Gut immune homeostasis: the immunomodulatory role of Bacillus clausii, from basic to clinical evidence.

INTRODUCTION: The gut microbiota affects the development of the gut immune system in early life. Perturbations to microbiota structure and composition during this period can have long-term consequences on the health of the individual, through its effects on the immune system. Research in the last few decades has shown that probiotic administration can reverse these effects in strain- and environment-specific ways. Bacillus clausii (B. clausii) has been in use for many decades as a safe and efficacious probiotic, but its mode of action has not yet been completely elucidated. AREAS COVERED: In this review, we discuss how the gut immune system works, the factors that affect its functioning, and the plethora of research highlighting its role in various diseases. We also discuss the known modes of action of Bacillus probiotics, and highlight the preclinical and clinical evidence that reveal how B. clausii acts to bolster gut defense. EXPERT OPINION: We anticipate that the treatment and/or prevention of dysbiosis will be central to managing human health and disease in the future. Discovering the pathophysiology of autoimmune diseases, infections, allergies, and some cancers will aid our understanding of the key role played by microbial communities in these diseases.

Recommendations for the adjuvant use of the poly-antibiotic-resistant probiotic Bacillus clausii (O/C, SIN, N/R, T) in acute, chronic, and antibiotic-associated diarrhea in children: consensus from Asian experts.

This paper proposes recommendations for probiotics in pediatric gastrointestinal diseases in the Asia-Pacific region. Evidence-based recommendations and randomized controlled trials in the region are included. Cultural aspects, health management issues and economic factors were also considered. Final recommendations were approved by utilizing a modified Delphi process and applying the Likert scale in an electronic voting process. Bacillus clausii was recommended as an adjunct treatment with oral rehydration solution for acute viral diarrhea. B. clausii may also be considered for prevention of antibiotic-associated diarrhea, Clostridium difficile-induced diarrhea, and as adjunct treatment of Helicobacter pylori. There is insufficient evidence for recommendations in other conditions. Despite a diversity of epidemiological, socioeconomical and health system conditions, similar recommendations currently apply to most Asia-Pacific countries. Ideally, these need to be validated with local randomized-controlled trials.

Bacillus clausii as adjunctive treatment for acute community-acquired diarrhea among Filipino children: a large-scale, multicenter, open-label study (CODDLE).

BACKGROUND: Diarrhea is among the main causes of pediatric mortality in the Philippines. Probiotics have been shown to be beneficial in the management of acute diarrhea. Accordingly, the aim of this population-based study was to assess the safety and effectiveness of Bacillus clausii as an adjunct to standard therapy in Filipino children with acute community-acquired diarrhea of viral origin or associated with antibiotic administration. METHODS: A total of 3178 patients (median age of 2 years) were enrolled in this open-label, multicenter, observational study, and were treated with one to two vials of Bacillus clausii in the following bacterial stains: O/C, SIN, N/R, and T (oral suspension of 2 billion spores per 5-mL vial) for 5 to 7 days. Diarrhea duration, number of stools per day, improvement in gastrointestinal symptoms, children's overall acceptability of Bacillus clausii therapy, and safety and tolerability were assessed. Concomitant treatment with oral rehydration solutions (26.6%), zinc (23.9%), and antibiotics prescribed for conditions other than diarrhea (13.6%) was recorded during the study. All other probiotics and antidiarrheals were prohibited. RESULTS: Therapy with Bacillus clausii was well-tolerated, and the adverse event rate was very low (0.09%). All reported adverse events, which included vomiting, erythematous rashes and stool color change, were mild to moderate. In more than half of the per-protocol population (1535/2916; 52.6%), diarrhea was resolved within the first 3 days of treatment with Bacillus clausii. There was no significant difference (p = 0.297) in mean diarrhea duration between patients with either antibiotic-associated (3.3 ± 1.3 days) or viral diarrhea (3.4 ± 1.3 days). However, children who only received Bacillus clausii supplementation without zinc had a significantly shorter diarrhea duration (3.3 ± 1.3 days) compared to zinc-treated children (3.6 ± 1.6 days; p < 0.001). Bacillus clausii significantly reduced the mean number of stools per day, from 5.2 ± 2.0 stools at baseline to 1.2 ± 0.6 stools at study end (p < 0.001). Similarly, the proportion of patients with loose stools decreased from 81.6% at baseline to 9.2% at end of treatment period. Acceptability of Bacillus clausii therapy was high. CONCLUSION: This study adds knowledge on the good safety profile and on the effectiveness of Bacillus clausii as an adjunct treatment for acute childhood diarrhea.

