A randomized clinical trial to stimulate the cholinergic anti-inflammatory pathway in patients with moderate COVID-19-pneumonia using a slow-paced breathing technique

Author: Elisabeth Maria Balint1,2, Beate Grüner3, Sophia Haase1, Mandakini Kaw-Geppert1, Julian F Thayer4, Harald Gündel1, Marc N Jarczok1
1 Clinic for Psychosomatic Medicine and Psychotherapy, University Hospital Ulm, Ulm, Germany.
2 Center for mental health, Privatklinik Meiringen, Meiringen, Switzerland.
3 Clinic for Internal Medicine III, Division of Infectious Diseases, University Hospital Ulm, Ulm, Germany.
4 Department of Psychological Science, University of California, Irvine, Irvine, CA, United States.
Conference/Journal: Front Immunol
Date published: 2022 Oct 3
Other: Volume ID: 13 , Pages: 928979 , Special Notes: doi: 10.3389/fimmu.2022.928979. , Word Count: 296

A characteristic problem occurring in COVID-19 is excessive elevations of pro-inflammatory cytokines (e.g. IL-6 and CRP) which are associated with worse clinical outcomes. Stimulation of the vagally-mediated cholinergic anti-inflammatory reflex by slow paced breathing with prolonged exhalation may present a clinically relevant way to reduce circulating IL-6.

Single-center randomized controlled clinical trial with enrolment of 46 patients hospitalized with confirmed severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) infection and moderate COVID-19 pneumonia (primary diagnosis). Differences between intervention (4sec inhalation, 6sec exhalation for 20 minutes 3x daily) and control group in IL-6 calculated using multilevel mixed-effect linear regression models with random slope including the covariates relevant comorbidities, COVID-19 medication, and age. Both groups received standard care.

Mean age was 57 years ± 13 years, N= 28 (60%) male, N=30 (65%) with relevant comorbidities. The model including group-by-time interaction revealed a significantly lower trajectory of IL-6 in the intervention group (effect size Cohens f2 = 0.11, LR-test p=.040) in the intention-to-treat sample, confirmed by per-protocol analysis (f2 = 0.15, LR-test p=.022). Exploratory analysis using the median split of practice time to predict IL-6 of the next morning indicated a dose-response relationship with beneficial effects of practice time above 45 minutes per day. Oxygen saturation remained unchanged during slow-paced breathing (95.1% ± 2.1% to 95.4% ± 1.6%).

Patients practicing slow-paced breathing had significantly lower IL-6 values than controls with a small to medium effect size and without relevant side effects. Further trials should evaluate clinical outcomes and an earlier start of the intervention. Slow-paced breathing could be an easy to implement, low-cost, safe and feasible adjuvant therapeutic approach to reduce circulating IL-6 in moderate COVID-19 pneumonia.

Clinical trial registration:
https://www.drks.de, identifier DRKS00023971, Universal Trial Number (UTN) U1111-1263-8658.

Keywords: CRP; Cholinergic anti-inflammatory reflex; IL-6, acute viral infection; TNF-alpha; dose-response relationship; moderate COVID-19 pneumonia; slow-paced breathing.

PMID: 36263035 PMCID: PMC9574246 DOI: 10.3389/fimmu.2022.928979