Introduction

The genus Aspergillus comprises over 300 described species, which differ in their morphology, physiology, and phylogenetic characteristics. Only a few dozen of these have been described as facultative human pathogens [1]. The spores of the mold are ubiquitous in the environment and persist even under varying environmental conditions. In humans, Aspergillus spp. can cause a variety of diseases [2].

This review article deals with the most relevant disease entities from a clinical perspective, which affect both infectious diseases and allergology. These include invasive aspergillosis (IA), which exclusively affects immunocompromised patients, chronic pulmonary aspergillosis (CPA) in patients with structural lung diseases, Aspergillus-associated sinusitis and hypersensitivities due to inhaled spores as allergic bronchopulmonary aspergillosis (ABPA). These entities are often difficult to distinguish from each other. Overall, the diagnosis and treatment of these rare diseases are complex and generally require a multidisciplinary approach.

Definitions and risk factors

Aspergillus species can cause a variety of diseases. If Aspergillus is detected in a sample, the correct interpretation of the findings will guide further diagnostics and treatment.

The sole detection of Aspergillus spp. on an external surface is not sufficient for the diagnosis of aspergillosis, as Aspergillus is a ubiquitous organism that is inhaled by breathing and can also be swallowed. Inhaled spores are either exhaled, removed via mucociliary clearance, or destroyed by macrophages. If these mechanisms are prevented by an underlying disease, the physiological defense is bypassed and very different clinical pictures can develop [3].

Invasive pulmonary aspergillosis (IPA) in immunocompromised patients is the most common opportunistic infection caused by molds and is characterized by the invasion of hyphae into the tissue. Accordingly, the final diagnosis of IPA is defined via histopathology. A typical risk constellation is pronounced immunosuppression, which is already present in acute leukemia at the time of diagnosis and is intensified by antileukemic therapy. The rate of patients with leukemia developing IA was up to 24% before the introduction of systemic prophylaxis [4]. The strongest predisposing factor is neutropenia, but Aspergillus is also a potentially pathogenic agent for other patient groups. These include recipients of solid organ transplants, especially after lung transplantation [5]. In patients receiving intensive care treatment, viral pneumonia and viral tracheitis pave the way for IPA. For example, severe coronavirus disease 2019 (COVID-19) pneumonia leads to IPA in up to 22% of cases [6]. Other sites of manifestation of IA are much rarer and include the upper respiratory tract, the central nervous system (CNS), and the gastrointestinal tract.

CPA requires a pre-existing change in lung structure, for example caverns after pulmonary tuberculosis. Spores cannot be sufficiently mobilized from damaged lung areas by mucociliary clearance. In addition, immune control is impaired in the pathologically dilated airways. At the same time, such preformed cavities provide ideal temperature and humidity conditions for the growth of Aspergillus fumigatus [7].

ABPA must be distinguished as a further chronic form. It is often associated with bronchiectasis in patients with bronchial asthma or cystic fibrosis (CF). It is based on a continuously ongoing inflammatory reaction that leads to tissue damage, but by definition there is no tissue invasion by Aspergillus hyphae [8].

Sinus mycoses are divided into invasive and non-invasive forms, both of which can occur in immunocompromised patients and most commonly affect the maxillary sinus. Here, local surgical measures are an obligatory part of treatment, whereas drug-based antifungal and immunomodulating therapy is predominantly used for the aforementioned entities.

Other disease entities in which Aspergillus spp. plays a role are exogenous allergic alveolitis, which can be caused as a hypersensitivity syndrome by a variety of antigens, or intoxications due to endogenously produced fungal toxins, which are not discussed here.

Invasive aspergillosis

IA typically manifests as an opportunistic infection in the airways of immunocompromised patients. Frequently detected species include A. fumigatus, A. flavus, A. niger and A. terreus [9]. The ubiquitous airborne fungal spores enter the upper and lower respiratory tract via inhalation, where they can multiply effectively in immunocompromised individuals. Invasive growth and angioinvasion can lead to hematogenous spread in all organ systems and even disseminate in patients with pronounced and persistent immunodeficiency [10, 11]. Due to high morbidity and mortality (up to 60%), adequate measures for prophylaxis and early detection are required in patients at increased risk, as well as comprehensive diagnostics and early initiation of treatment if IA is suspected [10,11,12].

