ABSTRACT
Elevated pro-inflammatory cytokines such as interleukin-6 (IL-6) have been observed in patients with COVID-19 and are associated with adverse clinical outcomes. Systemic immune response is co-regulated via the vagally-mediated cholinergic anti-inflammatory reflex. Specifically, a reduced release of pro-inflammatory cytokines such as IL-6 from acetylcholine-synthesizing T-cells in response to Vagus nerve stimulation has been demonstrated in animal and human studies. A known non-invasive and cost-effective way to stimulate efferent vagal activity is slow-paced breathing. The primary aim of this RCT was to determine if high-dose breath-assisted reflex stimulation results in a reduction of systemic inflammatory levels in COVID-19 patients. 48 hospitalized COVID-19 patients with moderate to severe symptoms from two isolation wards were randomized to intervention (3x20min app-assisted slow-paced breathing @6BPM) or TAU control group at the University Medical Center Ulm (Germany) during March & May 2021 (BEAT-COVID-study;DRKS00023971). Morning samples of IL-6, protocol adherence and self-reported total practice time (TPT) were collected bi-daily. Mixed effect linear regression models were used to explore groupXtime differences as well as dose-response analysis. Models were adjusted for age, ward, and TAU protocols. A total of 40 patients (age 55±14;67% male) were included to the final analysis. Feasibility of the applied breathing protocol was good, oxygenation was stable and no adverse events occurred. Adherence was closely monitored and sufficient in 17 out of 25 IG patients. Primary reason for non-adherence was worsening of symptoms with transfer to ICU. Reduction rate in inflammatory markers were not statistically different between IG and CG. Investigating the effect of categorized TPT on next morning IL-6 levels in 25 IG patients from 112 intervention days revealed significant lower IL-6 values when TPT exceeded 40min (b= -0.898ln[pg/ml];p=0.043). This is equivalent to a ratio of 59.3% reduction in circulating IL-6 compared to days with TPT <10min. This is the first clinical RCT to study immediate anti-inflammatory effects of a slow-paced breathing protocol in hospitalized COVID-19 patients. Although no between group differences were found in the reduction rate of systemic inflammatory markers, promising dose-response effects were observed.