Food allergy and infant feeding practices: Are they related?

BACKGROUND: Immunoglobulin (Ig)E-mediated food allergy is a growing health problem affecting up to 10% of children. It is well-established that early introduction to peanuts and eggs from 4 months of age has a preventive effect. In contrast, there is no consensus about the effect of breastfeeding on food allergy development. OBJECTIVE: To evaluate the effect of breastfeeding and cows' milk formula (CMF) feeding on the development of IgE-mediated food allergy. METHODS: Infants in the Cow's Milk Early Exposure Trial were followed for 12 months. The cohort was divided according to parental feeding preferences for the first 2 months of life: group 1: exclusive breastfeeding (EBF); group 2: breastfeeding with at least 1 daily meal of CMF; and group 3: feeding with CMF only. RESULTS: Among a total of 1989 infants, 1071 were on EBF (53.8%), 616 were breastfed with addition of CMF (31%), and 302 were fed with CMF only (15.2%), from birth. By 12 months, 43 infants developed an IgE-mediated food allergy (2.2%); 31 in the EBF group (2.9%), 12 in the breastfeeding and CMF combined group (1.9%), and none in the CMF feeding-only group (P = .002). Family atopic comorbidity did not affect the results. CONCLUSION: In this prospective cohort, breastfed infants developed significantly higher rates of IgE-mediated food allergy during the first year of life. Perhaps the mechanism is related to compounds ingested by the mother and secreted in the breastmilk. Future larger cohorts should validate these results and offer the lactating mother recommendations. TRIAL REGISTRATION: The COMEET study and its derivatives were approved by the Ethics Committee of Meir Medical Center, IRB number 011-16-MMC. It was registered at the National Institutes of Health Clinical Trials Registry: NCT02785679.

Chronic Urticaria in Elderly-New Insights.

BACKGROUND: Many medical conditions have a unique profile in older adults. Chronic urticaria (CU) is a common disease, but data regarding elderly patients are limited. OBJECTIVE: To describe the demographics, clinical characteristics, comorbidities, and outcome of elder patients with CU. METHODS: This retrospective, single-center study included patients older than 65 years, diagnosed with CU in our clinic. Data for the entire cohort were retrieved from electronic medical records. RESULTS: Of 1859 patients older than 65 years, 181 patients diagnosed with CU were included: 166 had chronic spontaneous urticaria (CSU) and 15 chronic inducible urticaria. Most patients with CSU were female (119, 72%). The mean age at diagnosis was 72 ± 5.9 years. Comorbidities included autoimmunity in 38 (22.9%), malignancy in 23 (13.8%), and atopy in 19 (11.5%). The time to referral to a specialist was 22.8 ± 53 months from the onset of symptoms. Specialist intervention improved patient outcomes. This was evident by reduced systemic steroid use (odds ratio [OR] = 0.145, [95% confidence interval (CI): 0.08-0.26], P < .001), all-cause hospitalization (OR = 0.09, [95% CI: 0.01-0.75], P = .01), emergency department visits (OR = 0.08, [95% CI: 0.08-0.35], P < .001), and primary physician visits (P < .001, Cramer's V = 0.528). CONCLUSIONS: Older people with CU have unique characteristics, including high prevalence of autoimmunity and malignancy and lower prevalence of atopy. Raising awareness of CU in elderly and prompt referral to an allergy specialist may improve outcomes.

Cow's milk allergy skin tests: fresh milk, commercial extracts, or both?

BACKGROUND: The diagnosis of food allergy is based on a history of immediate allergic reaction following food ingestion, and skin prick test (SPT) demonstrating sensitization with commercial extracts (CE) or fresh food (FF). For most food allergens, the SPT with FF is considered more accurate and predictive. Regarding cow's milk, the results are inconclusive. This retrospective study aimed to evaluate the accuracy of SPT with fresh milk compared to CE (cow's milk and casein) for evaluation of cow's milk allergy (CMA). METHODS: This study summarized the medical records of children, diagnosed with CMA. The data include demographics, skin tests and oral food challenge results, as well as atopic comorbidities. RESULTS: Records of 698 patients with the diagnosis of CMA were reviewed, 388 fulfilled the inclusion criteria. Overall, 134 patients (34.54%) had an additional atopic disease. The SPT wheal size with fresh milk was significantly larger than with CE (cow's milk and casein) at first evaluation or before oral food challenge (OFC). Combination of SPT results (CE and FF) gave the maximal odds ratio for reaction during OFC and SPT with fresh milk alone gave the minimal OR (34.18 and 4.74, respectively). CONCLUSIONS: SPT with CE for CMA evaluation is more reliable than SPT performed with fresh milk. In patients suspected of having IgE-mediated CMA, before deciding on performing OFC, it is advised to perform SPT with at least two different extracts, and always include casein. Fresh milk can serve as a backup if commercial extracts are not available. In cases that the SPT with fresh milk is 3 mm or less, there is 93.3% chance that the OFC will pass without reaction. Trial registration This study protocol was reviewed and approved by the Ethics Committee of Meir Medical Center, IRB Number 0083-18 MMC.