Preventive measures should be taken to avoid mold infections in the home environment of severely immunocompromised patients. Potential exposure exists from indoor plants, compost piles, gardening, poorly maintained ventilation, air conditioning, and plumbing. These sources should be avoided; if this is not possible, personal protective equipment with gloves and mouth and nose protection should be worn [13]. A so-called low-germ diet is now not considered beneficial for the prophylaxis of mold infections, even in cases of severe immunosuppression. In certain high-risk populations, primary antifungal prophylaxis with medication is indicated to reduce invasive mycoses, especially candidemia and IA. These include, in particular, patients with acute leukemia and patients after allogeneic stem cell transplantation with or without graft-versus-host disease (GvHD) or after lung transplantation [14, 15]. Drug prophylaxis should then be carried out with a mold-active triazole (e.g., posaconazole), which has even been shown to reduce overall mortality in acute myeloid leukemia [16].

In addition to these classic predisposing risk factors, other risk groups have emerged as a result of medical advances. These include patients with acute and chronic lung diseases (COVID-19, chronic obstructive pulmonary disease [COPD]), or those taking high doses of corticosteroids or other immunomodulating drugs [17]. Similarly, an increase in the incidence of IA has been recorded in recent years. The estimated annual incidence is currently over 300,000 cases worldwide [18].

The clinical presentation of IA is variable and depends largely on the location and extent of the infection. In addition to respiratory symptoms, such as cough, hemoptysis and pleuritic symptoms, extrapulmonary infection can lead to further symptoms such as focal neurological deficits in CNS infections or skin lesions due to septic embolism [17]. In immunocompromised patients with persistent fever during treatment with broad-spectrum antibiotics, IA should be clinically suspected and trigger interdisciplinary diagnostic investigations [10, 11].

Chest computed tomography (CT) should be performed to identify signs suggestive for IPA, the most common manifestation of IA [10]. Typical signs of IPA include solitary or multiple nodular lesions with or without cavities, which can form the tree-in-bud pattern in a peribroncholar location and can present with a surrounding ground glass infiltrate, the so-called halo sign (Fig. 1a; [17, 19]). The latter resembles hemorrhage adjacent to the focus of infection and typically occurs in patients with thrombocytopenia [19]. On CT angiography, the so-called vessel occlusion sign indicates angioinvasive growth and is associated with an increased risk of intrapulmonary hemorrhage [20, 21]. Positron emission tomography (PET-CT) can also be performed to identify other foci of infection if hematogenous spread to other organ systems is suspected [10, 11]. During antifungal therapy, the so-called “air crescent sign” often appears as a morphological correlate of the regression of the infiltrate with permanently destroyed lung tissue (Fig. 1b; [19]).

Fig. 1
figure 1

Invasive pulmonary aspergillosis (IPA) on thorax computed tomography (CT) thorax: a nodular infiltrate with surrounding halo sign, b air crescent sign

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Due to the variable appearance and interpretation of the radiologic examination, patients with fungal infiltrates should always undergo bronchoscopy with bronchoalveolar lavage (BAL) and biopsy for cultural, histologic, molecular genetic and serologic workup [10, 11, 19].

Microscopy typically reveals rather narrow hyphae (3–6 µm) with regular septation and acute-angled branching [22]. Since precise differentiation based solely on morphological criteria is not possible with certainty, cultural and/or molecular biological evidence should be performed to confirm the diagnosis [10, 11]. In addition to pathogen detection and species identification, culture also enables resistance testing, but has limited sensitivity [10, 11]. Both pathogen detection and identification of the causative species can also be achieved using molecular genetic tests in the form of polymerase chain reactions (PCR) [10, 11]. Fresh, untreated clinical samples are preferred to tissue embedded, as formalin can damage the deoxyribonucleic acid (DNA) [22, 23]. The serological detection of galactomannan, a cell wall component of Aspergillus, can be performed from BAL fluid as well as from serum [10, 11].

