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Background Attacks of hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency (C1‐INH‐HAE) usually begin during childhood or adolescence. However, limited data are available regarding indications and modalities of treatment of children. This study evaluated recombinant human C1‐INH (rhC1‐INH) for HAE attacks in children. Methods This open‐label, phase 2 study included children aged 2‐13 years with C1‐INH‐HAE. Eligible HAE attacks were treated intravenously with rhC1‐INH 50 IU/kg body weight (maximum, 4200 IU). The primary end‐point was time to beginning of symptom relief (TOSR; ≥20 mm decrease from baseline in visual analog scale [VAS] score, persisting for two consecutive assessments); secondary end‐point was time to minimal symptoms (TTMS

Background: The prevalence of peanut allergy (PA) is constantly on the rise. Atopic dermatitis (AD) is a major risk factor for developing food allergy. Some bath oils and skin creams used for treating AD contain peanut oil, and it has been suggested that exposure to peanut allergens through a disrupted skin barrier is a potential cause of PA. Our aim was to investigate whether application of peanut oil to irritated skin causes a systemic or respiratory allergic response to peanuts in an animal model. Methods: BALB/c mice underwent epicutaneous sensitization with either peanut oil (PM, n = 9) or phosphate buffered solution (controls, n = 9) daily for 5 consecutive days. Ten days after the last exposure the mice were challenged with intranasal peanut protein for 5 consecutive days. Bronchial alveolar lavage fluid was collected for cellular studies and measurement of cytokine levels. Sera were collected for immunoglobulin E (IgE) measurement. Results: Epicutaneous peanut oil sensitization increased leukocyte and eosinophil counts and interleukin-13 levels (p = 0.003, p = 0.0006 and p = 0.03, respectively), in addition to increasing total serum IgE (p = 0.03). Conclusions: The results suggest that topical application of peanut oil may play a role in the etiology of PA.

Summary Background Hereditary angio-oedema is a recurrent, oedematous disorder caused by deficiency of functional C1 inhibitor. Infusions of plasma-derived C1 esterase inhibitor deter attacks of hereditary angio-oedema, but the prophylactic effect of recombinant human C1 esterase inhibitor has not been rigorously studied. We aimed to assess the efficacy of recombinant human C1 esterase inhibitor for prophylaxis of hereditary angio-oedema. Methods We conducted this phase 2, multicentre, randomised, double-blind, placebo-controlled crossover trial at ten centres in Canada, the Czech Republic, Israel, Italy, Macedonia, Romania, Serbia, and the USA. We enrolled patients aged 13 years or older with functional C1-inhibitor concentrations of less than 50% of normal and a history of four or more attacks of hereditary angio-oedema per month for at least 3 months before study initiation. Patients were randomly assigned centrally (1:1:1:1:1:1), via an interactive response technology system with fixed allocation, to receive one of six treatment sequences. During each sequence, patients received intravenous recombinant human C1 esterase inhibitor (50 IU/kg; maximum 4200 IU) twice weekly, recombinant human C1 esterase inhibitor once weekly and placebo once weekly, and placebo twice weekly, each for 4 weeks with a 1 week washout period between crossover. All patients, investigators, and study personnel who participated in patient care were masked to group allocation during the study. The primary efficacy endpoint was the number of attacks of hereditary angio-oedema observed in each 4 week treatment period. Attack symptoms were recorded daily. The primary efficacy analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one injection of study medication. This study is registered with ClinicalTrials.gov, number NCT02247739. Findings Between Dec 29, 2014, and May 3, 2016, we enrolled 35 patients, of whom 32 (91%) underwent randomisation (intention-to-treat population) and 26 (81%) completed the study. The mean number of attacks of hereditary angio-oedema over 4 weeks was significantly reduced with recombinant human C1 esterase inhibitor twice weekly (2·7 attacks [SD 2·4]) and once weekly (4·4 attacks [3·2]) versus placebo (7·2 attacks [3·6]), with mean differences of −4·4 attacks (p Interpretation Prophylaxis with recombinant human C1 esterase inhibitor provided clinically relevant reductions in frequency of hereditary angio-oedema attacks and was well tolerated. In view of the pharmacokinetic profile of recombinant human C1 esterase inhibitor, our results suggest that efficacy of C1-inhibitor replacement therapy might not be a direct function of plasma trough concentrations of C1 inhibitor. Funding Pharming Technologies.

