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Arterial hypertension is associated with increased plasma levels of complement C3, C4, and C-reactive protein (CRP). The aim of the study was to compare these laboratory markers in patients with resistant arterial hypertension (RAH) and controlled arterial hypertension (CAH). Patients with RAH (n = 34), those with CAH (n = 34), and 26 normotensive controls were included. White blood cell count, erythrocyte sedimentation rates, and blood levels of complement components C3, C4, and high-sensitivity C-reactive protein (hs-CRP) were compared among the study groups. In the RAH group, serum C3 (183.9+/-47.5 mg/dL) and hs-CRP (6.9+/-5.8 mg/L) were higher than in the CAH group (C3, 123.1+/-42.3 mg/dL; P < .001, hs-CRP, 4.2+/-4.8; P = .021, respectively). Significant positive correlations between systolic blood pressure and C3 (r = 0.6481; P < .001) and hs-CRP (r = 0.3968; P = .02) were observed in the RAH group. RAH is associated with higher blood levels of C3 and CRP. [ABSTRACT FROM AUTHOR]

Although extensively studied in adults, nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity in children, especially in young children, remains poorly defined. Pediatricians, prescribing antipyretics for children, rarely encounter significant problems, but the few epidemiologic studies performed show conflicting results. Although it is clear that some patients with acetylsalicylic acid (ASA)-sensitive asthma have their clinical onset of disease in childhood and bronchoconstriction after ASA challenge is seen in 0 to 22% of asthmatic children so challenged, ibuprofen at antipyretic doses may cause acute respiratory problems only in a very small number of mild to moderate asthmatics. The recently elucidated mechanism of action of acetaminophen may explain some occurrences of adverse reactions in patients with cross-reactive NSAID hypersensitivity on the basis of its inhibitory activity on the newly described enzyme, cyclooxygenase (COX)-3. This nonspecific sensitivity to inhibition of COX is most likely genetically determined and shows a remarkable association with atopic disease even in the very young age group and possibly an increased predilection in specific ethnic groups. This review summarizes state-of-the-art published data on NSAID hypersensitivity in preschool children.

Abstract Background Symptomatic hypogammaglobulinemia in infancy and childhood (SHIC), may be an early manifestation of a primary immunodeficiency or a maturational delay in the normal production of immunoglobulins (Ig). We aimed to evaluate the natural course of SHIC and correlate in vitro lymphoproliferative and secretory responses with recovery of immunoglobulin values and clinical resolution. Methods Children, older than 1 year of age, referred to our specialist clinic because of recurrent infections and serum immunoglobulin (Ig) levels 2 SD below the mean for age, were followed for a period of 8 years. Patient with any known familial, clinical or laboratory evidence of cellular immunodeficiency or other immunodeficiency syndromes were excluded from this cohort. Evaluation at 6- to 12-months intervals continued up to 1 year after resolution of symptoms. In a subgroup of patients, in vitro lymphocyte proliferation and Ig secretion in response to mitogens was performed. Results 32 children, 24 (75%) males, 8 (25%) females, mean age 3.4 years fulfilled the inclusion criteria. Clinical presentation: ENT infections 69%, respiratory 81%, diarrhea 12.5%. During follow-up, 17 (53%) normalized serum Ig levels and were diagnosed as transient hypogammaglobulinemia of infancy (THGI). THGI patients did not differ clinically or demographically from non-transient patients, both having a benign clinical outcome. In vitro Ig secretory responses, were lower in hypogammaglobulinemic, compared to normal children and did not normalize concomitantly with serum Ig's in THGI patients. Conclusions The majority of children with SHIC in the first decade of life have THGI. Resolution of symptoms as well as normalization of Ig values may be delayed, but overall the clinical outcome is good and the clinical course benign.

Background: Chronic Spontaneous Urticaria (CSU) is an immune-mediated skin disease that may require prolonged treatments. Currently, there are no recommendations for treatment discontinuation once CSU symptoms are controlled, particularly among patients primarily diagnosed with severe CSU., Objective: In this real-life study we aimed to describe our experience of omalizumab (Oma) treatment withdrawal in CSU and define biomarkers related to these outcomes., Methods: CSU patients followed at our allergy clinic from January 2016 to December 2022 were included. Response to Oma therapy, and Oma-withdrawal outcomes among patients who reached complete remission for >6 months were analyzed., Results: During the study period 192/335(%) CSU patients were categorized as severe-CSU and entitled to receive Oma according to our country's regulations. Of them, 131/192(68%) were considered "Oma-responders", and 95/131(72.5%) patients underwent gradual treatment withdrawal. Successful Oma-withdrawal was documented in 47/95(49.5%) whereas 48/95(50.5%) patients experienced flare and were defined as unsuccessful OMA-withdrawal. The first was associated with shorter disease duration 7.1 ± 7.4 years vs. 10.7 ± 9.4 (P = 0.042), lower baseline-IgE 81.6 ± 84.1IU/ml vs. 324.7 ± 555.9 (P = 0.005), and lower baseline-eosinophils count 131.4 ± 110.5 vs. 195.6 ± 98.4 (P = 0.043) in comparison to failure of Oma-withdrawal group., Conclusion: OMA may be successfully withdrawn in up to 50% of severe CSU patients following complete remission of disease symptoms, utilizing a gradual withdrawal protocol. Oma-withdrawal failure was linked with longer duration of disease as well as high IgE and eosinophil counts prior to initiation of Oma therapy. These parameters may enable the design of a treatment withdrawal algorithm., Competing Interests: None., (© 2024 The Authors.)

