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Competing Interests: The authors declare that they have no conflict of interest.

Functional constipation (FC) is one of the most common disorders in childhood and has a negative impact on the quality of life of children. Scientific evidence regarding a causal relationship between FC and cow's milk allergy is controversial, as it is also reported by the latest European Society for Paediatric Gastroenterology, Hepatology and Nutrition-North American Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN-NASPGHAN) recommendations. In the case of FC, routine allergometric tests are not recommended and the cows' milk-free diet is only proposed in the case of laxative-resistant constipation and only following the advice of an expert. Instead, after a careful review of the literature and in view of the many clinical cases encountered in our clinical practice, we believe that it is useful to propose cows' milk-free diet as first line for the treatment of FC at least in pre-school children and in children with a personal or family history of atopy or with a previous diagnosis of cow's milk protein allergy., Competing Interests: The authors declare no conflicts of interest.

Routine diagnostic methods for allergies to plant-derived foods are based on skin prick test (SPT) with commercial extracts, prick-by-prick (PbP) with fresh food, serum-specific IgE measurement, and oral food challenge.We discuss the possibility and the advantages of performing, in patients with oral allergy syndrome (OAS) by fruit and vegetables (excluding nuts) PR-10 allergy, component-resolved diagnosis (CRD) by SPT and PbP with raw and cooked vegetables, rather than performing a CRD with in vitro tests by drawing blood.Based on our clinical experience and the studies published in the literature, we believe that, at least for the OAS by fruit and vegetables (excluding nuts) PR-10 allergy, the search for sensitizing allergens and related cross-reactive allergens with SPT and PbP can be performed routinely in clinical practice, even at the primary-care level., Competing Interests: None

Background: Some studies have showed that seasonality is an important determinant of vitamin D (vitD) status., Objective: We evaluated whether there are differences in individual trends of serum vitD level over one year in asthmatic and rhinitic children., Materials and Methods: Ninety-two asthmatic and rhinitic paediatric patients were followed up for one year and their serum vitD level was detected at three-month intervals, once in each season., Results: We observed higher vitD levels at the end of summer and lower at the end of winter. However, the individual seasonal trend was very variable and unpredictable. If it is true that in a given season the majority of patients followed one direction (increase or decrease of serum vitD levels), nevertheless a substantial percentage behaved differently and unpredictably. For example, at the end of spring, 70% of patients showed an increase in serum vitD levels, but 30% showed a decrease. In addition, five individuals had a value ≥50ng/ml in September and showed serum vitD levels ≥30ng/ml throughout the year; 16 patients presented vitD value ≥40ng/ml in September and always had ≥20ng/ml in the other months., Conclusions: The wide and unpredictable variability of the individual trend of serum vitD levels should be taken into account before deciding whether or not a drug supplementation is appropriate., (Copyright © 2019. Published by Elsevier España, S.L.U.)

