Biological therapy practice, biomarkers of severe asthma and novel approaches for attaining immunomodulation in upper airway disease.

The hybrid rDer p 2231 stimulated in PBMCs isolated from atopic patients, higher levels of IL-2, IL-10, IL-15 and IFN-γ, as well as lower levels of IL-4, IL-5, IL-13, TNF-α and GM-CSF. The use of hybrid molecules as a therapeutic model in D. pteronyssinus allergic mice led to the reduction of IgE production and lower eosinophilic peroxidase activity in the airways. We found increased levels of IgG antibodies, which blocked the IgE binding to the parental allergens in serum of atopic patients. Furthermore, the stimulation of splenocytes from mice treated with rDer p 2231 induced higher levels of IL-10 and IFN-γ and decreased the secretion of IL-4 and IL-5, when compared to parental allergens and D. pteronyssinus extract. (7).

Phototherapy for atopic eczema.

BACKGROUND: Atopic eczema (AE), also known as atopic dermatitis, is a chronic inflammatory skin condition that causes significant burden. Phototherapy is sometimes used to treat AE when topical treatments, such as corticosteroids, are insufficient or poorly tolerated. OBJECTIVES: To assess the effects of phototherapy for treating AE. SEARCH METHODS: We searched the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, and ClinicalTrials.gov to January 2021. SELECTION CRITERIA: We included randomised controlled trials in adults or children with any subtype or severity of clinically diagnosed AE. Eligible comparisons were any type of phototherapy versus other forms of phototherapy or any other treatment, including placebo or no treatment. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology. For key findings, we used RoB 2.0 to assess bias, and GRADE to assess certainty of the evidence. Primary outcomes were physician-assessed signs and patient-reported symptoms. Secondary outcomes were Investigator Global Assessment (IGA), health-related quality of life (HRQoL), safety (measured as withdrawals due to adverse events), and long-term control. MAIN RESULTS: We included 32 trials with 1219 randomised participants, aged 5 to 83 years (mean: 28 years), with an equal number of males and females. Participants were recruited mainly from secondary care dermatology clinics, and study duration was, on average, 13 weeks (range: 10 days to one year). We assessed risk of bias for all key outcomes as having some concerns or high risk, due to missing data, inappropriate analysis, or insufficient information to assess selective reporting. Assessed interventions included: narrowband ultraviolet B (NB-UVB; 13 trials), ultraviolet A1 (UVA1; 6 trials), broadband ultraviolet B (BB-UVB; 5 trials), ultraviolet AB (UVAB; 2 trials), psoralen plus ultraviolet A (PUVA; 2 trials), ultraviolet A (UVA; 1 trial), unspecified ultraviolet B (UVB; 1 trial), full spectrum light (1 trial), Saalmann selective ultraviolet phototherapy (SUP) cabin (1 trial), saltwater bath plus UVB (balneophototherapy; 1 trial), and excimer laser (1 trial). Comparators included placebo, no treatment, another phototherapy, topical treatment, or alternative doses of the same treatment. Results for key comparisons are summarised (for scales, lower scores are better): NB-UVB versus placebo/no treatment There may be a larger reduction in physician-assessed signs with NB-UVB compared to placebo after 12 weeks of treatment (mean difference (MD) -9.4, 95% confidence interval (CI) -3.62 to -15.18; 1 trial, 41 participants; scale: 0 to 90). Two trials reported little difference between NB-UVB and no treatment (37 participants, four to six weeks of treatment); another reported improved signs with NB-UVB versus no treatment (11 participants, nine