A systematic review and meta-analysis on absolute eosinophil counts and the risk of asthma in preschool children with wheezing: An EAACI Task Force Report.

Preschool children with wheezing disorders pose diagnostic and therapeutic challenges and consume substantial healthcare resources. Peripheral eosinophil blood count (EBC) has been proposed as a potential indicator for future asthma development. This review by the European Academy of Allergy and Clinical Immunology (EAACI) Preschool Wheeze Task Force aimed to provide systematic evidence for the association between increased EBC and the risk of future asthma, as well as to identify potential cutoff values. In February 2023, a search of PubMed, EMBASE, and Cochrane Library databases was conducted to identify studies comparing EBCs in preschool children with wheezing who continued to wheeze later in life and those who did not. Included observational studies focused on children aged <6 years with a wheezing disorder, assessment of their EBCs, and subsequent asthma status. No language or publication date restrictions were applied. Among the initial 3394 studies screened, 10 were included in the final analysis, involving 1225 patients. The data from these studies demonstrated that high EBC in preschool children with wheezing is associated with future asthma development, with odds ratios of 1.90 (95% CI: 0.45-7.98, p = .38), 2.87 (95% CI: 1.38-5.95, p < .05), and 3.38 (95% CI: 1.72-6.64, p < .05) for cutoff values in the <300, 300-449, and ≥450 cells/µL ranges, respectively. Defining a specific cutoff point for an elevated EBC lacks consistency, but children with EBC >300 cells/µL are at increased risk of asthma. However, further research is needed due to the limitations of the included studies. Future investigations are necessary to fully elucidate the discussed association.

Association of respiratory virus types with clinical features in bronchiolitis: Implications for virus testing strategies. A systematic review and meta-analysis.

BACKGROUND: Bronchiolitis is a leading cause of infant hospitalization, linked to respiratory syncytial virus (RSV) and rhinovirus (RV). Guidelines lack specific viral testing for bronchiolitis management. To establish effective management strategies, it is crucial to assess whether specific respiratory virus types are correlated with distinct examination features. METHODS: Through a systematic search of three databases, 21 studies were qualitatively analyzed, with 18 used for meta-analysis. Various outcomes like wheezing on auscultation, fever, atopic traits, and infection severity were evaluated. RESULTS: RSV-positive bronchiolitis was associated with a higher need for oxygen supplementation (OR 1.78, 95% CI 1.04-3.02) in 5 studies, while RV-positive bronchiolitis was more frequently linked to personal history of eczema (OR 0.60, 95% CI 0.41-0.88) in 6 studies. No significant differences were observed in the other outcomes examined. CONCLUSIONS: Bronchiolitis caused by RSV or RV presents with similar clinical features. Despite the associations between RSV-positive bronchiolitis and need for oxygen supplementation, and RV-positive bronchiolitis and a history of eczema, our study shows that viral etiology of bronchiolitis cannot be determined solely based on clinical presentation. Tailored management strategies, informed by accurate viral testing, seem crucial in clinical practice for enhancing patient outcomes in severe bronchiolitis.

Targeting the gut-lung axis by synbiotic feeding to infants in a randomized controlled trial.

