Yitzhak Katz

Early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy

BACKGROUND Despite guidelines recommending avoidance of peanuts during infancy in the United Kingdom (UK), Australia, and, until recently, North America, peanut allergy (PA) continues to increase in these countries. OBJECTIVE We sought to determine the prevalence of PA among Israeli and UK Jewish children and evaluate the relationship of PA to infant and maternal peanut consumption. METHODS A clinically validated questionnaire determined the prevalence of PA among Jewish schoolchildren (5171 in the UK and 5615 in Israel). A second validated questionnaire assessed peanut consumption and weaning in Jewish infants (77 in the UK and 99 in Israel). RESULTS The prevalence of PA in the UK was 1.85%, and the prevalence in Israel was 0.17% (P < .001). Despite accounting for atopy, the adjusted risk ratio for PA between countries was 9.8 (95% CI, 3.1-30.5) in primary school children. Peanut is introduced earlier and is eaten more frequently and in larger quantities in Israel than in the UK. The median monthly consumption of peanut in Israeli infants aged 8 to 14 months is 7.1 g of peanut protein, and it is 0 g in the UK (P < .001). The median number of times peanut is eaten per month was 8 in Israel and 0 in the UK (P < .0001). CONCLUSIONS We demonstrate that Jewish children in the UK have a prevalence of PA that is 10-fold higher than that of Jewish children in Israel. This difference is not accounted for by differences in atopy, social class, genetic background, or peanut allergenicity. Israeli infants consume peanut in high quantities in the first year of life, whereas UK infants avoid peanuts. These findings raise the question of whether early introduction of peanut during infancy, rather than avoidance, will prevent the development of PA.

Early exposure to cow's milk protein is protective against IgE-mediated cow's milk protein allergy.

BACKGROUND The diversity in the perceived prevalence, recovery, and risk factors for cows milk allergy (CMA) necessitated a large-scale, population-based prospective study. OBJECTIVE We sought to determine the prevalence, cross-reactivity with soy allergy, and risk factors for the development of CMA. METHODS In a prospective study the feeding history of 13,019 infants was obtained by means of telephone interview (95.8%) or questionnaire (4.2%). Infants with probable adverse reactions to milk were examined, skin prick tested, and challenged orally. RESULTS Ninety-eight percent of the cohort participated in the study. The cumulative incidence for IgE-mediated CMA was 0.5% (66/13,019 patients). The mean age of cows milk protein (CMP) introduction was significantly different (P < .001) between the healthy infants (61.6 +/- 92.5 days) and those with IgE-mediated CMA (116.1 +/- 64.9 days). Only 0.05% of the infants who were started on regular CMP formula within the first 14 days versus 1.75% who were started on formula between the ages of 105 and 194 days had IgE-mediated CMA (P < .001). The odds ratio was 19.3 (95% CI, 6.0-62.1) for development of IgE-mediated CMA among infants with exposure to CMP at the age of 15 days or more (P < .001). Sixty-four patients with IgE-mediated CMA tolerated soy, and none had a proved allergy to soy. CONCLUSIONS IgE-mediated CMA is much less common than generally reported. Early exposure to CMP as a supplement to breast-feeding might promote tolerance. Finally, soy is a reasonable feeding alternative in patients with IgE-mediated CMA.

Interleukin-17 enhances tumor necrosis factor α-induced synthesis of interleukins 1, 6, and 8 in skin and synovial fibroblasts: A possible role as a fine-tuning cytokine in inflammation processes

OBJECTIVE To compare the singular and combined effects of tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), and IL-17 on messenger RNA (mRNA) expression, translation, and secretion of IL-6, IL-8, and IL-1beta in fibroblasts. METHODS Fibroblasts were stimulated with the relevant cytokine(s), pulse labeled with 35S-methionine, and the newly synthesized proteins were immunoprecipitated and subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Gene expression was determined by Northern blot analysis. Secreted proteins were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS IL-17 alone was a weaker stimulator of the transcription, translation, and secretion of other interleukins than was TNFalpha or IL-1beta. IL-17 (10 ng/ml) stimulated the expression of IL-6 mRNA by 1.3-fold, while TNFalpha (1 ng/ml) increased it by 3.7-fold, and IL-1beta (0.1 ng/ml) increased it by >30-fold. Unlike TNFalpha and IL-1beta, IL-17 hardly affected the expression of IL-8 and IL-1beta mRNA. Translation of IL-6 was 6.2 times greater with IL-17, but TNFalpha and IL-1beta stimulated it 28.9- and 174-fold, respectively. ELISA-measured secretion of IL-6 and IL-8 increased by 6.7 and 5.8 times, respectively, with IL-17, compared with 52 and 269 times with TNFalpha stimulation and 1,356 and 1,084 times with IL-1beta stimulation. Yet, when IL-17 was combined with other cytokines, these activities were stimulated much beyond the sum of the individual effects. The combination of IL-17 and TNFalpha induced the expression of IL-6 or IL-1beta mRNA 7 times more than their additive stimulation, and that of IL-8 mRNA 3.8 times more. Likewise, the secretion of IL-6 and IL-8 was 20 times and 5 times higher, respectively, than expected. This synergism started after 4 hours of combined treatment, and decayed after 24-48 hours regardless of cytokine presence. It could be blocked with anti-IL-17 but not with anti-IL-1. CONCLUSION Our findings suggest that the primary role of IL-17 is to synergize with TNFalpha and to fine-tune the inflammation process. Therefore, IL-17 may be a potential target for therapeutic intervention.

