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.
ABSTRACT
Background: Up to 80% of patients suffering from persistent symptoms more than six months after a COVID-19 infection complain about a variety of psychosomatic symptoms with no organ cause. Most patients suffer from chronic fatigue, pain, depression or difficulty concentrating. Experimental studies showed that these symptoms could be significantly improved after an open administration of placebos (“open-label placebo”) or with heart rate variability (HRV) biofeedback such as paced breathing. However, we insufficiently understand which patients benefit from which treatment. Methods: Patients (m/f) without organic causes for the complaints are randomised to three groups: an open-label placebo intervention (OLP), a paced breathing training (PBT) or no additional treatment (TAU). To detect a mean effect using a 2x3 ANOVA, N=90 patients will be included, and predictor analyses are performed. The OLP group takes 2 placebos/day and receives the information that placebos can significantly improve symptoms, e.g. via the activation of “self-healing powers”. The PBT group receives a standardized training to breath at 6 breaths/min for 10 min/day. At inclusion (T0) and after four (T1) and eight weeks (T2), treatment expectations, fatigue (FSMC), somatoform complaints, depressiveness, anxiety (PHQ), general health (SF-36) and quality of life, as well as cognitive performance using Corsi Span and Colour Stroop tests, will be assessed by questionnaires and tests, and an ECG will be recorded. Results: Preliminary results point to effective reductions of fatigue and other symptoms for both interventions compared to TAU, dependent on patients' individual factors such as treatment expectations, symptom severity during Covid-19 infection and at inclusion. HRV data will be analysed at the end of the study. Preliminary results will be presented at the conference. Conclusion: Patients with functional post-COVID syndromes can benefit from psychosomatic interventions aiming to improve treatment expectations and heart rate variability, depending on individual patients' factors. Patient-tailored interventions should be further investigated.