Probiotic improves symptomatic and viral clearance in Covid19 outpatients: a randomized, quadruple-blinded, placebo-controlled trial.

Intestinal bacteria may influence lung homeostasis via the gut-lung axis. We conducted a single-center, quadruple-blinded, randomized trial in adult symptomatic Coronavirus Disease 2019 (Covid19) outpatients. Subjects were allocated 1:1 to probiotic formula (strains Lactiplantibacillus plantarum KABP022, KABP023, and KAPB033, plus strain Pediococcus acidilactici KABP021, totaling 2 × 109 colony-forming units (CFU)) or placebo, for 30 days. Co-primary endpoints included: i) proportion of patients in complete symptomatic and viral remission; ii) proportion progressing to moderate or severe disease with hospitalization, or death; and iii) days on Intensive Care Unit (ICU). Three hundred subjects were randomized (median age 37.0 years [range 18 to 60], 161 [53.7%] women, 126 [42.0%] having known metabolic risk factors), and 293 completed the study (97.7%). Complete remission was achieved by 78 of 147 (53.1%) in probiotic group compared to 41 of 146 (28.1%) in placebo (RR: 1.89 [95 CI 1.40-2.55]; P < .001), significant after multiplicity correction. No hospitalizations or deaths occurred during the study, precluding the assessment of remaining co-primary outcomes. Probiotic supplementation was well-tolerated and reduced nasopharyngeal viral load, lung infiltrates and duration of both digestive and non-digestive symptoms, compared to placebo. No significant compositional changes were detected in fecal microbiota between probiotic and placebo, but probiotic supplementation significantly increased specific IgM and IgG against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) compared to placebo. It is thus hypothesized this probiotic primarily acts by interacting with the host's immune system rather than changing colonic microbiota composition. Future studies should replicate these findings and elucidate its mechanism of action (Registration: NCT04517422).Abbreviations: AE: Adverse Event; BMI: Body Mass Index; CONSORT: CONsolidated Standards of Reporting Trials; CFU: Colony-Forming Units; eDRF: Electronic Daily Report Form; GLA: Gut-Lung Axis; GSRS: Gastrointestinal Symptoms Rating Scale; hsCRP: High-sensitivity C-Reactive Protein; HR: Hazard Ratio; ICU: Intensive Care Unit; OR: Odds Ratio; PCoA: Principal Coordinate Analysis; RR: Relative Risk; RT-qPCR: Real-Time Quantitative Polymerase Chain Reaction; SARS-CoV2: Severe acute respiratory syndrome coronavirus 2; SpO2: Peripheral Oxygen Saturation; WHO: World Health Organization.

Probiotic Effect on SARS‐CoV2 Immunity Is Associated to Type‐1 Interferons: A Post‐Hoc Analysis of a Randomized, Placebo‐Controlled Trial

Objectives and Hypothesis Gut microbiota has been reported to protect from lung viral infection in animal models by stimulating type‐I interferon signaling. Type‐I interferons can have direct antiviral activity while also stimulating antibody‐producing B cells. Antibodies against Severe Acute Respiratory Syndrome coronavirus 2 (SARS‐CoV2) have been correlated to faster infection clearance and protection against reinfection. A specific 4‐strain probiotic combination (Pediococcus acidilactici CECT7483 plus Lactoplantibacillus plantarum CECT7484, CECT7485 and CECT30292) was recently studied in a randomized, quadruple‐blinded, placebo‐controlled trial in 300 SARS‐CoV2‐infected, symptomatic ambulatory patients (NCT04517422). Study subjects did not receive corticosteroids or antivirals. Compared to placebo, probiotic intervention (2x109cfu/day for 30 days) achieved faster symptom clearance and increased SARS‐CoV2‐specific immunoglobulins M and G (IgM and IgG). We hypothesize these effects could be related to increased type‐I interferon signaling. Methods A random subset of 70 subjects (35 probiotic and 35 placebo) was selected out of the 300 participants in the clinical study. Stored serum samples collected on day 0 (baseline), 15 and 30 (end of intervention) were analyzed for interferon‐alpha 2a (IFNa) and interferon‐beta 1a (IFNb) using enzyme‐linked immunosorbent assay. Demographic data, baseline viral load, symptom duration and SARS‐CoV2‐specific IgM and IgG serum titers were retrieved from patient case report forms. Differences between probiotic and placebo were compared using Mann‐Whitney or Chi‐squared tests, as appropriate. Correlations between type‐I interferons and other variables were assessed by Spearman correlation. All procedures on study subjects had been approved by the Internal Review Board of Hospital General Dr. Manuel Gea (Mexico City) and adhered to Helsinki Declaration. Summary of Results In the selected subset of patients, study groups were comparable at baseline (all p>0.10, Table 1). Probiotic treatment was associated to a larger increase of IFNa on day 30 (p=0.007) and of IFNb on days 15 and 30 (both p<0.001), compared to placebo (Figure 1). Similarly, SARS‐CoV2‐specific IgM and IgG were higher on days 15 and 30 (all p<0.001) and duration of fever, cough, headache and myalgia were shorter (all p<0.05) in probiotic compared to placebo. Increase in IFNb across the study correlated to increase in SARS‐CoV2‐specific IgM (rho=0.55, p<0.001) and IgG (rho=0.61, p<0.001), and inversely correlated to duration of cough (rho=‐0.26, p=0.033) and fever (rho=‐0.24, p=0.042). Conversely, increase in IFNa correlated to increase in SARS‐CoV2‐specific IgM (rho=0.33, p=0.005) only. Neither increase in IFNa nor IFNb correlated to age, number of metabolic comorbidities or days from onset of symptoms. Conclusion Compared to placebo, oral administration of a specific 4‐strain probiotic combination resulted in significant increase in type‐I interferons in serum, especially IFNb, correlating to higher SARS‐CoV2‐specific IgM and IgG antibodies and faster clearance of some symptoms.