A wide spectrum of pathological conditions may result from the interaction of Aspergillus fumigatus and the immune system of its human host. Allergic bronchopulmonary aspergillosis is one of the most severe A. fumigatus-related diseases due to possible evolution toward pleuropulmonary fibrosis and respiratory failure. Allergic bronchopulmonary aspergillosis occurs almost exclusively in cystic fibrosis or asth- | ASPERGILLUS FUMIGATUS AND ITS INTERACTION WITH THE HUMAN HOSTThe Aspergillus genus comprises 339 species of filamentous fungi ubiquitous all over the world in human environment, for example, air, soil, cereals, fruit, plants, wet and decomposing organic matter.Airborne Aspergillus spp spores are present indoors and outdoors, with an estimated 10-1000 spores inhaled daily by each human. 4,5 A growing number of Aspergillus species are recognized as pathogenic for animals and humans; yet A. fumigatus (Figure 1) The pathophysiological continuum of A. fumigatus-host interaction is mirrored by laboratory and clinical frames of "asymptomatic"colonization, "benign" IgE sensitization to A. fumigatus, through A. fumigatus-induced cough and asthma, to aspergilloma and invasive aspergilloses. However, the first two stages lack consensus definitions. The growth of A. fumigatus in the airways, also termed "car- irreversible, calls for updating the immunological criteria have been accumulating since the turn of the century. 47,52,60 These calls are supported by novel tools with enhanced performance.We will describe hereafter the issues associated with the current ABPA immunological diagnostic criteria including total serum IgE,A. fumigatus-specific IgE, and A. fumigatus-specific IgG and precipitins against A. fumigatus.

Aspergillus sp. fungi cause various diseases in both immunocompetent and immunocompromised patients. The most frequent Aspergillus disorders include chronic pulmonary aspergillosis (CPA), a life-threatening disease that affects at least 3 million people worldwide, and allergic bronchopulmonary aspergillosis (ABPA), which affects approximately 4.8 million severe asthmatic patients globally. Diagnosis of such diseases involves IgG serological testing; however, the currently available anti-Aspergillus IgG detection assays are inappropriate for resource-poor laboratory settings, as they are expensive, rely on automated procedures, and require stable electrical power. Therefore, accurate CPA or ABPA diagnosis facilities are lacking in most low- and middle-income countries. We evaluated a novel anti-Aspergillus antibody immunochromatographic test (ICT) that requires minimal laboratory equipment. Two evaluations were performed: a single-center 4-month prospective study in a French reference laboratory (44 cases/257 patients) and a retrospective study in five French reference laboratories (262 cases and 188 controls). We estimated the ICT indices for the diagnosis of chronic aspergillosis, and the test results were compared to those of anti-Aspergillus IgG immunoblot (IB) assay. Of the 713 patients included in the study, 306 had chronic aspergillosis. Test sensitivity and specificity were 88.9% (95%CI[85–92]) and 96.3% (95%CI[94–98]) for the ICT and 93.1% (95%CI[90–96]) and 94.3% (95%CI[92–96]) for the IB, respectively. Agreement between the two assays was almost perfect (kappa = 0.86). As this ICT displays good diagnostic performance and complies with the ASSURED (Affordable, Sensitive, Specific, User-friendly, Equipment-free, and Delivered) criteria, we concluded that this anti-Aspergillus antibody ICT can be used to diagnose Aspergillus diseases in resource-poor settings.

Aspergillus fumigatus is the causative agent of allergic broncho-pulmonary aspergillosis. Prompt and accurate diagnosis may be difficult to achieve with current clinical and laboratory scores, which do not include immune responses to recombinant A. fumigatus allergens. We measured specific immunoglobulin E and G4 directed to recombinant A. fumigatus allergens in 55 cystic fibrosis patients without allergic broncho-pulmonary aspergillosis but sensitized to A. fumigatus and in nine patients with allergic broncho-pulmonary aspergillosis (two with cystic fibrosis and seven with asthma). IgG4 responses to recombinant A. fumigatus allergens were detected in all patients, but neither prevalence nor levels were different between the two patient groups. On the other hand, both prevalence and levels of IgE responses to Asp f 3, Asp f 4, and Asp f 6 helped distinguish allergic broncho-pulmonary aspergillosis from A. fumigatus sensitization with good negative and positive predictive values.

Molecular-based allergy diagnosis yields multiple biomarker datasets. The classical diagnostic score for allergic bronchopulmonary aspergillosis (ABPA), a severe disease usually occurring in asthmatic patients and people with cystic fibrosis, comprises succinct immunological criteria formulated in 1977: total IgE, anti-Aspergillus fumigatus (Af) IgE, anti-Af “precipitins,” and anti-Af IgG. Progress achieved over the last four decades led to multiple IgE and IgG(4) Af biomarkers available with quantitative, standardized, molecular-level reports. These newly available biomarkers have not been included in the current diagnostic criteria, either individually or in algorithms, despite persistent underdiagnosis of ABPA. Large numbers of individual biomarkers may hinder their use in clinical practice. Conversely, multivariate analysis using new tools may bring about a better chance of less diagnostic mistakes. We report here a proof-of-concept work consisting of a three-step multivariate analysis of Af IgE, IgG, and IgG4 biomarkers through a combination of principal component analysis, hierarchical ascendant classification, and classification and regression tree multivariate analysis. The resulting diagnostic algorithms might show the way for novel criteria and improved diagnostic efficiency in Af-sensitized patients at risk for ABPA.

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