Objectives: APS-associated heart valve disease (HVD) is well described. Nonetheless, limited data exist on clinical parameters associated with the course of primary APS (pAPS) patients with HVD. The goal of this study was to assess clinical features and related outcomes in patients with APS-associated HVD., Methods: In this multicentre retrospective study, we identified 33 pAPS patients with HVD (pAPS-HVD group) and compared their clinical course with 128 pAPS patients with normal heart valves on echocardiography (pAPS-control group)., Results: pAPS-HVD patients had more cerebrovascular events (56.3% vs 25%, P = 0.005) and livedo reticularis (24.2% vs 7.8%, P = 0.013) than pAPS-controls. Furthermore, catastrophic-APS (CAPS) (12.1% vs 2.4%, P = 0.034), recurrent thrombosis (33.3% vs 4.7%, P < 0.001) and need for advanced therapy (i.e. IVIG, plasmapheresis or rituximab) were more frequent in pAPS-HVD patients. Anti-β2-glycoprotein 1 IgG (84.8% vs 63.2%, P = 0.034), anti-cardiolipin IgG (90.9% vs 64.8%, P = 0.005) and triple positive aPL (75.8% vs 56.5%, P = 0.047) were commoner in pAPS-HVD patients vs pAPS-controls. Ten of the 33 patients with pAPS-HVD underwent valve surgery, which was associated with male gender, smoking, arterial limb ischaemia and livedo reticularis., Conclusion: pAPS-HVD patients had a more severe APS clinical course including CAPS and thrombotic events as well as a specific serology, namely IgG isotype aPL antibodies and triple positivity. Our data suggest that pAPS-HVD represents a high-risk subgroup of APS patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Allergic reactions to the coronavirus disease 2019 (COVID-19) vaccines have raised concerns, particularly as repeated doses are required. Skin tests with the vaccines excipient were found to be of low value, whereas the utility of skin tests with the whole vaccine is yet to be determined., Objective: To evaluate a panel of skin tests and the outcomes of subsequent doses of immunization among subjects who suffered an immediate allergic reaction to the BioNTech (BNT162b2) COVID-19 vaccine., Methods: Between March and December 2021, patients who experienced symptoms consistent with immediate allergic reactions to the BNT162b2 vaccine and were referred to the Sheba Medical Center underwent skin testing with polyethylene glyol (PEG)-containing medicines, Pfizer-BNT162b2, and Oxford-AstraZeneca vaccine (AZD1222). Further immunization was performed accordingly and under medical observation., Results: A total of 51 patients underwent skin testing for suspected allergy to the COVID vaccines, of which 38 of 51 (74.5%) were nonreactive, 7 of 51(13.7%) had no skin sensitization but suffered a clinical reaction during skin testing (mainly cough), and 6 of 51 (11.7%) exhibited immediate skin sensitization. Both skin sensitization and cough during testing were related to a higher use of adrenaline following immunization (P = .08 and P = .024, respectively). Further immunization with the BNT162b2 vaccine was recommended unless sensitization or severe reaction to previous immunization was evident. The latter were referred to be tested/receive the alternative AZD1222 vaccine. Ten patients underwent skin testing with AZD1222: 2 of 10 (20%) demonstrated skin sensitization to both vaccines; thus, 8 of 10 were immunized with the AZD1222, of which 2 of 8 (25%) had allergic reactions., Conclusions: Immediate allergic reactions to COVID-19 vaccines are rare but can be severe and reoccur. Intradermal testing with the whole vaccine may discriminate sensitized subjects, detect cross-sensitization between vaccines, and enable estimation of patients at higher risk., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Introduction: The little fire ant (LFA) is an invasive ant species, increasingly found in wide distribution in Israel. Although it's sting is painful and itchy, for the most part, no serious adverse effects have been reported so far. We describe the case of a young boy with recurrent, life threatening anaphylactic reactions after stings, all occurring during the summer months, in areas where LFA infestations have been identified. An ad hoc skin test, developed with the cooperation of the allergy and entomology team, identified an immediate IgE-mediated reaction to LFA whole body extract, present in our patients and absent in healthy controls. This report may be the first identifying the LFA as a potential cause of severe anaphylactic reactions, but unfortunately, given the wide spread of these pests, it may be that such unrecognized reactions have already been treated by medical teams and misclassified as idiopathic anaphylaxis.