The prevalence and natural course of food protein–induced enterocolitis syndrome to cow’s milk: A large-scale, prospective population-based study

BACKGROUND The prevalence and natural history for food protein-induced enterocolitis syndrome (FPIES) have not been determined. OBJECTIVE We sought to determine the prevalence, clinical manifestations, and rate of recovery for FPIES in a large-scale, population-based prospective study. METHODS In a prospective study the feeding history of 13,019 infants was obtained. Infants with probable adverse reactions to cows milk protein (CMP) were clinically examined, skin prick tested, and challenged orally. Diagnostic criteria for CMP-induced FPIES included age less than 9 months, delayed recurrent vomiting (usually with nausea), and lethargy after exposure to CMP in the absence of other IgE-mediated symptoms, such as rash, urticaria, and respiratory symptoms. In addition, a positive challenge response to milk resulted in the above-mentioned gastrointestinal symptoms, removal of milk from the diet resulted in the resolution of those symptoms, or both. RESULTS Ninety-eight percent of the cohort participated in the study. The cumulative incidence for FPIES was 0.34% (44/13,019 patients). The most common symptoms were recurrent vomiting (100%), lethargy (77%) diarrhea (25%), pallor (14%), and bloody diarrhea (4.5%). All patients had FPIES within the first 6 months of life. By the age of 3 years, 90% of the patients had recovered. We did not detect any concomitant reaction to soy. Eight patients with FPIES had IgE-mediated cows milk allergy (IgE-CMA). CONCLUSIONS The prevalence of FPIES is significant, and its clinical presentation is distinct from that of IgE-CMA. Most patients with FPIES recover, although a proportion might convert to IgE-CMA. The likelihood for a cross-reactivity to soy in this population was less than previously estimated.

Complement Factor H Gene Mutation Associated with Autosomal Recessive Atypical Hemolytic Uremic Syndrome

Atypical hemolytic uremic syndrome (HUS) presents with the clinical features of hypertension, microangiopathic hemolytic anemia, and acute renal failure. Both dominant and recessive modes of inheritance have been reported. This study describes the genetic and functional analysis of a large Bedouin kindred with autosomal recessive HUS. The kindred consists of several related nuclear families in which all parent unions of affected children are consanguineous. A previous report demonstrated that a dominant form of HUS maps to chromosome 1q and that complement factor H (CFH), a regulatory component of the complement system, lies within the region and is involved in the dominant disorder. Early-onset and persistent hypocomplementemia in this Bedouin kindred prompted us to evaluate the CFH gene. Linkage analysis was performed, demonstrating linkage between the disorder and the markers near the CFH gene. Mutation analysis of the CFH coding region revealed a single missense mutation. Functional analyses demonstrate that the mutant CFH is properly expressed and synthesized but that it is not transported normally from the cell. This is the first study reporting that a recessive, atypical, early-onset, and relapsing HUS is associated with the CFH protein and that a CFH mutation affects intracellular trafficking and secretion.

Consensus Communication on Early Peanut Introduction and the Prevention of Peanut Allergy in High-risk Infants

The purpose of this brief communication is to highlight emerging evidence to existing guidelines regarding potential benefits of supporting early, rather than delayed, peanut introduction during the period of complementary food introduction in infants. This document should be considered as interim guidance based on consensus among the following organizations: American Academy of Allergy, Asthma & Immunology; American Academy of Pediatrics; American College of Allergy, Asthma & Immunology; Australasian Society of Clinical Immunology and Allergy; Canadian Society of Allergy and Clinical Immunology; European Academy of Allergy and Clinical Immunology; Israel Association of Allergy and Clinical Immunology; Japanese Society for Allergology; Society for Pediatric Dermatology; and World Allergy Organization. More formal guidelines regarding early-life, complementary feeding practices and the risk of allergy development will follow in the next year from the National Institute of Allergy and Infectious Diseases – sponsored Working Group and the European Academy of Allergy and Clinical Immunology.