Background The severe life-threatening characteristics of hereditary angioedema (HAE) with C1-inhibitor deficiency (C1-INH-HAE) can affect anxiety levels among pediatric patients. This emotional burden together with the physical restrictions of C1-INH-HAE may decrease children's health-related quality of life (HRQoL). Objective (1) To compare anxiety state and trait between children with C1-INH-HAE and healthy controls (2) To examine the relationship between the level of anxiety of children with C1-INH-HAE, their disease activity/affected sites and their HRQoL (3) To predict the HRQoL of children with C1-INH-HAE based on their anxiety level and disease activity/affected sites. Methods Thirty-three children with C1-INH-HAE (aged 5-18 years) and 52 healthy controls were recruited from Israel and Hungary. All children completed the State Trait Anxiety Inventory for Children (STAIC), the Pediatric Quality of Life Inventory (Peds-QL) demographic questionnaire and a disease activity and site questionnaire. Disease activity was defined as the number of attacks in last year. Results Both anxiety state and trait were significantly higher among children with C1-INH-HAE as compared to the controls (44.74±10.56 vs. 38.76±10.67, p

Background The clinical expressions of hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) and its related burden may negatively affect patient quality of life. This study aimed to assess health-related quality of life (HRQoL) in children with C1-INH-HAE. Methods Children (N = 98: 34 C1-INH-HAE patients, 64 healthy controls) aged 3–18 years were recruited in Israel and Hungary. All individuals completed a demographic questionnaire, a disease activity and site questionnaire, and the Pediatric Quality of Life Inventory (PedsQL™) 4.0 Generic Core Scales (child self-report and maternal proxy report) to assess HRQoL. Results Among C1-INH-HAE patients, nine (26.5%) had 1–5 attacks/year, six (17.6%) had 6–18 attacks/year, eight (23.5%) had 25–60 attacks/year, and 11 (32.4%) were asymptomatic over the previous year. Children with C1-INH-HAE attacks demonstrated lower HRQoL than healthy control children across the total score, school, and psychosocial dimensions of the PedsQL™. The number of C1-INH-HAE attacks negatively correlated with the total HRQoL score (r = −0.48, p = 0.008), school-related HRQoL (r = −0.39, p = 0.02), and psychosocial HRQoL (r = −0.43, p = 0.01). Patients with multisite laryngeal, abdominal, and peripheral C1-INH-HAE attacks had a lower HRQoL compared with those who experienced solely peripheral attacks across the total score (p = 0.04), physical (p = 0.04), and school (p = 0.02) domains. There was no significant difference between asymptomatic C1-INH-HAE patients and healthy controls. Conclusions Children with symptomatic C1-INH-HAE demonstrate impaired HRQoL compared with healthy controls. HRQoL was affected by the frequency and site of C1-INH-HAE attacks and mostly in the school and physical domains.

Background For the prevention of attacks of hereditary angioedema (HAE), the efficacy and safety of subcutaneous human C1-esterase inhibitor (C1-INH[SC]; HAEGARDA, CSL Behring) was established in the 16-week Clinical Study for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy (COMPACT). Objective To assess the long-term safety, occurrence of angioedema attacks, and use of rescue medication with C1-INH(SC). Methods Open-label, randomized, parallel-arm extension of COMPACT across 11 countries. Patients with frequent angioedema attacks, either study treatment-naive or who had completed COMPACT, were randomly assigned (1:1) to 40 IU/kg or 60 IU/kg C1-INH(SC) twice per week, with conditional uptitration to optimize prophylaxis (ClinicalTrials.gov registration no. NCT02316353). Results A total of 126 patients with a monthly attack rate of 4.3 in 3 months before entry in COMPACT were enrolled and treated for a mean of 1.5 years; 44 patients (34.9%) had more than 2 years of exposure. Mean steady-state C1-INH functional activity increased to 66.6% with 60 IU/kg. Incidence of adverse events was low and similar in both dose groups (11.3 and 8.5 events per patient-year for 40 IU/kg and 60 IU/kg, respectively). For 40 IU/kg and 60 IU/kg, median annualized attack rates were 1.3 and 1.0, respectively, and median rescue medication use was 0.2 and 0.0 times per year, respectively. Of 23 patients receiving 60 IU/kg for more than 2 years, 19 (83%) were attack-free during months 25 to 30 of treatment. Conclusions In patients with frequent HAE attacks, long-term replacement therapy with C1-INH(SC) is safe and exhibits a substantial and sustained prophylactic effect, with the vast majority of patients becoming free from debilitating disease symptoms.

