Carlos A. Cuello-Garcia

World Allergy Organization-McMaster University Guidelines for Allergic Disease Prevention (GLAD-P): Probiotics

BackgroundPrevalence of allergic diseases in infants, whose parents and siblings do not have allergy, is approximately 10% and reaches 20–30% in those with an allergic first-degree relative. Intestinal microbiota may modulate immunologic and inflammatory systemic responses and, thus, influence development of sensitization and allergy. Probiotics have been reported to modulate immune responses and their supplementation has been proposed as a preventive intervention.ObjectiveThe World Allergy Organization (WAO) convened a guideline panel to develop evidence-based recommendations about the use of probiotics in the prevention of allergy.MethodsWe identified the most relevant clinical questions and performed a systematic review of randomized controlled trials of probiotics for the prevention of allergy. We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations. We searched for and reviewed the evidence about health effects, patient values and preferences, and resource use (up to November 2014). We followed the GRADE evidence-to-decision framework to develop recommendations.ResultsCurrently available evidence does not indicate that probiotic supplementation reduces the risk of developing allergy in children. However, considering all critical outcomes in this context, the WAO guideline panel determined that there is a likely net benefit from using probiotics resulting primarily from prevention of eczema. The WAO guideline panel suggests: a) using probiotics in pregnant women at high risk for having an allergic child; b) using probiotics in women who breastfeed infants at high risk of developing allergy; and c) using probiotics in infants at high risk of developing allergy. All recommendations are conditional and supported by very low quality evidence.ConclusionsWAO recommendations about probiotic supplementation for prevention of allergy are intended to support parents, clinicians and other health care professionals in their decisions whether to use probiotics in pregnancy and during breastfeeding, and whether to give them to infants.

Probiotics for the prevention of allergy: A systematic review and meta-analysis of randomized controlled trials

BACKGROUND Allergic diseases are considered a health burden because of their high and constantly increasing prevalence, high direct and indirect costs, and undesirable effects on quality of life. Probiotics have been suggested as an intervention to prevent allergic diseases. OBJECTIVE We sought to synthesize the evidence supporting use of probiotics for the prevention of allergies and inform World Allergy Organization guidelines on probiotic use. METHODS We performed a systematic review of randomized trials assessing the effects of any probiotic administered to pregnant women, breast-feeding mothers, and/or infants. RESULTS Of 2403 articles published until December 2014 identified in Cochrane Central Register of Controlled Trials, MEDLINE, and Embase, 29 studies fulfilled a priori specified inclusion criteria for the analyses. Probiotics reduced the risk of eczema when used by women during the last trimester of pregnancy (relative risk [RR], 0.71; 95% CI, 0.60-0.84), when used by breast-feeding mothers (RR, 0.57; 95% CI, 0.47-0.69), or when given to infants (RR, 0.80; 95% CI, 0.68-0.94). Evidence did not support an effect on other allergies, nutrition status, or incidence of adverse effects. The certainty in the evidence according to the Grading of Recommendation Assessment Development and Evaluation approach is low or very low because of the risk of bias, inconsistency and imprecision of results, and indirectness of available research. CONCLUSION Probiotics used by pregnant women or breast-feeding mothers and/or given to infants reduced the risk of eczema in infants; however, the certainty in the evidence is low. No effect was observed for the prevention of other allergic conditions.

Vitamin D supplementation in primary allergy prevention: Systematic review of randomized and non-randomized studies

To date, a systematic review of the evidence regarding the association between vitamin D and allergic diseases development has not yet been undertaken.

Using patient values and preferences to inform the importance of health outcomes in practice guideline development following the GRADE approach

BackgroundThere are diverse opinions and confusion about defining and including patient values and preferences (i.e. the importance people place on the health outcomes) in the guideline development processes. This article aims to provide an overview of a process for systematically incorporating values and preferences in guideline development.MethodsIn 2013 and 2014, we followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to adopt, adapt and develop 226 recommendations in 22 guidelines for the Ministry of Health of the Kingdom of Saudi Arabia. To collect context-specific values and preferences for each recommendation, we performed systematic reviews, asked clinical experts to provide feedback according to their clinical experience, and consulted patient representatives.ResultsWe found several types of studies addressing the importance of outcomes, including those reporting utilities, non-utility measures of health states based on structured questionnaires or scales, and qualitative studies. Guideline panels used the relative importance of outcomes based on values and preferences to weigh the balance of desirable and undesirable consequences of alternative intervention options. However, we found few studies addressing local values and preferences.ConclusionsCurrently there are different but no firmly established processes for integrating patient values and preferences in healthcare decision-making of practice guideline development. With GRADE Evidence-to-Decision (EtD) frameworks, we provide an empirical strategy to find and incorporate values and preferences in guidelines by performing systematic reviews and eliciting information from guideline panel members and patient representatives. However, more research and practical guidance are needed on how to search for relevant studies and grey literature, assess the certainty of this evidence, and best summarize and present the findings.