Three substance classes are currently available for the antifungal treatment of IA. The choice depends on the clinical condition of the patient, any pre-existing comorbidities, in particular renal impairment, the likelihood of azole resistance and/or the suspicion of other molds (e.g., Mucorales). When selecting the substance, it should also be considered whether antifungal prophylaxis has been carried out beforehand, as a change of substance class should be made if breakthrough infection is suspected [10, 11].

The recommended first-line therapy consists of voriconazole with level monitoring as part of therapeutic drug monitoring (TDM) [10, 11]. Alternatively, other azoles, such as isavuconazole and posaconazole, as well as liposomal amphotericin B can be used as second-line therapy [10, 11]. The latter should be considered as an option, particularly in cases of breakthrough mycoses or relevant drug interactions during azole therapy, but unlike triazoles, it can only be administered intravenously. Other therapeutic alternatives include echinocandins, such as caspofungin and micafungin, as well as combination therapies, primarily involving voriconazole, in cases of severe disease or as salvage therapy [10, 11]. New antifungal substances currently undergoing clinical trials, such as ibrexafungerp, fosmanogepix and olorofim, represent promising future treatment options, particularly in the context of increasing azole resistance and oral availability [24].

In addition to the patient’s immune status, the duration of therapy depends largely on the clinical and radiological response to therapy and typically extends over 12 weeks [10, 11]. Close clinical and radiological follow-up examinations are therefore essential. The 16-part “EQUAL Aspergillus Score” of the European Confederation of Medical Mycology (ECMM) can be used to monitor compliance with current guideline recommendations for IPA (Fig. 2; [25]).

Fig. 2
figure 2

EQUAL Aspergillus Score of the European Confederation of Medical Mycology (ECMM). CT computed tomography, BAL bronchoalveolar lavage, GM galactomannan, PAS periodic acid Schiff stain, PCR polymerase chain reactions, TDM therapeutic drug monitoring

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Chronic pulmonary aspergillosis

CPA is a chronic disease caused by Aspergillus spp. that usually occurs in immunocompromised or mildly immunosuppressed patients with previously damaged lungs. Predisposing diseases include chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, sarcoidosis, or tuberculosis. The disease can also occur after surgery, for example, after resection of a lung carcinoma [26]. In damaged lung sections, the mucociliary clearance of the lungs is limited and the mold can escape the immune system. It is estimated that around 3 million people worldwide are affected [27].

CPA occurs in various forms and both the clinical symptoms and the radiological appearance are nonspecific and often difficult to differentiate from the predisposing disease. Shortness of breath, cough, and weight loss are common symptoms [7]. This complicates the diagnosis and requires a high degree of clinical vigilance to initiate the diagnostic work-up.

The pillars of CPA diagnostics are CT imaging, Aspergillus detection from respiratory material using culture or PCR and serological testing. Invasive diagnosis using a lung biopsy is helpful, but not always feasible [28]. Radiologically, CPA presents heterogeneously. The various manifestations of CPA are defined on the basis of imaging [28]. The most common form is chronic cavitary pulmonary aspergillosis (CCPA); other forms include chronic fibrosing pulmonary aspergillosis (CFPA), Aspergillus nodules, and aspergilloma (Fig. 3). These phenotypes can overlap considerably, leading some experts to believe that the clinical and radiological features of CPA represent a continuum [29].

Fig. 3
figure 3

Aspergilloma in chronic pulmonary aspergillosis

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Another important component in the diagnosis is serological testing for Aspergillus antibodies. Aspergillus-specific IgG can be quantified using ELISA (enzyme-linked immunosorbent assay). The sensitivity of the marker depends, among others, on the form of CPA manifestation. In addition, the assay was developed to detect antibodies against Aspergillus fumigatus, meaning that the diagnostic significance of CPA caused by non-fumigatus Aspergillus spp. is limited [30].

The diagnosis of CPA can be made after exclusion of differential diagnoses if there is a corresponding clinical picture over 3 months, a suitable radiologic picture and positive microbiologic or immunologic evidence of Aspergillus spp.

Evidence regarding optimal treatment of CPA is limited and treatment strategies are as heterogeneous as the disease itself. Therapeutic management is highly dependent on the clinical presentation and subtype of the disease. Patients with clinically and radiologically stable aspergilloma, CCPA, or CFPA do not always require antifungal treatment [28]. Follow-up controls including pulmonary function, radiology, and serology may be sufficient until the onset of symptoms or radiographic progression of the disease.