BACKGROUND: Formula-fed infants are at increased risk of infections. Due to the cross-talk between the mucosal systems of the gastrointestinal and respiratory tracts, adding synbiotics (prebiotics and probiotics) to infant formula may prevent infections even at distant sites. Infants that were born full term and weaned from breast milk were randomized to prebiotic formula (fructo- and galactooligosaccharides) or the same prebiotic formula with Lactobacillus paracasei ssp. paracasei F19 (synbiotics) from 1 to 6 months of age. The objective was to examine the synbiotic effects on gut microbiota development. RESULTS: Fecal samples collected at ages 1, 4, 6, and 12 months were analyzed using 16S rRNA gene sequencing and a combination of untargeted gas chromatography-mass spectrometry/liquid chromatography-mass spectrometry. These analyses revealed that the synbiotic group had a lower abundance of Klebsiella, a higher abundance of Bifidobacterium breve compared to the prebiotic group, and increases in the anti-microbial metabolite d-3-phenyllactic acid. We also analyzed the fecal metagenome and antibiotic resistome in the 11 infants that had been diagnosed with lower respiratory tract infection (cases) and 11 matched controls using deep metagenomic sequencing. Cases with lower respiratory tract infection had a higher abundance of Klebsiella species and antimicrobial resistance genes related to Klebsiella pneumoniae, compared to controls. The results obtained using 16S rRNA gene amplicon and metagenomic sequencing were confirmed in silico by successful recovery of the metagenome-assembled genomes of the bacteria of interest. CONCLUSIONS: This study demonstrates the additional benefit of feeding specific synbiotics to formula-fed infants over prebiotics only. Synbiotic feeding led to the underrepresentation of Klebsiella, enrichment of bifidobacteria, and increases in microbial degradation metabolites implicated in immune signaling and in the gut-lung and gut-skin axes. Our findings support future clinical evaluation of synbiotic formula in the prevention of infections and associated antibiotic treatment as a primary outcome when breastfeeding is not feasible. TRIAL REGISTRATION: ClinicalTrials.gov NCT01625273 . Retrospectively registered on 21 June 2012.

Respiratory virus type to guide predictive enrichment approaches in the management of the first episode of bronchiolitis: A systematic review.

It has become clear that severe bronchiolitis is a heterogeneous disease; even so, current bronchiolitis management guidelines rely on the one-size-fits-all approach regarding achieving both short-term and chronic outcomes. It has been speculated that the use of molecular markers could guide more effective pharmacological management and achieve the prevention of chronic respiratory sequelae. Existing data suggest that asthma-like treatment (systemic corticosteroids and beta2-agonists) in infants with rhinovirus-induced bronchiolitis is associated with improved short-term and chronic outcomes, but robust data is still lacking. We performed a systematic search of PubMed, Embase, Web of Science, and the Cochrane's Library to identify eligible randomized controlled trials to determine the efficacy of a personalized, virus-dependent application of systemic corticosteroids in children with severe bronchiolitis. Twelve studies with heterogeneous methodology were included. The analysis of the available results comparing the respiratory syncytial virus (RSV)-positive and RSV-negative children did not reveal significant differences in the associatons between systemic corticosteroid use in acute episode and duration of hospitalization (short-term outcome). However, this systematic review identified a trend of the positive association between the use of systematic corticosteroids and duration of hospitalization in RSV-negative infants hospitalized with the first episode of bronchiolitis (two studies). This evidence is not conclusive. Taken together, we suggest the design for future studies to assess the respiratory virus type in guiding predictive enrichment approaches in infants presenting with the first episode of bronchiolitis. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42020173686.

World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) Guidelines update - IV - A quality appraisal with the AGREE II instrument.

Background: Since the publication of The World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) Guidelines in 2010, a number of other guidelines, expert opinions, and position papers relating to the management of cow's milk allergy (CMA) have been published. We aimed to systematically review the quality of the guidelines on CMA diagnosis and management in children and/or adults published between 2010 and 2020. Methods: The MEDLINE, EMBASE, ISI Web of Science, World Health Organization Global Index Medicus, and Turning Research into Practice databases as well as website guideline repositories were searched from January 2010 until May 2020. Any clinical practice recommendations and/or guidelines focusing on the diagnosis and management of CMA in children and/or adults developed or endorsed by professional scientific societies or organizations were included. The guidelines were evaluated using the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool, a 23-item tool organized within 6 domains and 2 global rating items. Results: We included 12 guidelines; 8 were developed by national and 4 by international organizations. The quality scores for each domain varied: of all domains, the clarity of presentation domain had the highest median score (92%; Q1-Q3 81-100%), whereas rigor of development had the lowest median score (30%; Q1-Q3 15-67%). The median scores (Q1-Q3) for individual domains were as follows: scope and purpose 82% (70-99%), stakeholder involvement 63% (21-79%), rigor of development 30% (15-67%), clarity of presentation 92% (81-100%), applicability 68% (57-75%), and editorial independence 75% (69-100%). The median overall score was 70% (58-89%). Only 1 guideline (from the National Institute for Health and Care Excellence [NICE]) achieved top ratings (100%) in five domains and the overall score. Three guidelines (from the NICE, the British Society for Allergy & Clinical Immunology [BSACI] and WAO) achieved the highest ratings (100%) in at least 3 domains and the overall score. Conclusion: The majority of identified guidelines were of good or very good quality. However, the weakest point was the rigor of development domain, mostly due to unclear description of strengths and limitations of the body of evidence and the procedure for updating the guidelines.