BACKGROUND: Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) causes swelling in the skin and upper airways and pain in the abdomen because of mucosal swelling. C1-INH-HAE is frequently misdiagnosed, leading to delays in diagnosis, inadequate treatment, and unnecessary procedures.OBJECTIVE: To evaluate the history of misdiagnosis in patients participating in the Icatibant Outcome Survey (IOS).METHODS: The IOS is an observational study in which safety and effectiveness of icatibant have been evaluated since 2009. As part of the IOS, patients record any misdiagnoses received before being diagnosed as having C1-INH-HAE.RESULTS: In January 2016, a total of 418 of 633 IOS patients with C1-INH-HAE type I or II had provided misdiagnosis data. Of these, 185 of 418 (44.3%) received 1 or more prior misdiagnoses. The most common misdiagnoses were allergic angioedema (103 of 185) and appendicitis (50 of 185). A variety of other misdiagnoses were reported, including a substantial number of gastrointestinal disorders (excluding appendicitis). Misdiagnosis rates were similar between males (41.1%) and females (46.5%) and between C1-INH-HAE type I (43.7%) and type II (51.6%). Patients with family members diagnosed as having C1-INH-HAE were significantly less likely to be misdiagnosed than patients without a family history (140 of 366 [41.7%] vs 38 of 58 [65.5%], respectively; P = .001). Patients with a prior misdiagnosis had longer median delay to C1-INH-HAE diagnosis (13.3 years) than patients without (1.7 years; P < .001).CONCLUSION: From this large database, approximately 50% of patients with C1-INH-HAE type I or II have previously had their conditions misdiagnosed, most commonly as allergic angioedema or appendicitis. Misdiagnosis results in marked delays in receiving the correct diagnosis, during which time patients cannot access effective, lifesaving treatment.TRIAL REGISTRATION: ClinicalTrials.gov: NCT01034969.

Management of patients with hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) is evolving worldwide. Evaluating the Israeli experience may provide valuable insights.To compare demographics and icatibant treatment patterns and outcomes in patients with C1-INH-HAE enrolled in the Icatibant Outcome Survey (IOS) in Israel with those in other countries.The IOS is an ongoing observational study that prospectively monitors real-world icatibant safety/tolerability and treatment outcomes.By July 2016, 58 patients from Israel and 594 patients from other countries were enrolled. Median age at diagnosis (16.7 vs. 21.3 years, P = 0.036) and median delay between symptom onset and diagnosis (0.8 vs. 6.6 years, P = 0.025) were lower in Israel compared with other countries, respectively. Differences in attack severity were not significant (P = 0.156); however, during follow-up, Israeli patients were less likely to miss7 days of work/school due to C1-INH-HAE-related complications (P = 0.007). A trend was also shown in Israel for earlier time to treatment (median 0.5 vs. 1.3 hours, P = 0.076), attack duration was shorter (median 5.0 vs. 9.0 hours, P = 0.026), and patients more often self-administered icatibant (97.2% vs. 87.5%, P = 0.003), respectively. However, Israeli patients were less likely to treat attacks (P = 0.036). Whereas patients in Israel reported exclusive use of danazol for long-term prophylaxis, those in other countries used various agents, including C1-INH.Recognition of C1-INH-HAE and timeliness of icatibant treatment appear more favorable, and attack duration shorter, in Israel compared with other countries.

Background There is limited knowledge regarding long term follow-up of milk allergic patients who tolerate baked milk (BM) products. Aim To evaluate the long-term safety and efficacy of this intervention. patients and methods Children 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. Results 85 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 Conclusions For 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.