Early, continuing exposure to cow's milk formula and cow's milk allergy: The COMEET study, a single center, prospective interventional study.

BACKGROUND: Cow's milk allergy (CMA) is a common food allergy among infants. Information regarding the best timing for first exposure to cow's milk formula (CMF) is controversial and more evidence is required. Few randomized control trials have tried to accurately assess the timing and preventive effect of exposure to CMF on small cohorts. OBJECTIVE: This study assessed the association between early, continuing exposure to CMF on the basis of the parents' preferences and the development of immunoglobulin E (IgE)-mediated CMA in a large birth cohort. METHODS: Newborns were prospectively recruited shortly before birth and divided into 2 groups according to parental feeding preference for the first 2 months of life: (1) exclusive breastfeeding (EBF); or (2) at least 1 meal of CMF (with or without breastfeeding) daily. Infants were followed up monthly until the age of 12 months. RESULTS: Among 1992 infants participating in the study, 1073 (53.86%) were in the EBF group until 2 months of age. IgE-mediated CMA was confirmed in 0.85% (n = 17); all were in the EBF group. Within this group, the prevalence of IgE-mediated CMA was 1.58% compared with 0 in the other groups (relative risk, 29.98; P < .001). Post hoc analysis revealed IgE-mediated CMA prevalence of 0.7% in the per-protocol EBF group vs 3.27% among breastfed infants who were exposed to a small amount of CMF during the first 2 months of life. A family atopic background did not affect the results. CONCLUSION: Early, continuing exposure to CMF from birth has the potential to prevent the development of IgE-mediated CMA and should be encouraged. However, the exposure needs to be consistent because occasional exposure increases the risk of developing IgE-mediated CMA and should be avoided.

The effect of asthma specialist intervention on asthma control among adults.

Background: Various ways to improve asthma control have been studied, with only a modest effect. Purpose: To evaluate the effect of asthma specialist visit on asthma control among adult asthma patients. Patients and methods: This matched cohort study included patients ages 21-50 with asthma and at least 1 visit to an asthma specialist. Patients were compared to adult asthma patients treated only by primary care physicians. The study outcomes, included use of asthma medication, healthcare visits, and mortality. All outcomes were compared one year before and after specialist visit. Results: 4166 pairs were included in the study. In the study group, a statistically significant decrease in the average number of relievers (1.5 ± 3.2 vs. 1.17 ± 2.9, p < 0.001) and systemic steroids purchased (0.53 ± 1.2 vs. 0.4 ± 1.2, p < 0.001), with an increase in average number of inhaled steroid purchased (1.6 ± 2.5 vs. 2.3 ± 33, p < 0.001) was seen over time. A significant decrease in the average number of PCP visits (9.5 ± 7.2 vs. 8.9 ± 7.3, p < 0.001), emergency department (ED) visits (0.46 ± 1 vs. 0.4 ± 0.9, p = 0.05) and all-cause hospitalization (0.03 ± 0.22 vs. 0.01 ± 1.9, p < 0.001) was seen in the study group but not in controls. Generalized linear modeling demonstrated an overall significant effect of specialist intervention for all parameters (p < 0.01), except ED visits (p = 0.06). During follow-up, eight (0.2%) study group patients vs. 19 (0.5%) controls died (p = 0.03). Conclusion: We found that asthma specialist intervention significantly improved asthma outcomes in adults. Referring adult asthma patients to an asthma specialist should be a goal of asthma management plans. Trial registration: Not relevant.

Changes in peripheral blood eosinophils may predict colorectal cancer - A retrospective study.