Sodium Picosulphate with Magnesium Citrate versus Polyethylene Glycol for Bowel Preparation in Children: A Systematic Review.

Purpose: To compare the effectiveness, tolerability, acceptability, and safety of sodium picosulphate with magnesium citrate (PS/Mg) and polyethylene glycol (PEG) in children (≤18 years) preparing for colonoscopy. Methods: Three electronic databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials) were searched till July 2020. Only randomized controlled trials (RCTs) were included. At least two authors independently selected studies and performed risk of bias assessment and data extraction. Results: Four RCTs (n=390), with overall good quality were included. A meta-analysis of two trials (n=224) found no statistically significant difference between the groups with respect to the proportion of patients who had excellent and good scores (≥6 points) according to the Boston Bowel Preparation Scale (relative risk: 0.99; 95% confidence interval [CI]: 0.90 to 1.08). Excellent and good scores were observed in both groups in approximately 90% of children. A meta-analysis of two other trials (n=150) showed no significant difference between the groups with respect to the mean total score for the Ottawa Bowel Preparation Scale (mean difference: 0.20; 95% CI: -0.74 to 1.14). Both regimens provided a comparable safety profile; however, PS/Mg was significantly superior to high volume PEG in terms of tolerability (abdominal pain, nausea, vomiting, bloating/flatulence/fullness) and acceptability (ease of formulation consumption, taste acceptance, need for nasogastric tube, compliance with full dose). Conclusion: PS/Mg provides a quality and safety profile similar to PEG for bowel cleansing; however, it has better acceptance and tolerance in children preparing for colonoscopy.

Oral immunotherapy in children with a food allergy-Where do we stand? - Review.

The number of hospitalisations due to an anaphylactic reaction to food is continuously increasing. Therefore, there is an urgent need to seek effective therapy. Currently, the only way to treat food allergies is to avoid allergens and to administer intramuscular adrenaline if an accidental allergen intake occurs. The only causal therapeutic strategy is specific oral immunotherapy. An increasing amount of data confirms this therapy's effectiveness and safety, but the results remain inconclusive due to the lack of long-term follow-up. In this state-of-the-art review, we briefly summarise the latest placebo-controlled randomised controlled trials on oral immunotherapy (OIT) to treat food allergy. During the paper's review, we asked the following questions: does the therapy permanently increase the amount of allergen consumed without symptoms? Does it significantly increase or decrease the occurrence of severe systemic reactions - requiring the administration of adrenaline or hospitalisation? Many authors describe outcomes such as an increase in the amount of allergen that can be safely ingested; however, significant clinical benefits such as decreased hospitalisations or anaphylaxis incidence are rarely included in the results. To date, there is no unified protocol of therapy, which makes comparisons between studies difficult because of significant differences in types, doses, and routes of administration of the allergen, timeline for up-dosing and maintenance, duration of the therapy, and primary outcomes of OIT.

Milk Fat Globule Membrane Supplementation in Children: Systematic Review with Meta-Analysis.

(1) Background: Milk fat globule membrane (MFGM), composing fat droplets responsible for lipid transport in breast milk, has been shown to possess immunological and antimicrobial effects. Standard formulas (SF) are devoid of MFGMs during the production process. The study's aim was to evaluate the safety and benefits of MFGMs supplementation in children. (2) Methods: We searched four databases for randomized controlled trials evaluating the supplementation of MFGMs in children. Growth parameters were chosen as the primary outcome. (3) Results: Twenty-four publications of seventeen studies were included. Meta-analyses assessing the primary outcomes at the age of 4 months included four studies (814 children) comparing the MFGM-supplemented formulas and SF, and two trials (549 children) comparing the MFGM-supplemented formulas and breastfeeding. The primary outcomes were non-inferior in all the experimental MFGM formulas compared to SF, or even represented more similar results to breastfed infants. The promising effects, including a lower incidence of acute otitis media and improved cognitive development, cannot be firmly confirmed due to the small amount of existing evidence. No significant adverse effects were reported in any of the assessed products. (4) Conclusions: The available data signaled beneficial effects and a good safety profile, requiring future research with well-designed trials.

