Long-term outcomes of pediatric infections: from traditional infectious diseases to long Covid.

There is limited evidence available on the long-term impact of SARS-CoV-2 infection in children. In this article, the authors analyze the recent evidence on pediatric long Covid and lessons learnt from a pediatric post-Covid unit in Rome, Italy. To gain a better understanding of the concerns raised by parents and physicians in relation to the potential long-term consequences of this novel infection, it is important to recognize that long-term effect of a post-infectious disease is not a new phenomenon.

The authors analyze the recent evidence on pediatric long Covid and lessons learnt from a pediatric post-Covid unit in Rome, Italy. Also, we analyze the long-term effects of other infectious diseases.

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.

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.

Therapeutic Effects of Vitamin D in Asthma and Allergy.

In recent years, low vitamin D status has been proposed as a putative risk factor for allergic diseases. A growing body of literature reports low vitamin D levels in atopic patients and supports an association between vitamin D deficiency and risk of adverse asthma and allergies outcomes. Therefore, it has been speculated that vitamin D supplementation may either prevent or reduce the risk of allergic diseases. Birth cohort studies addressing the role of vitamin D intake during pregnancy have shown conflicting results regarding allergy outcomes in offspring. Currently, only a few studies have tried to supplement vitamin D in asthmatic patients, often as an add-on therapy to standard asthma controller medications, and results are not all consistent. There is emerging data to show that vitamin D can enhance the antiinflammatory effects of glucocorticoids and potentially be used as adjuvant therapy in steroid-resistant asthma. Recent in vivo data suggest that vitamin D supplementation may also reduce the severity of atopic dermatitis. This review examines the existing relevant literature focusing on vitamin D supplementation in the treatment of allergic diseases.

Food allergy: the perspectives of prevention using vitamin D.

PURPOSE OF REVIEW: We reviewed the scientific publications in the last 2 years on the connections between vitamin D and food allergy, and endeavor to focus on the possible indications for supplementation in order to prevent allergies. RECENT FINDINGS: Ecological studies have suggested a possible relationship between sun exposure and atopic diseases such as asthma, atopic dermatitis and anaphylaxis. However, no direct evaluation of vitamin D status has been performed. Recent studies evaluating the relationship with vitamin D levels at birth or during pregnancy have shown conflicting results with the lower levels of vitamin D associated with eczema, the higher with increased food allergy prevalence. SUMMARY: Although the role of vitamin D in extraskeletal function is certainly intriguing and must not be underestimated, at the moment there is a lack of consistent data addressing the topic of vitamin D supplementation in the prevention of food allergies. However, in light of the vast amount of literature regarding the mechanisms connected with atopic diseases, an evaluation of serum levels of vitamin D and eventually supplementation must be considered as a further opportunity to understand and treat atopic diseases. In this regard, well designed trials on vitamin D supplementation to prevent food allergies are urgently needed.

Colostrum-derived B and T cells as an extra-lymphoid compartment of effector cell populations in humans.

Colostrum contains cellular components that convey immunological protection to offspring. In the present study the main subsets of lymphocytes present in colostrum and in peripheral blood of healthy screened mothers were compared through the evaluation of >15 different flow cytometry markers. Colostrum and peripheral blood samples were collected within 3 days after full-term delivery. Flow cytometry assays and laboratory tests were performed soon after collection. Among B cells, percentages of CD19(+)CD5(+) cells, pertaining to natural immunity system, were significantly higher in colostrum than in peripheral blood (33 vs. 5%, p = 0.047). CD4(+) T cells, effector cells (CD45RA(+)/CD27(-)) and effector memory cells (CD45RA(-)/CD27(-)) were significantly higher in colostrum (p < 0.001) than in peripheral blood, as well as activated CD4(+) T cells (HLA(-)DR(+)) (36% vs. 6% p = 0.0022) and CD4(+) terminally differentiated effector T cells (CD57(+)) (p < 0.001). With regards to CD8(+) T cells, a comparable significant increase in effector (p < 0.02) and effector memory cells (p < 0.001) was also observed. Moreover, an increased surface expression of HLA-DR and CD57 (p < 0.001) on CD8(+) T cells in colostrum was detected. Colostrum contains a different distribution of lymphocyte subsets with respect to peripheral blood from mothers, confirming the observation that lymphocytes probably migrate in milk in a selective way. Colostrum T and B lymphocytes appear to be enriched with subsets possessing effector functions or belonging to the innate immune system, what could transfer a prompt line of defence to offspring.

Analysis of urinary parameters as risk factors for nephrolithiasis in children with celiac disease.

PURPOSE: Intestinal malabsorption can cause urinary stone disease via enteric hyperoxaluria. It has been shown that celiac disease, a common malabsorption disorder, is associated with an increased risk of calcium oxalate kidney stones in adults. Since no published data are available in the pediatric population, we analyzed urinary excretion of electrolytes in children with celiac disease to assess the risk of nephrolithiasis. MATERIALS AND METHODS: The study population consisted of 115 children 1 to 16 years old (mean 5 years) with positive serological tests for celiac disease (anti-endomysium and anti-tissue transglutaminase antibodies) referred to us for jejunal biopsy to confirm the diagnosis. Assessment was requested because patients presented with poor growth, anemia, gastrointestinal disorders or a family history of celiac disease. After obtaining informed consent we performed urine tests to measure urinary variables and blood tests to exclude metabolic disorders and evaluate renal function. RESULTS: All patients had a biopsy confirmed diagnosis of celiac disease. Oxaluria was normal in all children studied. However, levels of urinary calcium were decreased in patients with celiac disease and were inversely associated with disease severity (p = 0.0004). CONCLUSIONS: In contrast to adults, increased urinary excretion of oxalate was not detectable in children presenting with celiac disease. Therefore, the risk of nephrolithiasis appears not to be increased compared to healthy children. The observed hypocalciuria probably further decreases the tendency to form kidney stones.

Immune regulatory cytokines in the milk of lactating women from farming and urban environments.

Children living on farms have fewer allergies. It is unclear whether breastfeeding in different environments contributes to preventing allergies by exposing offspring to different cytokines that can modulate immune responses. The aim of this study was to quantify and compare levels of Transforming Growth Factor-beta1 (TGF-beta1) and Interleukin-10 (IL-10) in the colostrum and mature milk of mothers living in towns at sea level (references) and mothers on farms. Milk samples were collected within 3 days postpartum (colostrum) and at the first month of the baby's life (mature milk). Sixty-nine reference mothers and 45 farm mothers participated in the study. TGF-beta1 concentrations were significantly higher both in the colostrum (p < 0.05) and in mature milk (p < 0.05) of farm mothers. In the reference mothers, a significant decrease in TGF-beta1 concentrations was observed between colostrum (650, range 0-8000 pg/ml) and mature milk (250, range 0-8000 pg/ml) (p < 0.05). In farm mothers, TGF-beta1 concentrations were 1102 pg/ml (range 0-14,500) in colostrum and remained high in mature milk (821 pg/ml, range 0-14,650). IL-10 concentrations were higher in the mature milk of farm mothers (p < 0.05). No significant differences in IL-10 were observed between colostrum and mature milk in the control group (15 pg/ml, range 0-1800, and 0 pg/ml, range 0-230) or in farm mothers (9.5 pg/ml, range 0-1775, and 14.2 pg/ml, range 0-930), respectively. Exposure to a farm environment is associated with higher concentrations of TGF-beta1 and IL-10 in breast milk when compared to exposure to an urban environment. Higher cytokine concentrations in breast milk may influence early modulation of the development of an immune response, leading to a reduced prevalence of allergy-related diseases in farm children.