Andrea Lo Vecchio

Probiotics as prevention and treatment for diarrhea

Purpose of review To critically appraise evidence on probiotic use for prevention and treatment of diarrhea in children and adults. Recent findings Several randomized controlled trials and meta-analyses suggested that probiotics are effective in primary and secondary prevention of gastroenteritis and its treatment. Selected Lactobacillus strains had a modest, although significant effect in primary prevention. Saccharomyces boulardii was effective in antibiotic-associated and in Clostridium difficile diarrhea. There is evidence that it might prevent diarrhea in day-care centers. Lactobacillus rhamnosus GG was associated with reduced diarrheal duration and severity, more evident in case of childhood Rotavirus diarrhea. Similar, although weaker, evidence was obtained with S. boulardii. Both strains are included in evidence-based recommendations for gastroenteritis management in children. Data on other Lactobacillus strains are preliminary. Probiotic efficacy was related to cause, early administration and bacterial load, and their mechanisms were associated with antiinfectious action in the intestine or, indirectly, to modulation of innate and adaptive immunity. Summary Probiotics have gained a role as adjunctive treatment of infantile gastroenteritis together with rehydration. Their efficacy is less convincing in adults, but promising in antibiotic-associated diarrhea. However, evidence of efficacy is limited to a few strains.

Disrupted Intestinal Microbiota and Intestinal Inflammation in Children with Cystic Fibrosis and Its Restoration with Lactobacillus GG: A Randomised Clinical Trial

Background & Aims Intestinal inflammation is a hallmark of cystic fibrosis (CF). Administration of probiotics can reduce intestinal inflammation and the incidence of pulmonary exacerbations. We investigated the composition of intestinal microbiota in children with CF and analyzed its relationship with intestinal inflammation. We also investigated the microflora structure before and after Lactobacillus GG (LGG) administration in children with CF with and without antibiotic treatment. Methods The intestinal microbiota were analyzed by denaturing gradient gel electrophoresis (DGGE), real-time polymerase chain reaction (RT-PCR), and fluorescence in situ hybridization (FISH). Intestinal inflammation was assessed by measuring fecal calprotectin (CLP) and rectal nitric oxide (rNO) production in children with CF as compared with healthy controls. We then carried out a small double-blind randomized clinical trial with LGG. Results Twenty-two children with CF children were enrolled in the study (median age, 7 years; range, 2–9 years). Fecal CLP and rNO levels were higher in children with CF than in healthy controls (184±146 µg/g vs. 52±46 µg/g; 18±15 vs. 2.6±1.2 µmol/L NO2 −, respectively; P<0.01). Compared with healthy controls, children with CF had significantly different intestinal microbial core structures. The levels of Eubacterium rectale, Bacteroides uniformis, Bacteroides vulgatus, Bifidobacterium adolescentis, Bifidobacterium catenulatum, and Faecalibacterium prausnitzii were reduced in children with CF. A similar but more extreme pattern was observed in children with CF who were taking antibiotics. LGG administration reduced fecal CLP and partially restored intestinal microbiota. There was a significant correlation between reduced microbial richness and intestinal inflammation. Conclusions CF causes qualitative and quantitative changes in intestinal microbiota, which may represent a novel therapeutic target in the treatment of CF. Administration of probiotics restored gut microbiota, supporting the efficacy of probiotics in reducing intestinal inflammation and pulmonary exacerbations. Trial Registration ClinicalTrials.gov NCT 01961661

The management of acute diarrhea in children in developed and developing areas: from evidence base to clinical practice

Introduction: Acute diarrhea remains a major problem in children and is associated with substantial morbidity, mortality and costs. While vaccination against rotavirus could reduce the burden of the disease, the persistent impact of intestinal infections requires effective treatment in adjunct to oral rehydration solutions, to reduce the severity and duration of diarrhea. Several therapeutic options have been proposed for acute diarrhea, but proof of efficacy is available for few of them, including zinc, diosmectite, selected probiotics and racecadotril. However, at present there is no universal drug, and therapeutic efficacy has only been shown for selected drugs in selected settings, such as: outpatients/inpatients, developed/developing countries and viral/bacterial etiology. Areas covered: This narrative review reports the opinions of experts from different countries of the world who have discussed strategies to improve the management of diarrhea. Expert opinion: More data are needed to optimize the management of diarrhea and highlight the research priorities at a global level; such priorities include improved recommendations on oral rehydration solution composition, and the reevaluation of therapeutic options in the light of new trials. Therapeutic strategies need to be assessed in different settings, and pharmacoeconomic analyses based on country-specific data are needed. Transfer to clinical practice should result from the implementation of guidelines tailored at a local level, with an eye on costs.