Background: Historically, treatment for hereditary angioedema (HAE) attacks has been administered by healthcare professionals (HCPs). Patient self-administration could reduce delays between symptom onset and treatment, and attack burden. The primary objective was to assess the safety of self-administered icatibant in patients with HAE type I or II. Secondary objectives included patient convenience and clinical efficacy of self-administration. Methods: In this phase IIIb, open-label, multicenter study, adult patients were trained to self-administer a single 30-mg icatibant subcutaneous injection to treat their next attack. Icatibant-naïve patients were treated by an HCP prior to self-administration. Evaluations included adverse event (AE) reporting, a validated questionnaire for convenience, and visual analog scale for efficacy. Results: A total of 151 patients were enrolled; 104 had an attack requiring treatment during the study, and 97 patients (19 naïve) were included in the self-administration cohort. Recurrence or worsening of HAE symptoms (22 of 97) was the most commonly reported AE; rescue medications including icatibant (N = 3) and C1-inhibitor concentrate (N = 6) were used in 13 cases. Overall, 89 of 97 patients used a single injection of icatibant. No serious AEs or hospitalizations were reported. Most patients (91.7%) found self-administration preferable to administration in the clinic. The median time to symptom relief (3.8 h) was comparable with results from controlled trials of icatibant. Conclusions: With appropriate training, patients were successfully able to recognize HAE attacks and decide when to self-administer icatibant. This, coupled with the patient-reported high degree of satisfaction, convenience and ease of use supports the adoption of icatibant self-administration in clinical practice. Fil: Aberer, W.. Medical University Graz; Austria Fil: Maurer, M.. Charite – Universitatsmedizin; Alemania Fil: Reshef, A.. The Sheba Medical Center; Israel Fil: Longhurst, H.. Bart’s and The London Hospital; Reino Unido Fil: Kivity, S.. The Tel Aviv Medical Center; Israel Fil: Bygum, A.. Odense University Hospital; Dinamarca Fil: Caballero, T.. Biomedical Research Network on Rare Diseases; España Fil: Bloom, B.. Global Clinical Research; Estados Unidos Fil: Nair, N.. Global Clinical Research; Estados Unidos Fil: Malbrán, Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Hospital Británico de Buenos Aires; Argentina

Background Acetylsalicylic acid (ASA; aspirin) is a well-known inducer of pseudoallergic response in patients with chronic rhinosinusitis with polyps (CRSwPs). The mechanism that leads to this response remains unclear. This study was designed to measure and compare the local and systemic inflammatory response to aspirin challenge in patients with CRSwPs who develop either a nasobronchial response (NBR) or a nasal response (NR), and compare it with nonresponders (non-Rs). Methods The three groups underwent nasal wash before ASA challenge, and inflammatory mediators were measured in the nasal wash as well as in serum. Results A total of 25 CRSwP patients were enrolled. The NBR patients (n = 13) had a significantly longer mean disease duration and a higher mean serum leukotriene E4 (LTE4) level than the NR (n = 6) and non-R (n = 6) patients (39.2 ± 9.7 months, 21 ± 8.8 months, and 22.8 ± 11.2 months, respectively, and 4221 ± 1205 pg/mL, 1430 ± 605 pg/mL, and 857 ± 461 pg/mL, respectively). The NBR and NR patients had a larger mean number of nasal eosinophils than the non-R group (52.8 ± 28.8 cells/μL, 47 ± 21.3 cells/μL, and 19.3 ± 13.4 cells/μL, respectively). The tryptase, albumin, nasal LTE4, and prostaglandin E2 levels were not significantly different between the three groups in any examined combination. Conclusion The nasal eosinophil and serum LTE4 levels correlate with aspirin sensitivity.

Urticaria and angioedema occur in up to 20 % of the population during their lifetime. Chronic urticaria and some hereditary angioedema states are more frequent in women and fluctuate during the hormonal cycle. This review describes the course of urticarial and angioedema states during pregnancy, as well as a possible role for sex hormones in the pathogenesis of different diseases, both chronic and cyclic urticarial diseases and diseases that occur only in pregnancy.

Aging is associated with altered decreased barrier function in the skin, which can lead to different types of immunoglobulin E (IgE)-mediated sensitization to environmental allergens. Yet, allergen-specific respiratory sensitization among the elderly is not well described. The aim of this study was to investigate the effect of aging on allergic pulmonary inflammation induced by epicutaneous sensitization of mechanically irritated skin in mice. For this purpose, 6-week-, 6-month-, and 18-month-old female BALB/c mice, underwent epicutaneous sensitization with ovalbumin (OVA) or phosphate buffered saline (PBS), followed by an inhaled OVA challenge. Blood OVA-specific IgE levels measured after epicutaneous sensitization, as well as, bronchial alveolar lavage fluids (BALF) leucocyte, eosinophil, and cytokine levels measured after OVA inhalation challenge were similar among the 6-week-old (young) and 6-month-old (adult) groups. However, significantly decreased levels of systemic OVA IgE, and BALF leukocyte, eosinophil and T helper cell type 2 cytokine levels, were measured after OVA inhalation challenge in elderly (18-month-old) mice compared to the other groups of mice. In addition, interleukin-10 (IL-10), a regulatory suppressor cytokine, was more abundant in the BALF of the elderly group after epicutaneous sensitization and inhalation challenge. Our results suggest that elderly mice have a reduced allergic response to induced sensitization with OVA, possibly regulated by increased IL-10 levels.