Beta-lactam (BL) allergy suspicion is common in children and constitutes a major public health problem, with an impact on patient's health and on medical costs. However, it has been found that most of these reactions are not confirmed by a complete allergic workup. The diagnostic value of the currently available allergy tests has been investigated intensively recently by different groups throughout the world. This has led to major changes in the management of children with a suspected BL allergy. Particularly, it is now well accepted that skin tests can be skipped before the drug provocation test in children with a benign non-immediate reaction to BL. However, there is still a debate on the optimal allergic workup to perform in children with a benign immediate reaction. In addition, management of children with severe cutaneous adverse drug reactions remains difficult. In this review, based on a selection of the most relevant studies found in the literature, we will review and discuss the diagnosis of different forms of BL allergy in children., (© 2021 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Importance: Allergic reactions among some individuals who received the Pfizer-BioNTech (BNT162b2) COVID-19 vaccine discourage patients with allergic conditions from receiving this vaccine and physicians from recommending the vaccine., Objective: To describe the assessment and immunization of highly allergic individuals with the BNT162b2 vaccine., Design, Setting, and Participants: In a prospective cohort study from December 27, 2020, to February 22, 2021, 8102 patients with allergies who applied to the COVID 19 vaccine referral center at the Sheba Medical Center underwent risk assessment using an algorithm that included a detailed questionnaire. High-risk patients (n = 429) were considered "highly allergic" and were immunized under medical supervision., Exposures: Pfizer-BioNTech (BNT162b2) COVID-19 vaccine., Main Outcomes and Measures: Allergic and anaphylactic reactions after the first and second doses of BNT162b2 vaccine among highly allergic patients., Results: Of the 429 individuals who applied to the COVID-19 referral center and were defined as highly allergic, 304 (70.9%) were women and the mean (SD) age was 52 (16) years. This highly allergic group was referred to receive immunization under medical supervision. After the first dose of the BNT162b2 vaccine, 420 patients (97.9%) had no immediate allergic event, 6 (1.4%) developed minor allergic responses, and 3 (0.7%) had anaphylactic reactions. During the study period, 218 highly allergic patients (50.8%) received the second BNT162b2 vaccine dose, of which 214 (98.2%) had no allergic reactions and 4 patients (1.8%) had minor allergic reactions. Other immediate and late reactions were comparable with those seen in the general population, except for delayed itch and skin eruption, which were more common among allergic patients., Conclusions and Relevance: The rate of allergic reactions to BNT162b2 vaccine, is higher among patients with allergies, particularly among a subgroup with a history of high-risk allergies. This study suggests that most patients with a history of allergic diseases and, particularly, highly allergic patients can be safely immunized by using an algorithm that can be implemented in different medical facilities and includes a referral center, a risk assessment questionnaire, and a setting for immunization under medical supervision of highly allergic patients. Further studies are required to define more specific risk factors for allergic reactions to the BNT162b2 vaccine.

Primary immunodeficiency disorders (PID) are a group of heterogeneous disorders characterized by recurrent infections, autoimmunity, increased lymphoproliferative disorders and other malignancies. PID is classified into cellular or humoral disorders or a combination of both. We evaluated the clinical differences among adult patients with three variants of PID: common variable immunodeficiency (CVID), idiopathic CD4 lymphopenia (ICL) and combined immunodeficiency (CID). We retrospectively compared demographics, immunological characteristics, clinical presentations and outcomes of CVID, CID and ICL patients followed from 2012 to 2018. In our cohort, we identified 44 adult patients diagnosed with CVID (22), CID (11) and ICL (11). Malignancy was associated with CID, as seven of 11 patients in this group were diagnosed with malignancy compared to CVID (three of 22) or ICL (two of 11) (P = 0·002 and 0·03, respectively). Malignancies were also linked to male gender [odds ratio (OR) = 5, 95% confidence interval (CI) = 1·12-22·18) P = 0·0342] and a low ratio of CD4/CD8 < 0·8 (OR = 5·1, 95% CI = 1·22-21·28, P = 0·025). Among CID and ICL, two of 11 patients died in each group, while no death was documented among CVID group (P = 0·04). Autoimmune manifestations did not differ between groups. Similarly, the rate of infections was similar between groups, although infectious agents vary. CID is associated with a high risk of malignancy compare to CVID or ICL. Among adults with PID, male gender, low CD4 and a CD4/CD8 ratio of < 0·8 may serve as risk factors of concomitant malignancy. Surveillance of lymphocyte subpopulations should be considered for all adults., (© 2021 British Society for Immunology.)