Lung function testing and inflammation markers for wheezing preschool children: A systematic review for the EAACI Clinical Practice Recommendations on Diagnostics of Preschool Wheeze.

BACKGROUND: Preschool wheeze is highly prevalent; 30%-50% of children have wheezed at least once before age six. Wheezing is not a disorder; it is a symptom of obstruction in the airways, and it is essential to identify the correct diagnosis behind this symptom. An increasing number of studies provide evidence for novel diagnostic tools for monitoring and predicting asthma in the pediatric population. Several techniques are available to measure airway obstruction and airway inflammation, including spirometry, impulse oscillometry, whole-body plethysmography, bronchial hyperresponsiveness test, multiple breath washout test, measurements of exhaled NO, and analyses of various other biomarkers. METHODS: We systematically reviewed all the existing techniques available for measuring lung function and airway inflammation in preschool children to assess their potential and clinical value in the routine diagnostics and monitoring of airway obstruction. RESULTS: If applicable, measuring FEV1 using spirometry is considered useful. For those unable to perform spirometry, whole-body plethysmography and IOS may be useful. Bronchial reversibility to beta2-agonist and hyperresponsiveness test with running exercise challenge may improve the sensitivity of these tests. CONCLUSIONS: The difficulty of measuring lung function and the lack of large randomized controlled trials makes it difficult to establish guidelines for monitoring asthma in preschool children.

Preschool wheezing and asthma in children: A systematic review of guidelines and quality appraisal with the AGREE II instrument.

BACKGROUND: Asthma-like symptoms in preschool children, such as wheezing and dyspnea, are common time- and resource-consuming diagnostic and management challenges. Quality of wheezing and asthma recommendations varies. The purpose of this study, carried out by the European Academy of Allergy and Clinical Immunology (EAACI) Task Force for Preschool Wheeze, was to systematically review and assess the quality of guidelines for diagnosis and treatment of preschool wheezing and/or asthma. METHODS: The Cochrane Library, MEDLINE, and EMBASE were searched until June 2018. The methodological rigor, quality, and transparency of relevant guidelines were assessed with the use of the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool. RESULTS: We identified 26 guidelines. The quality scores for each domain varied. Of all domains, clarity and presentation had the highest mean score, whereas applicability and stakeholder involvement had the lowest. The scores (median) for individual domains were as follows: score and purpose 86%; stakeholder involvement 49%; rigor of development 54%; clarity of presentation 85%; applicability 51%; and editorial independence 63%. CONCLUSION: Although several guidelines on asthma management in children are available, however, their quality varies. Additionally, there is a considerable gap in reliable recommendations on the management and treatment of non-asthmatic preschool wheeze.

Bacterial lysate therapy for the prevention of wheezing episodes and asthma exacerbations: a systematic review and meta-analysis.

Wheezing and asthma are a growing cause of morbidity in children and adults. Treatment is aimed at prevention of disease exacerbations and preservation of lung function. Respiratory viruses are involved in ∼40-60% of exacerbations. Bacterial lysates prevent recurrent respiratory tract infections and might reduce exacerbations. Moreover, immunomodulatory effects have been observed in human and animal studies. Here we aimed to assess the effects of bacterial lysate therapy on preschool wheezing episodes and asthma exacerbation frequency. We performed a systematic literature review based on the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) statement and a meta-analysis using Cochrane Review Manager. Out of 2016 retrieved articles, 22 studies were included, of which five provided sufficient data for a meta-analysis.The use of bacterial lysates showed a decrease of both wheezing episodes (mean difference -2.35 (-3.03- -1.67), p<0.001) and asthma exacerbations in children (mean difference -0.90 (-1.23- -0.57), p<0.001). Additionally, antibiotic use was reduced, and the duration of wheezing episodes was also decreased. No data for adults with asthma are currently available. The immunomodulatory effect seems to be dependent on increased T-helper (Th)1-cell activation and Th2-cell suppression.These favourable effects of bacterial lysates indicate that they show promise as add-on therapy in preschool wheezing and childhood asthma.

