Long COVID (also known as post-COVID or post-acute sequelae of SARS-CoV-2, PASC) refers to a syndrome affecting multiple organs and causing numerous symptoms, including muscle fatigue and cognitive disturbances, that persist at least three months after recovery from acute COVID-19 disease. The estimated prevalence of Long COVID varies widely, with current estimates of at least 10% of patients with a SARs-CoV-2 infection developing a prolonged and debilitating disease, resulting in an estimated 65 million cases worldwide. Even though Long COVID was identified over 3 years ago, there is still a high unmet medical need with currently few specific treatments for post-COVID symptoms.
Study design: In this multicentric, double-blind, randomized controlled trial (RCT), 200 Asian adult patients with symptoms of post-COVID fatigue and muscle weakness were randomized into two equal groups (n=100) receiving either:
- Oral supplements containing a systemic enzyme complex (4 capsules per day) and probiotic complex (2 capsules per day) for 14 days or
- Placebo (maltodextrin) (2 capsules per day) for 14 days
Inclusion criteria included self-reported ongoing fatigue and muscle weakness as well as RT-PCR confirmed diagnosis of COVID-19 any time in the past followed by a negative RT-PCR test. Exclusion criteria included severe to critical health condition as well as numerous other parameters.
Primary endpoints included improvements of assessment of physical and mental fatigue on day 14 using the Calder Fatigue Scale (CFQ-11) tool, a validated self-reporting questionnaire assessing both physical and mental fatigue.
Pulse rate, respiratory rate, blood pressure, oxygen saturation, and body temperature were collected for all patients at baseline, at specific time points during the study, and at the end of study. All vital signs were in the normal range.
Results: 91% of participants taking the supplemental protocol met the criterion of being fatigue free on day 14 compared to only 15% of participants taking the placebo. A significantly greater reduction in total fatigue was seen in the test arm compared to the control arm even during earlier time points. Improvements were identified in both physical and mental fatigue subscales. No adverse events were reported in either arm, suggesting high safety and tolerability of both supplements.
Strengths of this study: There was a relatively large sample size of 200 participants as well as a robust study design with strict exclusion criteria and statistical analysis, including Intention to Treat analysis. The fatigue evaluation questionnaire used a validated bimodal scoring system which allows for differentiation of “cases” vs “non-cases”. Participants in the test arm were recruited between 4 and 874 days following their acute COVID infection, suggesting the supplemental protocol is efficacious for early as well as longer term fatigue. The results are in good agreement with a previous case series and open-label pilot study using the same supplementation in patients hospitalized with mild to moderate COVID-19.
Weaknesses: The data collected was based on a self-reported assessment of either mental or physical fatigue, using only the CFQ-11 questionnaire. The data would have been strengthened by using at least one other tool to assess mental and physical fatigue. It also would have been useful to obtain pre- and post-trial blood samples to detect if there are any changes in inflammatory or immune markers. The treatment period in the study was a one-time intervention of 14 days only, with no longer term follow-up to determine if there was any recurrence of fatigue. Finally, because the test participants received both systemic enzymes and probiotics, it is not possible to differentiate between the treatment effect provided by the systemic enzymes and the treatment effect provided by the probiotics. It is also not possible to determine whether there is an additive, synergistic, or even subtractive effect when using both types of supplements together. Both acute and Long COVID are known to cause dysbiosis and therefore, the treatment effect could have been solely due to the probiotics.
Conclusion statement: This interventional trial shows a marked treatment effect using a combination of oral enzymes and probiotics in indicators of both physical and mental fatigue following an acute SARs-Co-V2 infection. Infections other than with SARs-Co-V2 also cause post-viral illnesses with symptoms of fatigue and muscle weakness suggesting this treatment protocol may have additional benefits, possibly in other ME/CFS cases. Clinical use of oral enzyme supplements is controversial, due to in part to theoretical concerns that larger proteins such as enzymes would likely be cleaved and/or denatured prior to absorption across the intestinal wall. However, this well-designed RCT adds to growing clinical and empirical data indicating that oral supplementation of enzymes may provide clinical benefits in some patients.
References:
