The Clinical Implications of Aspergillus Fumigatus Sensitization in Difficult-To-Treat Asthma Patients

Mistry, Heena; Soberanis, Hilda Maria Ajsivinac; Kyyaly, Mohammed Aref; Azim, Adnan; Barber, Clair; Knight, Deborah; Newell, Colin; Haitchi, Hans Michael; Wilkinson, Tom; Howarth, Peter H.; Seumois, Grégory; Vijayanand, Pandurangan; Arshad, Syed Hasan; Kurukulaaratchy, Ramesh

doi:10.1016/j.jaip.2021.08.038

Cited by 23 publications

(17 citation statements)

References 46 publications

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“…A key limitation is the individual contributions of HDM, Aspergillus fumigates, and Alternaria alternata to corticosteroid insensitivity were not determined. Studies show that sensitization to more than one allergen, particularly fungal allergens, are associated with corticosteroid insensitivity in patients with difficult-to-treat or severe asthma ( Bush, 2020 ; Roberts et al, 2020 ; Mistry et al, 2021 ). Airway inflammation and AHR persist in multiple allergen models despite corticosteroid treatment ( Duechs et al, 2014 ; Zhou et al, 2017 ), suggesting that these may be more reflective of severe asthma.…”

Section: Discussionmentioning

confidence: 99%

Chronic Allergen Challenge Induces Corticosteroid Insensitivity With Persistent Airway Remodeling and Type 2 Inflammation

et al. 2022

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Type 2-high severe asthma is described as a distinct endotype with Th2 inflammation, high eosinophil lung infiltration, impaired lung function, and reduced corticosteroid sensitivity. While the inflammatory milieu is similar to mild asthma, patients with type 2-high severe asthma likely have underlying mechanisms that sustain asthma pathophysiology despite corticosteroid treatments. Acute and chronic allergen models induce robust type 2 inflammatory responses, however differences in corticosteroid sensitivity remains poorly understood. In the present study, we sensitized and challenged mice with ovalbumin (OVA; acute model) or mixed allergens (MA; chronic model). Corticosteroid sensitivity was assessed by administering vehicle, 1, or 3 mg/kg fluticasone propionate (FP) and examining key asthmatic features such as airway inflammation, remodeling, hyperresponsiveness, and antioxidant capacity. Both acute and chronic allergen exposure exhibited enhanced AHR, immune cell infiltration, airway inflammation, and remodeling, but corticosteroids were unable to fully alleviate inflammation, AHR, and airway smooth muscle mass in MA-challenged mice. While there were no differences in antioxidant capacity, persistent IL-4+ Th2 cell population suggests the MA model induces type 2 inflammation that is insensitive to corticosteroids. Our data indicate that chronic allergen exposure is associated with more persistent type 2 immune responses and corticosteroid insensitivity. Understanding differences between acute and chronic allergen models could unlock underlying mechanisms related to type 2-high severe asthma.

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Section: Discussionmentioning

confidence: 99%

Chronic Allergen Challenge Induces Corticosteroid Insensitivity With Persistent Airway Remodeling and Type 2 Inflammation

et al. 2022

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“…This molecule is a manganese superoxide dismutase (MnSod) and typically cross-reacts with other fungi allergens, i.e., Alternaria (Alt a 14) and Mallasezia (Mala a 14), and possibly with birch, olive, and ambrosia pollens [ 23 , 30 , 31 ]. Aspergillus fumigatus sensitization in difficult asthma identifies a more severe form of airway disease associated with greater morbidity, treatment need, and airways dysfunction/damage, but fewer psychophysiological comorbidities [ 8 , 32 ]. Importantly, severe asthma with fungal sensitivity (SAFS) is differentiated from allergic bronchopulmonary aspergillosis by the absence of bronchiectasis and fungal growth in the lungs and sensitivity to antifungal treatments [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, severe asthma with fungal sensitivity (SAFS) is differentiated from allergic bronchopulmonary aspergillosis by the absence of bronchiectasis and fungal growth in the lungs and sensitivity to antifungal treatments [ 33 ]. The clinical course of asthma with fungal sensitization is similar to the clinical picture of asthma without sensitization to fungi except for the lower age of symptom onset and significantly higher levels of IgE and IL-33 in the serum [ 8 , 34 , 35 ]. However, studies focused on fungal sensitization in asthmatics are heterogeneous and have, to date, included differing asthma severities, making their conclusions difficult to interpret, particularly in the context of severe asthma [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

