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Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I interferons (IFNs)1,2, conferring a predisposition to life-threatening COVID-19 pneumonia3. Here we report that patients with autosomal recessive NIK or RELB deficiency, or a specific type of autosomal-dominant NF-κB2 deficiency, also have neutralizing autoantibodies against type I IFNs and are at higher risk of getting life-threatening COVID-19 pneumonia. In patients with autosomal-dominant NF-κB2 deficiency, these autoantibodies are found only in individuals who are heterozygous for variants associated with both transcription (p52 activity) loss of function (LOF) due to impaired p100 processing to generate p52, and regulatory (IκBδ activity) gain of function (GOF) due to the accumulation of unprocessed p100, therefore increasing the inhibitory activity of IκBδ (hereafter, p52LOF/IκBδGOF). By contrast, neutralizing autoantibodies against type I IFNs are not found in individuals who are heterozygous for NFKB2variants causing haploinsufficiency of p100 and p52 (hereafter, p52LOF/IκBδLOF) or gain-of-function of p52 (hereafter, p52GOF/IκBδLOF). In contrast to patients with APS-1, patients with disorders of NIK, RELB or NF-κB2 have very few tissue-specific autoantibodies. However, their thymuses have an abnormal structure, with few AIRE-expressing medullary thymic epithelial cells. Human inborn errors of the alternative NF-κB pathway impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases.

Food allergies (FAs) are on the rise worldwide. A previous cross-sectional study from 2002 in Israel estimated the prevalence of IgE-mediated FA among young children at 0.85%. Although sesame was found to be a common allergen, peanuts were found to be a rare allergen.

This paper presents the largest cohort to date of infants under 1 year of age treated with mebendazole. We evaluated the occurrence of mebendazole-associated clinical and laboratory toxicity as safety data in this age group are currently lacking.

Suspected adverse reactions to amoxicillin are common, but there are no known factors that can predict amoxicillin allergy in children. In addition, methods used for the diagnosis of amoxicillin allergy are not standardized and their role in diagnosis is not clear.

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The widespread use of 7-valent pneumococcal conjugate vaccine (PCV7) has changed acute otitis media (AOM) bacteriology. Only scattered data with regard to this effect of PCV13 have been published so far.

Infantile feeding disorders (IFDs) are a common cause of food refusal, failure to thrive, and vomiting, but they may be difficult to diagnose. We have previously identified certain patterns of pathological feeding and behaviors as high-risk characteristics for IFDs and subsequently developed the diagnostic Wolfson criteria. Here, we evaluate these high-risk behaviors and prospectively compare the Wolfson criteria with 2 existing classifications of IFD, the Chatoor and that in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV).

Infantile feeding disorders (IFDs) are a common cause of food refusal, failure to thrive, and vomiting, but they may be difficult to diagnose. We have previously identified certain patterns of pathological feeding and behaviors as high-risk characteristics for IFDs and subsequently developed the diagnostic Wolfson criteria. Here, we evaluate these high-risk behaviors and prospectively compare the Wolfson criteria with 2 existing classifications of IFD, the Chatoor and that in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Infants and young children referred for food refusal were invited to participate by completing a feeding pattern questionnaire. Following physicians' interview and examination, patients were scored by all 3 criteria and enrolled in a structured treatment program for IFD. Infants whose food refusal was associated with an organic cause served as a comparison group. The ability of the criteria to detect IFD and to predict response to therapy was compared with an intention-to-treat analysis. Eighty-five infants with new-onset IFD and 55 controls were included. The Wolfson criteria, Chatoor, and DSM-IVaccurately diagnosed 100%, 77%, and 56% of the patients with IFD, respectively. Anticipatory gagging occurred in 47% of the children with IFD compared to 2% controls (P< 0.001). The response to therapy was similar among the 3 criteria (73–76%), suggesting that the Wolfson criteria did not incorrectly diagnose organic disease as IFD. The 20 infants who were diagnosed as having IFD by Wolfson but not by Chatoor responded equally well (80%) to an IFD treatment program. Diagnostic criteria of IFD that are based on food refusal, pathological feeding, and anticipatory gagging have a higher detection rate than the present criteria and are simpler to implement.

Food refusal, poor feeding, and somatic symptoms such as vomiting, gagging, irritability and failure to thrive (FTT) are commonly found in both infantile feeding disorders (IFD) and common treatable medical conditions. Present diagnostic classifications for diagnosing IFD are complex and difficult to apply in daily practice, leading to underdiagnosis and delay in diagnosis of IFD. We attempted to identify parental and infantile behaviour patterns or symptoms that could help distinguish between organic or behavioural causes for these symptoms.