In the case of therapy, this is usually characterized by an alternation between watch-and-wait episodes and antifungal therapy using an oral azole antifungal agent, on an outpatient basis. The azoles most commonly used in CPA are itraconazole and voriconazole. Both drugs showed clinical improvement in the majority of patients in clinical studies [31, 32]. It has also been shown that 12 months of treatment with itraconazole is superior to 6 months of treatment in terms of the frequency of recurrence [33]. Therapeutic drug monitoring should be performed when using these azoles.

If azole therapy is not possible due to adverse effects, drug interactions, toxicity or azole resistance, intravenous therapy with amphotericin B or echinocandins must be used [28]. In the future, further drugs will be available for outpatient use. The oral beta-D-glucan synthase inhibitos ibrexafungerp or the echinocandin rezafungin, which only needs to be administered once a week, are promising new substances that will have a place in CPA therapy. In addition, various inhaled antifungal agents are currently undergoing clinical trials [24]. Surgical resection can be considered for localized findings and is associated with a long-term treatment response [26].

If left untreated, CPA has a high mortality rate. Complication management is of great importance. Pulmonary hemorrhages in particular can be life-threatening and require immediate intervention if severe [34]. The monitoring of treatment response is not standardized. Clinical assessment, quality of life assessment and pulmonary function testing as well as follow-up imaging and Aspergillus serology are used for follow-up [35].

There is also an ECMM EQUAL score for CPA to monitor compliance with current guideline recommendations (Fig. 4; [36]).

Fig. 4
figure 4

ECMM EQUAL chronic pulmonary aspergillosis (CPA) score for measuring the QUALITY of clinical treatment of chronic pulmonary aspergillosis

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In summary, CPA is a complex disease that is presumably underdiagnosed and for which various fundamental management issues have not yet been adequately investigated. Initiatives such as the European CPAnet network aim to promote and structure clinical research on CPA [29].

Allergic bronchopulmonary aspergillosis

ABPA is a complex immunological disease of the bronchial system triggered by Aspergillus species [8]. Colonization of the airways precedes clinical manifestation. If other molds or yeasts cause this clinical picture, it is referred to as allergic bronchopulmonary mycosis (ABPM), which, however, occurs much less frequently than ABPA [37] and is not the subject of this article. In most cases, the underlying disease is bronchial asthma or CF. However, cases without these pre-existing conditions have also been described [38], for example, in patients with COPD or non-CF-associated bronchiectasis.

In patients with bronchial asthma, an ABPA prevalence of 2.5% is reported [39]. A prevalence of 11.3% in a recent review article of global data [40] and 5.7% in a population-based study from India [41] appears to be too high, at least for the geographical conditions in this country. However, the prevalence undoubtedly increases with increasing severity of asthma and with proven sensitization to Aspergillus [40].

In an acute episode of ABPA (either at initial diagnosis or in a recurrence), the symptoms of poorly controlled asthma are usually present, especially dyspnea and cough. Typically, patients also report a feeling of thoracic pressure and an increased secretion burden that is difficult to mobilize. Coughing up solid lumps of mucus (so-called mucus plugs) should always be a sign of ABPA. Rarer symptoms include fever, hemoptysis, weight loss, and night sweats. However, up to 20% of patients are asymptomatic at the time of diagnosis [42].

After the first description by Hinson in Great Britain in 1952, Rosenberg et al. established diagnostic criteria for the first time in 1977 [43], which were last modified in 2021 ([44]; Tables 1 and 2).

Table 1 Rosenberg–Patterson diagnostic criteriaa of allergic bronochopulmonary aspergillosis (ABPA; from Rosenberg et al. [43])
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Table 2 Modified International Society for Human and Animal Mycology (ISHAM) criteria 2021 (from Saxena et al. [44])
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Imaging, which today is primarily performed with thin-slice CT of the thorax in cases of suspected ABPA, is not discussed in detail here and reference is made to the relevant literature [45]. Reference is only made to the diagnostic value of high-attenuation mucus (HAM), which has almost 100% specificity in the diagnosis of ABPA [46].