Prebiotics for the prevention of allergies: A systematic review and meta-analysis of randomized controlled trials

Prevalence of allergic diseases in infants is approximately 10% reaching 20 to 30% in those with an allergic first‐degree relative. Prebiotics are selectively fermented food ingredients that allow specific changes in composition/activity of the gastrointestinal microflora. They modulate immune responses, and their supplementation has been proposed as an intervention to prevent allergies.

Reply: To PMID 26044853.

To the Editor: We thank Szajewska et al for raising important issues in the discussion about the use of probiotics with the intent of prevention of development of allergies in children. Please allow us to begin by clarifying that in our systematic review we attempted only to summarize the currently available evidence about the health effects of probiotics in this setting and we deliberately refrained from making any recommendations for clinical practice. Specific recommendations were provided by the World Allergy Organization (WAO) guideline panel in a separate document. We believe that authors of systematic reviews should not make clinical recommendations. They typically review only the studies of health effects of interventions and do not seek information about other factors required to make a decision whether or not to use an intervention, for example, patients’ values and preferences, acceptability, resource requirements, and feasibility of implementation. This point of view is shared by Cochrane as expressed in the Cochrane Handbook for Systematic Reviews of Interventions (chapter 12: Interpreting results and drawing conclusions, 12.7.2 Implications for practice). Thus, allow us to discuss only the evidence synthesis and abstain from discussion of clinical recommendations and implications for practice. Szajewska et al pointed out that our review did not answer a few specific questions: which probiotics should be used, in what dose, and when should the probiotic supplementation be stopped. Our review was designed to summarize the evidence required to answer the questions determined by the WAO guideline panel. Both the WAO guidelines and our systematic review did not intend to be comprehensive and answer all questions in this area. As much as we agree with Szajewska et al that the answer to the above questions would be beneficial, it was either beyond the scope of our project or impossible to answer on the basis of currently available data, which we discuss in the next paragraph. Any clinical practice guidelines should be reviewed and updated once new evidence becomes available. We are confident that the WAO guideline panel will address these and similar questions in the update of the guidelines if they determine that clinicians seek advice in this area and the information to answer them is available. Szajewska et al suggest that we should have refrained from pooling data on different probiotics to avoid misleading consumers, parents, and health care professionals. Our choice to combine the results of all studies followed a standard approach in systematic reviews designed to summarize information for decision making by attempting a meta-analysis of all studies and investigating heterogeneity. We saw inconsistency not only in results among studies of different probiotics but also among studies that used the same strain (Fig 1). In our view, the magnitude of heterogeneity did not provide a compelling reason not to combine the results. We recognize that decisions concerning which results should or should not be combined are inevitably subjective and consensus may be difficult to reach in many cases. We agree with Szajewska et al that the conclusion that all probiotics are equal would be premature. However, on the basis of available data from randomized trials in humans, we also believe that it is too early for an opposite conclusion, that is, that probiotics differ in their effect on the development of eczema. The available evidence from randomized trials does not allow excluding the possibility that the effect of probiotics is a class effect or that, indeed, there are differences among the strains. We also emphasized in our review that because of the very inconsistency in study results and other limitations one might have only very low confidence that observed effects reflect the actual effect of each and all probiotics. Furthermore, we identified a study that directly compared the effects of 2 strains of probiotics: Lactobacillus rhamnosus HN001 with Bifidobacterium animalis subsp lactis HN019. This study found a reduced risk of developing eczema in those children who received HN001 (hazard ratio, 0.57; 95% CI, 0.39-0.83). The estimate of the effect of HN019 was not statistically significant; however, point estimate and the CI did not exclude an appreciable benefit (hazard ratio, 0.79; 95% CI, 0.56-1.11). Thus, on the basis of currently available data from experimental studies in humans, we believe that one cannot confidently determinewhether the effects of various strains are similar or whether there are some strains whose effects are different (larger or smaller) from those of other strains. We share the view of Szajewska et al that data on the effects of individual probiotic strains are needed. Until they become available, clinicians, parents, and others will need to make decisions under uncertainty about the magnitude of benefits from different strains of probiotics. Carlos A. Cuello-Garcia, MD Jan L. Bro _ zek, MD, PhD Alessandro Fiocchi, MD Ruby Pawankar, MD, PhD Juan Jos e Yepes-Nu~ nez, MD, MSc Luigi Terracciano, MD Shreyas Gandhi, BHSc Arnav Agarwal, BHSc Yuan Zhang, MSc Holger J. Sch€ unemann, MD, MSc, PhD From the Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, Ontario, Canada; the Tecnologico de Monterrey School of Medicine, Monterrey, Mexico; the Department of Medicine, McMaster University, Hamilton, Ontario, Canada; the Pediatric Hospital Bambino Ges u, Vatican City; the Department of Pediatrics, Nippon Medical School, Tokyo, Japan; the School of Medicine, University of Antioquia, Medell ın, Colombia; the Department of Child and Maternal Medicine, University of Milan Medical School at the Melloni Hospital, Milan, Italy; and the Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada E-mail: brozekj@mcmaster.ca. The World Allergy Organization supported this study. Disclosure of potential conflict of interest: C. A. Cuello-Garcia has received consultancy fees and travel support, paid through McMaster University, from the World Allergy Organization (WAO). J. L. Bro _ zek has received research support paid to McMaster University and travel support from the WAO. A. Fiocchi has received travel support from the WAO; has received consultancy fees from GlaxoSmithKline; and has received travel support and lecture fees from Danone. R. Pawankar is employed by Nippon Medical School in Tokyo; has received research support from the Ministry of Education of Japan; and receives royalties from Springer. J. J. Yepes-Nu~nez has received consultancy fees and fees for the creation of WAO clinical practice guidelines paid to McMaster University from the WAO and has received travel support from the WAO. L. Terracciano has received travel support from the WAO and has received consultancy fees from Heinz-Plada. S. Gandhi and Y. Zhang have received consultancy fees paid to McMaster University from the WAO and travel support from the WAO. H. J. Sch€unemann has received consultancy fees, travel support, and payment for systematic reviews from the WAO. A. Agarwal declares no relevant conflicts of interest.