Postbiotics-A Step Beyond Pre- and Probiotics.

As an imbalance in the intestinal microbiota can lead to the development of several diseases (e.g., type 1 diabetes, cancer, among others), the use of prebiotics, probiotics, and postbiotics to alter the gut microbiome has attracted recent interest. Postbiotics include any substance released by or produced through the metabolic activity of the microorganism, which exerts a beneficial effect on the host, directly or indirectly. As postbiotics do not contain live microorganisms, the risks associated with their intake are minimized. Here, we provided a critical review of postbiotics described in the literature, including their mechanisms of action, clinical characteristics, and potential therapeutic applications. We detailed the pleiotropic effects of postbiotics, including their immunomodulatory, anti-inflammatory, antioxidant, and anti-cancer properties. Although the use of postbiotics is an attractive strategy for altering the microbiome, further study into its efficacy and safety is warranted.

Cow's Milk-Related Symptom Score in Presumed Healthy Polish Infants Aged 0-6 Months.

PURPOSE: The Cow's Milk-related Symptom Score (CoMiSS™), which considers crying, regurgitation, stools, skin and respiratory symptoms, was developed as an awareness tool for evaluating cow's milk-related symptoms. The scoring ranges from 0 to 33. A score ≥12 was proposed as being likely cow's milk-related and suggestive of allergy to cow's milk. This study aimed to determine the age-related CoMiSS™ values in presumed healthy infants in Poland. METHODS: This was a cross-sectional study conducted in well-child clinics in two locations. Parents of the presumed healthy infants aged ≤6 months were approached during a routine checkup/vaccination visit. The exclusion criteria were as follows: presence of acute or chronic diseases, preterm delivery, treatment with therapeutic formula, and use of any food supplements (except vitamins) or medications. RESULTS: Data from 226 infants were obtained (median age [Q1-Q3], 4 months [3-4]). The overall median (Q1-Q3) and mean (standard deviation) CoMiSS™ values were 4 (2-7) and 4.7 (3.5), respectively. The 95th percentile was 11. Scores on some, albeit not all, components of the CoMiSS™ significantly differed between age groups (crying, stools) or feeding type groups (stools and skin symptoms). Eleven children (4.9%) scored ≥12. CONCLUSION: This study adds to earlier age-related CoMiSS™ data by providing CoMiSS™ values in presumed healthy infants in Poland.

Effects of prenatal and/or postnatal supplementation with iron, PUFA or folic acid on neurodevelopment: update.

Neurodevelopment has been linked, among other factors, to maternal and early infant diets. The objective of this review, which is part of the NUTRIMENTHE research project 'The effect of diet on the mental performance of children' (www.nutrimenthe.com), was to update current evidence on the effects of nutritional interventions such as iron, folic acid or n-3 long-chain polyunsaturated fatty acid (LCPUFA) supplementation during pregnancy and/or in early life on the mental performance and psychomotor development of children. In May 2014, we searched MEDLINE and The Cochrane Database of Systematic Reviews for relevant studies published since 2009. The limited updated evidence suggests that iron supplementation of infants may positively influence the psychomotor development of children, although it does not seem to alter their mental development or behaviour. The use of multivitamin-containing folic acid supplements during pregnancy did not benefit the mental performance of the offspring. Evidence from randomised controlled trials (RCT) did not show a clear and consistent benefit of n-3 LCPUFA supplementation during pregnancy and/or lactation on childhood cognitive and visual development. Caution is needed when interpreting current evidence, as many of the included trials had methodological limitations such as small sample sizes, high attrition rates, and no intention-to-treat analyses. Taken together, the evidence is still inconclusive. Large, high-quality RCT to assess the effects of supplementation with iron, LCPUFA or folic acid are still needed to further clarify the effects of these, and other nutrients, on neurodevelopment. Recent recommendations from scientific societies are briefly presented.