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Atopy and Multisensitizations in Specific IgE Microarrays and Their Impact on Severe Asthma

Romantowski

Górska

Moszkowska

et al. 2022

Life

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(1) Asthma is a chronic inflammatory airway disease. Around 3–10% of patients experience severe refractory asthma. These patients with high symptom intensity and frequent exacerbations present a challenge for allergologists. Their allergic vs. non-allergic profile might be different from the standard asthmatic group and this difference is vital in qualifying for anti-IgE biologicals. The aim of the study was to analyze multiple sensitizations in patients with severe asthma and assess their impact on the course of the disease. (2) Forty-two patients with severe asthma according to GINA were enrolled. They experienced at least two exacerbations during the past year and had uncontrolled asthma despite high inhaled steroid use. A microarray serum Alex test (allergen-specific IgE to 295 extracts and components) was performed together with Complete Blood Count tests, the Asthma Control Questionnaire (ACQ), the Mini Asthma Quality of Life Questionnaire (MiniAQLQ), and spirometry. (3) There were 29 female and 13 male patients. The patient mean age was 50.4 (22–70). In 25 (60%) patients, inhalant sensitizations were detected. In 9 (21%) cases, a new perennial allergen was discovered that might enable anti-IgE treatment in the future. In the entire studied group, 8 patients (19%) would still not qualify for anti-IgE, anti-IL4, or anti-IL5 treatment. A linear regression analysis revealed that a Canis familiaris allergen (Can f 1) correlated with worse asthma control in ACQ. An Aspergillus allergen (Asp f 6) correlated negatively with Forced Expiratory Volume in one second (FEV1). (4) The study presents the usefulness of the ALEX test in 21% of patients with severe asthma in qualification for anti-IgE treatment. It highlights the impact of canine and Aspergillus sensitizations on worse control in patients with severe asthma.

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“…It is estimated that 9% of cystic fibrosis patients ( 183 ) and 2.5% of adult asthmatics ( 184 ) suffer from ABPA. Furthermore, nearly 35–50% of patients with cystic fibrosis ( 183 ) and 24% of patients with severe asthma ( 185 ) have sensitization to A. fumigatus . Although many fungi are associated with the disease, A. fumigatus is by far the most common cause of ABPA ( 186 ) due to its marked thermotolerance and small size and surface properties of its conidia that can reach terminal airways ( 187 , 188 ).…”

Section: Effects Of Fungal Sensitization/infection On Asthma Pathogen...mentioning

confidence: 99%

Impact of Therapeutics on Unified Immunity During Allergic Asthma and Respiratory Infections

Flores-Torres

Samarasinghe

2022

Front. Allergy

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Graphical AbstractInterplay between infectious agents and allergic milieu. Respiratory infections caused by viruses, bacteria and fungi play an important role in asthma pathogenesis. The immune milieu in allergic asthma may be both defective and protective during respiratory infections. Some bacteria are linked to steroid-resistant neutrophilic asthma and an aberrant immune response. Thermotolerant fungi generally induces a T2 immune response in asthma and are linked to asthma severity and higher corticosteroid requirement. Steroid-resistant neutrophilic asthma is associated with increased airway bacterial burden and reduced bacterial diversity. Corticosteroids and antibiotics induce dysbiosis in asthmatics, which may cause immune system alterations. Biologics and antivirals may be beneficial in some patients. However, the effect of eosinophil depletion on antiviral immunity in asthmatics remains unknown. Influenza and COVID-19 vaccination are recommended in asthmatics, but pneumococcal vaccine benefits are still under debate.

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The Clinical Implications of Aspergillus Fumigatus Sensitization in Difficult-To-Treat Asthma Patients

Cited by 23 publications

References 46 publications

Chronic Allergen Challenge Induces Corticosteroid Insensitivity With Persistent Airway Remodeling and Type 2 Inflammation

Chronic Allergen Challenge Induces Corticosteroid Insensitivity With Persistent Airway Remodeling and Type 2 Inflammation

Atopy and Multisensitizations in Specific IgE Microarrays and Their Impact on Severe Asthma

Impact of Therapeutics on Unified Immunity During Allergic Asthma and Respiratory Infections

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