Asp f 4
Summary
Asp f 4 is a species-specific allergen of the ubiquitous environmental mold Aspergillus fumigatus (A. fumigatus), an agent of allergic fungal airway diseases (AFAD) affecting upper and lower airways, such as allergic fungal rhinosinusitis (AFRS), severe asthma with fungal sensitization (SAFS), and allergic bronchopulmonary aspergillosis (ABPA). Asp f 4 is a major allergen in ABPA, and a minor one in other AFAD, and therefore may contribute to the diagnosis of ABPA.
Epidemiology
Worldwide distribution
A. fumigatus is a cosmopolitan, thermotolerant airborne fungus affecting human health through multiple pathways: allergy, infection, direct toxicity [1].
The prevalence of Asp f 4 sensitization is highly variable depending on the study population in terms of geography, underlying lung condition, i.e. asthma, cystic fibrosis (CF), or chronic obstructive pulmonary disease (COPD), stage of AFAD, method of assessment (skin prick test, blood tests) and cut-off values. Despite wide variations, Asp f 4 sensitization presents with higher prevalence and higher levels in ABPA as compared to asthmatic patients and healthy individuals. Early reports in European asthmatic patients sensitized to A. fumigatus showed Asp f 4 sensitization in 92% of ABPA cases and in 25% of those without ABPA [2]. A similar figure of 84% for Asp f 4 sensitization was reported in 2020 in ABPA patients with asthmatic background, compared to 32% in A. fumigatus-sensitized asthmatic patients from India [3]. Conversely, the prevalence of Asp f 4 sensitization was only 33-36% in ABPA patients among two cohorts of Japanese asthmatics, compared to 6-20% of A. fumigatus-sensitized asthmatics without ABPA [4, 5]. In
Chinese asthmatic patients from Guangzhou, Asp f 4 sensitization was found in 61% of ABPA patients and in 33% of A. fumigatus-sensitized asthmatic patients without ABPA [6]. Considering CF patients with A. fumigatus-sensitization without ABPA, the prevalence of Asp f 4 sensitization varied from 0% in Swiss and British studies [7, 8] to 38% in a French one [9], increasing to 75% [8], 80% [7] or even 100% [9] in ABPA patients from the same cohorts. Similar figures were reported in a pediatric CF cohort from the US, with Asp f 4 sensitization present in 82% of ABPA patients and in 35% of A. fumigatus-sensitized patients without ABPA [10]. Among German and Polish self-reported asthmatic patients with A. fumigatus sensitization, 31% displayed Asp f 4 sensitization, but 17% of non-asthmatic subjects exposed to mold also displayed Asp f 4 sensitization [11].
Asp f 4 sensitization may be higher in atopic dermatitis (AD). In a Japanese cohorts, Asp f 4 sensitization was more frequent in AD patients without asthma (38%), followed by asthmatic patients with AD (20%) compared to asthmatic patients free of AD (6%) [4].
Asp f 4 sensitization was found in 10% of A. fumigatus sensitized German patients with allergic rhinitis, usually associated to sensitization to other molecular components [12]. In COPD patients, the prevalence of Asp f 4 sensitization was 1%, not different from 0% in controls [13].
Asp f 4 sensitization is usually absent in subjects (healthy, asthmatic, or CF) lacking detectable skin or blood A. fumigatus sensitization [3, 5, 14].
Clinical Relevance
Detailed information regarding A. fumigatus is available in the whole allergen section.
Clinical relevance of Asp f 4 IgE in ABPA
The diagnosis of ABPA is often complicated by symptoms due to underlying conditions and a complex pathophysiology combining IgE and IgG responses, sputum and systemic eosinophilia, and much debated fungal colonization [20, 21]. While Asp f 1 and Asp f 2 are major allergens and markers of genuine sensitization to A. fumigatus, Asp f 4 sensitization is a marker of a more complex sensitization pattern, associated with ABPA [20]. Detection of IgE to Asp f 4 had a 50-84% diagnostic sensitivity for ABPA in asthmatic patients and 67% in CF patients, with a specificity of 68-92% [22, 23].
Along with the prevalence of Asp f 4 sensitization, Asp f 4 IgE levels are higher in ABPA [2, 9, 22, 23]. Median levels of IgE to Asp f 4 in ABPA patients vary among cohorts, and may reach 15 kUA/L [6, 8, 9, 23, 24], supporting the observation that statistically determined cut-off levels in a given population perform better than fixed cut-offs [23]. Using population-based cut-offs, the reported area under the receiver operating curve of Asp f 4 was 0.740 to 0.970 in different populations [9, 22, 23].
Diagnostic performance of Asp f 4 is improved when used in conjunction with other A. fumigatus molecular allergens [23-25]. As an example, a meta-analysis revealed that the presence of either Asp f 4 or Asp f 6 sensitization detected ABPA with a pooled specificity of 99% in asthmatic patients, and 93.9% in CF patients [22].
Disease severity and prediction
Asp f 4 sensitization and increasing levels of Asp f 4 IgE in asthmatic or CF patients are statistically associated to an increased risk of ABPA, as explained above. In CF patients with ABPA, a strong correlation (r = 0.89, p<0.01) was reported between levels of Asp f 4 IgE and the levels of thymus and activation-regulated chemokine (TARC), a marker of clinically active ABPA in CF patients, involved in Th2 responses through recruitment of CCR4+ and CCR8+ Th2 cells [26].
Asp f 4 sensitization is associated with bronchiectasis in patients with AFAD, but not in COPD patients [13, 27]. Asp f 4 sensitization has not been described as associated with poorer lung function [27].
Cross-reactive molecules
Asp f 4 sequence exhibits an identity of 80% or higher with only 6 other proteins from the Aspergillus genus [28].
Diagnostics
Disease Severity
Asp f 4 sensitization, especially at high levels, is a specific marker of ABPA in A. fumigatus-sensitized asthmatic and CF patients [22]. Asp f 4 sensitization is associated with bronchiectasis in AFAD [27].
Cross-Reactivity
Asp f 4 is considered as a species-specific A. fumigatus allergen [19].
Exposure
Asp f 4 sensitization occurs through inhalation upon exposure to A. fumigatus [15].
References
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