Asthma in combination with rhinitis and eczema is associated with a higher degree of type-2 inflammation and symptom burden than asthma alone

Asthma is common and often accompanied by rhinitis and eczema, especially in the presence of allergy. (1) Increased total immunoglobulin E (IgE) is associated with polysensitization and atopic multimorbidity. (1) There is some evidence linking allergic multimorbidity to increased levels of other type-2 inflammatory markers, such as fractional exhaled nitric oxide (FENO) (2), blood eosinophils (B-Eos) (1), and eosinophil activation markers (3), but the evidence is scarce and to some extent conflicting. The aim of this study was to investigate type-2 inflammatory markers, IgE sensitization, and respiratory and food hypersensitivity symptoms in young asthmatics (aged 10–35 years) with allergic multimorbidity. Furthermore, we investigated eventual differences between adolescents and young adults with regard to the relation between type-2 inflammatory markers and allergic multimorbidity. For methodology, please see the Online Supplement and Online Figure S1. Subject demographics are supplied in the Online Table S1. We found that asthmatics with allergic multimorbidity (either having rhinitis or both rhinitis and eczema) had a higher degree of type-2 inflammation, as assessed by FENO, total IgE, B-Eos count, and plasma eosinophil-derived neurotoxin (P-EDN), but not serum eosinophil cationic protein (S-ECP), both before and after adjustments for age, sex, BMI, sensitization to airborne allergens, and use of inhaled and nasal corticosteroids (Table 1). Stratifying for age with 18 years as cut-off, we found that higher levels of FENO were only associated with allergic multimorbidity in subjects younger than 18 years (Online supplement Table S2). Furthermore, an interaction with the age groups (< or ≥18 years) was noted with regard to the relation between allergic multimorbidity and elevated levels of FENO (asthma vs asthma, rhinitis: p=0.032 and asthma vs asthma, rhinitis, eczema: p=0.048, both p-values for the interaction terms with age groups). No significant interactions with age groups were found for the relation between allergic multimorbidity and the other type-2 inflammation markers. p-value vs asthma Adjusted** p-value vs asthma p-value vs asthma Adjusted** p-value vs asthma Asthmatics with allergic multimorbidity were more likely to be IgE-sensitized to both aeroallergens and food allergens (Figure 1). Subjects with multimorbidity were more likely to report respiratory symptoms when exposed to aeroallergens, allergic reactions to food (Figure 1), as well as wheezing and asthma attacks within the preceding 12 months (Online Table S3), and were more likely to use antihistamines and nasal steroids within the last 12 months (Online Table S4). Our main finding is that commonly used type-2 inflammation markers, such as FENO and B-Eos count, are increased in subjects with allergic multimorbidity. Previous findings in the literature have not been consistent.(4) We could show, for the first time, that the increase in FENO was more pronounced for asthmatics with allergic multimorbidity under the age of 18, suggesting that FENO, as a marker of airway inflammation, is more closely related to allergic multimorbidity in children than adults. Besides FENO, total IgE and B-Eos also differed between the groups in subjects aged under 18 years, but these findings were also found to some extent in adults (Online Table S2), and therefore, no interactions with age groups were found on the relation between these last-named inflammatory markers and allergic multimorbidity. Among the eosinophil activation markers, we found that P-EDN, but not S-ECP was related to allergic multimorbidity. This might be due to the fact that S-ECP reflects not only the presence of eosinophils, but also the degree of eosinophil activation, while P-EDN mainly reflects the former. (5) We also found that both total IgE and sensitization to aeroallergens and food allergens related to allergic multimorbidity. These results are in accordance with previous findings (1) Finally, a higher burden of symptoms was noted among those with allergic multimorbidity, both with regard to allergic reactions to food and aeroallergens, and to asthma attacks and wheezing during the previous year. These results are in line with our previous studies, showing that allergic multimorbidity increases the likelihood of reporting an allergic reaction to food (4) and comorbidities increase disease severity (6). We acknowledge that the main limitation of the study is the use of self-reported symptoms to define rhinitis, eczema, and food hypersensitivity. Some degree of asthma overdiagnosis cannot be excluded despite the requirement of a medical asthma diagnosis in combination with use of anti-inflammatory treatment. In conclusion, asthmatics with allergic multimorbidity had a higher degree of type-2 inflammation and a higher burden of asthma and allergy symptoms. Asthmatics with allergic multimorbidity and persistent type-2 inflammation despite optimal treatment might benefit from specific type-2 treatment. Magnus P. Borres is an employee of Thermo Fisher Scientific. Kjell Alving has received research material from Thermo Fisher Scientific and Hemocue. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.