Background Pulmonary function is often affected by the inhalation of metal particles. The resulting pathology might trigger various lung diseases, e.g., parenchymal lung fibrosis and granulomatous lung disorders. We previously demonstrated that 6 % of tissue-proven sarcoid patients had a positive beryllium lymphocyte proliferation test (BeLPT), thus correcting the diagnosis to chronic beryllium disease. The aim of this study was to examine if MEmory Lymphocyte Immnuno Stimulation Assay (MELISA®), currently used for non-pulmonary diseases, can identify metals other than beryllium that can also trigger sensitization and induce granulomatous disease. Methods This pilot study included 13 sarcoid-like patients who underwent MELISA®. Eleven patients also underwent BeLPT. Biopsy samples were tested for metal content by scanning electron microscope. Eleven study patients had been exposed to metals at the workplace and 2 had silicone implants. Results Two patients who had undergone BeLPT were positive for beryllium. MELISA® detected 9 patients (9/13, 69 %) who were positive for at least one of the tested metals: 4 reacted positively to nickel, 4 to titanium, 2 to chromium, 2 to beryllium, 2 to silica, and one each to palladium, mercury and lead. Conclusion It is proposed that MELISA® can be exploited to also identify specific sensitization in individuals exposed to inhaled particles from a variety of metals.

BACKGROUND Hereditary angioedema is characterized by recurrent attacks of angioedema of the skin, larynx, and gastrointestinal tract. Bradykinin is the key mediator of symptoms. Icatibant is a selective bradykinin B2 receptor antagonist. METHODS In two double-blind, randomized, multicenter trials, we evaluated the effect of icatibant in patients with hereditary angioedema presenting with cutaneous or abdominal attacks. In the For Angioedema Subcutaneous Treatment (FAST) 1 trial, patients received either icatibant or placebo; in FAST-2, patients received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days. Icatibant was given once, subcutaneously, at a dose of 30 mg. The primary end point was the median time to clinically significant relief of symptoms. RESULTS A total of 56 and 74 patients underwent randomization in the FAST-1 and FAST-2 trials, respectively. The primary end point was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1 trial (P=0.14) and in 2.0 hours with icatibant versus 12.0 hours with tranexamic acid in the FAST-2 trial (P

We compared exhaled breath condensate (EBC) and induced sputum (IS) for assessing inflammation in pulmonary diseases in patients with obstructive lung disease (n = 20), persistent cough6 months (n = 20), interstitial lung disease (n = 25) and controls (n = 10). EBC was collected by suspending a Teflon perfluoroalkoxy tube installed in an ice-filled container and connected to a polypropylene test tube. IS was recovered after 20' inhalation of 3% saline with an ultrasonic nebulizer, and 300 cells were differentially counted in cytospin Giemsa-stained slides. H(2)0(2) was measured by a method based on oxidation of phenolsulfonphthalein (phenol red) mediated by horseradish peroxidases and H(2)0(2). Pulmonary function tests were performed by conventional methods. H(2)0(2) levels in EBC and % eosinophils in IS were significantly different between groups. A positive and significant correlation was found between % eosinophils in IS and the levels of H(2)0(2) in EBC for each group and for all patients combined.

BackgroundChronic rhinosinusitis (CRS) is an inflammatory/allergic disease with unclear pathophysiology, but it has been linked to an imbalance in the production of eicosanoids, which are metabolites of arachidonic acid, and results from phospholipids hydrolysis by phospholipase A2(PLA2). As of yet, the role of PLA2in CRS has hardly been studied, except for a report that group II PLA2expression is elevated in interleukin (IL) 1β or tumor necrosis factor α-stimulated CRS nasal tissues with and without polyps. The PLA2families include extracellular (secretory) and intracellular isoforms, which are involved in the regulation of inflammatory processes in different ways. Here we comprehensively investigated the expression of PLA2s, particularly those reported to be involved in respiratory disorders, in superantigen (SAE)-stimulated nasal polyps from patients with CRS with polyps, and determined their role in inflammatory cytokine production by inhibition of PLA2expression.MethodsThe release of IL-5, IL-13, IL-17, and interferon γ by nasal polyps dispersed cells (NPDC) was determined concomitantly with PLA2messenger RNA expression, under SAE stimulation, with or without dexamethasone, as a regulator of PLA2expression.ResultsStimulation of NPDCs by SAE-induced cytokine secretion with enhanced expression of several secretory PLA2and Ca2+-independent PLA2, while suppressing cytosolic PLA2expression. All these were reverted to the level of unstimulated NPDCs on treatment with dexamethasone.ConclusionThis study further supports the key role of secretory PLA2in the pathophysiology of respiratory disorders and presents secretory PLA2inhibition as a therapeutic strategy for the treatment of CRS and airway pathologies in general.

Air pollution triggers and exacerbates airway inflammation. Particulate material (PM) in ambient is characterized as being coarse (PM 10, aerodynamic diameter range 2.5?10??m), fine (PM 2.5, 2.5?0.1??m) and ultrafine (UFP, nano-sized,?

Summary Background Growing evidence suggests that inducible nitric oxide synthase (iNOS) is the main source of the high output of exhaled nitric oxide (NO) in asthma. Treatment of asthmatic patients with glucocorticoids reduces high levels of exhaled NO mainly by inhibiting the transcription of iNOS. A similar reduction in exhaled NO was recently observed in patients treated with the leukotriene receptor antagonists, but the exact interaction between these drugs and iNOS remains obscure. Objective The purpose of this study was to evaluate the effect of a leukotriene receptor antagonist

Study objectives Accurate prediction of the effect of atmospheric changes, including pollutants, on emergency department (ED) visits for respiratory symptoms would be useful, but has proven difficult. The main difficulty is the limitation of the classical linear models and logistic regression with multiple variables to handle the multifactorial effect. Design and setting To predict ED visits, we have created a computer-based model called an artificial neural network (ANN) using a back-propagation training algorithm and genetic algorithm optimization. This ANN was fed meteorologic and air pollution input variables and trained to predict the number of patients admitted to the ED with respiratory symptoms of asthma, COPD, and acute and chronic bronchitis on the corresponding day. One thousand twenty data sets were extracted from an ED admittance database at the Barzilai Medical Center (Ashkelon, Israel), and randomized to a network training set (n = 816) and a test set (n = 204). Results The neural network performed best when the predictor variables used were temperature, relative humidity, barometric pressure, SO 2 , and oxidation products of nitric oxide, and the data presented as peak value 24 h prior to ED admission and the average during the 7 days before the ED visit. The neural network was able to predict the test set with an average error of 12%. Conclusion Based on meteorologic and pollution data, the use of an ANN can assist in the prediction of ED visits related to respiratory conditions.

Objective: Administration of infliximab is associated with a well-recognised risk of infusion reactions. Lack of a mechanism-based rationale for their prevention, and absence of adequate and well-controlled studies, has led to the use of diverse empirical administration protocols. The aim of this study is to perform a systematic review of the evidence behind the strategies for preventing infusion reactions to infliximab, and for controlling the reactions once they occur. Methods: We conducted extensive search of electronic databases of MEDLINE [PubMed] for reports that communicate various aspects of infusion reactions to infliximab in IBD patients. Results: We examined full texts of 105 potentially eligible articles. No randomised controlled trials that pre-defined infusion reaction as a primary outcome were found. Three RCTs evaluated infusion reactions as a secondary outcome; another four RCTs included infusion reactions in the safety evaluation analysis; and 62 additional studies focused on various aspects of mechanism/s, risk, primary and secondary preventive measures, and management algorithms. Seven studies were added by a manual search of reference lists of the relevant articles. A total of 76 original studies were included in quantitative analysis of the existing strategies. Conclusions: There is still paucity of systematic and controlled data on the risk, prevention, and management of infusion reactions to infliximab. We present working algorithms based on systematic and extensive review of the available data. More randomised controlled trials are needed in order to investigate the efficacy of the proposed preventive and management algorithms.

Chronic spontaneous urticaria (CSU) is a common, debilitating disease that is frequently resistant to standard therapy. Omalizumab, anti-immunoglobulin-E humanized monclonal antibody, was recently shown to be effective in treating resistant CSU.To investigated the treatment of CSU with omalizumab in Israel.We conducted a multicenter retrospective analysis of patients with refractory CSU treated with omalizuamb in Israel during 2012-2013. Complete improvement was defined as resolution of symptoms with no need for other medications, or satisfactory when patients' condition improved but required regular or intermittent doses of antihistamines.Forty-three patients received omalizumab off-label for refractory CSU. Their mean age was 45 +/- 12 years and CSU duration was 4.3 +/- 4 years. In this cohort, 98% were unsuccessfully treated with high dose H(1)-antihistamines, 88% with systemic glucocorticoids and 30% with cyclosporine and/ or other immune-modulators. Fourteen patients received only one injection of omalizumab, while the other 29 received on average of 4.3 +/- 3.2 injections; 30 patients received 150 mg/ month and 13 received 300 mg/month. Following omalizumab therapy, disease remitted within weeks in 86% of patients, of whom half achieved complete remission. The latter was associated with usage of high dose omalizumab, 300 mg/month vs. 150 mg/month (P = 0.02) and repeated therapy (i.e., multiple injections vs. a single injection) (P = 0.0005).Omalizumab is an effective and safe treatment for refractory CSU with rapid onset of action for inducing and maintaining remission. Treating CSU patients mandates an individual approach, because while low dose omalizumab will suffice for some patients others might need higher doses and prolonged therapy.

Allergic diseases have increased significantly in developed countries for reasons yet to be determined. We studied the epidemiology of bronchial asthma (B.A.) and chronic rhinitis (Ch.R.) among Israeli school children from two neighboring towns, one Jewish (Zichron Yaakov, school population = 585) and the other Arab (Paradis, school population = 658). The children (age range 8-17 years, 567 males, 676 females) shared the same climate and had similar demographic characteristics. They received similar medical care and had the same rates of hospitalization and emergency room visits. The Jewish children had a higher prevalence of B.A. (13.7% vs. 9.4%), Ch.R. (19.7% vs. 9.7%), and stuffy nose (31% vs. 14%) than their Arab counterparts. In addition to ethnicity, parental smoking habits were the major differentiating factor between the two groups: 20% of the mothers and 29% of the fathers from Zichron Yaakov and 2% of the mothers and 60% of the fathers from Paradis were smokers. Smoking fathers increased the rate of B.A. in both towns as well as emergency room visits, but not the rate of Ch.R. or stuffy nose. A familial history of B.A. was the main determinant for having childhood asthma or chronic rhinitis. We conclude that in addition to family history and ethnicity, smoking among mothers was the major contributing factor for the higher prevalence of atopic diseases among Jewish schoolchildren compared to their Arab counterparts.

Exercise-induced asthma is a common phenomenon, the mechanism of which is undetermined. Eosinophils have been suggested as playing a role in its occurrence. We studied the effect of exercise-induced asthma on the cellular and mediator composition of spontaneously obtained sputum. Twenty-five patients with bronchial asthma were investigated by studying sputum spontaneously obtained before and following challenge. One group with ( n =9) and one without ( n =9) exercise-induced asthma performed exercise challenge. A third group ( n =7) performed methacholine challenge. The sputum was analysed using Giemsa staining for differential cell count, measuring eosinophil cationic proteins and mixtures of leukotrienes (D4, E4 and C4) in the liquid phase using ELISA. The group with exercise-induced asthma had a mean drop of 23·7±7·4% in FEV 1 , significantly ( P =0·001) higher than the group without it. Following challenges, there were significant increases in sputum eosinophils only in the group with exercise-induced asthma (from 8·1±13·9% to 18·3±20·2%, P =0·0017) and not in control groups (from 0·9±0·9% to 1·5±1·5% ) or in those who had methacholine challenge (from 23·6±27·2% to 22·3±23·8%). Eosinophil cationic proteins did not change significantly in any group. In the liquid phase of the sputum, the amount of leukotrienes increased following exercise in six of the seven patients with exercise-induced asthma in whom it was measured. The influx of eosinophils to the airway in patients who develop exercise-induced asthma can be partially explained by the leukotrienes in the airways of those patients.

Sarcoidosis (SA) and diffuse interstitial fibrosis (DIF) are characterized by alveolitis, mast cell hyperplasia and increased fibroblast proliferation. Stem cell factor (SCF) stimulates proliferation of hematopoietic progenitor cells involved in mast and stromal cell interaction. We assessed the role of SCF secreted by alveolar fibroblasts (AFb) in the development of fibrosis of DIF and SA in six patients with SA and six patients with DIF. Bronchoalveolar lavage (BAL) was performed by conventional methods. A total of 500 cells were differentially counted from Giemsa-stained cytopreps. AFb and supernatants were recovered from long-term cultures of BAL cells and from 24 h cultures of confluent AFb. Levels of SCF were measured by ELISA. Alpha actin content of AFb was characterized by immunohistochemistry. The expression of AFb mRNA for IL1-alpha and beta, TGF-beta, IFN-gamma, IL-2, IL-4, IL-5 and IL-6 was determined by RT-PCR. There was a lymphocytic predominance in the SA patients and an increase in neutrophils and eosinophils in DIF. SCF secreted by AFb from DIF was significantly higher than in SA. TNF + IL-1 significantly decreased the secretion of SCF by AFb. There was a positive correlation between SCF levels and the percentage eosinophils but not for metachromatic cells. Alpha-actin expression of AFb in DIF was significantly higher than in SA. Cytokine mRNA was extracted from AFb of two SA and two DIF patients. The profile showed that only in stimulated AFb isolated from the DIF patients can IL-5 transcripts be visualized. In conclusion, AFb can contribute to the onset of fibrosis by secreting SCF and IL-5 which, in turn, may recruit eosinophils.