Background: Chronic Spontaneous Urticaria (CSU) is a relatively common immune mediated disease that can be effectively treated nowadays. Nevertheless, for some patients remission cannot be achieved following current treatment recommendations, defined as resistant CSU (r-CSU). Treating r-CSU is challenging, and, currently, there are no recommended interventions. In this real-life study we describe successful therapy of 18 r-CSU patients using an "intensified protocol" of anti-IgE-antibody (omalizumab) concomitantly with an immunosuppressant. We defined the r-CSU phenotype and compared it to omalizumab-responsive CSU (Or-CSU) phenotype., Methods: Clinical and serological data of 72 CSU patients (ie, 18 r-CSU and 54 age and sex matched Or-CSU) were retrospectively collected and analyzed. All patients were diagnosed with CSU for ≥6 months and treated at the Sheba Medical Center during 2013-2018., Results: Of 289 CSU patients, 18 (6%) were diagnosed with r-CSU and treated with the "intensified protocol" including omalizumab and cyclosporine-A (16p), methotrexate (1p), and azathioprine (1p). Of which, 14/18 (78%) achieved complete remission, 2/18 (11%) partial remission, and 2/18 (11%) no remission. During follow-up no serious adverse events were documented. r-CSU patients received higher doses of antihistamine (p < 0.0001) and omalizumab (425 ± 58 mg/month vs. 283 ± 86 mg/month; p < 0.0001) compared to Or-CSU. The r-CSU phenotype was linked with concomitant autoimmunity (p = 0.0005) and a lower level of IgE prior to initiation of therapy (p = 0.027)., Conclusion: r-CSU may be a distinct CSU phenotype characterized by severe disease, concomitant autoimmunity, and lower baseline-IgE levels (low "autoallergy"). An "intensified protocol" with omalizumab and an immunosuppressive agent was found to be efficacious and safe for r-CSU. Further larger studies are required to verify these results., Competing Interests: The authors have nothing to declare., (© 2020 The Authors.)

Introduction: Hemophilia is a rare bleeding disorder caused by a deficiency of the plasma coagulation factors VIII and IX (hemophilia A [HA] and hemophilia B [HB], respectively). Replacement therapy with clotting factor concentrates is the mainstay of treatment. Unlike in patients with HB, anaphylaxis in patients with HA is extremely rare., Methods: A retrospective study of prospectively collected data on patients with hemophilia who experienced anaphylaxis was conducted in our center. Demographic and clinical data were collected, and laboratory workups that included thrombin generation were conducted., Results: Our first patient underwent successful immune tolerance induction (ITI) following the administration of rituximab. The second patient was transitioned to emicizumab. The third patient receives recombinant activated VIIa (rFVIIa) on demand. Thrombin generation was performed following current medical management protocols for supporting hemostasis., Discussion: Our case series illustrates the difficulty in managing patients with anaphylaxis to replacement therapy. In the era of novel therapies, such as emicizumab, the management of HA patients who experience anaphylaxis to replacement therapy is becoming easier and may obviate the need for ITI. Current treatment strategies for HB patients with such anaphylaxis, however, are limited to rFVIIa, and it continues to pose a challenge., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Innate immunity is one of two immune defence system arms. It is present at birth and does not require 'learning' through exposure to foreign organisms. It activates various mechanisms collectively to eliminate pathogens and hold an infection until the adaptive response are mounted. The innate immune system consists of four elements: the epithelial barrier, cells (e.g. macrophages, NK cells), plasma proteins (e.g. complement) and cytokines. These components act in concert to induce complex processes, as well as recruitment, activation and differentiation of adaptive responses. The innate response is more than just the 'first line of defence', as it essentially withholds the vast majority of any intruder, has a complex interplay with the adaptive arm and is crucial for survival of the host. Finally, yet importantly, a myriad of diseases has been linked with innate immune dysregulation. In this mini-review we will shed some light on these conditions, particularly regarding autoinflammatory ones., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Drug hypersensitivity reactions (DHR) constitute a major and common public health problem, particularly in children. One of the most severe manifestations of DHR is anaphylaxis, which might be associated with a life-threatening risk. During those past decades, anaphylaxis has received particularly a lot of attention and international consensus guidelines have been recently published. Whilst drug-induced anaphylaxis is more commonly reported in adulthood, less is known about the role of drugs in pediatric anaphylaxis. Betalactam antibiotics and non-steroidal anti-inflammatory drugs are the most commonly involved drugs, probably related to high prescription rates. Diagnosis relies on the recognition of symptoms pattern and is based on complete allergic workup, particularly including skin tests and/or specific IgE. However, the real diagnostic value of those tests to diagnose immediate reactions in children remains not well defined for a significant number of the drugs. Generally, a drug provocation test is discussed to confirm or exclude an immediate-onset drug-induced hypersensitivity. Although avoidance of the incriminated drug (and related drug) is the rule, rapid desensitization is useful in selected subgroups of patients. There is a need for large, multicentric studies, to evaluate the real diagnostic value of the currently available skin tests. Moreover there is also a need to develop new diagnostic tests in the future to improve the management of these children., (© 2019 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: Feeding jejunostomy (FJ) tubes are routinely placed during esophagectomy. However, their effect on immediate postoperative outcomes in this patient population is not clear., Objectives: To evaluate the effect of FJ tube placement during esophagectomy on postoperative morbidity and mortality., Methods: The National Surgical Quality Improvement Program database was used to evaluate the effect of FJ tube placement during esophagectomy on 30-day postoperative morbidity and mortality rates. A propensity score-matched cohort was used to compare postoperative outcomes of patients with and without FJ tubes., Results: An FJ tube was placed in 45% of 2059 patients undergoing esophagectomy. The anastomotic leak rate was 13.5%. Patients with FJ tubes were more likely to have preoperative radiation therapy (59.6% vs 54.9%, p = 0.041), transhiatal esophagectomy (21.5% vs 19.2%, p = 0.012), a malignant diagnosis (93.2% vs 90.4%), and longer operative time (393 min vs 348 min, p < 0.001). In a case-matched cohort, mortality (2% vs 2.4%, p = 0.618) and severe morbidity (38.2% vs 34.6%, p = 0.128) were comparable between patients with and without FJ tubes. FJ tube placement was associated with higher overall morbidity (46% vs 38.6%, p = 0.002), superficial wound infection (6.3% vs 2.9%, p = 0.001), and return to the operating room (16.7% vs 12.5%, p = 0.016). In a subgroup of patients with anastomotic leak, FJ was associated with shorter hospital stay (20.1 days vs 24.3 days, p = 0.046)., Conclusion: These mixed findings support selective rather than routine FJ tube placement during esophagectomy.

