Efficacy of a Probiotic Consisting of Lacticaseibacillus rhamnosus PDV 1705, Bifidobacterium bifidum PDV 0903, Bifidobacterium longum subsp. infantis PDV 1911, and Bifidobacterium longum subsp. longum PDV 2301 in the Treatment of Hospitalized Patients with COVID-19: a Randomized Controlled Trial
Vladimir Ivashkin, Victor Fomin, Sergey Moiseev, Michail Brovko, Roman Maslennikov, Anatoly Ulyanin, Victoria Sholomova, Maria Vasilyeva, Elizaveta Trush, Oleg Shifrin, Elena Poluektova
Probiotics and Antimicrobial Proteins, doi:10.1007/s12602-021-09858-5
The treatment of coronavirus disease (COVID-19) and COVID-19-associated diarrhea remains challenging. This study aimed to evaluate the efficacy of a multi-strain probiotic in the treatment of COVID-19. This was a randomized, controlled, singlecenter, open-label trial (NCT04854941). Inpatients with confirmed COVID-19 and pneumonia were randomly assigned to a group that received a multi-strain probiotic (PRO group) or to the control group (CON group). There were 99 and 101 patients in the PRO and CON groups, respectively. No significant differences in mortality, total duration of disease and hospital stay, incidence of intensive care unit admission, need for mechanical ventilation or oxygen support, liver injury development, and changes in inflammatory biomarker levels were observed between the PRO and CON groups among all included patients as well as among subgroups delineated based on age younger or older than 65 years, and subgroups with chronic cardiovascular diseases and diabetes. Diarrhea on admission was observed in 11.5% of patients; it resolved earlier in the PRO group than in the CON group (2 [1-4] vs. 4 [3-6] days; p = 0.049). Hospital-acquired diarrhea developed less frequently in the PRO group than in the CON group among patients who received a single antibiotic (0% vs. 12.5%; p = 0.023) unlike among those who received > 1 antibiotic (10.5% vs. 13.3%; p = 0.696). The studied probiotic had no significant effect on mortality and changes in most biomarkers in COVID-19. However, it was effective in treating diarrhea associated with COVID-19 and in preventing hospital-acquired diarrhea in patients who received a single antibiotic.
Supplementary Information The online version contains supplementary material available at https:// doi. org/ 10. 1007/ s12602-021-09858-5.
Author Contribution The idea and design of the study were developed by Vladimir Ivashkin and Elena Poluektova. Material preparation, data collection, and analysis were performed by all authors. The first draft of the manuscript was written by Roman Maslennikov, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Declarations Ethics Approval The study was approved by the local ethics committee (Conclusion №. 34-20 of September 9, 2020) in accordance with the Declaration of Helsinki. Consent to Participate Informed consent was obtained from all individual participants included in the study. Consent for Publication Patients' personal data are not published.
Conflicts of Interest The authors declare no competing interests.
References
Agamennone, Krul, Rijkers, A practical guide for probiotics applied to the case of antibiotic-associated diarrhoea in the Netherlands, BMC Gastroenterol,
doi:10.1186/s12876-018-0831-xBozkurt, Quigley, The probiotic Bifidobacterium in the management of Coronavirus: a theoretical basis, Int J Immunopathol Pharmacol,
doi:10.1177/2058738420961304Cangemi, Lacy, Management of irritable bowel syndrome with diarrhoea: a review of nonpharmacological and pharmacological interventions, Ther Adv Gastroenterol,
doi:10.1177/1756284819878950Ceccarelli, Borrazzo, Pinacchio, Oral bacteriotherapy in patients with COVID-19: a retrospective cohort study, Front Nutr,
doi:10.3389/fnut.2020.613928D'ettorre, Ceccarelli, Marazzato, Challenges in the management of SARS-CoV2 infection: the role of oral bacteriotherapy as complementary therapeutic strategy to avoid the progression of COVID-19, Front Med,
doi:10.3389/fmed.2020.00389Di, Gai, Protective efficacy of probiotics on the treatment of acute rotavirus diarrhea in children: an updated metaanalysis, Eur Rev Med Pharmacol Sci,
