Allergen

Summary

Aspergillus fumigatus (A. fumigatus) is a saprotroph and opportunistic filamentous fungus widely distributed in the environment. A. fumigatus is a spore-forming, thermotolerant fungus that reproduces asexually through spores in the form of conidia. It is a cosmopolitan pathogen distributed all over the five continents (Europe, Asia, America, Africa and Australia). Inhalation is the main route of exposure to Aspergillus spores. A. fumigatus is the causal agent of allergic and infectious diseases affecting dozens of millions of people globally. Allergic bronchopulmonary aspergillosis (ABPA) is the most severe Aspergillus-related allergic disease, affecting 1-2.5% of asthmatic patients and up to 10% of cystic fibrosis patients during their lifetime. Other significant allergic Aspergillus-related diseases are allergic fungal rhinosinusitis (AFRS) and severe asthma with fungal sensitization (SAFS). Up to now, 23 allergens of A. fumigatus have been characterized. Among them, Asp f 1 and Asp f 2 are major allergens, Asp f 3 has extensive cross-reactivity, and Asp f 4 and Asp f 6 are associated with ABPA diagnosis. Moreover, Asp f 1 and Asp f 2 are markers of genuine sensitization to A. fumigatus. Cross-reactivity has been mainly observed between A. fumigatus and other fungal species.

Epidemiology

Worldwide Distribution

In the vast majority of humans, daily inhalation of A. fumigatus spores does not result in disease, thanks to effective mucociliary clearance and innate immune defenses involving neutrophils and macrophages. However, A. fumigatus is the causal agent of allergic and infectious diseases affecting dozens of millions of people worldwide.

Aspergillus-related allergic (type I hypersensitivity, IgE) diseases mainly affect asthmatic and cystic fibrosis (CF) patients, although rhino-sinusal forms may develop in otherwise nonaffected subjects. Aspergillus sensitization, evidenced by skin or blood specific IgE tests, is associated with poorer lung function in adults and children with asthma, CF and chronic obstructive bronchopulmonary disease (COPD).

Hypersensitivity pneumonitis (type III hypersensitivity, IgG) due to A. fumigatus may develop in the context of occupational exposure, for example in farmers and in rural, malt, or stucco workers.

Allergic bronchopulmonary aspergillosis (ABPA), the most severe Aspergillus-related allergic disease, has an estimated global prevalence of almost 5,000,000, affecting mostly asthmatic and CF patients.

ABPA is estimated to affect 1-2.5% of asthmatic patients and up to 10% of CF patients. These figures may vary with the severity of asthma, comorbidities, fungal ecology, diagnostic criteria, and country of residence. Considering the subgroup of A. fumigatus-sensitized asthma, a systematic review and meta-analysis found that ABPA diagnostic criteria were met by 40% of patients (95% CI 27–53, range 6% - 68%). A. fumigatus sensitization (AFS) itself is a frequent finding in bronchial asthma, demonstrated in 28% of patients (95% CI 24–34, range 15% - 48%). The prevalence of ABPA was found to be high (70%) in severe asthmatic patients as shown in a study among 50 severe asthmatic patients. Finally, the prevalence of ABPA appeared as significantly higher in industrialized than in developing countries (25.6% vs. 12.7%, p = 0.0001). Also, it was reported significantly higher in adults than in children (10.1% vs. 8.9%, p<0.0001).

Other allergic Aspergillus-related diseases are allergic fungal rhinosinusitis (AFRS) and severe asthma with fungal sensitization (SAFS).The prevalence of AFRS is reported to range from 2.7 to 19%. AFRS is a unique form of immune-mediated non-invasive fungal rhinosinusitis. It is definitely higher in arid and tropical climates, such as in the Asia-Pacific region, Australia, Thailand, Malaysia, India, the Middle East, Saudi Arabia, North Africa, and southeastern and southwestern parts of the US, especially the Mississippi basin. Reported prevalence in general population may be as high as 100 to 500 per 100,000 in India and Israel. Climate influence is prominent, as demonstrated by a prevalence of 0.4% in Northern US states compared to over 10% in Southern ones. AFRS can be caused by A. fumigatus, but also by other Aspergillus species, e.g. A. flavus, and by dematiaceous fungi.