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used in the pediatric population as antipyretics/analgesics and anti-inflammatory medications. Hypersensitivity (HS) reactions to NSAID in this age group, while similar to adults, have unique diagnostic and management issues. Although slowly accumulating, published data in this age group are still relatively rare and lacking a unifying consensus. This work is a summary of current knowledge and consensus recommendations utilizing both published data and expert opinion from the European Network of Drug Allergy (ENDA) and the Drug Hypersensitivity interest group in the European Academy of Allergy and Clinical Immunology (EAACI). This position paper summarizes diagnostic and management guidelines for children and adolescents with NSAIDs hypersensitivity., (© 2018 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: Rett syndrome is an X-linked dominant neurodevelopmental disorder manifesting with severe intellectual disability in females caused by various mutations in the MECP2 gene. Brain-derived neurotrophic factor (BDNF) is one of the main proteins regulated by the MECP2 protein; its overexpression in the MeCP2 mouse model partially corrects the Rett phenotype. Pharmacologic manipulations that lead to increased BDNF in individuals with Rett syndrome are expected to have a positive effect on the disorder. Glatiramer acetate, a well-known and safe multiple sclerosis immune modulator, increases BDNF levels in multiple sclerosis animal models and patients responding to treatment, as well as in Rett mouse models., Methods: Fourteen patients with mutation-proven Rett syndrome were recruited for a clinical trial with glatiramer acetate. Baseline data and follow-up data were collected during the trial, which had to be stopped because of a severe adverse event. Our objective is to describe this unexpected potentially life-threatening event in response to glatiramer in patients with Rett syndrome., Results: Four of 14 patients with Rett syndrome who were recruited and treated with daily injections of glatiramer acetate as part of an open-label clinical trial developed an exaggerated immediate postinjection response, which was experienced as life threatening in three of the patients, necessitating arrest of the trial., Conclusion: Despite the known safety profile of glatiramer acetate in adult and pediatric patients with multiple sclerosis, its use in Rett syndrome should be cautiously reconsidered. The described severe adverse event can be related to these patients' primary autonomic nervous system dysfunction., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The term "swelling" has been used in the old scriptures to illustrate a change of normal figure and, as such, an expression of illness. It should be noted that in ancient times, human diseases were very often regarded a punishment from God. Hence, it is not surprising that one of the oldest tests for infidelity involved swelling as an inflicted punishment. The great Greek physician Hippocrates (377-460 BC), considered one of the most outstanding figures in the history of medicine and "Father of the Western Medicine," already used the term oídēma to describe swelling of organs. It took many centuries later until the first description of angioedema as a distinct medical entity was minted by Quinke in 1882. The historical progression in angioedema research has been characterized by intermittent "leaps" in interest and scientific achievements. As an example, it took 75 years from the accurate description of hereditary angioedema (HAE) by Osler (1888), until a group of researchers headed by Donaldson (1963) disclosed the central role of C1 inhibitor in angioedema pathophysiology. What followed was a result of a collective effort by many researchers and scientific groups who were able to elucidate the intricate connections between the implicated biochemical pathways. Still, scientific progress was hardly translated into effective therapy, and another 45 years had to elapse until the renewed interest in HAE was boosted by studies on the efficacy and safety of novel therapies about 10 years ago. In the twenty-first century, HAE ceased to be an "orphan disease" and its future is far more optimistic. It is better managed now by specialized angioedema centers, harmonized clinical guidelines, educational programs, laboratory services, and continued basic and clinical research. Patient associations worldwide are offering support and guidance, and governments and healthcare systems are gradually addressing patient and family needs.