Evaluation of the Quality of Guidelines for Acute Gastroenteritis in Children With the AGREE Instrument

Aim: The aim of the study was to assess the quality of clinical practice guidelines (CPGs) using the Appraisal of Guidelines for Research and Evaluation (AGREE) instrument, a validated international tool. Materials and Methods: CPGs were identified by searching MEDLINE (1966–January 2009) and Embase (1988–January 2009), CPG databases, and relevant Web sites of agencies and organizations that produce and/or endorse guidelines. Included in the study were CPGs in English that addressed the management of acute gastroenteritis in children. Retrieved CPGs were evaluated with the AGREE instrument for quality assessment by 6 independent reviewers. AGREE consists of 6 domains for a total of 23 items. Results: Nine CPGs were identified. Four were evidence based (EB) and 2 of these included tables of evidence. Eight CPGs (88%) scored <50% for “applicability,” 7 (77%) for “stakeholder involvement,” and 6 (66%) for “editorial independence.” Compared with non-EB CPGs, EB CPGs had higher quality scores for all AGREE domains, with a better score for “rigor of development” (P < 0.001), “stakeholder involvement” and “clarity of presentation” (P < 0.01), and applicability (P < 0.05). Over time, the quality of guidelines tended to improve. The main recommendations of CPGs were similar. However, there were differences in the treatment of diarrhea, namely based on the settings and circumstances in which CPGs were produced. Conclusions: The overall quality of CPGs on acute gastroenteritis management in children is fair. Aims, target population, synthesis of evidence, formulation of recommendations, and clarity of presentation are points of strength. Weak issues are applicability, including identification of organizational barriers and adherence parameters, and cost/efficacy analysis.

The applicability and efficacy of guidelines for the management of acute gastroenteritis in outpatient children: a field-randomized trial on primary care pediatricians.

OBJECTIVE To evaluate the applicability and efficacy of guidelines for the management of acute gastroenteritis (AGE) as used by pediatricians. STUDY DESIGN This was a national, open, randomized, controlled intervention trial. The intervention consisted of a 2-hour course based on the guidelines for management of AGE. Seventy-five randomly selected primary care pediatricians underwent training in AGE management (group A), and 75 pediatricians who were not specifically trained served as controls (group B). Each pediatrician enrolled 10 children age 1-36 months with acute-onset diarrhea. Outcome measures were guidelines applicability, duration of diarrhea, and difference in body weight between the first visit and 5-7 days later. RESULTS The baseline features of the children were similar in groups A (n = 617) and B (n = 692). A total of 404 of the 617 children in group A (65.5%) were fully treated according to the guidelines, compared with 20 of the 692 children in group B (3%). Most violations involved administration of unnecessary drugs or diets. The duration of diarrhea was shorter in group A (intention-to-treat: 83.3 vs 90.9 hours; P < .001). Weight gain was marginally, but statistically significantly, higher in the children treated according to the guidelines (per-protocol analysis: +16.5 gr vs -13.5 gr; P < .05). CONCLUSIONS Guidelines for AGE have good applicability and excellent efficacy. Adjunctive medical interventions are associated with a longer duration of diarrhea.

Pneumococcal and influenza vaccination rates and their determinants in children with chronic medical conditions

BackgroundTo investigate the rates of pneumococcal and influenza vaccinations and their determinants in children with chronic medical conditions.Patients and MethodsChildren with HIV infection, cystic fibrosis, liver transplantation and diabetes mellitus were enrolled. Physicians of regional Reference Centres for each condition, primary care paediatricians and caregivers of children provided information through specific questionnaires. For diabetes, 3 Reference Centres were included.ResultsLess than 25% of children in each group received pneumococcal vaccination. Vaccination rates against influenza were 73% in patients with HIV-infection, 90% in patients with cystic fibrosis, 76% in patients with liver transplantation, and ranged from 21% to 61% in patients with diabetes mellitus. Reference Centres rather than primary care paediatricians had a major role in promoting vaccinations. Lack of information was the main reason for missing vaccination. Awareness of the severity of pneumococcus infection by key informants of at-risk children was associated with higher vaccination rate.ConclusionsVaccination rates in children with chronic conditions were poor for pneumococcus and slightly better for influenza. Barriers to vaccination include lack of awareness, health care and organization problems.