Food protein-induced enterocolitis (FPIES) is a non-IgE cell- mediated food allergy that can be severe and lead to shock. Despite the potential seriousness of reactions, awareness of FPIES is low; high-quality studies providing insight into the pathophysiology, diagnosis, and management are lacking; and clinical outcomes are poorly established. This consensus document is the result of work done by an international workgroup convened through the Adverse Reactions to Foods Committee of the American Academy of Allergy, Asthma & Immunology and the International FPIES Association advocacy group. These are the first international evidence-based guidelines to improve the diagnosis and management of patients with FPIES. Research on prevalence, pathophysiology, diagnostic markers, and future treatments is necessary to improve the care of patients with FPIES. These guidelines will be updated periodically as more evidence becomes available., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background. Oral food challenge (OFC) is the gold standard for the diagnosis of food allergy (FA), but it is risky, expensive and time-consuming. Many studies aimed to avoid OFC by finding a cut off (CO) of skin prick test (SPT) to predict a positive outcome of OFC. Unfortunately the results of these studies are poorly reproducible for various reasons, including the absence of known protein concentration in the extracts. It has also been documented that some doctors mistakenly attributed some symptom/disease, for example recurrent respiratory infections of the upper airways, to the FA, expecially cow milk allergy (CMA). These doctors often performed SPT in their studies to confirm, if the result was positive, their diagnostic suspicion and prescribe an elimination diet without seeking the advice of allergy specialist (AS) and without making an OFC. Objective. To test the diagnostic performances of SPT with fresh cow's milk and commercial extracts of casein, beta-lactoglobulin, alpha-lactoalbumin at known protein concentrations (Milk Prick Four [MP4] test). To look for 2 clusters of SPT CO with positive predictive value (PPV) > 95%, one for AS, one for general practitioner (GP). Methods. A prospective study was carried out on 191 children referred by their GP to the allergy center for suspected immediate-type CMA (iCMA). Based on the history, the allergist has divided the children into two groups: a) group A, children with suspected (subgroup A1, 55 children) or known (subgroup A2, 27 children) diagnosis of iCMA; b) group B, 109 children with a clinical history incompatible with iCMA suspicion according to the AS (in this case the GP was wrong to send those patients to the allergy center). SPT with MP4 test was performed on all patients, and OFC was performed on all patients of group A. CO with PPV > 95% was calculated separately for the entire population of 191 children (CO for GP) and for the only group A (CO for AS). Results. Fresh cow's milk SPT was the most sensitive single prick test (sensitivity [SE] 94%, negative predictive value [NPV] 98%). The positivity to any of 3 SPT extracts (performed at the same time) had the same SE and NPV of the single fresh cow's milk SPT. Moreover, fresh cow's milk SPT or any of 3 SPT extract had 100% SE and 100% NPV, having excluded 2 children with Food Protein Induced Enterocolitis Syndorme from data analysis. MP4 CO for GP allow a total savings of 4% of OFC, a percentage that rises to 22% in the subgroup A2, and does not give false positives. MP4 CO for AS allow a total saving of 33% of OFC, rising to 67% in the subgroup A2, but they give a 7/82 false positives in group A. SPT CO of alpha-lactoalbumin had the best performance in both settings. Conclusion. MP4 is a safe and cheap test, easy to perform. All doctors may be confident in excluding iCMA if fresh cow's milk SPT is negative. GP could perform SPT to fresh milk at his own clinic, and safely diagnose iCMA by using our CO for GP, although this may happen only in a few cases. MP4 test performed by AS can help save a greater number of OFC, especially among children with known diagnosis of iCMA.

Background: Food Protein-Induced Enterocolitis Syndrome (FPIES) is a non-IgE-mediated paediatric disorder triggered by the ingestion of specific food proteins. Many features of this syndrome are not yet well defined., Objective: The aim of our study was to describe demographic features, causative agents, clinical features, treatments and outcomes of children suffering from acute FPIES at three Italian of Pediatric Allergology Centers., Methods: A retrospective study was performed over a 7-year period (2004-2010). Hospital medical record databases and hospital outpatient electronic charts were screened for the diagnosis of FPIES. Information on the first and subsequent FPIES' episodes was collected., Results: We diagnosed 66 children with FPIES. The number of diagnoses significantly increased between 2008 and 2010 (P < 0.001). We collected a total of 165 FPIES episodes (median per child 2, range 1-10). Cow's milk was the most common trigger food (65%), followed by fish, egg, rice, soy, corn, poultry and goat's milk. Fifty-six (85%) children reacted to a single food. Mean documented time from ingestion to symptom onset was 2.4 h (SD 0.7 h). Vomiting was the most common symptom (98%). Among patients diagnosed with OFC, 78% reacted after eating a whole serving size of the trigger food per age. Skin prick tests (SPT) for trigger foods were negative in 97% of cases. Thirty-two/66 children (48%) achieved tolerance at a mean age of 29 months (SD 17 months). Age of achieved tolerance for cow's milk was significantly lower compared to that of other foods (24 ± 8 vs. 53 ± 17 months, P < 0.0006)., Conclusion and Clinical Relevance: This article provides new insights on FPIES in Italy by describing its largest series, and shows how a significant increase in the FPIES diagnosis has been observed in the last few years. We also discussed selected management aspects of this syndrome where different phenotypes can be found., (© 2012 Blackwell Publishing Ltd.)

Fish is a common cause of food allergy. The reactions usually occur after its ingestion. In most immunoglobulin E-mediated reactions, the allergens are gastroresistant and heat-stable proteins of low molecularweight (parvalbumin). On the other hand, isolated contact urticaria following the handling of raw fish but without symptoms after its ingestion was found among cooks and professional fish handlers. In these cases, the fish allergens are gastrosensitive and thermolabile, as demonstrated by the decrease in the diameter of the wheal in the skin-prick test using cooked fish. To the best of our knowledge isolated fish contact urticaria in children has not been previously reported. We analyze the features of three pediatric cases of contact urticaria from cod (one of them was sensitized to parvalbumin), with tolerance after ingestion of this fish on oral food challenge.