Background: Colorectal cancer (CRC) is a leading cause of morbidity and mortality worldwide. Eosinophils are traditionally associated and studied in context of allergic diseases. However, recent data implicate their involvement in mucosal tumors, especially in CRC where they may have an anti-tumorigenic function.Our objective was to evaluate whether trends in peripheral blood eosinophil numbers are associated with future diagnosis of CRC. Methods: This retrospective cohort study included adult patients diagnosed with CRC compared to matched controls. We evaluated the linear change in the absolute number of eosinophils (ANE) in peripheral blood over time, described as a correlation coefficient (r). The timeline started 7 years and ended 3 months before diagnosis of CRC. Results: We included 8334 CRC patient/control pairs. Over the study period, no linear correlation was found between levels of eosinophils and time in either group. In a subset of patients (1350, 8.1%), a positive linear correlation was found between levels of eosinophils and time. CRC was significantly more common in these patients (59% vs. 41%, p < 0.01). In a logistic regression, positive r was found to be an independent predictor for CRC (OR 1.31, 95%CI: 1.22-1.41, p < 0.001) with high specificity (0.93) but low sensitivity (0.1). Conclusion: We found higher risk for CRC in patients with a positive linear increase in peripheral eosinophils over time. This may be an indirect clue that eosinophils play a role in the pathogenesis of CRC. Linear changes in ANE may be used in the future to improve screening measures for CRC. Trial registration: Not relevant.

Hyper IgE Syndrome in an Isolated Population in Israel.

Introduction: Hyper IgE syndromes (HIES) are a group of rare primary immunodeficiency characterized by high levels of serum IgE, cold abscesses, pulmonary infections, and eczema. ZNF341 deficiency was described in 2018 in 11 patients clinically diagnosed previously with HIES. Eight of those patients, all offspring of consanguineous couples, are from three families who live in a Muslim village in Israel which has approximately 15,000 residents. Objective: Our study aimed to evaluate the prevalence of ZNF341 mutation in the population of the village. Methods: Three hundred DNA samples of females were included in the study. The samples belong to females that were referred to the Meir Medical Center for prenatal genetic testing before pregnancy, during 2017-2019: 200 samples were from the village, and 100 samples of Muslim females were from other villages.All samples were tested by Sanger sequencing for the ZNF341 mutation (c.904C>T, NM_001282933.1). Results: Heterozygous nonsense mutation in ZNF341 was found in ten samples (5%) of the study group compared to zero in the control group (p<0.01). Conclusion: The carrier frequency of the mutation in ZNF341 in the studied village population is 1:20. This high frequency is probably due to founder mutation and consanguineous marriages.

Clinical history in suspected cases of immediate allergy to beta-lactam.

BACKGROUND: Mislabeling patients as allergic to beta lactams poses an increased risk of morbidity, healthcare costs, and even mortality. This study aimed to define the accuracy of medical history, taken by a specialist, in diagnosing immediate reaction to beta lactams. METHODS: All patients labeled as allergic to beta lactam were interviewed by a specialist in allergy and clinical immunology and defined as suspected of having a history of immediate or non-immediate reaction. When indicated, skin tests to major and minor determinants and oral graded challenge to the culprit drug were performed. RESULTS: A total of 909 patients were evaluated. A total of 798 (87.7%) were labeled as allergic to penicillin. In 108 (11.9%) cases, the allergist suspected an immediate reaction based on clinical history. Skin test or challenge proven diagnosis of IgE-mediated allergy to beta lactam were significantly more prevalent in the group with an allergist's suspicion of an immediate allergy (23.1% vs. 5%, p < 0.01). The sensitivity and negative predictive values of an anamnesis of immediate reaction were high (0.9 and 0.95, respectively), but the specificity and positive predictive value were low (0.37 and 0.23, respectively). CONCLUSION: Medical history taken by an allergist can exclude immediate hypersensitivity reaction, but it is not specific enough to confirm the diagnosis. Skin testing and graded challenge in suspected cases of immediate hypersensitivity reaction are indicated.

Chronic urticaria in children - New insights from a large cohort.