weeks of treatment). NB-UVB may increase the number of people reporting reduced itch after 12 weeks of treatment compared to placebo (risk ratio (RR) 1.72, 95% CI 1.10 to 2.69; 1 trial, 40 participants). Another trial reported very little difference in itch severity with NB-UVB (25 participants, four weeks of treatment). The number of participants with moderate to greater global improvement may be higher with NB-UVB than placebo after 12 weeks of treatment (RR 2.81, 95% CI 1.10 to 7.17; 1 trial, 41 participants). NB-UVB may not affect rates of withdrawal due to adverse events. No withdrawals were reported in one trial of NB-UVB versus placebo (18 participants, nine weeks of treatment). In two trials of NB-UVB versus no treatment, each reported one withdrawal per group (71 participants, 8 to 12 weeks of treatment). We judged that all reported outcomes were supported with low-certainty evidence, due to risk of bias and imprecision. No trials reported HRQoL. NB-UVB versus UVA1 We judged the evidence for NB-UVB compared to UVA1 to be very low certainty for all outcomes, due to risk of bias and imprecision. There was no evidence of a difference in physician-assessed signs after six weeks (MD -2.00, 95% CI -8.41 to 4.41; 1 trial, 46 participants; scale: 0 to 108), or patient-reported itch after six weeks (MD 0.3, 95% CI -1.07 to 1.67; 1 trial, 46 participants; scale: 0 to 10). Two split-body trials (20 participants, 40 sides) also measured these outcomes, using different scales at seven to eight weeks; they reported lower scores with NB-UVB. One trial reported HRQoL at six weeks (MD 2.9, 95% CI -9.57 to 15.37; 1 trial, 46 participants; scale: 30 to 150). One split-body trial reported no withdrawals due to adverse events over 12 weeks (13 participants). No trials reported IGA. NB-UVB versus PUVA We judged the evidence for NB-UVB compared to PUVA (8-methoxypsoralen in bath plus UVA) to be very low certainty for all reported outcomes, due to risk of bias and imprecision. There was no evidence of a difference in physician-assessed signs after six weeks (64.1% reduction with NB-UVB versus 65.7% reduction with PUVA; 1 trial, 10 participants, 20 sides). There was no evidence of a difference in marked improvement or complete remission after six weeks (odds ratio (OR) 1.00, 95% CI 0.13 to 7.89; 1 trial, 9/10 participants with both treatments). One split-body trial reported no withdrawals due to adverse events in 10 participants over six weeks. The trials did not report patient-reported symptoms or HRQoL. UVA1 versus PUVA There was very low-certainty evidence, due to serious risk of bias and imprecision, that PUVA (oral 5-methoxypsoralen plus UVA) reduced physician-assessed signs more than UVA1 after three weeks (MD 11.3, 95% CI -0.21 to 22.81; 1 trial, 40 participants; scale: 0 to 103). The trial did not report patient-reported symptoms, IGA, HRQoL, or withdrawals due to adverse events. There were no eligible trials for the key comparisons of UVA1 or PUVA compared with no treatment. Adverse events Reported adverse events included low rates of phototoxic reaction, severe irritation, UV burn, bacterial superinfection, disease exacerbation, and eczema herpeticum. AUTHORS' CONCLUSIONS: Compared to placebo or no treatment, NB-UVB may improve physician-rated signs, patient-reported symptoms, and IGA after 12 weeks, without a difference in withdrawal due to adverse events. Evidence for UVA1 compared to NB-UVB or PUVA, and NB-UVB compared to PUVA was very low certainty. More information is needed on the safety and effectiveness of all aspects of phototherapy for treating AE.

EAACI guideline: Preventing the development of food allergy in infants and young children (2020 update).

