Asp f 6
Summary
Asp f 6 is a phylogenetically conserved mitochondrial manganese superoxide dismutase (MnSOD) from the ubiquitous environmental mold Aspergillus fumigatus (A. fumigatus), an agent of allergic fungal airway diseases (AFAD) which include severe asthma with fungal sensitization (SAFS) and allergic bronchopulmonary aspergillosis (ABPA). Asp f 6 sensitization occurs mainly in patients with ABPA, but not with other AFAD, and therefore may contribute to the diagnosis of ABPA. Cross-reactivity to Asp f 6 is frequent in atopic dermatitis (AD), as a result of sensitization to Mala s 11 from Malassezia sympodialis, and to human MnSOD.
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 6 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 6 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 found that Asp f 6 sensitization was specific of ABPA, with a prevalence of 55% [2, 3]. Later studies showed that Asp f 6 sensitization is also found, albeit with lower prevalence figures, outside ABPA. For example, 89% of ABPA and 44% of A. fumigatus-sensitized, non-ABPA Indian asthmatics displayed detectable Asp f 6 sensitization in a 2020 study [4]. Conversely, the prevalence of Asp f 6 sensitization was only 38-50% in ABPA patients among two cohorts of Japanese asthmatics, compared to 9-31% of A. fumigatus-sensitized asthmatics without ABPA [5, 6]. In Chinese asthmatic patients from Guangzhou, Asp f 6 sensitization was found in 70% of ABPA patients and in 15% of A. fumigatus-sensitized asthmatic patients without ABPA [7]. Considering CF patients with A. fumigatus-sensitization without ABPA, the prevalence of Asp f 6 sensitization varied from 0% in a Swiss study [8] to 20% in a French one [9], and 25 in a British one [10], increasing to 55% - 89% in ABPA patients from the same cohorts [8-10]. Lower figures were reported in a pediatric CF cohort from the US, with Asp f 6 sensitization present in 25% of ABPA patients and in none of 23 A. fumigatus-sensitized patients without ABPA [11]. Among German and Polish self-reported asthmatic patients with A. fumigatus sensitization, 15% displayed Asp f 6 sensitization, but 17% of non-asthmatic subjects exposed to mold also displayed Asp f 6 sensitization [12].
In patients suffering of AD, Asp f 6 sensitization can be detected with increasing prevalence from 0-5% in mild AD to 27-40% in severe AD [13, 14]. In a Japanese cohort, Asp f 6 sensitization was more frequent in AD patients with (62%) or without (56%) asthma, compared to asthmatic patients free of AD (9%) [5].
Asp f 6 sensitization was found in 6% A. fumigatus sensitized German patients with allergic rhinitis, usually associated to sensitization to other molecular components [15]. In COPD patients, the prevalence of Asp f 6 sensitization was 1%, not different from 0% in controls [16].
Asp f 6 sensitization is usually absent in subjects (healthy, asthmatic, or CF) lacking detectable skin or blood A. fumigatus sensitization [4, 6].
Clinical Relevance
Detailed information regarding A. fumigatus is available in the whole allergen section.
Clinical relevance of Asp f 6 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 6 sensitization is a marker of a more complex sensitization pattern, associated with ABPA [20]. In a meta-analysis, detection of IgE to Asp f 6 offered a 42.6% (95%CI 8-75.7) pooled diagnostic sensitivity for ABPA in asthmatic patients and 51.3% (95%CI 20-75.7) in CF patients, with a pooled specificity of 94.9% (95%CI 70.1-99.9) in asthma and 97.5% (95%CI 87.3-99.9) in CF [22].
Along with the prevalence of Asp f 6 sensitization, Asp f 6 IgE levels are higher in asthmatic or CF patients with ABPA than in counterparts who are A. fumigatus-sensitized but free of ABPA [2, 9, 23, 24]. Median levels of IgE to Asp f 6 in ABPA patients are similar among cohorts from various locations, usually comprised between 2 and 3 kUA/L [7, 9, 10, 23, 24]. Using population-based cut-offs, the reported area under the receiver operating curve of Asp f 6 was 0.830 to 0.896 in different populations [9, 23].
Diagnostic performance of Asp f 6 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 improved the sensitivity for detecting ABPA in asthmatics up to 89.3% (95%CI 78.8-95.5) and in CF to 57% (95%CI 17.6-88.3), while pooled specificity reached 99% in asthmatic patients, and 93.9% in CF patients [22].
Clinical relevance of Asp f 6 IgE in AD
Asp f 6 sensitization detected in AD patients is considered as a marker of extended cross-reactivity among human and fungal MnSOD, with Mala s 11, a MnSOD from Malassezia sympodialis, a more probable primary sensitizer than A. fumigatus. In AD patients, Asp f 6 sensitization may occur in the absence of detectable sensitization to A. fumigatus extract and major allergens, supporting the hypothesis of a cross-reaction rather than a genuine sensitization [26, 27].
Disease severity and prediction
Asp f 6 sensitization and increasing levels of Asp f 6 IgE in asthmatic or CF patients are statistically associated to an increased risk of ABPA, as explained above [24, 28].
In AD patients, Asp f 6 sensitization is associated with disease severity [13, 14, 26] and autoreactivity to human MnSOD and Malassezia sympodialis Mala s 11, homologues of Asp f 6 [17, 26, 29].
Cross-reactive molecules
Asp f 6 cross-reacts with other eukaryotic MnSOD through sequential and conformational epitopes. Clinically, the most relevant cross-reactivity involves both IgE and T cells and is found with MnSOD from other Aspergillus species, with Mala s 11 from Malassezia sympodialis, and with human MnSOD, forming the basis of auto-antigenicity and autoreactivity seen in AD [29-32]. MnSOD may be considered as a panallergen due to cross-reactivity among members of this family [32].
Diagnostics
Disease Severity
Asp f 6 sensitization, especially at high levels, is a specific marker of ABPA in A. fumigatus-sensitized asthmatic and CF patients [17, 22], and an indicator of AD severity and autoreactivity [13, 14, 17, 26].
Cross-Reactivity
Asp f 6 exhibits clinically relevant cross-reactivity with fungal MnSOD, mainly Mala s 11 from Malassezia sympodialis, and with human MnSOD, and is therefore considered a marker of autoreactivity in AD [17, 29].
Exposure
Asp f 6 sensitization occurs through inhalation upon exposure to A. fumigatus [17].
References
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