Background: The diagnostic gold standard for food allergy is an oral food challenge (OFC) with the suspected food. Usually, an OFC is stopped at the onset of mild objective symptoms for fear of severe reactions, but there is no consensus on this issue., Objectives: To investigate the effectiveness and side effects of a new model of oral milk challenge in order to increase the diagnostic accuracy of cow's milk protein allergy and reduce the number of useless elimination diets. This model is characterized by a conservative diagnostic protocol and "step-up cow's milk dosing." The secondary aim was to investigate possible factors influencing severe reactions., Methods: Sixty-six children (median age 1 year, range 1-18) with suspected immunoglobulin E (IgE)-mediated cow's milk allergy performed a conservative OFC, i.e., the OFC was continued even in the presence of subjective, even repeated, or mild local or multiple organ objective symptoms. If the first objective reaction occurred when the quantity of milk was > 10 ml, the investigator would decide whether to continue the OFC or prescribe a gradual increase in milk feeding at home., Results: Symptoms developed during the OFC in 42.4% of the children. Local, generalized and severe generalized reactions developed in 11 (16.7%), 11 (16.7%) and 6 (9.1%) children, respectively. Only 14/28 (50%) who developed objective symptoms during the OFC were considered to be affected by cow's milk allergy. In the remaining 14 both subjective and objective symptoms developed and the OFC was continued without further symptoms. Epinephrine was administered to 6 of the 28 children (21.4%) who developed objective symptoms. All but one had subjective symptoms following the early doses of milk, whereas all children who later tolerated milk had their first subjective or mild symptoms following doses > or = 10 ml., Conclusions: This new model of OFC criteria led to frequent severe allergic reactions; hence its use in daily practice seems inadvisable. However, our study provides evidence that a severe allergic reaction does not invariably occur if, the offending food continues to be administered after the onset of symptoms. If mild symptoms appear at doses > 10 ml, continued milk administration, on the same day or in subsequent days, seems to facilitate the development of tolerance and may reduce the number of useless elimination diets.

Unlabelled: Preschool children frequently suffer from acute respiratory tract infections (ARTI). Immunostimulants (ISs) are often administered to reduce their impact. This study aimed to establish the efficacy of ISs in the prevention of pediatric ARTI through the analysis of systematic reviews (SRs). We explored Medline database in October 2010 limiting our search to SRs, that included studies on the effectiveness of ISs in the prevention of pediatric ARTI. Six SRs with meta analysis (MA) were found. The studies included showed a low methodological quality and a high statistical heterogeneity. All papers published on journals with impact factor > 1 and a Jadad score > 3 reviewed the efficacy of OM-85. The number needed to treat (NNT) was between 2 and 11, depending on the setting., Conclusions: Pediatric ARTI are a social and health care problem. When they impair the quality of life of the family a course of OM-85 might be warranted. Although scientific knowledge of clinicians may be improved by SRs, MA and aggregation of results may not always be the best way to accomplish this.

Specific Oral Tolerance (SOTI) is a promising therapy of food allergy, specially for IgE-mediated cow milk allergy (CMA) in pediatric age. Randomized controlled trials have reported that about 35% of children, at least 5 years of age, became full tolerant to cow milk proteins after SOTI. Regard to the safety, literature describes about 200 children who underwent SOTI, with no fatal events. Nevertheless, a considerable percentage of those children (15%-20%) had to stop SOTI, because of important adverse effects. Numerous protocols have been described, some audacious and other prudent, however all demand an intense commitment either of the doctors and of the families. The information about the follow up of the children who underwent SOTI are still insufficient. For these reasons, we think that SOTI is still an experimental therapy., (Copyright (c) 2009 John Wiley & Sons A/S)

Objective: To evaluate pediatric studies of the effect on asthma symptoms of treatment with proton pump inhibitors (PPI) used to treat gastroesophageal reflux disease (GERD)., Methods: We entered the MeSH terms "gastroesophageal reflux AND asthma AND children" in the PubMed tool Clinical Queries, selecting "therapy" and "broad, sensitive search." The search ended on April 14, 2008. We included only clinical trials performed in pediatric patients., Results: Four studies were considered to be relevant, although only 1 was a randomized, double-blind, placebo-controlled trial. The 3 nonrandomized trials showed that PPIs benefited patients with asthma. The randomized, double-blind, placebo-controlled trial found that omeprazole did not improve asthma symptoms. An improved (although not statistically significant) score was observed in the quality of life questionnaire in children with a reflux index greater than 10% and in those with more severe asthma treated with omeprazole compared with the placebo group., Conclusions: Scant data in these studies mean that we cannot make solid recommendations. However, in specific cases, we think that treatment of asthma symptoms with a PPI is valid as long as at least 2 conditions are satisfied: asthma must not respond to standard treatment, and 1 instrumental parameter of GERD severity must be satisfied, that is, a reflux index greater than or equal to 10 must be present.