Chronic diarrhoea in children

Chronic diarrhoea in children shows an age related spectrum. In infants and young children a major role is related to persistent intestinal infections, intolerance to specific nutrients such as cows milk protein, and toddlers diarrhoea. In older children and adolescents, inflammatory bowel diseases are strongly increasing and nonspecific diarrhoea is also frequent. Coeliac disease is a major cause of diarrhoea throughout childhood. In neonates, congenital diarrhoea is a rare but severe syndrome that includes several highly complex diseases. In children, diagnosis should be based on noninvasive techniques. Endoscopy should be decided based on clinical criteria, but also driven by noninvasive tests to assess the digestive absorptive functions and intestinal inflammation. A stepwise approach may reduce the need of endoscopy, also in the light of its relatively limited diagnostic yield compared to adult patients. Treatment of chronic diarrhoea in children is also substantially different from what is generally done in adults and includes a major role for nutritional interventions. Therefore chronic diarrhoea in children is a complex age-specific disorder that requires an age-specific management that is in many aspects distinct from that in adults.

Fecal microbiota transplantation for Clostridium difficile infection: benefits and barriers.

Purpose of review The incidence and severity of Clostridium difficile infection (CDI) have increased worldwide in the past two decades. A principal function of the gut microbiota is to protect the intestine against colonization by exogenous pathogens. Increasingly, the gut microbiota have been shown to influence susceptibility to other genetic and environmentally acquired conditions. Transplantation of healthy donor fecal material in patients with CDI may re-establish the normal composition of the gut microbiota and has been shown to be effective in recurrent CDI. We intend to review the most recent data on fecal microbiota transplantation (FMT) and critically discuss potential advantages and handicaps of this new therapeutic approach. Recent findings Evidence from case series and only one randomized clinical trial suggests that FMT is able to restore the wide diversity of microflora, improve C. difficile-related symptoms and prevent CDI recurrence. Summary FMT is a promising treatment option for serious and recurrent CDI, and current evidence (although weak) demonstrates consistent and excellent efficacy in clinical outcomes. However, many questions should be answered before it may be recommended as routine standard treatment. Mechanisms of action need to be better understood. Long-term follow-up studies are needed to determine long-lasting effects (including the association with autoimmune diseases).

Rapid Adoption of Lactobacillus rhamnosus GG for Acute Gastroenteritis

BACKGROUND AND OBJECTIVES: A 2007 meta-analysis showed probiotics, specifically Lactobacillus rhamnosus GG (LGG), shorten diarrhea from acute gastroenteritis (AGE) by 24 hours and decrease risk of progression beyond 7 days. In 2005, our institution published a guideline recommending consideration of probiotics for patients with AGE, but only 1% of inpatients with AGE were prescribed LGG. The objective of this study was to increase inpatient prescribing of LGG at admission to >90%, for children hospitalized with AGE, within 120 days. METHODS: This quality improvement study included patients aged 2 months to 18 years admitted to general pediatrics with AGE with diarrhea. Diarrhea was defined as looser or ≥3 stools in the preceding 24 hours. Patients with complex medical conditions or with presumed bacterial gastroenteritis were excluded. Admitting and supervising clinicians were educated on the evidence. We ensured LGG was adequately stocked in our pharmacies and updated an AGE-specific computerized order set to include a default LGG order. Failure identification and mitigation were conducted via daily electronic chart review and e-mail communication. Primary outcome was the percentage of included patients prescribed LGG within 18 hours of admission. Intervention impact was assessed with run charts tracking our primary outcome over time. RESULTS: The prescribing rate increased to 100% within 6 weeks and has been sustained for 7 months. CONCLUSIONS: Keys to success were pharmacy collaboration, use of an electronic medical record for a standardized order set, and rapid identification and mitigation of failures. Rapid implementation of evidence-based practices is possible using improvement science methods.

A core outcome set for clinical trials in acute diarrhoea

Objective Core outcome sets are the baseline for what should be measured in clinical research and, thus, should serve as a guide for what should be collected and reported. The Consensus Group on Outcome Measures Made in Pediatric Enteral Nutrition Clinical Trials, established in 2012, agreed that consensus on a core set of outcomes with agreed-upon definitions that should be measured and reported in clinical trials was needed. To achieve this goal, six working groups (WGs) were setup, including WG on acute diarrhoea, whose main goal was to develop a core outcome set for trials in acute diarrhoea. Methods The first step identified how published outcomes related to acute diarrhoea were reported. The second focused on the methodology for determining which outcomes to measure in clinical trials. The third employed a two-phase questionnaire study using the Delphi technique to define clinically important outcomes to clinicians and parents. Results For therapeutic studies, the five most important outcome measures were diarrhoea duration, degree of dehydration, need for hospitalisation (or duration of hospitalisation for inpatients), the proportion of patients recovered by 48 h and adverse effects. The prophylactic core outcome set included prevention of diarrhoea, prevention of dehydration, prevention of hospitalisation and adverse effects. Conclusions The outcome sets for therapy and prevention can be recommended for use in future trials of patients with gastroenteritis. Their envisioned goal is to decrease study heterogeneity and to ease the comparability of studies. WGs next step is to determine how to measure the outcomes included in the core set.