BACKGROUND: This guideline from the European Academy of Allergy and Clinical Immunology (EAACI) recommends approaches to prevent the development of immediate-onset / IgE-mediated food allergy in infants and young children. It is an update of a 2014 EAACI guideline. METHODS: The guideline was developed using the AGREE II framework and the GRADE approach. An international Task Force with representatives from 11 countries and different disciplinary and clinical backgrounds systematically reviewed research and considered expert opinion. Recommendations were created by weighing up benefits and harms, considering the certainty of evidence and examining values, preferences and resource implications. The guideline was peer-reviewed by external experts, and feedback was incorporated from public consultation. RESULTS: All of the recommendations about preventing food allergy relate to infants (up to 1 year) and young children (up to 5 years), regardless of risk of allergy. There was insufficient evidence about preventing food allergy in other age groups. The EAACI Task Force suggests avoiding the use of regular cow's milk formula as supplementary feed for breastfed infants in the first week of life. The EAACI Task Force suggests introducing well-cooked, but not raw egg or uncooked pasteurized, egg into the infant diet as part of complementary feeding. In populations where there is a high prevalence of peanut allergy, the EAACI Task Force suggests introducing peanuts in an age-appropriate form as part of complementary feeding. According to the studies, it appears that the most effective age to introduce egg and peanut is from four to 6 months of life. The EAACI Task Force suggests against the following for preventing food allergy: (i) avoiding dietary food allergens during pregnancy or breastfeeding; and (ii) using soy protein formula in the first 6 months of life as a means of preventing food allergy. There is no recommendation for or against the following: use of vitamin supplements, fish oil, prebiotics, probiotics or synbiotics in pregnancy, when breastfeeding or in infancy; altering the duration of exclusive breastfeeding; and hydrolysed infant formulas, regular cow's milk-based infant formula after a week of age or use of emollients. CONCLUSIONS: Key changes from the 2014 guideline include suggesting (i) the introduction of peanut and well-cooked egg as part of complementary feeding (moderate certainty of evidence) and (ii) avoiding supplementation with regular cow's milk formula in the first week of life (low certainty of evidence). There remains uncertainty in how to prevent food allergy, and further well-powered, multinational research using robust diagnostic criteria is needed.

Preventing food allergy in infancy and childhood: Systematic review of randomised controlled trials.

BACKGROUND: This systematic review of ways to prevent immediate-onset/IgE-mediated food allergy will inform guidelines by the European Academy of Allergy and Immunology (EAACI). METHODS: The GRADE approach was used. Eleven databases were searched from 1946 to October 2019 for randomized controlled trials (and large prospective cohort studies in the case of breastfeeding). The studies included heterogeneous interventions, populations, and outcomes and so were summarized narratively. RESULTS: Forty-six studies examined interventions to reduce the risk of food allergy in infancy (up to 1 year) or early childhood. The following interventions for pregnant or breastfeeding women and/or infants may have little to no effect on preventing food allergy, but the evidence is very uncertain: dietary avoidance of food allergens, vitamin supplements, fish oil, probiotics, prebiotics, synbiotics, and emollients. Breastfeeding, hydrolyzed formulas, and avoiding cow's milk formula may not reduce the risk of cow's milk protein allergy; however, temporary supplementation with cow's milk formula in the first week of life may increase the risk of cow's milk allergy. Introducing well-cooked egg, but not pasteurized raw egg, from 4 to 6 months probably reduces the risk of hen's egg allergy. Introducing regular peanut consumption into the diet of an infant at increased risk beginning from 4 to 11 months probably results in a large reduction in peanut allergy in countries with a high prevalence. These conclusions about introducing peanut are based on moderate certainty evidence, from single trials in high-income countries. CONCLUSIONS: Sixty percent of the included studies were published in the last 10 years, but much still remains to be understood about preventing food allergy. In particular, there is a need to validate the potential benefits of early introduction of food allergens in a wider range of populations.

Statistical Approaches in the Studies Assessing Associations between Human Milk Immune Composition and Allergic Diseases: A Scoping Review.

A growing number of studies are focusing on the associations between human milk (HM) immunological composition and allergic diseases. This scoping review aims to identify statistical methods applied in the field and highlight pitfalls and unmet needs. A comprehensive literature search in MEDLINE and Embase retrieved 13,607 unique records. Following title/abstract screening, 29 studies met the selection criteria and were included in this review. We found that definitions of colostrum and mature milk varied across the studies. A total of 17 out of 29 (59%) studies collected samples longitudinally, but only 12% of these used serial (longitudinal) analyses. Multivariable analysis was used in 45% of the studies, but statistical approaches to modelling varied largely across the studies. Types of variables included as potential confounding factors differed considerably between models. Discrimination analysis was absent from all studies and only a single study reported classification measures. Outcomes of this scoping review highlight lack of standardization, both in data collection and handling, which remains one of the main challenges in the field. Improved standardization could be obtained by a consensus group of researchers and clinicians that could recommend appropriate methods to be applied in future prospective studies, as well as already existing datasets.