Context: Reports evaluating faculty knowledge of the Accreditation Council for Graduate Medical Education (ACGME) core competencies in community hospitals without a dedicated residency program are uncommon., Objective: Faculty evaluation regarding knowledge of ACGME core competencies before a residency program is started., Design: Physicians at the Kaiser Permanente Fontana Medical Center (N = 480) were surveyed for their knowledge of ACGME core competencies before starting new residency programs., Main Outcome Measures: Knowledge of ACGME core competencies., Results: Fifty percent of physicians responded to the survey, and 172 (71%) of respondents were involved in teaching residents. Of physicians who taught residents and had complete responses (N = 164), 65 (39.7%) were unsure of their knowledge of the core competencies. However, most stated that they provided direct teaching to residents related to the knowledge, skills, and attitudes stated in each of the 6 competencies as follows: medical knowledge (96.3%), patient care (95.7%), professionalism (90.7%), interpersonal and communication skills (86.3%), practice-based learning (85.9%), and system-based practice (79.6%). Physician specialty, years in practice (1-10 vs > 10), and number of rotations taught per year (1-6 vs 7-12) were not associated with knowledge of the competencies (p > 0.05); however, full-time faculty (teaching 10-12 rotations per year) were more likely to provide competency-based teaching., Conclusion: Objective assessment of faculty awareness of ACGME core competencies is essential when starting a residency program. Discrepancy between knowledge of the competencies and acclaimed provision of competency-based teaching emphasizes the need for standardized teaching methods that incorporate the values of these competencies., Competing Interests: Statement The author(s) have no conflicts of interest to disclose.

Background: Children with a diagnosis of cross-reactive hypersensitivity to both paracetamol and nonsteroidal anti-inflammatory drugs are limited in their choice of antipyretics., Objective: The aim of this pilot study is to evaluate the feasibility of using a Chinese proprietary medicine, Yin Qiao San (YQS), for fever relief., Methods: A single centre, open label, prospective clinical trial exploring the tolerability and feasibility of using YQS for fever relief in children who are unable to use conventional antipyretic medications. Children between 1-18 years of age with hypersensitivity to multiple antipyretics were recruited. Eligible participants underwent an oral provocation test with YQS. Children who passed the oral provocation test were instructed to take a prescribed dose of YQS when the temperature was >38.0℃ and continued till the fever settled. Time taken for fever resolution and any adverse events were collected., Results: A total of 21 children, mean age 10.7 years, had a diagnosis of paracetamol and ibuprofen hypersensitivity. All except one patient successfully tolerated an oral challenge of YQS. Of the 88 doses of YQS taken for fever over 38.0℃, 16 (18%) had documented temperature reduction 2 hours after ingestion and 30 (34%) had documented temperature reduction 4 hours after ingestion. There were 2 reports of urticaria after YQS use which were attributed to flare of recurrent spontaneous urticaria during the illness. None of the patients developed symptoms of circulatory compromise or respiratory distress., Conclusion: YQS is generally well tolerated in patients with paracetamol and ibuprofen hypersensitivity.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used throughout the world to treat pain and inflammation; however, they can trigger several types of drug hypersensitivity reactions (DHRs) in all age groups. Although most such reactions occur through activation of the leukotriene pathway without specific immunological recognition (cross-intolerance), a significant number of DHRs to NSAIDs are due to immunological mechanisms (selective reactions [SRs]). SRs are thought to be induced by specific IgE antibodies or by T cells. In this manuscript, we focus on SRs, which are of great concern in children and adolescents and comprise a heterogeneous set of clinical pictures ranging from mild entities such as urticaria/angioedema to potentially life-threatening conditions such as Stevens-Johnson syndrome/toxic epidermal necrolysis. Paracetamol and ibuprofen are the most frequent elicitors of IgE-mediated SRs, although pyrazolones have also been implicated. T cell-mediated reactions are infrequent in children but have been associated with ibuprofen, naproxen, and dipyrone. In this review, we analyze the available literature on SRs in children and adolescents, with emphasis on epidemiological data, mechanisms, and drugs involved, as well as on diagnostic procedures.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used worldwide and are responsible for several types of drug hypersensitivity reactions (DHRs) in all age groups. The 2 major groups of DHRs to NSAIDs are those induced by immunological mechanisms (selective reactions) and those where inflammatory mediators are released through activation of the prostaglandin-leukotriene pathway without specific immunological recognition (cross-intolerance). In the present review, we focus on cross-intolerance reactions, which are the most frequent DHRs and are becoming a topic of major interest in children and adolescents. Paracetamol and ibuprofen are the drugs that most frequently cause DHRs in children; other NSAIDs are responsible for reactions in adolescents. In vivo and in vitro tests are of limited diagnostic value, with some exceptions for the less common selective reactions. In cross-intolerance, the clinical history and controlled administration are in many instances the only way to establish a diagnosis and look for alternatives. The clinical history is diagnostic when consistent symptoms occur repeatedly after exposure to NSAIDs with different chemical structures. Cutaneous and respiratory symptoms often co-occur in young children. The natural history of these reactions in children is unknown, and some patients can develop tolerance over time. Atopy remains a major risk factor for cross-intolerant reactions. The increasing interest in hypersensitivity to NSAIDs with improvements in patient phenotyping and the information provided by pharmacogenetics will improve our understanding and management of these reactions in the near future.