Food refusal, poor feeding, and somatic symptoms such as vomiting, gagging, irritability and failure to thrive (FTT) are commonly found in both infantile feeding disorders (IFD) and common treatable medical conditions. Present diagnostic classifications for diagnosing IFD are complex and difficult to apply in daily practice, leading to underdiagnosis and delay in diagnosis of IFD. We attempted to identify parental and infantile behaviour patterns or symptoms that could help distinguish between organic or behavioural causes for these symptoms. We screened 226 children with poor feeding. After exclusion criteria, we divided the remaining 151 into 2 groups. The nonorganic group (n = 83) included patients with onset of symptoms before age 2, persistent food aversion longer than 1 month, and a response to behavioural intervention. The second group consisted of children (n = 68) presenting with similar characteristics, who responded to medical or nutritional therapy in which a final diagnosis of gastro-esophageal reflux disease, milk allergy, or idiopathic or nutritional FTT was made. Poor intake, poor weight gain, or vomiting did not discriminate between organic and nonorganic causes. Factors indicating the presence of a behavioural cause included food refusal, food fixation, abnormal parental feeding practices, onset after a specific trigger, and presence of anticipatory gagging (P< 0.0001 for all). Integration of a few structured questions regarding infant behaviour, parental feeding practices, infant symptoms, and triggers for the onset of symptoms may help clinicians distinguish between organic and nonorganic causes for food refusal or low intake FTT.

Knowledge about the natural history of food allergy, especially sesame, is scarce.

Pediatric-onset Crohn disease (CD) may differ in genotype or phenotype from adult-onset CD. Genome-wide screening recently identified a protective mutation (R381Q) in the interleukin-23 (IL-23) receptor gene located on chromosome 1. The aims of our study were to evaluate whether this mutation is associated with CD in our population and to find whether it may have an impact on age of onset or a specific location phenotype in a pediatric- and adult-onset CD population.

Pediatric-onset Crohn disease (CD) may differ in genotype or phenotype from adult-onset CD. Genome-wide screening recently identified a protective mutation (R381Q) in the interleukin-23 (IL-23) receptor gene located on chromosome 1. The aims of our study were to evaluate whether this mutation is associated with CD in our population and to find whether it may have an impact on age of onset or a specific location phenotype in a pediatric- and adult-onset CD population. A total of 438 individuals (143 with pediatric-onset CD [age <18 years], 139 with adult-onset CD, and 157 control subjects) evaluated for age at onset and disease location were genotyped for the R381Q mutation in the IL-23 receptor gene by pyrosequencing. Mutant allele incidences were 5.7% in the normal cohort and only 2.28% in the CD cohort (P= 0.01). Carriers were found to constitute 8.9% of the normal cohort and only 4.6% of the CD cohort (P= 0.029). Homozygotes were found in only the control cohort. The mean age of onset for all of the patients with the mutation (including both age groups) was 17.8 ± 6.1 years versus 21.3 ± 12.4 years for patients without the mutation (P=0.08). The mutation was not associated with differences in sex, site of disease, or ethnicity. We did not find evidence of allelic interaction with CARD15. We confirmed the findings that the IL-23 receptor gene coding variant allele R381Q appears to decrease susceptibility to CD in an Israeli Jewish population. We found a trend toward earlier age of onset, but no interactions with CARD15 or modifying effect on disease location.

Granulomas may be found in 30–70% of patients with Crohn's disease (CD). The etiology of granuloma formation in CD is presently unknown. Elevated levels of TNF-α are found within granuloma tissue, and are required to maintain granuloma formation in animal models. TNF-α production has been shown to influenced by TNF-α promoter polymorphisms. We hypothesized that heterogeneity for granulomas in CD might be influenced by the TNF-α promoter genotype. Patients with confirmed CD that had undergone full colonoscopy with multiple biopsies and/or surgical resection, served as the study group. One hundred healthy individuals served as a control population for genotyping. Patients and controls underwent genotyping for four TNF-α polymorphisms: 238G/A, 308 G/A,857 C/T, and 863 C/A. Inclusion and exclusion criteria were met in 155 patients (1–68 y). Polymorphisms in the TNF promoter were found in 16.6% (238G/A), 14.5% (308 G/A), 36.6% (857 C/T) and 30.7% (863G/A). No significant association was found for any of the individual polymorphisms with presence or absence of granulomas. In conclusion, we did not find an association between individual polymorphisms in the TNF-α promoter and presence of granulomas in CD. The reason for heterogeneity in granuloma formation in patients with CD remains elusive.

