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Allergic Bronchopulmonary Aspergillosis: A Disease that Raises Many Questions
Aspergilosis broncopulmonar alérgica: una enfermedad con muchos interrogantes
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In the healthy host, these spores are eliminated quickly. However, in susceptible subjects, a hypersensitivity reaction occurs due to the defective elimination of these conidia from the airways, associated with innate and adaptive immunity defects, causing an inflammatory reaction with mast cell degranulation, recruitment of a large number of inflammatory cells (neutrophils and eosinophils), and IgE synthesis (total and specific).<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">1</span></a> Its pathogenesis, then, is characterized in immunological terms by immediate hypersensitivity (type-I), antigen–antibody complexes (type-III), and response by inflammatory cells such as eosinophils (type-IVb). Although ABPA was first described in 1952,<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">2</span></a> proper diagnosis and treatment still depend on scant information, as there are few controlled trials (most publications are case series) that address these knowledge gaps.</p><p id="par0015" class="elsevierStylePara elsevierViewall">ABPA mainly affects patients with cystic fibrosis (CF) and asthma, and although genetic predisposition appears to be a factor, the reasons why some subjects are susceptible and others not remain to be clarified. Approximately 9% of CF patients have ABPA,<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">3</span></a> compared to 0.7%–3.5% of asthmatics (approximately 4.8 million cases worldwide).<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">4</span></a> Despite this high prevalence, ABPA is still underdiagnosed, partly because clinical suspicion in CF is complicated, as symptoms and radiological and functional findings that support an ABPA diagnosis are often common in this condition, and asthma patients also have overlapping symptoms. Moreover, the disease is sometimes asymptomatic. In recent decades, however, the number of cases reported has increased, probably indicating a greater awareness among professionals.</p><p id="par0020" class="elsevierStylePara elsevierViewall">The ABPA diagnostic criteria proposed by Rosenberg<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">5</span></a> in 1977, which require a combination of clinical, radiological and immunological findings (8 major and 3 minor criteria), remain in force. However, these criteria have several limitations, including the lack of consensus on the number of major and minor criteria required and the cut-off values of the various immunological tests. Indeed, several groups have proposed different ways of diagnosing ABPA in asthma and CF,<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">1,6,7</span></a> and there are still no clearly standardized and validated diagnostic criteria. The ISHAM group,<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">1</span></a> for example, published a set of highly practical recommendations that contain easily obtained variables, i.e., the existence of a predisposing disease (asthma, COPD, cystic fibrosis, etc.) together with 2 mandatory analytical criteria, and another 2 of 3 additional criteria (analytical and radiological), with well-established cut-off points, so they are very useful in routine clinical practice. However, the lack of standardization means that the disease is not correctly diagnosed in many countries (in developing countries up to one third of cases are misdiagnosed as pulmonary tuberculosis), and diagnosis is also often late, with a diagnostic delay of up to 10 years. It is therefore recommended to rule out ABPA in any patient with CF or asthma, regardless of severity or level of control.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">1</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">It is important to recognize ABPA in order to establish early diagnosis and treatment to improve symptoms and prevent or delay the development of bronchiectasis and pulmonary fibrosis, which are manifestations of permanent lung damage associated with worse health outcomes.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Treatment objectives include reduction of inflammation, control of symptoms, prevention of exacerbations, and mitigation of onset or progression to chronic lesions. The natural history of ABPA is characterized by repeated exacerbations, so most patients require long-term treatment.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">1</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Treatment of ABPA includes anti-inflammatory drugs (glucocorticoids) to suppress the immune hyperresponse, and antifungal agents to attenuate (or eliminate) the fungal burden in the airways. Oral glucocorticoids are currently the first line of treatment, as they are the most effective therapy, although there is no clear agreement on dosing protocols and duration. However, their significant side effects mean that they must be used judiciously. By reducing the fungal burden, antifungal agents reduce the antigenic stimulus and can act as steroid-sparing agents, so they are positioned as second-line treatment. Itraconazole 400<span class="elsevierStyleHsp" style=""></span>mg/day is usually recommended, although itraconazole doses have never actually been standardized in the treatment of ABPA, and lower doses (200<span class="elsevierStyleHsp" style=""></span>mg/day) have also been found to be clinically effective. Several reviews have also emphasized the weakness of evidence on the safety and efficacy of the azoles,<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">8,9</span></a> and the duration of treatment, when they should be started, and the best protocol are all still unclear.