BACKGROUND: Chronic spontaneous urticaria is well-described in adults, but less so in children. The aim of this study is to describe the demographics, clinical characteristics, comorbidities, and outcomes of children with chronic, spontaneous urticaria. METHODS: This retrospective study followed children up to 18 years old, diagnosed with chronic spontaneous urticaria, between the years 2002-2018, and treated in a tertiary referral allergy and clinical immunology center. Data including demographics, clinical characteristics, comorbidities, treatments, and outcomes were extracted from electronic medical records. RESULTS: Records of 380 children coded to have chronic urticaria were reviewed, of which 250 (65.8%) fulfilled the diagnostic criteria for chronic spontaneous urticaria. There were 136 females (54.4%). Mean age at diagnosis was 11.4 years, and 122 (48%) were adolescents. The average duration of chronic spontaneous urticaria was 12.25 ± 15.2 months. The urticaria in 208 children )83.2%) resolved within 24 months. Eighty-seven patients (34.8%) had at least one atopic disease. Atopic comorbidities included atopic dermatitis in 17.2%, allergic rhinitis in 16%, asthma in 13.2%, and food allergy in 3.2%. Eighteen patients (7.2%) had a concomitant autoimmune disease. Nine (3.6%) had thyroid disease. CONCLUSIONS AND CLINICAL RELEVANCE: Chronic spontaneous urticaria in children is a self-limited disease with favorable prognosis. Atopic diseases are more prevalent in children with chronic spontaneous urticaria than in the general pediatric population, increasing the possibility of a special subgroup of TH2-related chronic urticaria in children.

Exclusive Bee Venom Allergy: Risk Factors and Outcome of Immunotherapy.

INTRODUCTION: Venom immunotherapy (VIT) is considered to be the gold-standard treatment for patients with Hymenoptera venom allergy. Data regarding VIT in bee venom (BV) allergic patients are scarce. AIM: The aim of this study was to evaluate the outcome of VIT in patients with exclusive BV allergy and to try to define risk factors for VIT-induced systemic reactions (VIT-ISR) and VIT failure. METHODS: This is a retrospective study including data from all BV allergic patients that were treated by VIT in the Allergy Unit at the Meir Medical Center in the years 1995-2018. RESULTS: Two hundred and forty-seven patients with exclusive BV allergy were included; 206 (83.4%) preferred to undergo rush buildup. Sixty-nine patients (27.9%) had at least 1 reaction during buildup, with the c-kit mutation being the only significant risk factor (100 vs. 28.9%, p = 0.02). Female gender (25.4 vs. 13.3%, p = 0.04), conventional buildup schedule (26.8 vs. 14.1%, p = 0.04), and c-kit mutation (100 vs. 16.8%, p < 0.01) but not tryptase level were found to be significantly more frequent in recurrent reactors. Females (20.3 vs. 9%, p = 0.03), patients with severe systemic reaction to the index sting (24.3 vs. 9.5%, p = 0.004), and c-kit mutation (66 vs. 12%, p = 0.05) but not tryptase level were found to be risk factors for severe systemic reactions. CONCLUSION: Despite the considerably high rate of VIT-ISR in patients with exclusive BV allergy, VIT can be performed safely and efficiently. C-kit mutation, and not basal serum tryptase level, seems to be a preferable biomarker for VIT-ISR in these patients.

Characterization of chronic urticaria and associated conditions in a large population of adolescents.

BACKGROUND: Although chronic spontaneous urticaria (CSU) affects all age groups, data regarding CSU in adolescents is scarce. OBJECTIVE: To characterize the epidemiology, demographics, and comorbidities associated with CSU in a large, cross-sectional nationwide population of adolescents. METHODS: Medical records of 16-year-old candidate conscripts to the Israeli Defense Forces were reviewed. Data were collected on the prevalence and severity of CSU, as well as the demographics, medical comorbidities, medication use, and blood test results of affected individuals. RESULTS: Medical records of 1,108,833 consecutive 16-year-old adolescents were reviewed. A total of 6617 (0.6%) adolescents received CSU diagnoses. CSU was increased in female conscripts (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.07-1.19, P < .001) and adolescents with higher socioeconomic scores (OR 1.92, 95% CI 1.56-2.32, P < .001). Individuals with CSU were significantly more likely to have allergic diseases, including food allergy (OR 7.31, 95% CI 6.13-8.72), allergic rhinitis (OR 2.9, 95% CI 2.71-3.11), atopic dermatitis (OR 2.35, 95% CI 2.03-2.72), and asthma (OR 1.46, CI 1.35-1.57). CONCLUSION: Our work provides an account of CSU in a large cohort of adolescents. We found a strong link between CSU and atopic diseases. Further investigation is needed to decipher the mechanism underlying this observed association.

