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 × 10 9 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; SpO 2 : Peripheral Oxygen Saturation; WHO: World Health Organization
Background: Probiotics have been proposed as adjuvants for Coronavirus Disease 2019 (Covid19) but randomized controlled trials (RCT) are lacking. Methods: Single-center, quadruple-blinded RCT. Symptomatic Covid 19 outpatients (aged 18 to 60 years) with positive SARS-CoV2 nucleic acids test were randomized to active (n=150; ≥2x109 colony-forming units (CFU) of probiotic strains Lactiplantibacillus plantarum KABP022, KABP023 and KAPB033, plus strain Pediococcus acidilactici KABP021) or placebo (n=150), take orally once daily for 30 days. Oral acetaminophen was allowed and controlled as co-intervention. Primary endpoint included: i) proportion of patients in complete remission (both symptoms and nucleic acids test) or progressing to moderate or severe disease with hospitalization; ii) death rate and duration on Intensive Care Unit (ICU). Safety was assessed in all patients. This study is registered at ClinicalTrials.gov (NCT04517422). Findings: 300 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%). Remission was achieved by 78 of 147 (53.1%) in the active group compared to 41 of 146 (28.1%) in placebo (P<0.0001; ARR=25.0% [95%CI 14.1-35.9%]), still significant after multiplicity correction for the primary endpoint. No hospitalizations or deaths occurred during the study, precluding the assessment of efficacy on these endpoints. No serious adverse events occurred during the study. Replication studies with this probiotic formula are warranted.
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