Efficacy, immunogenicity, and safety of a quadrivalent inactivated influenza vaccine in children aged 6-35 months: A multi-season randomised placebo-controlled trial in the Northern and Southern Hemispheres.

BACKGROUND: A quadrivalent split-virion inactivated influenza vaccine (VaxigripTetra™, Sanofi Pasteur; IIV4) containing two A strains (H1N1 and H3N2) and B strains from both lineages (Victoria and Yamagata) was approved in Europe in 2016 for individuals aged ≥ 3 years. This study examined the efficacy and safety of IIV4 in children aged 6-35 months. METHODS: This was a phase III randomised controlled trial conducted in Latin America, Asia, Africa, and Europe during the Northern Hemisphere 2014/2015 and 2015/2016 and Southern Hemisphere 2014 and 2015 influenza seasons. Healthy children aged 6-35 months not previously vaccinated against influenza were randomised to receive two full doses 28 days apart of IIV4, placebo, the licensed trivalent split-virion inactivated vaccine (IIV3), an investigational IIV3 containing a B strain from the alternate lineage. The primary objective was to demonstrate efficacy against influenza illness caused by any strain or vaccine-similar strains. RESULTS: The study enrolled 5806 participants. Efficacy, assessed in 4980 participants completing the study according to protocol, was demonstrated for IIV4. Vaccine efficacy was 50.98% (97% CI, 37.36-61.86%) against influenza caused by any A or B type and 68.40% (97% CI, 47.07-81.92%) against influenza caused by vaccine-like strains. Safety profiles were similar for IIV4, placebo, and the IIV3s, although injection-site reactions were slightly more frequent for IIV4 than placebo. CONCLUSIONS: IIV4 was safe and effective for protecting children aged 6-35 months against influenza illness caused by vaccine-similar or any circulating strains. CLINICAL TRIAL REGISTRATION: EudraCT no. 2013-001231-51.

Thrombocytopenia associated with dengue hemorrhagic fever responds to intravenous administration of anti-D (Rh(0)-D) immune globulin.

Severe thrombocytopenia and increased vascular permeability are two major characteristics of dengue hemorrhagic fever (DHF). An immune mechanism of thrombocytopenia due to increased platelet destruction appears to be operative in patients with DHF (see Saito et al., 2004, Clin Exp Immunol 138: 299-303; Mitrakul, 1979, Am J Trop Med Hyg 26: 975-984; and Boonpucknavig, 1979, Am J Trop Med Hyg 28: 881-884). The interim data of two randomized placebo controlled trials in patients (N = 47) meeting WHO criteria for dengue hemorrhagic fever (DHF) with severe thrombocytopenia (platelets < or = 50,000/mm(3)) reveal that the increase in platelet count with anti-D immune globulin (WinRho SDF), 50 microg/kg (250 IU/kg) intravenously is more brisk than the placebo group. The mean maximum platelet count of the anti-D-treated group at 48 hours was 91,500/mm(3) compared with 69,333/mm(3) in the placebo group. 75% of the anti-D-treated group demonstrated an increase of platelet counts > or = 20,000 compared with only 58% in the placebo group. These data suggest that treatment of severe thrombocytopenia accompanying DHF with anti-D may be a useful and safe therapeutic option.