Long-Term Follow-Up After Penicillin Allergy Delabeling in Ambulatory Patients.

BACKGROUND: Unverified penicillin allergy label has negative health implications. To address this, several delabeling methods have been proposed. OBJECTIVES: To appraise the long-term outcomes of the penicillin allergy evaluation in ambulatory patients, focusing on subsequent use of penicillins in individuals found not allergic. A secondary objective was to examine the consistency between the evaluation's recommendations and the allergy label. METHODS: A retrospective medical records review and phone survey were carried out in ambulatory patients who were evaluated for suspected penicillin allergy in our allergy unit. Patients with an uneventful oral challenge test (OCT) were interviewed regarding subsequent use of penicillins. Medical records were examined for antibiotic prescriptions and purchases. The records were also investigated for existing/erased penicillin allergy label and its consistency with the allergy evaluation. RESULTS: Six hundred thirty-nine patients with an uneventful OCT were available for the survey. During a 56-month follow-up, 70% (447 patients) had used penicillins at least once. One hundred ninety-two patients (30%) did not use penicillins. The main reason for not using penicillins was lack of a clinical indication. Three hundred thirty-five patients (51.22%) carried a penicillin allergy label in their electronic medical file in spite of an uneventful OCT. CONCLUSIONS: Penicillin allergy annulling via OCT has proven to be effective. Most of the patients who previously avoided penicillins have reused penicillins safely.

ZNF341 controls STAT3 expression and thereby immunocompetence.

Signal transducer and activator of transcription 3 (STAT3) is a central regulator of immune homeostasis. STAT3 levels are strictly controlled, and STAT3 impairment contributes to several diseases including the monogenic autosomal-dominant hyper-immunoglobulin E (IgE) syndrome (AD-HIES). We investigated patients of four consanguineous families with an autosomal-recessive disorder resembling the phenotype of AD-HIES, with symptoms of immunodeficiency, recurrent infections, skeletal abnormalities, and elevated IgE. Patients presented with reduced STAT3 expression and diminished T helper 17 cell numbers, in absence of STAT3 mutations. We identified two distinct homozygous nonsense mutations in ZNF341, which encodes a zinc finger transcription factor. Wild-type ZNF341 bound to and activated the STAT3 promoter, whereas the mutant variants showed impaired transcriptional activation, partly due to nuclear translocation failure. In summary, nonsense mutations in ZNF341 account for the STAT3-like phenotype in four autosomal-recessive kindreds. Thus, ZNF341 is a previously unrecognized regulator of immune homeostasis.

Oral Challenge without Skin Testing Safely Excludes Clinically Significant Delayed-Onset Penicillin Hypersensitivity.

BACKGROUND: Penicillins are the drug family most commonly associated with hypersensitivity reactions. Current guidelines recommend negative skin tests (ST) before re-administering penicillins to patients with previous nonimmediate reactions (NIR). OBJECTIVE: The objective of this study was to examine whether ST are necessary before re-administering penicillin to patients with NIR. METHODS: Patients with NIR to penicillins starting longer than 1 hour after last dose administration or starting any time after the first treatment day or patients with vague recollection of their reaction underwent penicillin ST. Disregarding ST results, patients were challenged with the relevant penicillins. One-tenth of the therapeutic dose followed by the full dose was administered at 1-hour interval and patients continued taking the full dose for 5 days. RESULTS: A total of 710 patients with alleged BL allergy were evaluated. Patients with a history of immediate reaction (52, 7.3%) or cephalosporin allergy (16, 2.2%) were excluded. Of the remaining 642 patients, 62.3% had negative ST, 5.3% positive ST, and 32.4% equivocal ST. A total of 617 (96.1%) patients were challenged. Immediate reaction was observed in 9 patients (1.5%): 1-positive ST, 7-negative ST, and 1-equivocal ST (P = .7). Late reaction to the first-day challenge occurred in 24 patients (4%). An at-home challenge was continued by 491 patients. Complete 5-day and partial challenges were well tolerated by 417 (85%) and 44 patients (8.9%), respectively, disregarding ST results. Thirty patients (6.1%) developed mild reactions to the home challenge regardless of their ST results. CONCLUSION: A 5-day oral challenge without preceding ST is safe and sufficient to exclude penicillin allergy after NIR developing during penicillin treatment.