All the criteria published to date include allergological–immunological parameters. These include: Total IgE, Aspergillus-specific IgE and IgG as well as eosinophilia in the blood count. Specific IgEs against the Aspergillus components Asp f 1, f 2, f 4, and f 6 can also increase sensitivity and specificity [47].

Total IgE is well suited as a screening parameter; values < 500 kU/l rule out ABPA (and ABPM) with a high degree of probability. This cut-off value has replaced the old value of 1000 kU/l in the new diagnostic criteria of the International Society for Human and Animal Mycology (ISHAM) due to higher sensitivity, but the values are often significantly higher [44]. However, there are also cases of ABPA with a total IgE < 300 kU/l [42].

The detection of type 1 sensitization to Aspergillus is mandatory for the diagnosis of ABPA, so that ABPA can be ruled out in its absence. The more sensitive intradermal test has now largely been replaced by the prick test due to its lack of availability [48].

However, studies have shown that the specific IgE against A. fumigatus has a better sensitivity than the skin test, so that it has replaced the skin test in the more recent criteria [44].

It is also possible to determine specific IgEs against five Aspergillus components (Asp f 1, f 2, f 3, f 4, and f 6). As early as the 1990s, studies in adult asthmatics and CF patients showed that the detection of IgE antibodies against the Aspergillus components Asp f 4 and f 6 has a high specificity for the presence of ABPA [49, 50]. A study from India was able to demonstrate a further increase in sensitivity when IgE against the two major components Asp f 1 and Asp f 2 was determined instead of the total extract [51].

One advantage of component diagnostics over the total extract is the more reliable extract quality, although cross-reactions are also possible with the components, for example of Asp f 3 with Candida spp. and Penicillium spp. and of Asp f 6 with Malassezia sympodiali [52].

Aspergillus-specific IgG is not an obligatory diagnostic criterion; an Aspergillus IgG in the reference range does not rule out ABPA if sufficient other criteria are met. In Germany, the determination is predominantly carried out using ELISA-based methods, mostly with the FEIA-ImmunoCAP, which has a better sensitivity compared to immunoprecipitation [53]. Determining a suitable cut-off is a challenge and the information in the literature on this varies considerably [54].

Eosinophilia is anchored in all diagnostic criteria and here, too, the previous cut-off of 1000 eosinophils/µl blood was recently reduced to 500/µl [44, 55]. Eosinophilia is more pronounced with a higher secretion load and regional differences must be taken into account. The following median values (25–75 percentile) of eosinophils in ABPA patients were determined in studies in three countries with different sociodemographic structures: India 800/µl (400–1400), Japan 1075/µl (640–1797), France 165/µl (65–360) [42]. Eosinophilia is very characteristic of ABPA, but is not an obligatory diagnostic criterion.

In sputum culture, Aspergillus spp. is only detected in a maximum of 60% of ABPA patients. In addition, Aspergillus is often found in the airway secretions of CF patients, but also asthmatics on steroid therapy, without the presence of ABPA [56]. A BAL is not routinely recommended in the context of ABPA diagnostics. Therefore, culture only plays a subordinate role in ABPA diagnostics, but is of great importance in the diagnosis of ABPM [57].

In the treatment of acute ABPA, systemic steroids (primarily prednisolone) and azole antifungals (itraconazole) play the leading role [42, 58]. Asymptomatic patients do not need to be treated. In most cases, systemic steroid therapy is started during an episode. Doses of 0.5 mg/kg body weight at the beginning are usually sufficient, as higher doses do not have a better effect but cause more side effects [59]. Alternatively, azoles can be used as monotherapy, which have a similarly good effect as steroids [60, 61]. Azoles can be supplemented in the course of treatment if steroids are not sufficiently effective or a reduction is not possible [62]. With itraconazole, serum levels should be monitored approximately 1–2 weeks after the start of therapy as part of TDM due to variable absorption, and liver values should also be checked.