Background: We have noticed changes in paediatric anaphylaxis triggers locally in Singapore., Objective: We aimed to describe the demographic characteristics, clinical features, causative agents and management of children presenting with anaphylaxis., Methods: This is a retrospective study of Singaporean children presenting with anaphylaxis between January 2005 and December 2009 to a tertiary paediatric hospital., Results: One hundred and eight cases of anaphylaxis in 98 children were included. Food was the commonest trigger (63%), followed by drugs (30%), whilst 7% were idiopathic. Peanut was the top food trigger (19%), followed by egg (12%), shellfish (10%) and bird's nest (10%). Ibuprofen was the commonest cause of drug induced anaphylaxis (50%), followed by paracetamol (15%) and other nonsteroidal anti-inflammatory drugs (NSAIDs, 12%). The median age of presentation for all anaphylaxis cases was 7.9 years old (interquartile range 3.6 to 10.8 years), but food triggers occurred significantly earlier compared to drugs (median 4.9 years vs. 10.5 years, p < 0.05). Mucocutaneous (91%) and respiratory features (88%) were the principal presenting symptoms. Drug anaphylaxis was more likely to result in hypotension compared to food anaphylaxis (21.9% vs. 2.7%, Fisher's exact probability < 0.01). There were 4 reported cases (3.6%) of biphasic reaction occurring within 24 h of anaphylaxis., Conclusion: Food anaphylaxis patterns have changed over time in our study cohort of Singaporean children. Peanuts allergy, almost absent a decade ago, is currently the top food trigger, whilst seafood and bird's nest continue to be an important cause of food anaphylaxis locally. NSAIDs and paracetamol hypersensitivity are unique causes of drug induced anaphylaxis locally.

Introduction: Activation of the coagulation cascade resulting in thrombin production is a prominent feature of exacerbations in chronic spontaneous urticaria (CU). Autologous serum skin test (ASST) causes wheal-and-flare reactions in 30% to 50% of CU cases., Objective: The aim of this study was to evaluate the clinical and laboratory data in patients with CU with positive and negative ASST. To understand the role of platelets in CU, we investigated the relation between CU clinical severity, platelet count and their mean platelet volume (MPV)., Methods: Clinical and laboratory data were prospectively collected from 373 patients with CU who attended our Allergy and Clinical immunology Clinic during the period 2003 to 2007. The laboratory data were compared with 46 healthy subjects., Results: There were no significant differences in platelet counts between the groups, nevertheless the platelets in ASST-positive CU patients were characterized by a higher MPV (9.12 +/- 1.25 fl), than that in ASST-negative patients (7.95 +/- 1.08 fl; P = 0.039) and control group (7.72 +/- 1.04 fl; P = 0.007). There was a significant positive correlation between CU severity score and MPV in ASST-positive patients (r = 0.44; P < 0.001) but not in ASST-negative patients. Higher levels of C-reactive protein (5.31 +/- 2.74 mg/L) were measured in the ASST-positive CU group compared with the ASST-negative CU group (2.53 +/- 1.27; P = 0.029) and the control group (2.34 +/- 1.38; P = 0.003)., Conclusion: CU with positive ASST is characterized with higher clinical severity, increased MPV and C-reactive protein.

Hereditary angioedema (HAE) is a rare genetic disorder, manifested by recurrent bouts of swelling in various tissues. The biochemical basis leading to HAE manifestations is either a quantitative or qualitative deficiency in plasma C1 esterase inhibitor (C1-INH). Its proposed physiological role is regulation of vascular permeability, by inhibiting certain steps in the complement, coagulation and the fibrinolytic pathways. Recent evidence implies that bradykinin, a plasma kinin, is the main mediator of HAE, Leading to vasodilatation and hyperpermeability of small vessels. Bradykinin receptors have been recently identified, Leading to significant progress in our understanding of the physiologic mechanisms leading to edema. HAE is characterized by edema of the extremities, face, tongue, Larynx, genitalia and severe abdominal pains. Edema of the tongue and Larynx are life-threatening, and fataloutcomes have been described. Diagnosis of HAE is frequently missed, due to the rarity, non-specific symptoms and lack of awareness of physicians to the diagnosis and treatment. In this review, the authors describe the mechanisms of HAE and the clinical approach to diagnosis and management, according to accepted international guidelines. Furthermore, new treatment modalities that have recently been developed are presented: novel molecules targeting bradykinin, either by inhibiting its generation from plasma kininogens or by direct inhibition of its specific receptors on blood vessels, replacement therapy with human recombinant C1-INH produced in transgenic rabbits. HAE is a chronic disabling diseasewith serious consequences for the patients and their families, severely affecting the quality of life. Recently, new clinical guidelines were published and treatment centers, specializing in the management of HAE were established. The authors are convinced that the increased awareness of the medical staff, in addition to new data and novel treatments, will reduce the burden of the disease, improve its grim prognosis and enable a better quality of life for HAE patients.