Granulomas may be found in 30–70% of patients with Crohn's disease (CD). The etiology of granuloma formation in CD is presently unknown. Elevated levels of TNF-a are found within granuloma tissue, and are required to maintain granuloma formation in animal models. TNF-a production has been shown to influenced by TNF-a promoter polymorphisms. We hypothesized that heterogeneity for granulomas in CD might be influenced by the TNF-a promoter genotype. Patients with confirmed CD that had undergone full colonoscopy with multiple biopsies and/or surgical resection, served as the study group. One hundred healthy individuals served as a control population for genotyping. Patients and controls underwent genotyping for four TNF-a polymorphisms: 238G/A, 308 G/A,857 C/T, and 863 C/A. Inclusion and exclusion criteria were met in 155 patients (1–68 y). Polymorphisms in the TNF promoter were found in 16.6% (238G/A), 14.5% (308 G/A), 36.6% (857 C/T) and 30.7% (863G/A). No significant association was found for any of the individual polymorphisms with presence or absence of granulomas. In conclusion, we did not find an association between individual polymorphisms in the TNF-a promoter and presence of granulomas in CD. The reason for heterogeneity in granuloma formation in patients with CD remains elusive.

The varicella Oka/Merck vaccine has been shown to be very effective in clinical practice; however, several recent studies reported reduced effectiveness. The varicella Oka/GSK vaccine (Varilrix; GlaxoSmithKline Biologicals), which has been subjected to fewer effectiveness studies, was licensed in Israel for voluntary use in 2000. This study was planned to estimate the effectiveness of the varicella Oka/GSK vaccine among children 1–5 years of age.

The increased consumption of foods containing sesame seeds is paralleled by an increase in reported sesame-induced allergic reactions.

We generated purine nucleoside phosphorylase (PNP)-deficient mice to gain insight into the mechanism of immune deficiency disease associated with PNP deficiency in humans. Similar to the human disease, PNP deficiency in mice causes an immunodeficiency that affects T lymphocytes more severely than B lymphocytes. PNP knockout mice exhibit impaired thymocyte differentiation, reduced mitogenic and allogeneic responses, and decreased numbers of maturing thymocytes and peripheral T cells. T lymphocytes of PNP-deficient mice exhibit increased apoptosis in vivo and higher sensitivity to gamma irradiation in vitro. We propose that the immune deficiency in PNP deficiency is a result of inhibition of mitochondrial DNA repair due to the accumulation of dGTP in the mitochondria. The end result is increased sensitivity of T cells to spontaneous mitochondrial DNA damage, leading to T cell depletion by apoptosis.

Implementation of newborn screening (NBS) programs for severe combined immunodeficiency (SCID) have advanced the diagnosis and management of affected infants and undoubtedly improved their outcomes. Reporting long-term follow-up of such programs is of great importance.

Members of the Jak family play a critical role in signal transduction mediated by cytokine and hormone receptors. In this study, we report the cloning and characterization of human Jak2. The predicted amino acid sequence shows 91% homology to the described murine Jak2, but with a significant difference in the extreme C-terminal sequence. Using the human cDNA as a probe, we localized the gene for human Jak2 to chromosome 9p23-24. Human Jak2 mRNA is highly expressed in the spleen, lymph nodes, and peripheral blood lymphocytes (PBLs). A polyclonal antibody raised against the unique C-terminus of human Jak2 was used to characterize Jak2 protein. Levels of Jak2 protein expression increased significantly in mitogen- and anti-IgM–stimulated B cells and to a lesser degree in activated T cells. In addition, high levels of Jak2 protein were detected in pre-B leukemia cells.

Chronic mucocutaneous candidiasis is a heterogenous group of disorders, associated with a variety of autoimmune disorders and a broad spectrum of immune aberrations. We describe 2 patients with chronic mucocutaneous candidiasis who had cerebrovascular disease with severe neurologic sequelae. Results of angiography of cerebral vessels and brain biopsy in one were consistent with the diagnosis of cerebral vasculitis. (J Pediatr 1998;133:571-4)

The effects of phosphoramidon, a metalloproteinase inhibitor, on the pressor and renal actions of big-endotheiin (BET), the precursor of porcine Endothelin-1 (ET), was studied in rats. In control rats, BET (0.3, 1.0, and 3.0 nmol/kg) elicited a marked increase in mean arterial blood pressure (from 110 ± 7 to 105 ± 7, 120 ± 8, 147 ± 6 mm Hg, respectively), and a prominent, dose-dependent, diuretic and natriuretic response (fractional sodium excretion (FENa) increased from 0.4 ± 0.2 to 0.8 ± 0.2, 3.1 ± 0.1, and 8.5 ± 1.7%, respectively). Pretreatment with phosphoramidon (10 mg/kg + 0.25 mg/kg/min) completely abolished the increase in blood pressure induced by BET, but the diuretic-natriuretic effects were only partially inhibited (FENa increased from 2.0 ± 0.9 to 3.7 ± 1.5, 3.9 ± 1.3, and 4.3 ± 1.2%, respectively, P< 0.05). Rats treated with phosphoramidon only had no natriuresis over time (FENa changed from 1.9 ± 0.5 to 2.3 ± 0.3, 1.6 ± 0.4, 1.7 ± 0.6 respectively, P—NS). The data suggest that, unlike the vascular type of the enzyme, the renal endothelin converting enzymeis relatively insensitive to phosphoramidon. Further, diuresis and natriuresis can be induced by BET in the absence of any pressor effect. [P.S.E.B.M. 1994, Vol 205]