</p><p id="par0040" class="elsevierStylePara elsevierViewall">In the search for more effective and safe treatments, taking into account that the response to <span class="elsevierStyleItalic">Aspergillus</span> is mainly mediated by a T2 response that generates IL-5 and IgE, trials of new biological treatments for asthma such as omalizumab (anti-IgE) or anti-IL5/antieosinophils have shown very promising results.</p><p id="par0045" class="elsevierStylePara elsevierViewall">In fact, several case series with omalizumab have been published,<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">10</span></a> but currently only 1 randomized, placebo-controlled study is available, which is limited by its small sample size (13 patients) and single-center, open-label design.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">11</span></a> A clinical trial did begin,<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">12</span></a> but ended earlier than expected due to adverse events probably caused by an unrealistic design that involved the administration of a daily dose of omalizumab. In the published cases using omalizumab in ABPA, a significant reduction in exacerbations and use of oral corticosteroids was detected,<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">10,11</span></a> and the doses used in asthma appear to be sufficient despite these patients’ higher IgE levels.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Case series with mepolizumab and benralizumab as monotherapy for ABPA have also shown good results.<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">13,14</span></a> Furthermore, given the eosinophilia and increased IgE characteristic of ABPA, omalizumab has been used synergically in combination with an anti-IL5.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">15</span></a> These new treatments appear to be a good alternative, especially as corticosteroid-sparing agents or in patients who refuse steroid treatment. However, due to the lack of clinical trials, the ideal dose, length of treatment, and the medium to long-term side effects remain to be determined.</p><p id="par0055" class="elsevierStylePara elsevierViewall">Although almost 70 years have passed since the first description of a patient with ABPA, there are still large gaps in our knowledge, and evidence on epidemiology, pathogenesis, diagnosis, and treatment is limited. More effective and less toxic treatments are needed for the management of this complex disorder. Given the results of case studies with the newly available drugs and the lack of controlled trials, a greater commitment to research is needed to help answer the questions raised.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflict of Interests</span><p id="par0060" class="elsevierStylePara elsevierViewall">Alicia Padilla Galo has participated in scientific papers and/or scientific consultancy with the following companies: ALK-Abelló, Astra-Zeneca, Boehringer, Chiesi, Grifols, GSK, Menarini, Mundipharma, Novartis, Orion, Pfizer, Praxis, Teva, and Zambon.</p><p id="par0065" class="elsevierStylePara elsevierViewall">Borja Valencia Azcona states that he has no conflict of interest.</p><p id="par0070" class="elsevierStylePara elsevierViewall">Casilda Olveira has participated in training activities and expert committees sponsored by Glaxo, Chiesi, Gilead, Praxis, Vertex, Novartis, Teva and Zambon.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflict of Interests" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Padilla-Galo A, Valencia Azcona B, Olveira C. Aspergilosis broncopulmonar alérgica: una enfermedad con muchos interrogantes. Arch Bronconeumol. 2020;56:424–425.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:15 [ 0 => array:3 [ "identificador" => "bib0080" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Developments in the diagnosis and treatment of allergic bronchopulmonary aspergillosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "R. Agarwal" 1 => "I.S. Sehgal" 2 => "S. Dhooria" 3 => "A.N. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 4 | 6 | 10 |
| 2024 October | 56 | 25 | 81 |
| 2024 September | 49 | 22 | 71 |
| 2024 August | 73 | 36 | 109 |
| 2024 July | 43 | 26 | 69 |
| 2024 June | 51 | 30 | 81 |
| 2024 May | 79 | 41 | 120 |
| 2024 April | 29 | 30 | 59 |
| 2024 March | 44 | 26 | 70 |
| 2024 February | 36 | 20 | 56 |
| 2023 November | 2 | 0 | 2 |
| 2023 August | 1 | 0 | 1 |
| 2023 May | 6 | 4 | 10 |
| 2023 April | 4 | 4 | 8 |
| 2023 March | 15 | 5 | 20 |
| 2023 February | 40 | 18 | 58 |
| 2023 January | 33 | 30 | 63 |
| 2022 December | 57 | 24 | 81 |
| 2022 November | 61 | 36 | 97 |
| 2022 October | 65 | 39 | 104 |
| 2022 September | 44 | 30 | 74 |
| 2022 August | 64 | 48 | 112 |
| 2022 July | 38 | 43 | 81 |
| 2022 June | 33 | 36 | 69 |
| 2022 May | 45 | 33 | 78 |
| 2022 April | 41 | 30 | 71 |
| 2022 March | 45 | 40 | 85 |
| 2022 February | 13 | 28 | 41 |
| 2020 October | 1 | 0 | 1 |
| 2020 July | 1 | 1 | 2 |
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