Probiotics for treating eczema.

BACKGROUND: Eczema is a common chronic skin condition. Probiotics have been proposed as an effective treatment for eczema; their use is increasing, as numerous clinical trials are under way. This is an update of a Cochrane Review first published in 2008, which suggested that probiotics may not be an effective treatment for eczema but identified areas in which evidence was lacking. OBJECTIVES: To assess the effects of probiotics for treating patients of all ages with eczema. SEARCH METHODS: We updated our searches of the following databases to January 2017: the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library, the Global Resource of Eczema Trials (GREAT) database, MEDLINE, Embase, PsycINFO, the Allied and Complementary Medicine Database (AMED), and Latin American Caribbean Health Sciences Literature (LILACS). We searched five trials registers and checked the reference lists of included studies and relevant reviews for further references to relevant randomised controlled trials (RCTs). We also handsearched a number of conference proceedings. We updated the searches of the main databases in January 2018 and of trials registries in March 2018, but we have not yet incorporated these results into the review. SELECTION CRITERIA: Randomised controlled trials of probiotics (live orally ingested micro-organisms) compared with no treatment, placebo, or other active intervention with no probiotics for the treatment of eczema diagnosed by a doctor. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by Cochrane. We recorded adverse events from the included studies and from a separate adverse events search conducted for the first review. We formally assessed reporting bias by preparing funnel plots, and we performed trial sequential analysis for the first primary outcome - eczema symptoms at the end of active treatment.We used GRADE to assess the quality of the evidence for each outcome (in italic font). MAIN RESULTS: We included 39 randomised controlled trials involving 2599 randomised participants. We included participants of either gender, aged from the first year of life through to 55 years (only six studies assessed adults), who had mild to severe eczema. Trials were undertaken in primary and secondary healthcare settings, mainly in Europe or Asia. Duration of treatment ranged from four weeks to six months, and duration of follow-up after end of treatment ranged from zero to 36 months. We selected no standard dose: researchers used a variety of doses and concentrations of probiotics. The probiotics used were bacteria of the Lactobacillus and Bifidobacteria species, which were taken alone or combined with other probiotics, and were given with or without prebiotics. Comparators were no treatment, placebo, and other treatments with no probiotics.For all results described in this abstract, the comparator was no probiotics. Active treatment ranged from six weeks to three months for all of the following results, apart from the investigator-rated eczema severity outcome, for which the upper limit of active treatment was 16 weeks. With regard to score, the higher the score, the more severe were the symptoms. All key results reported in this abstract were measured at the end of active treatment, except for adverse events, which were measured during the active treatment period.Probiotics probably make little or no difference in participant- or parent-rated symptoms of eczema (13 trials; 754 participants): symptom severity on a scale from 0 to 20 was 0.44 points lower after probiotic treatment (95% confidence interval (CI) -1.22 to 0.33; moderate-quality evidence). Trial sequential analysis shows that target sample sizes of 258 and 456, which are necessary to demonstrate a minimum mean difference of -2 and -1.5, respectively, with 90% power, have been exceeded, suggesting that further trials with similar probiotic strains for this outcome at the end of active treatment may be futile.We found no evidence suggesting that probiotics make a difference in QoL for patients with eczema (six studies; 552 participants; standardised mean difference (SMD) 0.03, 95% CI -0.36 to 0.42; low-quality evidence) when measured by the participant or the parent using validated disease-specific QoL instruments.Probiotics may slightly reduce investigator-rated eczema severity scores (24 trials; 1596 participants). On a scale of 0 to 103 for total Severity Scoring of Atopic Dermatitis (SCORAD), a score combining investigator-rated eczema severity score and participant scoring for eczema symptoms of itch and sleep loss was 3.91 points lower after probiotic treatment than after no probiotic treatment (95% CI -5.86 to -1.96; low-quality evidence). The minimum clinically important difference for SCORAD has been estimated to be 8.7 points.We noted significant to extreme levels of unexplainable heterogeneity between the results of individual studies. We judged most studies to be at unclear risk of bias; six studies had high attrition bias, and nine were at low risk of bias overall.We found no evidence to show that probiotics make a difference in the risk of adverse events during active treatment (risk ratio (RR) 1.54, 95% CI 0.90 to 2.63; seven trials; 402 participants; low-quality evidence). Studies in our review that reported adverse effects described gastrointestinal symptoms. AUTHORS' CONCLUSIONS: Evidence suggests that, compared with no probiotic, currently available probiotic strains probably make little or no difference in improving patient-rated eczema symptoms. Probiotics may make little or no difference in QoL for people with eczema nor in investigator-rated eczema severity score (combined with participant scoring for eczema symptoms of itch and sleep loss); for the latter, the observed effect was small and of uncertain clinical significance. Therefore, use of probiotics for the treatment of eczema is currently not evidence-based. This update found no evidence of increased adverse effects with probiotic use during studies, but a separate adverse events search from the first review revealed that probiotic treatment carries a small risk of adverse events.Results show significant, unexplainable heterogeneity between individual trial results. Only a small number of studies measured some outcomes.Future studies should better measure QoL scores and adverse events, and should report on new probiotics. Researchers should also consider studying subgroups of patients (e.g. patients with atopy or food allergies, adults) and standardising doses/concentrations of probiotics given.

