Clinical and Immunologic Effects of Paraprobiotics in Long-COVID Patients: A Pilot Study.

Background and objectives: After the enormous health burden during the acute stages of the COVID-19 pandemic, we are now facing another important challenge, that is, long-COVID, a clinical condition with often disabling signs and symptoms of the neuropsychiatric, gastrointestinal, respiratory, cardiovascular, and immune systems. While the pathogenesis of this syndrome is still poorly understood, alterations of immune function and the gut microbiota seem to play important roles. Because affected individuals are frequently unable to work for prolonged periods and suffer numerous health compromises, effective treatments represent a major unmet medical need. Multiple potential therapies have been tried, but none is approved yet. Approaches that are able to influence the immune system and gut microbiota such as probiotics and paraprobiotics, i.e., nonviable probiotics, seem promising candidates. We, therefore, evaluated the clinical and immunologic effects of paraprobiotics in a small pilot study.

Methods: A total of 6 patients with long-COVID were followed systematically for more than 12 months after disease onset using standardized validated questionnaires, a smartphone app, and wearable sensors to assess neurocognitive function, fatigue, depressiveness, autonomic nervous system alterations, and quality of life. We then offered patients defined paraprobiotics for 4 weeks and evaluated them at the end of the treatment period using the same questionnaires, smartphone app, and wearable sensors. In addition, a comprehensive immunophenotyping and gut microbiota analysis was performed before and after treatment.

Results: Improvements in several of the neurologic symptoms such as dysautonomia, fatigue, and depression were documented using both patient-reported outcomes and data from the smartphone app and wearable sensors. Of interest, the expression of activation markers on some immune cell populations such as B cells and nonclassical monocytes and the expression of toll-like receptor 2 (TLR2) on T cells were reduced after paraprobiotics treatment.

Discussion: Our results suggest that paraprobiotics might exert positive effects in patients with long-COVID most likely by modulating immune cell activation and expression of TLR2 on T cells. Further studies with paraprobiotics should confirm the promising observations of this small pilot study and hopefully not only improve the outcome of long-COVID but also unravel the pathomechanisms of this condition.

Classification of evidence: This study provides Class IV evidence that paraprobiotics increase the probability of favorable changes of clinical and immunologic markers in patients with long-COVID.