SAFS is another phenotype of severe asthma associated with fungal sensitization in adults having overlapping characteristics with ABPA. However, it is distinct from ABPA as it presents without serious bronchopulmonary impairment (bronchiectasis and mucus plugging) and is diagnosed only on exclusion of ABPA. As per a multi-national prevalence estimate analysis of 43 reports, the average global incidence of SAFS was observed to be 154 cases/100,000 cases. Further, the incidence in South and Central America was found to be significantly higher than other continents like Asia, Europe, Africa or North America. Prevalence rate of SAFS due to Aspergillus species (spp.) sensitization was found to be 18.3% among the 109 uncontrolled severe asthmatic patients in a cross-sectional study in Singapore. Similarly a Japanese study on 124 severe asthma patients reported sensitization prevalence of Aspergillus spp.to be 11%. Aspergillus-related infections can be divided into invasive and non-invasive forms, with the former preferentially affecting immunocompromised patients. Invasive aspergillosis (IA) has an estimated global annual incidence of 4.10 cases/100,000 cases, and chronic pulmonary aspergillosis (CPA) is estimated at a global annual incidence of 22 cases/1,000,000 cases as per a global and multi-national prevalence study. A high mortality rate is associated with such infections.

Pediatric issues

Allergic A. fumigatus-related diseases such as ABPA, SAFS, and AFRS are slightly less frequent in children than in adults. ABPA occurrence in children younger than 4 years is infrequent.

Environmental Characteristics

Living environment

Soil is the main habitat of Aspergillus spp. which has adapted to grow in adverse environmental conditions. The most prominent outdoor places where it grows are plants and dead and decayed organic matter. Freshwater and marine habitats are also favorable niches. In indoor environments it is mostly found on the surfaces of buildings, household appliances, in drinking water, and on dust. A. fumigatus can grow at 37°C, explaining its ability to colonize the airways and induce potentially severe infections in immunocompromised hosts.

Worldwide distribution

A. fumigatus is a cosmopolitan, coping with virtually all environments: deserts, forests, wetland, and cultivated soils around the world. Further, it is a ubiquitous pathogen distributed all over the globe covering all the five continents (Europe, Asia, America, Africa and Australia).

Route of Exposure

Main

Large amounts of conidia are released from the mycelial mass in the atmosphere. Humans are estimated to inhale 100 to 1,000 conidia each day from the atmosphere. Due to their small size, in the absence of efficient muco-ciliary clearance, Aspergillus conidia easily reach lung alveoli and may cause colonization even in normal subjects, and respiratory tract infections in susceptible hosts.

Secondary

Other secondary route of A. fumigatus exposure may include transmission through contaminated water, also referred to as ‘wet route of transmission’. This may include drinking of contaminated water, accidental inhalation of fluid into the lungs or even through contact with exposed wounds. The widespread presence of A. fumigatus in stagnant water and water supply systems in hospitals poses considerable infectious risks for immunocompromised patients. This source of contamination from potable water supply of hospitals still poses a hazard risk for immunocompromised patients as per a recent study.

Clinical Relevance

Aspergillus spp. is known to cause a spectrum of lung disorders including allergic (AFRS, ABPA, IgE-mediated asthma, SAFS) and infectious diseases (invasive aspergillosis, chronic pulmonary aspergillosis).

Allergic rhinitis and rhinosinusitis

AFRS is classified as a form of non-invasive, eosinophilic, chronic fungal rhinosinusitis. From a pathophysiologic viewpoint, AFRS is closely related to ABPA, exhibiting inflammation, Th2-skewed anti-A. fumigatus lymphocyte responses with eosinophil involvement, while IgE production is inconsistently demonstrated. AFRS is rarely found alone, as it has been demonstrated that 66% of AFRS patients may have co-existing allergic rhinitis (AR), 90% of them are fungi-sensitized (increased IgE levels) and approximately 50% may have co-existing asthma. Sensitization is more frequent in patients with atopic diseases; conversely, apparent monosensitization to molds is infrequent. In atopic patients, fungal antigenic material is released and induces a chain of immunologic reactions favoring the development of AFRS. In a study on 131 AR patients, 32 (24.4%) displayed Aspergillus sensitization, of whom 28 had associated sinusitis; however, only 2 patients met all the criteria for allergic Aspergillus rhinosinusitis. AFRS can be complicated by concomitant fungal presence and persistence in non-invasive forms, e.g. mycetoma (aspergilloma), a fungal ball in the sinonasal cavities, or even invasive forms with local or systemic infection. The latter group is beyond the scope of the allergy referral, as their treatment relies on antifungal medication and surgery.

Asthma

The two most important conditions associated with sensitization to Aspergillus spp. in asthmatic patients are ABPA and SAFS.

Allergic bronchopulmonary aspergillosis (ABPA)

ABPA is an immune-mediated lung disease due to hypersensitivity to Aspergillus that mostly occurs in individuals suffering from asthma and CF, however it can also occur in non-asthmatics. Sensitized individuals may develop allergic reactions on recurrent inhalation of Aspergillus spores, that is mainly a type I (IgE-mediated) allergic reaction. Additionally, type-III (IgG-mediated immune complex) and type IV (cell-mediated, mainly eosinophils) reactions also play a role.

Typically, ABPA follows a flare and relapse pattern. Asthma exacerbations, poor asthma control, recurrent pulmonary infiltrate resulting in irreversible bronchial remodeling with bronchiectasis form the natural history of ABPA. Another distinctive feature of ABPA is expectoration of brownish mucous plugs (mucus along with fungal hyphae and eosinophils), observed in 5-69% of the patients and representing the clinical counterpart of the computed tomography scan “mucoid impactions”. Asthma severity in ABPA patients can range from mild intermittent asthma to severe persistent asthma that may be corticosteroid dependent. In CF patients, ABPA-related exacerbation with reduced lung function can be accompanied by hemoptysis, increased microbial colonization, pneumothorax, and worsened nutritional status. In both asthmatic and CF patients, untreated ABPA results in severe lung damage with central bronchiectasis, fibrosis and respiratory failure.

The diagnosis of ABPA in asthma or CF patients is complicated due to overlapping clinical features and involves clinical history, immunological findings (such as increased levels of both total serum IgE and A. fumigatus–sIgE as well as Aspergillus-specific IgG), radiological observations. The ISHAM (International Society for Human and Animal Mycology) working group has proposed a classification of ABPA in seven stages, ranging from asymptomatic (serological) expression to respiratory failure.

A prospective study on 35 severe asthmatic ABPA patients reported the prevalence of serological ABPA at 68.5%, compared 31.4% for that of the full-blown form of ABPA with bronchiectasis.

Severe asthma with fungal sensitization (SAFS)

Aspergillus species sensitization has been reported to enhance asthma severity, resulting in worsening of asthma control. A subset of patients diagnosed with severe asthma and fungal sensitization was defined as SAFS. In contrast to ABPA, SAFS does not result in mucoid impactions or bronchiectasis. Additionally, it is associated only with severe asthma, unlike ABPA that can also occur in mild and moderate asthmatic patients.

A retrospective study conducted in United Kingdom (UK) among 135 patients with severe asthma reported a prevalence of 60% for SAFS due to A. fumigatus. In Singapore and Japan, the reported prevalence of Aspergillus spp. sensitization among severe asthmatic patients was 11.7% (n=206) and 11% (n=124) respectively. The occurrence of SAFS was reported at a younger age as compared to patients without fungal sensitization. In accordance to this study, another study conducted in UK on 82 children (4-17 years) reported presence of SAFS in 46% children with onset of asthma at early age.

Atopic Dermatitis (AD)

A cross-sectional study in China conducted among 59 AD patients without respiratory disease found Aspergillus spp. sensitization in 81.4% of patients along with other fungal sensitizations like Penicillium spp. or Candida spp. The contribution of cross-reactions is probably important as suggested by a retrospective study conducted in the Czech Republic, which found only 8% of 60 AD patients were sensitized to Asp f 1, a marker of genuine sensitization to A. fumigatus.

Other Diseases

Due to its ability to interact with multiple players of the host immune response, A. fumigatus induces a continuous spectrum of allergic and infectious diseases. (see above, “Epidemiology” section).

Prevention And Therapy

Prevention Strategies

Avoidance

Aspergillus spp. is an environmental pathogen (health-care-acquired linked with humid and dusty environment), infection may occur due to contamination of the health-care facility. The implicated environmental vehicles are mainly air filters, air conditioners, damaged ventilation system, air filter frames etc. To prevent the spread of A. fumigatus spores, HEPA filtration limits the conidial air counts. A protected environment with high efficiency HEPA filtration along with laminar flow, least air leakage in the room, increased number of hourly air changes, as well as regular maintenance of HEPA filtration systems are recommended in hospital rooms (particularly for immunocompromised patients).

Cross-Reactivity

Extensive cross-reactivity is linked to the homology between allergens found in A. fumigatus and other allergenic molds, mainly Cladosporium, Penicillium, Alternaria and Malassezia.

The table below provides the list of most common cross-reactive A. fumigatus allergens with other fungal allergens:

Explained Results

Allergen information

A. fumigatus is a common aeroallergen of the indoor and outdoor environments. It is a saprotroph and opportunistic filamentous fungus. Major allergens Asp f 1 and Asp f 2 are markers of genuine sensitization to A. fumigatus.

Clinical information

A. fumigatus is the causal agent of potentially severe allergic (allergic rhino-sinusitis, ABPA, IgE-mediated asthma, SAFS) and infectious diseases with high rates of morbidity and mortality.

Cross-reactivity

Aspergillus fumigatus shows important cross-reactivity, mainly with other fungi and yeast species.

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