Levels of Growth Factors and IgA in the Colostrum of Women from Burundi and Italy.

Colostrum is produced in the first days postpartum. It is a known source of immune mediators for a newborn within the first week of life. Although it is still unclear if colostrum composition varies between populations, recent data suggest differences. Hepatocyte growth factor (HGF); transforming growth factor-ß (TGF-ß) 1, 2, and 3; and immunoglobulin A (IgA) are key immunological components of colostrum that stimulate neonatal gastrointestinal and immune system development. We aimed to investigate the differences in the concentration between immune markers in the colostrum of mothers living in Burundi and Italy, and to identify the factors associated with differences. In this cross-sectional birth cohort study, a total of 99 colostrum samples from Burundian (n = 23) and Italian (n = 76) women were collected at 0 to 6 days postpartum. A clinical chemistry analyser was used for IgA quantification and electro-chemiluminescence, for HGF and TGFß1-3 assessment. A univariate analysis and multivariate linear regression model were used for statistical testing. The concentrations of TGF-ß2 (p = 0.01) and IgA (p < 0.01) were significantly higher in the colostrum from the women residing in Burundi than in Italy, both in a univariate analysis and upon the adjustment for confounding factors. A similar trend is seen for HGF, reaching statistical significance upon a multivariate analysis. We found a moderate to strong positive correlation between the TGF-ß isoforms and IgA concentration in both countries (p < 0.01), with stronger concentration in the colostrum from Burundi. The results of this study are in support of previous data, suggesting that concentration of the immune active molecules is higher in the human milk of women residing in developing countries. However, with a small sample size, caution must be applied, as the findings require further confirmation. Future work should also be focused on other factors (e.g., lipid and microbial composition), as well as the investigation into colostrum and between populations comparison, adjusting for potential confounders.

Formula Milk Supplementation on the Postnatal Ward: A Cross-Sectional Analytical Study.