Non–IgE-mediated gastrointestinal food allergy

Non-IgE-mediated gastrointestinal food-induced allergic disorders (non-IgE-GI-FAs) account for an unknown proportion of food allergies and include food protein-induced enterocolitis syndrome (FPIES), food protein-induced allergic proctocolitis (FPIAP), and food protein-induced enteropathy (FPE). Non-IgE-GI-FAs are separate clinical entities but have many overlapping clinical and histologic features among themselves and with eosinophilic gastroenteropathies. Over the past decade, FPIES has emerged as the most actively studied non-IgE-GI-FA, potentially because of acute and distinct clinical features. FPIAP remains among the common causes of rectal bleeding in infants, while classic infantile FPE is rarely diagnosed. The overall most common allergens are cows milk and soy; in patients with FPIES, rice and oat are also common. The most prominent clinical features of FPIES are repetitive emesis, pallor, and lethargy; chronic FPIES can lead to failure to thrive. FPIAP manifests with bloody stools in well-appearing young breast-fed or formula-fed infants. Features of FPE are nonbloody diarrhea, malabsorption, protein-losing enteropathy, hypoalbuminemia, and failure to thrive. Non-IgE-GI-FAs have a favorable prognosis; the majority resolve by 1 year in patients with FPIAP, 1 to 3 years in patients with FPE, and 1 to 5 years in patients with FPIES, with significant differences regarding specific foods. There is an urgent need to better define the natural history of FPIES and the pathophysiology of non-IgE-GI-FAs to develop biomarkers and novel therapies.

Hypocomplementemic autosomal recessive hemolytic uremic syndrome with decreased factor H.

Abstract. We describe the clinical course, complement components, and pathological findings of 10 infants with autosomal recessive hemolytic uremic syndrome (HUS). All patients were members of one extended highly inbred Bedouin kindred. The median age of presentation was 2 weeks (range 1–20 weeks). Eight patients died, 2 patients are alive, on dialysis. Renal biopsies revealed thrombotic microangiopathy with a predominant early arteriolar involvement and subsequent development of ischemic glomerular changes. Immunofluorescence was positive for C3 in glomeruli. All patients had low complement components levels during and between relapses, and in some this was evident soon after birth and prior to the onset of symptoms. This deficiency could not be normalized by repeated plasma transfusions. Biosynthetic labelling of patients’ fibroblasts demonstrated normal rates of C3 protein synthesis. Serum factor H levels were greatly decreased or absent in 4 patients tested and moderately decreased in 15 of 23 healthy unaffected siblings and patients. This defect may cause complement activation and consumption, possibly at the endothelial cell level.

Extrahepatic synthesis of complement proteins in inflammation

The demonstration of local complement protein synthesis leads to speculation as to the biological significance of this phenomenon. A narrative review is provided to illuminate several queries. It is difficult to establish a causal role for the locally produced complement because participation of systemic complement cannot be excluded. It is also difficult to discern whether local complement synthesis is a beneficial response to an inflammatory event or whether it promotes tissue damage. Finally, it remains to be seen if the roles of local and systemic complement differ in these respects. Extrahepatic expression of complement components of the activation pathways may provide a rapid response to microbial invasion. Once produced and activated, these proteins evoke a phlogistic response composed of cells and soluble mediators of inflammation. Many cells, not only synthesize complement proteins, but can also be stimulated via their complement receptors. This positive feedback may enhance local immune defense, especially in organs isolated from plasma components. In addition, local environmental factors in different organs may differentially regulate complement synthesis. These factors may include pro-inflammatory molecules and non-immune effectors, such as tissue ischemia/reoxygenation and drugs. Local complement dysregulation due to inhibition of activity of a complement regulatory component was shown to cause disease and restoration of the capacity to regulate the complement pathway restored health. Extrahepatic complement synthesis may also modulate local cellular responses, as to decrease detrimental damage of the inflammatory reaction. The demonstration that complement proteins play a significant role in the clearance of apoptotic cells suggests that local synthesis and activation of complement may contribute not only to tissue damage but also to tissue repair.

Reviews and feature articleConsensus communication on early peanut introduction and the prevention of peanut allergy in high-risk infants

The purpose of this brief communication is to highlight emerging evidence to existing guidelines regarding potential benefits of supporting early, rather than delayed, peanut introduction during the period of complementary food introduction in infants. This document should be considered as interim guidance based on consensus among the following organizations: American Academy of Allergy, Asthma & Immunology, American Academy of Pediatrics, American College of Allergy, Asthma & Immunology, Australasian Society of Clinical Immunology and Allergy, Canadian Society of Allergy and Clinical Immunology, European Academy of Allergy and Clinical Immunology, Israel Association of Allergy and Clinical Immunology, Japanese Society for Allergology, Society for Pediatric Dermatology, and World Allergy Organization. More formal guidelines regarding early-life, complementary feeding practices and the risk of allergy development will follow in the next year from the National Institute of Allergy and Infectious Diseases-sponsored Working Group and the European Academy of Allergy and Clinical Immunology.