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Background: Longitudinal data addressing the impact of asthma severity on mortality are lacking. We aimed to explore all-cause and cause-specific mortality according to asthma severity.

Methods: The present registry-based cohort study is based on Danish data from the NORdic Dataset for aSThmA Research (NORDSTAR) research collaboration platform. Adult patients with severe asthma were matched on age and sex to 10 patients with mild-to-moderate asthma and followed from 2000 to 2020. Patients with COPD diagnosed prior to inclusion were excluded. Absolute and relative measures of all-cause and cause-specific mortality were compared between severe and mild-to-moderate asthma.

Results: We included 11 881 and 118 810 patients with severe and mild-to-moderate asthma, respectively. All-cause mortality was significantly higher in patients with severe asthma compared to patients with mild-to-moderate asthma, both in absolute measures of the cumulative mortality (34% (95% CI 32–35%) versus 20% (95% CI 19–20%); p<0.001) after 20 years of follow-up and in relative measures (hazard ratio (HR) 1.99, 95% CI 1.90–2.09; p<0.001). The HR of all-cause mortality was attenuated after adjustment for oral corticosteroid (OCS) use (HR 1.30, 95% CI 1.23–1.37; p<0.001) and type 2 (T2) inflammatory markers (HR 1.34, 95% CI 1.09–1.64; p<0.001). The increased cumulative mortality risk was mainly due to respiratory diseases (12.6% (95% CI 11.7–13.6%) versus 3.3% (95% CI 3.2–3.5%); p<0.001), with cancer (7.5% (95% CI 6.8–8.3%) versus 5.9% (95% CI 5.7–6.2%); p<0.001) and cardiovascular diseases (4.7% (95% CI 4.1–5.3%) versus 3.8% (95% CI 3.6–4.0%); p<0.001) also contributing. Although rare, the relative risk of asthma-related deaths was three-fold in severe asthma patients (HR 2.95, 95% CI 2.08–4.18; p<0.001).

Conclusions: In this nationwide cohort, severe asthma was associated with a significantly higher mortality risk compared to mild-to-moderate asthma. The increased risk was primarily driven by respiratory-related deaths, with OCS use and T2 inflammation as contributing mortality risk factors.