Biologics and inhaled antimycotics (especially amphotericin B) have become increasingly important in recent years [63], particularly in cases of inadequate response to therapy or the occurrence of side effects to standard therapy and as an alternative in patients who are permanently dependent on steroids. To date, most data exist for omalizumab. Based on their mode of action, other asthma biologics (anti-ll‑5, anti-Il-4/-13, and anti-TSLP) are also promising candidates for a therapeutic response depending on the prevailing immunology. However, further study data are required for a final therapy recommendation.

Allergic and non-allergic sinus mycoses

Aspergillus spores spread aerogenically, are inhaled, and manifest themselves as the most common pathogenic fungi in the nasal cavity and paranasal sinuses. Occasionally, translocation into the paranasal sinuses occurs during dental procedures [64]. Anaerobic conditions in poorly ventilated paranasal sinuses favor disease progression [65, 66].

Fungal sinusitis accounts for around 6% of cases of chronic sinusitis and is caused in descending order of frequency by A. fumigatus followed by A. flavus and A. niger. The most common site of infection is the maxillary sinus [67].

A distinction is made between invasive and non-invasive forms of Aspergillus-induced sinus diseases [64, 68,69,70]. The latter also include allergic rhinitis and allergic fungal rhinosinusitis (allergic fungal rhinosinusitis, AFRS).

Sinus mycoses: invasive forms

Invasive forms of sinus mycoses are more common in immunocompromised patients such as diabetics, transplant recipients, patients with poorly controlled human immunodeficiency virus (HIV) infection and patients undergoing chemotherapy [64, 68].

Pathogens that can cause invasive fungal sinusitis most commonly include Aspergillus spp, Mucorales, Alternaria spp, Auricularia spp, Bipolaris spp, Candida spp, and Pseudallescheria boydii [69, 70]. Among the Aspergillus species, spores of A. fumigatus, A. flavus, or A. niger are particularly common [71, 72]. Histologic evidence of granulomas is associated with a better prognosis, whereas cases with fungal rhinosinusitis that do not show a granulomatous reaction are associated with a poor prognosis and have a high persistence and recurrence rate [69]. Invasive aspergillomas can destroy the bony borders of the paranasal sinuses, adjacent orbit, or skull base, leading to life-threatening intra-orbital infection or meningoencephalitis [73, 74].

The initial symptoms often described are nasal obstruction, rhinorrhea and olfactory disturbances, persistent headaches, posterior rhinorrhea, and cacosmia.

Nasal endoscopy may reveal the presence of purulent secretions, marked edema, or polyps in the middle nasal passage. A sinonasal aspergilloma is often only present on one side and must then be differentiated from an inverted papilloma or sinus malignancy [75].

Imaging diagnostics such as high-resolution CT is mandatory and shows characteristic lesions for an aspergilloma with lysis of the bony walls of the sinuses, especially the maxillary sinus [75,76,77]. The medial wall or orbital floor is frequently affected. Magnetic resonance imaging (MRI) should be performed in cases where there is bone erosion at the base of the skull to rule out meningeal involvement [76]. Complications such as encephalitis are often associated with severe cephalgia and clouding of consciousness, and in the case of orbital cellulitis also with headaches and double vision or visual disturbances.

In general, treatment is based on surgical debridement and systemic steroid therapy. Depending on the extent and location of the aspergilloma, the surgical approach should be either external or via functional endoscopic sinus surgery (FESS). Aspergillomas often develop in the maxillary sinus due to dental pathology; it may then be necessary to extract the affected teeth or close an existing oroantral fistula [64].

Due to frequent superinfections, culture with susceptibility testing is mandatory, as are mycological diagnostics and histological examination [78,79,80]. The targeted use of antifungal or antibiotic agents is recommended [65, 68].

Sinus mycoses: non-invasive forms and inhalation allergy to Aspergillus antigens

Non-invasive forms of sinus mycoses are often attributed to allergic sensitization and then defined as allergic fungal rhinosinusitis (AFRS). IgE-mediated allergic rhinitis to spore antigens of Aspergillus also play a role [69].

The main symptoms of AFRS and allergic rhinitis are nasal obstruction, headaches, a feeling of pressure or swelling in the face, olfactory disorders, increased susceptibility to infection and (anterograde or postnasal) secretion.