Background: The global spread of tuberculosis necessitates the development of an effective vaccine and new treatment modalities. That requires a better understanding of the differences in regulation of the immune responses to Mycobacterium tuberculosis between individuals who are susceptible or resistant to the infection. Previous immune studies in young Ethiopian immigrants to Israel did not demonstrate anergy to purified protein derivative or a Th2-like cytokine profile., Objectives: To evaluate the profile of Th1 and Th2 cytokine production in immigrant TB patients, in comparison with asymptomatic control subjects., Methods: The present study included (part 1): 39 patients with acute TB (group 1), 34 patients with chronic relapsing TB (group 2), 39 Mantoux-positive asymptomatic TB contacts (group 3), and 21 Mantoux-negative asymptomatic controls (group 4). Patients were mainly immigrants from Eastern Europe and Ethiopia. Levels of interferon gamma, interleukin 2 receptor, IL-6 and IL-10 were measured in serum and in non-stimulated and PPD-stimulated peripheral blood mononuclear cell culture supernatants, using commercial ELISA kits. In addition (part 2), levels of IFNgamma and IL-12p40 were evaluated in 31 immigrant Ethiopian patients and 58 contact family members., Results: Patients with acute disease tended to secrete more cytokines than contacts, and contacts more than chronic patients and controls, without a specific bias. None of the patients showed in vitro anergy. Discriminant probability analysis showed that from the total of 12 available parameters, a cluster of 6 (IFNgamma-SER, IFNgamma-PPD, IL-2R-SER, IL-10-SER, IL-10-NS and IL-6-PPD) predicted an 84% probability to become a TB contact upon exposure, 71% a chronic TB patient and 61% an acute TB patient. Family-specific patterns of IFNgamma were demonstrated in the second part of the study., Conclusions: Firstly, no deficiency in cytokine production was demonstrated in TB patients. Secondly, acute TB patients secreted more cytokines than contacts, and contacts more than unexposed controls. Thus, neither anergy nor a cytokine dysregulation explains susceptibility to acute TB disease in our cohort, although chronic TB patients produced less cytokines than did acute patients and less than asymptomatic contacts. Thirdly, a certain cytokine configuration may predict a trend of susceptibility to acquire, or not acquire, clinical TB. It is presently unclear whether this finding may explain the disease spread in large populations. Finally, the familial association of IFNgamma secretion levels probably points towards a genetic regulation of the immune response to Mycobacterium tuberculosis.

Background: Since 1984, several waves of Ethiopian immigrants have settled in Israel. On arrival they were found to be highly infected with intestinal parasites and to have increased serum immunoglobulin E and eosinophilia., Objectives: To study serum IgE levels in Ethiopian children growing up in the environment of Israel., Methods: We assessed four groups of children of Ethiopian origin: a) adolescents examined on their arrival to Israel (group 1, n=11); b) adolescents born in Ethiopia and living in Israel for more than 7 years (group 2, n=10); c) children of Ethiopian origin born in Israel, without a history of allergy or asthma (group 3, n=15); and d) asthmatic children of Ethiopian origin born in Israel (group 4, n=8). A thorough clinical interview and examination as well as laboratory work up (including serum IgE levels, stool parasites and absolute eosinophil count) were performed., Results: Group 1 (11 newly arrived Ethiopian adolescents) had a mean eosinophil count of 688 cells/ml (0-1739) and a mean serum IgE of 1043 IU/ml (253-2932), P< 0.0009 as compared to group 2. Helminthic parasites were observed in 8/11 individuals; after 1 year of follow-up and anti-parasitic treatment, serum IgE levels did not change significantly. Group 2 (10 Ethiopian born adolescents living in Israel for on average 10 years, 7-15 years) had a normal leukocyte count, MEC 192 cells/ml (range 54-289), serum IgE 142 IU/ml (range 14-399 IU/ml) and no parasites in stool. Group 3 (15 Ethiopian children born in Israel) had a normal leukocyte count, MEC 128 cells/ml (0-324), serum IgE 55 IU/ml (7-189 IU/ml), similar to age-matched Israeli controls. In group 4 (8 Israeli born children of Ethiopian descent diagnosed with asthma), serum IgE showed significant elevation compared to Israeli age-matched asthmatic children (P< 0.005)., Conclusions: High levels of IgE found in Ethiopian children on arrival to Israel declined to Israeli control levels after several years of living in the new environment. Ethiopian children born in Israel had normal levels of IgE, suggesting that environment is the main factor affecting IgE levels in this population. Israeli born Ethiopian children with asthma had significantly increased serum IgE levels compared to asthmatics of Israeli origin. These findings suggest that both environmental and genetic factors determine the level of serum IgE in these children.