Systematic review with meta-analysis: Lactobacillus rhamnosus GG for treating acute gastroenteritis in children - a 2019 update.

BACKGROUND: Recently, evidence from a large randomised controlled trial (RCT) negated efficacy of Lactobacillus rhamnosus GG for treating acute gastroenteritis in children. AIM: To review RCTs in which L rhamnosus GG was used to treat acute gastroenteritis in children. METHODS: The Cochrane Library, MEDLINE, and EMBASE databases were searched from May 2013 (end of last search) to January 2019. The primary outcomes were stool volume and duration of diarrhoea. RESULTS: Eighteen RCTs (n = 4208) were included. Compared with placebo or no treatment, L rhamnosus GG use had no effect on stool volume but was associated with a reduced duration of diarrhoea (15 RCTs, n = 3820, mean difference, MD -0.85 day, 95% CI -1.15 to -0.56). L rhamnosus GG was effective when used at a daily dose of ≥1010 CFU or <1010 CFU; however, the latter produced results of borderline significance. L rhamnosus GG was more effective when used in European countries compared with non-European countries, particularly when considered by region. L rhamnosus GG use was associated with a reduced duration of hospitalisation. One RCT found that L rhamnosus GG had no effect on the total clinical severity score at 14 days after enrolment. CONCLUSIONS: Despite a recent large RCT demonstrating no effect of L rhamnosus GG, current evidence shows that, overall, L rhamnosus GG reduced both the duration of diarrhoea (with a higher impact in European countries) and hospitalisation in inpatients. These findings should be viewed in the context of the high heterogeneity and methodological limitations of the included trials.

Bronchiolitis needs a revisit: Distinguishing between virus entities and their treatments.

Current data indicate that the "bronchiolitis" diagnosis comprises more than one condition. Clinically, pathophysiologically, and even genetically three main clusters of patients can be identified among children suffering from severe bronchiolitis (or first wheezing episode): (a) respiratory syncytial virus (RSV)-induced bronchiolitis, characterized by young age of the patient, mechanical obstruction of the airways due to mucus and cell debris, and increased risk of recurrent wheezing. For this illness, an effective prophylactic RSV-specific monoclonal antibody is available; (b) rhinovirus-induced wheezing, associated with atopic predisposition of the patient and high risk of subsequent asthma development, which may, however, be reversed with systemic corticosteroids in those with severe illness; and (c) wheeze due to other viruses, characteristically likely to be less frequent and severe. Clinically, it is important to distinguish between these partially overlapping patient groups as they are likely to respond to different treatments. It appears that the first episode of severe bronchiolitis in under 2-year-old children is a critical event and an important opportunity for designing secondary prevention strategies for asthma. As data have shown bronchiolitis cannot simply be diagnosed using a certain cutoff age, but instead, as we suggest, using the viral etiology as the differentiating factor.

Effects of infant formula supplemented with prebiotics compared with synbiotics on growth up to the age of 12 mo: a randomized controlled trial.

BACKGROUND: Growth is an essential outcome measure for evaluating the safety of infant formulas (IF). We investigated the effects of consumption of IF supplemented with prebiotics (fructooligosaccharides, FOS, and galactooligosaccharides, GOS) compared with synbiotics (FOS/GOS and Lactobacillus paracasei ssp. paracasei strain F19) on the growth of healthy infants. METHODS: 182 full-term infants who were weaned completely from breast milk to IF at 28 d of age were randomly assigned to receive prebiotic- or synbiotic-supplemented, otherwise identical, IF until 6 mo of age (intervention period). RESULTS: A total of 146 (80%) infants were included in the intention-to-treat analysis at 6 mo. Anthropometric parameters were similar in the two groups during the intervention and follow-up period until 12 mo of age. Compared with the prebiotic group, a significant reduction in the cumulative incidence of lower respiratory tract infections was found in the synbiotic group; however, the confidence interval of the estimate was wide, resulting in uncertainty. CONCLUSION: The lack of a significant difference between the formula-fed groups in growth, or the occurrence of serious adverse events, supports the safety of using IF supplemented with synbiotics. Further studies are needed to evaluate the effects of such formula on lower-respiratory tract infections.