A Randomized Controlled Trial of the Efficacy of Systemic Enzymes and Probiotics in the Resolution of Post-COVID Fatigue.

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• Multi-enzymes and specific probiotic strains are reported to show positive results in reducing mental and physical fatigue of post-COVID-19 infected patients.
• These multi-enzymes (Peptizyme SP, an enteric coated serratiopeptidase, bromelain, amylase, lysozyme, peptidase, catalase, papain, glucoamylase and lactoferrin) and probiotics (Bacillus coagulans, Bacillus subtilis, and Bacillus clausii) have also shown early effects (from day four of the intervention) on mental and physical fatigue.

This study reports on a randomized, multicentric, double-blind, placebo-controlled trial that was conducted in n=200 subjects with post-COVID-19 fatigue and without active SARSCoV-2 infection, living in India. This study sought to assess the efficacy of a multi-enzyme formulation administered with a probiotic complex on COVID-19-induced fatigue.

Subjects were between the ages of 18 and 75 years, with RT-PCR, confirmed diagnosis of COVID-19 at any time followed by an RT-PCR negative test who experienced fatigue and muscle weakness. Subjects were randomized to a test arm (n = 100), an oral supplement of a systemic enzyme complex and a probiotic complex for 14 days, or the control arm (n = 100) which used a placebo.

The multi-enzyme supplement formulation included Peptizyme SP, an enteric coated serratiopeptidase, bromelain, amylase, lysozyme, peptidase, catalase, papain, glucoamylase and lactoferrin. The probiotic supplement included, a blend of Bacillus coagulans LBSC (DSM 17654), Bacillus subtilis PLSSC (ATCC SD 7280) and Bacillus clausii 088AE (MCC 0538).

Treatment efficacy was compared using the Chalder Fatigue scale (CFQ-11), at various time points from days 1 to 14. At endpoint, 200/200 subjects finished the study.

Primary clinical outcomes were:

• The supplemental treatment resulted in the resolution of fatigue by 182 of 200 (91%) in the test arm compared to 30 of 200 (15%) in the control arm on day 14 (p<0.001)
• A beneficial effect was seen even at earlier time points, with a greater proportion of patients in the test arm being fatigue- free on days 4 (16% vs. 0%), 8 (44% vs. 2%), and 11 (87% vs. 7%) vs. the control arm (p<0.001).

The supplements were well tolerated with no adverse events reported.

Secondary clinical outcomes were:

• Subjects in the test arm showed a significant reduction in total as well as physical and mental fatigue scores at all time points vs. the control arm (p<0.001)
• On day 14, there was a significant reduction in all individual measures of physical fatigue (tiredness, need to rest, drowsiness, ability to do things, energy level, muscle strength and feeling of weakness) as well as mental fatigue (concentration, focus and memory) in the test arm vs. the control arm (p<0.001).

• There have been reports of post-viral fatigue syndrome up to 12 months in other coronavirus infections such as severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS). A lengthy post-infection fatigue impairs quality of life and has a significant impact on individuals, employers, and the healthcare system. It is therefore essential for clinicians to have early interventions to promote recovery of COVID-19 patients.
• Based on this study, practitioners could therefore consider multi-enzymes and probiotics together with other evidence-based multidisciplinary care approaches to improve functional status and quality of life in patients suffering from post-viral fatigue from COVID-19.

• The treatment period of the study was a one-time intervention of 14 days with no long-term follow-up. A long-term follow-up of patients in future studies is needed to evaluate the potential of recurring fatigue.
• Future studies are also needed to replicate these findings and to test for certain inflammatory and immunity markers to provide further insight into the mechanism of action of supplementing with multi-enzymes, Bacillus coagulans, Bacillus subtilis, and Bacillus clausii.
• Additionally, further investigation is needed to evaluate the effectiveness of multi-enzymes, Bacillus coagulans, Bacillus subtilis, and Bacillus clausii in patients with persistent fatigue for six months or beyond to address the needs of patients suffering from chronic fatigue.
• All the subjects in the study were of Indian ethnicity, therefore further studies of other ethnicities are required.
• This study was capped at 75-year-olds, thus studies in older subjects are warranted.
• Conflict of interest statement: This study was fully funded by the manufacturer of the specialty enzymes and probiotics and the authors are paid employees of the manufacturer.