It has been suggested that changes in dietary habits, particularly increased consumption of omega-6 polyunsaturated fatty acids (PUFA) and decreased consumption of omega-3 PUFAs may explain the increase in atopic disease seen in recent years. Furthermore, it seems possible that it is mainly prenatal or very early life environmental factors that influence the development of allergic diseases. It has also been suggested that intrauterine risk factors may act differently if mother themselves suffer from allergic disease. The aim of this study was to investigate whether the consumption of fish, butter and margarine during pregnancy might influence the development of allergic sensitizations in the offspring. The study population was divided into the offspring of allergic and non-allergic mothers. This was a retrospective cohort study enrolling 295 offspring of allergic mothers and 693 of non-allergic mothers. Information regarding maternal intake of fish, butter and margarine during pregnancy as well as other prenatal and perinatal confounding factors were retrospectively assessed by parental report via a standardized questionnaire. Atopy was determined by skin-prick tests (SPT) to eight prevalent inhalant allergens and two foods. In the allergic mothers' group there is no clear correlation between maternal intakes of fish, butter and margarine and sensitizations to food or inhalants. In the non-allergic mothers' group there was no correlation between butter and margarine intake and food or inhalant sensitizations. On the contrary, a protective effect of fish intake on SPT positivity was observed. In particular, frequent maternal intake ('2-3 times/wk or more') of fish reduced the risk of food sensitizations by over a third (aOR 0.23; 95% CI: 0.08-0.69). A similar trend, even if not significant, was found for inhalants. Finally, even in the whole study population, i.e. allergic group plus non-allergic group, there was a similar trend between increased consumption of fish and decreased prevalence of SPT positivity for foods. This study shows that frequent intake of fish during pregnancy may contrast the development of SPT sensitizations for foods in the offspring of mothers without atopic disease. Therefore, larger prospective studies are needed, enrolling mothers with and without allergic disease, to confirm these results.

Aims: To evaluate the clinical efficacy of sublingual immunotherapy (SLIT) in respiratory allergy in children., Methods: A systematic literature review was conducted. The search was focused on all the double blind (and double dummy if necessary) studies., Search Strategy: Medline, Embase, Cochrane Controlled Trial Register, Abstract of Cochrane Airways Group, hand search, and archives of some SLIT producers. All the selected studies were assessed and evaluated for quality in a standardised independent way., Results: Eight randomised, double blind, placebo controlled studies on SLIT were selected. Five studies were run with house dust mite (HDM), one with olive pollen, one with wall pellitory (Parietaria) pollen, and one with grass pollen. A quantitative evaluation of the studies was not possible because the outcomes and the results of single studies were presented according to different criteria. Therefore only qualitative analysis was performed. No clinically relevant results were shown, independently from statistical significance, in the use of SLIT for respiratory allergies due to seasonal allergens (olive, wall pellitory, and grass pollens) and, on the whole, for rhinoconjunctivitis due to HDM in children. For mild to moderate persistent asthma due to HDM, statistically significant and low to moderate relevant clinical effects were observed., Conclusions: SLIT can be currently considered to have low to moderate clinical efficacy in children of at least 4 years of age, monosensitised to HDM, and suffering from mild to moderate persistent asthma. This benefit seems to be adjunctive with respect to the environmental preventive measures against HDM.

