be desirable to verify the value of the two parameters Asp f 1 and f 2 in a study including European patients, since genetic differences of the patients as well as variations of the Aspergillus strains in India and Europe may well play a role [17].

Conclusion
ABPA may additionally be present even in mild or moderate asthma. Therefore, in any type of asthma and in cystic fibrosis, total IgE determination is useful to avoid overlooking ABPA. If total IgE values exceed 500 kU/L and there is simultaneous evidence of Aspergillus sensitization in the specific IgE or in the skin test, ABPA should then be considered. The IgE antibodies against the Aspergillus components Asp f 1, f 2, f 4, and f 6 make a valuable further contribution in the diagnosis of ABPA.