Breastfeeding rates are low in the UK, where approximately one quarter of infants receive a breastmilk substitute (BMS) in the first week of life. We investigated the reasons for early BMS use in two large maternity units in the UK, in order to understand the reasons for the high rate of early BMS use in this setting. Data were collected through infant feeding records, as well as maternal and midwife surveys in 2016. During 2016, 28% of infants received a BMS supplement prior to discharge from the hospital maternity units with only 10% supplementation being clinically indicated. There was wide variation in BMS initiation rates between different midwives, which was associated with ward environment and midwife educational level. Specific management factors associated with non-clinically indicated initiation of BMS were the absence of skin-to-skin contact within an hour of delivery (p = 0.01), and no attendance at an antenatal breastfeeding discussion (p = 0.01). These findings suggest that risk of initiating a BMS during postnatal hospital stay is largely modifiable. Concordance with UNICEF Baby Friendly 10 steps, attention to specific features of the postnatal ward working environment, and the targeting of midwives and mothers with poor educational status may all lead to improved exclusive breastfeeding rates at hospital discharge.

Diet during pregnancy and infancy and risk of allergic or autoimmune disease: A systematic review and meta-analysis.

BACKGROUND: There is uncertainty about the influence of diet during pregnancy and infancy on a child's immune development. We assessed whether variations in maternal or infant diet can influence risk of allergic or autoimmune disease. METHODS AND FINDINGS: Two authors selected studies, extracted data, and assessed risk of bias. Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to assess certainty of findings. We searched Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica dataBASE (EMBASE), Web of Science, Central Register of Controlled Trials (CENTRAL), and Literatura Latino Americana em Ciências da Saúde (LILACS) between January 1946 and July 2013 for observational studies and until December 2017 for intervention studies that evaluated the relationship between diet during pregnancy, lactation, or the first year of life and future risk of allergic or autoimmune disease. We identified 260 original studies (964,143 participants) of milk feeding, including 1 intervention trial of breastfeeding promotion, and 173 original studies (542,672 participants) of other maternal or infant dietary exposures, including 80 trials of maternal (n = 26), infant (n = 32), or combined (n = 22) interventions. Risk of bias was high in 125 (48%) milk feeding studies and 44 (25%) studies of other dietary exposures. Evidence from 19 intervention trials suggests that oral supplementation with nonpathogenic micro-organisms (probiotics) during late pregnancy and lactation may reduce risk of eczema (Risk Ratio [RR] 0.78; 95% CI 0.68-0.90; I2 = 61%; Absolute Risk Reduction 44 cases per 1,000; 95% CI 20-64), and 6 trials suggest that fish oil supplementation during pregnancy and lactation may reduce risk of allergic sensitisation to egg (RR 0.69, 95% CI 0.53-0.90; I2 = 15%; Absolute Risk Reduction 31 cases per 1,000; 95% CI 10-47). GRADE certainty of these findings was moderate. We found weaker support for the hypotheses that breastfeeding promotion reduces risk of eczema during infancy (1 intervention trial), that longer exclusive breastfeeding is associated with reduced type 1 diabetes mellitus (28 observational studies), and that probiotics reduce risk of allergic sensitisation to cow's milk (9 intervention trials), where GRADE certainty of findings was low. We did not find that other dietary exposures-including prebiotic supplements, maternal allergenic food avoidance, and vitamin, mineral, fruit, and vegetable intake-influence risk of allergic or autoimmune disease. For many dietary exposures, data were inconclusive or inconsistent, such that we were unable to exclude the possibility of important beneficial or harmful effects. In this comprehensive systematic review, we were not able to include more recent observational studies or verify data via direct contact with authors, and we did not evaluate measures of food diversity during infancy. CONCLUSIONS: Our findings support a relationship between maternal diet and risk of immune-mediated diseases in the child. Maternal probiotic and fish oil supplementation may reduce risk of eczema and allergic sensitisation to food, respectively.

Immune Components in Human Milk Are Associated with Early Infant Immunological Health Outcomes: A Prospective Three-Country Analysis.

