The German Asthma Net: Patients without any type 2 biomarker signal are exceedingly rare

Severe asthma is a type 2 inflammation (T2) driven disease, in practice measured by fraction of exhaled nitric oxide (FeNO), blood eosinophil counts (BEC), and allergy-triggered symptoms. However, clinical studies also show a type-2-low (NT2) endotype of unclear relevance. This longitudinal study assesses NT2 in the German Asthma Net (GAN), an international, multi-centre, real-life severe asthma registry through Kruskal-Wallis and Chi² tests. ERS/ATS- and ERS task-force-defined NT2 includes FeNO<40ppb, BEC<300/µL, and no allergic trigger in patients without systemic corticosteroids (OCS). Of 2064 included patients, 57% were female, 32% OCS-dependent, 61% had ≥2 exacerbations/year. Ninety-six percent of patients showed ≥1 T2 signature, and of 89 patients without T2 signature, 49 patients were OCS dependent. Of 40 NT2 patients, 17 patients had historical T2 values, of whom 13 started targeted treatment, and 4 patients had T2 presence on follow-ups with 1 biologic start. High FeNO was seen in 46%, high BEC in 69%. Only 3 patients showed a repetition of NT2 at follow-up, and 16 had no follow-up. Compared to T2, the 40 NT2 patients had less total Immunglobulin E (p=0.001), higher age (p=0.012), and more LAMA use (76% vs 58%, p=0.035), and trends to more frequent high doses of inhaled corticosteroids (beclomethasone equivalent ≥2000µg) with 35% vs 23% (p=0.09) and fewer severe exacerbations (35% vs 54%, p=0.067), without differences in lung function values, degree of asthma control, quality of life, chronic rhinosinusitis, or gastrointestinal reflux (p>0.05). Conclusively, 1.9% of 2064 severe asthma patients had no current T2 signature, with more than half presenting T2 markers at other time points.