Decoding Allergic Fungal Airway Diseases

Fungal sensitization is common in patients with airway diseases, and more than 80 species of fungi have been associated with symptoms of airway allergy.[1] Allergic Fungal Airway Disease (AFAD) is an all-inclusive term used to describe allergic airway diseases caused or exacerbated by fungi. It is a broad term and includes a heterogeneous group of conditions ranging from mild, clinically unimportant disease to distinct subtypes like allergic bronchopulmonary aspergillosis/mycosis (ABPA/ABPM). The spectrum of AFAD includes fungal asthma, fungal bronchitis, Aspergillus fumigatus-associated asthma (AFAA), ABPA/ABPM, severe asthma with fungal sensitization (SAFS), as well as fungal allergies complicating bronchiectasis and chronic obstructive pulmonary disease (COPD).[2] Pharmacological treatment must be individualized depending on the severity of the underlying condition, as the umbrella of AFAD includes distinct entities with variable clinical behavior. Fungi can worsen asthma by various mechanisms. Environmental fungi such as Alternaria and Cladosporium are not thermotolerant and cannot colonize the airways. They act as seasonal aeroallergens only. Thermotolerant filamentous fungi like A. fumigatus and Penicillium species germinate in the airways, colonizing the lungs and causing persistent airway inflammation that can lead to lung damage. Aspergillus species are usually found indoors and are the common fungi associated with airway diseases.[3] According to a recent systematic review, the prevalence of Aspergillus sensitization (AS) ranged from 1.6% to 73% with a pooled prevalence of 25.1% among adult asthmatics attending secondary and tertiary care respiratory clinics.[4] A third mechanism postulated as a cause for worsening asthma control is fungal sensitization caused by dermatophytic infection of nails and skin, due to cross-reactive T-cells.[5] Considering the high prevalence of AS in asthmatics, screening for A. fumigatus sensitisation using fungus-specific IgE is recommended in all newly diagnosed asthmatic adults at tertiary care and difficult-to-treat asthmatic children. AS is diagnosed by a positive skin prick test or detectable Aspergillus IgE in serum. Elevated A. fumigatus specific IgE (>0.35 kUA/L) is the most sensitive test for diagnosing AS and should be performed as the initial test in suspected fungal allergies. Skin prick tests for the diagnosis of immediate hypersensitivity to fungal antigens are generally considered less reliable. If A. fumigatus specific IgE is normal, sensitization to other fungi such as Alternaria and Cladosporium should be ruled out. ABPM is considered in those with an ABPA-like presentation but normal A. fumigatus-IgE. The diagnosis of ABPM also requires the repeated growth of the causative fungus from sputum. If A. fumigatus specific IgE is elevated, further investigations are done to diagnose/rule out ABPA as per revised ISHAM working group criteria.[6] In ABPA, serum total IgE is >500 IU/mL. A diagnosis of SAFS is considered in patients who do not meet the diagnostic criteria for ABPA or ABPM but have severe asthma and raised fungus-specific IgE.[7] Induced sputum yields fungi in a high (around 70%) proportion of asthmatics.[8] However, the role of sputum fungal culture is limited in diagnosing AFADs, as there is often dissociation between colonizing fungi and sensitizing fungi. The sensitizing fungus might be different from the colonizing fungus.[4] Repeated isolation of a fungus from the respiratory sample favors the presence of a sensitizing agent. Sputum cultures are also useful to detect antifungal drug resistance. Strict preventive measures must be taken to remove or minimize further exposure to molds in patients with AFADs. This involves patient education on allergen avoidance, environmental controls to remove dampness and use of air filtration systems. Pharmacotherapy of AFAA involves standard asthma treatment in a step-wise manner with the lowest possible dose of inhaled corticosteroid required. On the other hand, the use of antifungal therapy in conditions like ABPA, SAFS, and fungal bronchitis can result in improvement in symptoms, better asthma control and reduction in the requirement of corticosteroids. It must be kept in mind that drug interactions with inhaled corticosteroids can induce a cushingoid state in patients on oral azole therapy if the steroid dosage is not reduced. Biologics used for the treatment of severe asthma, such as omalizumab, mepolizumab, benralizumab, dupilumab, and tezepelumab, are likely to be useful for refractory cases of ABPA but are yet to be specifically approved for ABPA. Allergy to thermotolerant fungi is linked to an eosinophilic endotype of severe airway disease, especially in asthmatics. These patients are at risk of progressive, irreversible lung damage. Early identification of such patients can be achieved by screening newly diagnosed adult asthmatics in tertiary care.