Clinically characteristic for the presence of AFRS due to Aspergillus is the presence of a thick, viscous secretion with characteristic histologic findings rich in eosinophilic granulocytes. In the United States, the diagnosis is accepted as confirmed if all 5 main criteria of the Bent–Kuhn classification are met (Table 3; [81]).

Table 3 Main criteria of the Bent–Kuhn classification [81]
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The exaggerated immune response to ubiquitous fungal spores as well as the presence of biofilms appear to be of particular importance in AFRS [82]. The exact pathomechanism is still unclear. It is likely that planktonic fungi are continuously released from the biofilm and the mucosa is invaded by macrophages, which phagocytose the fungal hyphae but do not kill them [82]. Mycotic biofilms consist of mold complexes that are able to colonize both biotic and abiotic surfaces. They cause an evasion of the immune defense and have reduced sensitivity to antifungals while retaining the ability to release hyphae. Numerous studies using different detection methods have shown the presence of biofilms in the sinonasal mucosa of patients with chronic rhinosinusitis. Confocal laser scanning microscopy with fluorescence in situ hybridization is the gold standard for detecting biofilms [82].

In people with atopy, rhinoconjunctivitis and rhinosinusitis, exposure to damp indoor spaces is a risk factor for the development of bronchial asthma. Rhinosinusitis associated with mold exposure doubles the risk of developing bronchial asthma [83].

The sensitizing potential of molds is considered to be lower compared to other environmental allergens such as pollen or house dust mites. Nevertheless, the prevalence of inhalation allergies to mold allergens is around 3–5% in northern and central Europe, but up to 10% in southern Europe [84]. Climate change could contribute to an increase in northern and central Europe [85].

Of the more than 1 million mold species worldwide, around 350 species have so far been listed as potentially sensitizing at www.allergome.org. The WHO (World Health Organization)/IUIS (International Union of Immunological Societies) criteria for classifying an allergen currently take into account 107 mold proteins from 43 mold species (www.allergen.org). Only a few molds are available as test allergen solutions and typical indoor fungal allergen extracts are largely missing [86]. The AllFam database of allergen families (http://www.meduniwien.ac.at/allfam/) summarizes the common phylogenetic, structural, and functional properties of allergens (Table 4). The sensitization rates were classified as minor allergen (< 50% sensitization in the study group) or major allergen (> 50% sensitization in the study group) and the corresponding AllFam IDs were included. However, not all of these components are commercially available for the diagnosis of mold sensitization to A. fumigatus [87].

Table 4 Aspergillus fungal allergens with their biological function, molecular weight (MW), sensitization frequency (major/minor allergen) and AllFam identification number
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From an allergological point of view, after a patient has been sensitized to mold fungi, dose-dependent exposure is not the only decisive factor for the clinical reaction. Sensitization with the formation of specific IgE antibodies and the triggering of allergic reactions occurs at the level of proteins or peptide components [88]. This means that spores or intact mold mycelia are not required; rather, allergenicity is dependent on the proteins or peptides and also on the susceptibility of the exposed person, so that an antigen becomes an allergen and sensitization or an allergy can be triggered upon repeated contact. The detection of IgE antibodies directed against these proteins in affected patients is used in the diagnosis and treatment of allergic diseases [89, 90].

Conclusion

Diseases associated with Aspergillus spp. are complex entities that require rational, targeted, and multidisciplinary cooperation and a high degree of expertise in diagnosis and treatment. Guidelines and simplified diagnostic and therapeutic algorithms of the microbiology, infectious diseases and allergology societies are available and can provide support in this regard. Excellence Centers of the ECMM are certified in the diagnosis and treatment of mycoses, advise treating colleagues in the selection of targeted diagnostics as well as the selection and management of therapy and are available for the evaluation of inclusion in a clinical study. ECMM experts have developed “EQUAL scores” for various entities of invasive mycoses, which weight current guideline recommendations for diagnosis and treatment using a point value and, thus, make them measurable. These recommendations are available for chronic pulmonary aspergillosis (CPA), invasive aspergillosis (IA), and other mold infections and have been partially validated in clinical studies [36, 91,92,93,94,95]. EQUAL Score Cards are available in a handy pocket format and can be downloaded free of charge in many languages at www.ecmm.info/equal-scores.