Early Mobilization in Critically Ill Children: A Systematic Review

Objective To characterize how early mobilization is defined in the published literature and describe the evidence on safety and efficacy on early mobilization in critically ill children. Study design Systematic search of randomized and nonrandomized studies assessing early mobilization‐based physical therapy in critically ill children under 18 years of age in MEDLINE, Embase, CINAHL, CENTRAL, the National Institutes of Health, Evidence in Pediatric Intensive Care Collaborative, Physiotherapy Evidence Database, and the Mobilization‐Network. We extracted data to identify the types of mobility‐based interventions and definitions for early, as well as barriers, feasibility, adverse events, and efficacy outcomes (mortality, morbidities, and length of stay). Results Of 1199 titles found, we included 11 studies (2 pilot trials and 9 observational studies) and 1 clinical practice guideline in the analyses. Neurodevelopmentally appropriate increasing mobility levels have been described for critically ill children, and “early” mobilization was defined as either a range (within 48‐72 hours) from admission to the pediatric intensive care unit or when clinical safety criteria are met. Current evidence suggests that early mobilization is safe and feasible and institutional practice guidelines significantly increase the frequency of rehabilitation consults, improve the proportion of patients who receive early mobilization, and reduce the time to mobilization. However, there were inconsistencies in populations and interventions across studies, and imprecision and risk of bias in included studies that precluded us from pooling data to evaluate the efficacy outcomes of early mobilization. Conclusions The definition of early mobilization varies, but seems to be feasible and safe in critically ill children. The efficacy for early mobilization in this population is yet undetermined because of the low certainty of the evidence available.

A Scoping Review and Survey Provides the Rationale, Perceptions, and Preferences for the Integration of Randomized and Non-Randomized Studies in Evidence Syntheses and GRADE Assessments

OBJECTIVES To review the literature and obtain preferences and perceptions from experts regarding the role of randomized studies (RSs) and nonrandomized studies (NRSs) in systematic reviews of intervention effects. STUDY DESIGN AND SETTING Scoping review and survey of experts. Using levels of certainty developed by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group, experts expressed their preferences about the use of RS and NRS in health syntheses. RESULTS Of 189 respondents, 123 had the expertise required to answer the questionnaire; 116 provided their extent of agreement with approaches to use NRS with RS. Most respondents would include NRS when RS was unfeasible (83.6%) or unethical (71.5%) and a majority to maximize the body of evidence (66.3%), compare results in NRS and RS (53.5%) and to identify subgroups (51.7%). Sizable minorities would include NRS and RS to address the effect of randomization (29.5%) or because the question being addressed was a public-health intervention (36.5%). In summary of findings tables, most respondents would include both bodies of evidence-in two rows in the same table-when RS provided moderate, low, or very-low certainty evidence; even when RS provided high certainty evidence, a sizable minority (25%) would still present results from both bodies of evidence. Very few (3.6%) would, under realistic circumstances, pool RS and NRS results. CONCLUSIONS Most experts would include both RS and NRS in the same review under a wide variety of circumstances, but almost all would present results of two bodies of evidence separately.

Children with intellectual disabilities: taking care of our weak

— Carlos Cuello-García, MD C hildren with intellectual disabilities, those with significant limitations in both intellectual functioning and in adaptive behavior covering many everyday social and practical skills, are known to have an increased risk of death and comorbidities. In studies from different countries, the prevalence of this condition lies approximately 10 per 1000 live births. The study published in this volume of The Journal by Bourke et al closes a gap in knowledge about children with intellectual disability and their survival into adulthood. Bourke et al, using a population-based dataset of more than 25 000 over a 25-year period, compared children with and without disabilities in Australia to assess the risks of morbidities and mortality. Their results highlight that children with intellectual disability experience higher mortality at all ages compared with those without intellectual disability, with the greatest burden being for those with severe intellectual disability. But we must wonder, how different is this risk in Australia, a high-income country with one of the best healthcare systems in the world, compared with those in other countries, either with the same or different level of economic development? How many deaths in children from disabilities could be prevented by simply having good health coverage? Gandhi, among others, said it in a similar fashion: “A nation’s greatness is measured by how it treats its weakest members.” The message is for everyone to keep improving on identifying possible modifying factors to prevent morbidities and improve health outcomes in children with disabilities. Article page 232 ▶