doi:10.26355/eurrev_202009_23057Ivashkin, Fadeeva, Skhirtladze, Intestinal microbiota in the pathogenesis of chronic heart failure, Ital J Med,
doi:10.4081/itjm.2020.1185Kamkin, Interim guidelines for the prevention, diagnosis and treatment of new coronaviral infection
Kawahara, Makizaki, Oikawa, Oral administration of Bifidobacterium bifidum G9-1 alleviates rotavirus gastroenteritis through regulation of intestinal homeostasis by inducing mucosal protective factors, PLoS One,
doi:10.1371/journal.pone.0173979Kumar, Hecht, Priyamvada, Probiotic Bifidobacterium species stimulate human SLC26A3 gene function and expression in intestinal epithelial cells, Am J Physiol Cell Physiol,
doi:10.1152/ajpcell.00194.2014Li, Cheng, Xu, The role of probiotics in coronavirus disease-19 infection in Wuhan: a retrospective study of 311 severe patients, Int Immunopharmacol,
doi:10.1016/j.intimp.2021Li, Xu, Ye, Efficacy of Lactobacillus rhamnosus GG in treatment of acute pediatric diarrhea: a systematic review with meta-analysis, World J Gastroenterol,
doi:10.3748/wjg.v25.i33.4999Mahooti, Miri, Abdolalipour, Ghaemi, The immunomodulatory effects of probiotics on respiratory viral infections: a hint for COVID-19 treatment?, Microb Pathog,
doi:10.1016/j.micpath.2020.104452Manna, Chowdhury, Chakraborty, Mandal, Probiotics-derived peptides and their immunomodulatory molecules can play a preventive role against viral diseases including COVID-19, Probiotics Antimicrob Proteins,
doi:10.1007/s12602-020-09727-7Maslennikov, Ivashkin, Efremova, Poluektova, Shirokova, Probiotics in hepatology: an update, World J Hepatol,
doi:10.4254/wjh.v13.i9.1154Maslennikov, Ivashkin, Ufimtseva, Poluektova, A clinical variant of coronavirus disease 2019 with diarrhoea as the initial symptom compared with other variants,
doi:10.23736/S2724-5985.21.02827-0Maslennikov, Poluektova, Ivashkin, Diarrhoea in adults with coronavirus disease-beyond incidence and mortality: a systematic review and meta-analysis, Infect Dis (Lond),
doi:10.1080/23744235.2021.1885733Mirzaei, Attar, Papizadeh, The emerging role of probiotics as a mitigation strategy against coronavirus disease 2019 (COVID-19), Arch Virol,
doi:10.1007/s00705-021-05036-8Mohamadian, Chiti, Shoghli, COVID-19: virology, biology and novel laboratory diagnosis, J Gene Med,
doi:10.1002/jgm.3303Mullish, Marchesi, Mcdonald, Probiotics reduce self-reported symptoms of upper respiratory tract infection in overweight and obese adults: should we be considering probiotics during viral pandemics?, Gut Microbes,
doi:10.1080/19490976.2021.1900997Olaimat, Aolymat, Holy, The potential application of probiotics and prebiotics for the prevention and treatment of COVID-19, NPJ Sci Food,
doi:10.1038/s41538-020-00078-9Patra, Saxena, Sahu, Systematic network and meta-analysis on the antiviral mechanisms of probiotics: a preventive and treatment strategy to mitigate SARS-CoV-2 infection, Probiotics Antimicrob Proteins,
doi:10.1007/s12602-021-09748-wRasinkangas, Tytgat, Ritari, Characterization of highly mucus-adherent non-GMO derivatives of Lacticaseibacillus rhamnosus GG, Front Bioeng Biotechnol,
doi:10.3389/fbioe.2020.01024Szajewska, Kołodziej, Systematic review with metaanalysis: Lactobacillus rhamnosus GG in the prevention of antibiotic-associated diarrhoea in children and adults, Aliment Pharmacol Ther,
doi:10.1111/apt.13404Tariq, Saha, Furqan, Prevalence and mortality of COVID-19 patients with gastrointestinal symptoms: a systematic review and meta-analysis, Mayo Clin Proc
Trush, Poluektova, Beniashvilli, The evolution of human probiotics: challenges and prospects, Probiotics Antimicrob Proteins,
doi:10.1007/s12602-019-09628-4Valdés-Varela, Hernández-Barranco, Ruas-Madiedo, Gueimonde, Effect of Bifidobacterium upon Clostridium difficile growth and toxicity when co-cultured in different prebiotic substrates, Front Microbiol,
doi:10.3389/fmicb.2016.00738Zolnikova, Komkova, Potskherashvili, Application of probiotics for acute respiratory tract infections, Ital J Med,
doi:10.4081/itjm.2018.931