Abstract: Objective. To assess the value of high-resolution computed tomography (HRCT) in determining the extent and significance of lung disease in children with antibody deficiency states. Materials and methods. Seventy HRCT scans performed on 37 children with various antibody deficiency disorders over a 5-year period were retrospectively scored using a previously described demerit scoring system (0–25 with 0 = worst, 25 = best). Points are subtracted from 25 with increasing severity of disease. The potential correlations between CT scores and clinical factors, including age at diagnosis, age at CT, type of immunoglobulin deficiency, length of respiratory symptoms before diagnosis, number of pneumonias before diagnosis, type, length and success of therapy, patient compliance and pulmonary function tests (PFTs), were assessed. Results. Of the 37 children, a demonstrated 22 abnormal scans (CT score ≤ 22). All nine demonstrated bronchiectasis with a lower lobe and right middle lobe predominance. Statistically significant correlations were seen between severity of lung disease (CT score) and length of respiratory symptoms before diagnosis (p = 0.01), success of therapy (P = 0.001) and PFTs (P = 0.0008). Of seven children who were followed with repeated scans, 4 of the 7 demonstrated CT scores which improved on high-dose intravenous immunoglobulin replacement therapy. Conclusion. HRCT is a useful adjunct to demonstrate the extent and severity of lung disease at diagnosis and during therapy. Correlation with clinical factors suggests a higher risk group needing more aggressive management.

ABSTRACTFollowing the introduction of the 7- and 13-valent pneumococcal conjugate vaccines, we observed an inverse relationship between the increasing rate of immunized children and the proportion of middle ear fluid cultures collected during acute mastoiditis episodes that tested positive for Streptococcus pneumoniaeamong a subset of children 0 to 6 years old who had initially presented with severe acute otitis media and had bacterial cultures collected during tympanocentesis or from spontaneous otorrhea.

A 10-year prospective cohort study followed the evolution of antibodies in children less than 4 years of age with hypogammaglobulinemia. Three patterns were identified: in group 1, immunoglobulins and antibody production normalized; in group 2, patients continued to have low IgG levels; and in group 3, IgG levels normalized but antibody levels were transient. Statistical analysis showed that invasive infection or low tetanus antibodies at presentation were associated with the development of significant humoral immunodeficiency. (J Pediatr 1998;133:144-6)

BackgroundThere is limited knowledge regarding long term follow-up of milk allergic patients who tolerate baked milk (BM) products.AimTo evaluate the long-term safety and efficacy of this intervention.patients and methodsChildren with IgE-mediated milk allergy underwent an oral challenge with BM. Those who tolerated BM underwent baked cheese pizza (BC) challenge after 6 months. Six months later, a challenge with unheated milk was offered to patients who tolerated BC.Results85 children (median 5.2 years; range 15 months to 15 years) were prospectively followed for a median of 29 months (range 15–50 months). Fifteen (18%) reacted to the initial BM challenge. Reactions were mild in most cases an only 3 had anaphylaxis. Among 70 (82%) children who initially tolerated BM challenge, 26 (37%) tolerated unheated milk at last follow up, 16 (23%) tolerated BM/BC and 25 (36%) avoided all forms of milk despite successful initial BM/BC challenges. Another 3 patients (4%) were lost to follow-up. Predictive parameters of reactivity to initial BM challenge include age (median – 7; range 2.5–15 years vs. 3.5; range 1–14.5 years; p=0.02), mild respiratory symptoms (67% vs. 26%, p<0.01) as part of the reported allergic reaction to milk, asthma (53% vs. 14.3%, p<0.01) and a larger SPT to casein (median 14; range 8–28 mm vs. 6; range 0–18 mm; p<0.01)ConclusionsFor most of our patients, ingestion of BM was found to be safe and well tolerated. However, initial successful challenge with BM/BC does not always guarantee ongoing consumption of these products. Better predictors of response are needed for patient selection and long term outcomes.