Discussion

Overall, there was general agreement that diseases associated with type 2 inflammation commonly coexist, although there is a lack of evidence to determine the extent of overlap in patients with three or more coexisting diseases. For some conditions, such as asthma with CRSwNP, there was agreement that coexisting type 2 inflammation-driven diseases may be associated with more severe disease. For patients with comorbid atopic dermatitis and asthma, the general perception is that their asthma will be mild, as demonstrated in the randomised, placebo-controlled phase 3 SOLO 1 and SOLO 2 studies of dupilumab in patients with atopic dermatitis.33,49 However, in our clinical experience, patients with comorbid atopic dermatitis and asthma often have severe asthma. There is an urgent need for further understanding about the overall impact of the coexistence of type 2 inflammation-driven diseases on the total symptom burden in the individual patient. Such an understanding may also help to optimise patient management.
In this initiative, consensus on how and whether to use multidisciplinary team conferences to manage patients with coexisting type 2 inflammation-driven diseases was not reached. Although it was acknowledged that a holistic approach to identifying type 2 inflammation-driven comorbidities by a single healthcare provider would be ideal, it was recognised that the increasing specialisation of medicine would preclude this.
Given the frequent clinical coexistence of type 2 inflammation-driven diseases such as atopic dermatitis, asthma, chronic rhinitis, CRSwNP and eosinophilic esophagitis, it was agreed that there is a need for routine assessment of type 2 inflammation-driven diseases that are not routinely evaluated within each specialty. To provide an operational approach to screening patients, a short question guide was proposed for patients to complete in the waiting room prior to their consultation. The aim of the question guide is to aid clinicians from different specialties to recognise comorbidities and enable them to detect, address and refer appropriately. This may be an important tool to prevent deterioration of patients’ health and improve their quality of life. Moreover, patient education may promote further awareness of the importance of addressing multi-organ disease. Both clinicians and patients need to be aware of the importance of the coexistence of multi-organ diseases driven by type 2 inflammation. In addition, our initiative highlighted the need for validated biomarkers of type 2 inflammation that are relevant to atopic dermatitis.
Atopic dermatitis lesions are primarily Th2 and Th22 skewed, with variable contributions of the Th1 and Th17 cytokine pathways depending on the disease subtype, including a particularly high activation of Th17 cytokine pathways in Asian patients compared with other ethnic populations.50-54 Patients with chronic atopic dermatitis have a higher proportion of Th1 cells in the skin infiltrate compared with patients with acute atopic dermatitis.55,56 It has been shown that patients with atopic dermatitis have significantly higher rates of autoimmune comorbidities (including autoimmune diseases of the skin, gastrointestinal tract and connective tissue) compared with healthy individuals.57 These associated autoimmune diseases are likely not driven by type 2 inflammation, but there is a strong overlap in genetic risk alleles between autoimmune diseases and atopic dermatitis.58-60
This consensus approach was limited by the relatively low number of participants, and their geographic concentration (six Nordic countries) may limit the applicability of our recommendations in less-developed areas of the world. Additionally, the experts had diverse specialties and some of them did not necessarily have sufficient clinical experience with certain type 2 inflammation-driven diseases outside their area of expertise. The scope of our initiative did not include other type 2 inflammation-driven diseases such as eosinophilic chronic rhinosinusitis without nasal polyps.61 In addition, the term ‘chronic rhinitis’ was used in this multidisciplinary modified Delphi consensus initiative because those who are not experts in otorhinolaryngology are generally unable to diagnose non-allergic rhinitis subsets or chronic rhinosinusitis without nasal polyps. However, we recognise that the term ‘chronic rhinitis’ may include some subsets that are not primarily driven by type 2 inflammation. Finally, although the modified Delphi process is an accepted methodology, it is based on expert opinion and is thus open to possible bias, particularly given the relatively low number of participants.
In conclusion, our initiative achieved a consensus definition of type 2 inflammation; characterised its role as an immunopathological driver of asthma, atopic dermatitis, chronic rhinitis, CRSwNP and eosinophilic esophagitis; and reached consensus on the presence of overlap between these diseases. Further studies to characterise the overlap between the diseases are warranted. Our conclusions should be used as a framework to further understand the extent of type 2 inflammation-driven multi-organ disease and improve the holistic management and care for patients with type 2 inflammation-driven disease.