Background: It has been suggested that environmental factors early in life, particularly related to hygiene and infections, seem to be involved in the increase of asthma and allergic disease observed recently in developed countries. The possible effect of these factors also in utero have yet to be completely clarified. The aim of this study was to investigate the association between infective and uterus related complications during pregnancy, as well as related drug factors, with atopic and nonatopic asthma in children., Methods: This was a case-controlled study enrolling 338 children with asthma and 467 controls, who had never suffered from wheeze or asthma. Fever episodes, flu episodes, threatened abortions and related drug factors were retrospectively assessed by parental report via a standardized questionnaire. Atopy was determined by skin-prick tests to 10 prevalent allergens at the time of examination., Results: Flu episodes during pregnancy were significantly associated with development of asthma in children [adjusted odds ratio (aOR) 1.91; 95% confidence interval (95% CI) 1.1-3.2], mainly with nonatopic asthma. Fever episodes showed similar results (aOR 2.16; 95% CI 1.2-3.9), but were associated with both atopic and nonatopic asthma. The effect seems mainly due to flu and fever episodes contracted in the third trimester. Exposure to isoxsuprine was significantly associated with asthma (aOR 1.54; 95% CI 1.08-2.19) while threatened abortions were more frequent in the asthma group than in controls, although the difference was statistically significant only when such events occurred in the second trimester (aOR 2.06; 95% CI 1.07-3.94). Both threatened abortions and exposure to isoxsuprine were associated only with nonatopic asthma., Conclusions: This study confirms that prenatal infective complications may contribute to the development of asthma in children and show a possible role for a new risk factor for asthma, that is exposure to isoxsuprine. Therefore, larger prospective studies, capable of separating atopic and nonatopic asthma, would serve to confirm these results and to explain the possible mechanism through which these factors may act.

A young Down's syndrome patient developed tricuspid valve endocarditis several years after undergoing surgical closure of a congenital ventricular septal defect. Fungal etiology was established by PCR amplification of the Candida albicans ERG11 gene. Although antifungal therapy was administered, surgical replacement of the infected valve was required to eliminate the infection.

A model of antigen-specific T-cell proliferative responses based on reciprocal patterns of responses to dietary and inhalant allergens has been suggested, the former being frequent in infancy but rare in adults, whereas the latter are preserved and expand between infancy and adulthood. We have evaluated the age-related variations of mononuclear cell reactivity to food allergens. The cord blood mononuclear cells (CBMC) of 30 neonates without family history of atopy and the peripheral blood mononuclear cells (PBMC) of 20 healthy children and of 40 healthy adults were stimulated in vitro with beta-lactoglobulin (BLG) or ovalbumin (OVA) and the cultures were harvested after 7 days. Neonates, children and adults were compared for the percentages of positive responses and for the magnitude of response. Adult subjects showed significantly lower percentages of positive responses and reduced magnitude of response than those observed in neonates and children either in BLG or in OVA cultures. We have not observed a decrease of food allergen mononuclear cell reactivity between neonates and children for the frequency of positive responses. The magnitude of response of neonates was significantly lower than that of children in BLG cultures. Our results seem to confirm the loss of mononuclear cell reactivity to food allergens in adult age. However, other reports show conflicting data. We suggest that a rigorous standardization of the methodological steps of in vitro mononuclear cell stimulation with allergen is necessary.

To evaluate the possible effect of zinc treatment on immune disorders in children with Down's syndrome (DS), 38 noninstitutionalized DS children were investigated. Twenty-four patients (63.2%) had plasmatic zinc levels lower than 0.70 microgram/dl ("hypozinkemic," LZn) and 14 patients (36.8%) had levels higher than 0.75 microgram/dl ("normozinkemic," NZn). No correlation was found between the zinc deficiency and recurrence and/or intensity of infections. The absolute numbers of peripheral lymphocytes, the percentages of B lymphocytes, total T cells, and serum IgG, IgA, and IgM levels did not differ between the DS children and the controls. Eight (21%) patients had CD4+ T cell counts below the lowest value for the controls. Seventeen (44%) DS patients had increased levels of CD8+ T cells. The mean percentage of Leu 7+ cells in DS subjects (22.8 +/- 12.9%) was significantly higher than that in controls (15.8 +/- 4.8%) (P less than 0.01). Notably, Ig levels and numbers of lymphocytes in each subset did not show any significant difference in NZn and LZn trisomic subjects. On the contrary the peripheral blood mononuclear cells (PBMCs) from LZn DS children showed a significantly lower proliferative response to phytohemagglutinin (PHA) (S.I. = 23.4 +/- 22.4) than that of PBMCs from NZn DS children (S.I. = 46.1 +/- 21.5, P less than 0.01). A significant increase in DNA synthesis was obtained after oral administration of zinc sulfate (20 mg/kg/day, for 2 months). The lymphocyte response to PHA appeared to be normal in all patients up to 6 months after the end of the zinc treatment and it became low in half of the patients 22 months after therapy.

The second child of a mother with idiopathic thrombocytopenic purpura was given 400 mg/kg per day polyethylenglycol-treated gammaglobulins during the first 5 days of life. Thrombocytes increased from 15 X 10(9)/l to 200 X 10(9)/l within 10 days and remained at this level afterwards.