The role of breastfeeding in improving allergy outcomes in early childhood is still unclear. Evidence suggests that immune mediators in human milk (HM) play a critical role in infant immune maturation as well as protection against atopy/allergy development. We investigated relationships between levels of immune mediators in colostrum and mature milk and infant outcomes in the first year of life. In a large prospective study of 398 pregnant/lactating women in the United Kingdom, Russia and Italy, colostrum and mature human milk (HM) samples were analysed for immune active molecules. Statistical analyses used models adjusting for the site of collection, colostrum collection time, parity and maternal atopic status. Preliminary univariate analysis showed detectable interleukin (IL) 2 and IL13 in HM to be associated with less eczema. This finding was further confirmed in multivariate analysis, with detectable HM IL13 showing protective effect OR 0.18 (95% CI 0.04-0.92). In contrast, a higher risk of eczema was associated with higher HM concentrations of transforming growth factor ß (TGFß) 2 OR 1.04 (95% CI 1.01-1.06) per ng/mL. Parental-reported food allergy was reported less often when IL13 was detectable in colostrum OR 0.10 (95% CI 0.01-0.83). HM hepatocyte growth factor (HGF) was protective for common cold incidence at 12 months OR 0.19 (95% CI 0.04-0.92) per ng/mL. Data from this study suggests that differences in the individual immune composition of HM may have an influence on early life infant health outcomes. Increased TGFß2 levels in HM are associated with a higher incidence of reported eczema, with detectable IL13 in colostrum showing protective effects for food allergy and sensitization. HGF shows some protective effect on common cold incidence at one year of age. Future studies should be focused on maternal genotype, human milk microbiome and diet influence on human milk immune composition and both short- and long-term health outcomes in the infant.

Colostrum and Mature Human Milk of Women from London, Moscow, and Verona: Determinants of Immune Composition.

Cytokines and growth factors in colostrum and mature milk may play an important role in infant immune maturation, and may vary significantly between populations. We aimed to examine associations between environmental and maternal factors, and human milk (HM) cytokine and growth factor levels. We recruited 398 pregnant/lactating women in the United Kingdom, Russia, and Italy. Participants underwent skin prick testing, questionnaire interview, and colostrum and mature milk sampling. HM cytokine and growth factor levels were quantified by electro-chemiluminescence. We found significant geographical variation in growth factor levels, but no evidence of variation between sites in cytokine detectability. There was an inverse correlation between time of milk sampling and growth factor levels in colostrum for Hepatocyte Growth Factor (HGF) and TGFß1 and TGFß3, but not TGFß2, and levels were significantly higher in colostrum than mature milk for all growth factors. The kinetics of decline were different for each growth factor. Cytokines were present at much lower levels than growth factors, and the decline over time was less consistent. HM growth factors and cytokine levels vary between populations for unknown reasons. Levels of HM mediators decline at different rates postpartum, and these findings suggest specific biological roles for HM growth factors and cytokines in early postnatal development.

Effects of Pre-Natal Vitamin D Supplementation with Partial Correction of Vitamin D Deficiency on Early Life Healthcare Utilisation: A Randomised Controlled Trial.

BACKGROUND: Some observational studies have suggested that higher prenatal Vitamin D intake may be associated with improved health outcomes in childhood. However there have been mixed results in this area with some negative studies, especially for effects on atopic and respiratory outcomes. We examined the effect of prenatal Vitamin D on healthcare utilisation in the first three years of life. METHODS: In an ethnically stratified randomised controlled trial conducted at St Mary's Hospital London, 180 women at 27 weeks gestation were allocated to no Vitamin D, 800 IU ergocalciferol daily until delivery, or a single oral bolus of 200,000 IU cholecalciferol. Participants were randomised in blocks of 15 using computer-generated numbers and investigators were blinded to group assignment. Supplementation increased maternal and cord blood 25(OH) vitamin D concentrations, but levels remained lower than current recommendations. Primary health economic outcome was overall cost of unscheduled healthcare utilisation in the first three years of life as documented in the child's electronic health record. Secondary outcomes included cost attributable to: primary and secondary healthcare visits, respiratory and atopic complaints, cost in years 1, 2 and 3 of life and cost and frequency of prescribed medication. All costs were calculated as pounds sterling. Differences between groups were analysed using unpaired t-test or Mann-Whitney U test, and analysis of variance for adjusted analyses. RESULTS: We assessed 99/180 (55%) complete electronic health records, control (n = 31), daily (n = 36) and bolus (n = 32). We found no difference in total healthcare utilisation costs between the control and daily (mean difference in costs in pounds sterling 1.02, 95%CI -1.60, 1.65; adjusted 1.07, 95%CI -1.62, 1.86) or control and bolus groups (mean difference -1.58, 95%CI -2.63, 1.06; adjusted -1.40, 95%CI -2.45, 1.24). There were no adverse effects of supplementation reported during the trial. CONCLUSIONS: We found no evidence that prenatal vitamin D supplementation from 27 weeks gestation to delivery, at doses which failed to completely correct maternal vitamin D deficiency, influence overall healthcare utilisation in children in the first 3 years. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN68645785.

Prenatal vitamin d supplementation and child respiratory health: a randomised controlled trial.

BACKGROUND: Observational studies suggest high prenatal vitamin D intake may be associated with reduced childhood wheezing. We examined the effect of prenatal vitamin D on childhood wheezing in an interventional study. METHODS: We randomised 180 pregnant women at 27 weeks gestation to either no vitamin D, 800 IU ergocalciferol daily until delivery or single oral bolus of 200,000 IU cholecalciferol, in an ethnically stratified, randomised controlled trial. Supplementation improved but did not optimise vitamin D status. Researchers blind to allocation assessed offspring at 3 years. Primary outcome was any history of wheeze assessed by validated questionnaire. Secondary outcomes included atopy, respiratory infection, impulse oscillometry and exhaled nitric oxide. Primary analyses used logistic and linear regression. RESULTS: We evaluated 158 of 180 (88%) offspring at age 3 years for the primary outcome. Atopy was assessed by skin test for 95 children (53%), serum IgE for 86 (48%), exhaled nitric oxide for 62 (34%) and impulse oscillometry of acceptable quality for 51 (28%). We found no difference between supplemented and control groups in risk of wheeze [no vitamin D: 14/50 (28%); any vitamin D: 26/108 (24%) (risk ratio 0.86; 95% confidence interval 0.49, 1.50; P = 0.69)]. There was no significant difference in atopy, eczema risk, lung function or exhaled nitric oxide between supplemented groups and controls. CONCLUSION: Prenatal vitamin D supplementation in late pregnancy that had a modest effect on cord blood vitamin D level, was not associated with decreased wheezing in offspring at age three years. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN68645785.

Twice weekly fluconazole prophylaxis for prevention of invasive Candida infection in high-risk infants of <1000 grams birth weight.

OBJECTIVES: We tested the hypothesis that twice weekly prophylactic dosing of fluconazole prevents invasive candidiasis without promoting resistant Candida species in high-risk, preterm infants. STUDY DESIGN: We compared our previous dosing schedule (Group A) to a less frequent dosing schedule of twice a week (Group B) of fluconazole prophylaxis for up to 6 weeks in a prospective, randomized, double-blind clinical trial in preterm infants weighing <1000 grams at birth and with an endotracheal tube and/or central vascular catheter over a 24-month period. Weekly surveillance cultures were obtained on study patients. RESULTS: Candida colonization was documented in 5 (12%) of 41 Group A and in 4 (10%) of 40 Group B infants. Candida sepsis developed in two (5%) of Group A and one (3%) of Group B infants (risk difference, -0.02; 95% confidence interval, -0.14-0.10; P=.68). All fungal isolates remained sensitive to fluconazole, and no drug side effects were documented. CONCLUSIONS: Twice weekly dosing of prophylactic fluconazole can decrease Candida colonization and invasive infection, cost, and patient exposure in high-risk, preterm infants weighing <1000 grams at birth. We speculate that lower and less frequent dosing may delay or prevent the emergence of antifungal resistance.