Background: The immunomodulatory activity of macrophages was shown to be a crucial mechanism in the pathogenesis of asthma. Methods: Induced sputum (IS) and methacholine challenge (MC) were carried out in 21 atopic subjects. Suppressive activity (SA) of sputum macrophages (SMO) was investigated on autologous peripheral lymphocytes (APL) proliferation in 12 of these patients and compared to the MC. Results: In 10 of the 21 patients, the FEV1 was >80%; five of these had a nonreactive MC. Eosinophils and metachromatic cells correlated well (r=0.6442; P=0.0029), but not with the MC. The SA of SMO correlated (P=0.0152) with the MC: SMO enhanced APL proliferation in five patients with a positive MC, while SMO showed SA in five with a negative MC. Only two patients with suppressive SMO had a positive MC. Cytokine profiles from five patients showed that two patients with a negative MC had interleukin (IL)-1α and β, IL-6, and transforming growth factor (TGF)-β transcripts, while two patients with a positive MC transcripted IL-4 and IL-5. One patient with a borderline MC transcripted IL-5, but not IL-4. Conclusions: These data support the theory that patients with reduced suppressive bronchial macrophages display clinical bronchial hyperreactivity.

To establish the relationship between air pollution levels and bronchial asthma-associated emergency room (ER) visits, we adapted artificial network technology to conduct this study which focused on three different pollutants, sulphur dioxide, nitrogen oxide and ozone. The study population was comprised of adults presenting to the emergency room of a large metropolitan hospital in Israel during a 3-month period with acute exacerbation of bronchial asthma and who had a past history of intermittent airway disease compatible with bronchial asthma. The range of mean daily pollutants levels for the whole period were: O3 = 15-26 micrograms m-3, NOx = 36-108 micrograms m-3, NO = 16-70 micrograms m-3, and SO2 = 11-32 micrograms m-3. The data sets were composed of input air pollution levels and output ER visits. The first 126 data sets used for the training phase showed that maximal ER visits were mainly associated with the highest cumulative values of air pollution and mostly with nitrogen oxide. In phase two, an attempt was made to predict ER visits based on air pollution level in 49 data sets. The study findings demonstrated that ordinary network technology can be used for learning the effect of air pollution ER visits and, although limited in accuracy, to also predict future ER visits.

Background Fourteen workers exposed to hard metals and aluminum oxide were evaluated. Methods Six heavily exposed workers underwent bronchoscopy and bronchoalveolar lavage, and five workers underwent transbronchial biopsy. Results Microchemical analysis of transbronchial biopsies showed a high lung burden of exogenous particles, especially metals related to their hard metals exposure. Lung tissue and cellular changes, which were associated with exposure to hard metal and aluminum oxide, corresponded well with the microanalytic test results. Conclusions Three workers had at biopsy diffuse interstitial inflammatory changes: two of them were asymptomatic with normal chest X-ray films, and one had clinically evident disease with severe giant cell inflammation. Two other workers showed focal inflammation. The worker showing clinical disease and one asymptomatic worker with interstitial inflammatory changes had elevated bronchoalveolar lavage fluid-eosinophilia counts. These two were father (with clinical disease) and son (asymptomatic). Am. J. Ind. Med. 34:177–182, 1998. © 1998 Wiley-Liss, Inc.

In vitro studies have suggested that basophils are involved in the asthmatic response to isocyanate. Classified by the type of airway response, three groups of patients exposed to isocyanate were studied: 1) nonreactive (n = 3), 2) immediate responders (n=4), and 3) late responders (n =4). Basophil histamine release to concanavalin A (conA), FMLP, and anti-IgE was evaluated before and during the airway response. Histamine release significantly (P=0.009 for conA and 0.03 for anti-IgE) increased after exposure to isocyanate only in the group which had late bronchial response. Additionally, good correlation was found between baseline FEV 1 /FVC% and degree of histamine release of basophils stimulated with conA. These findings support a role for basophils in the late asthmatic response to isocyanate.

Summary Background While inhalation of corticosteroids (CST) is considered very effective in most asthmatic patients, some require a high dose of orul prcdnisonc to control the disease. Basophils, which participate in inflammation, are responsive to cortiseosteroids by suppressing histamine release. Objectives We investigated the in vivo (oral prednisone) and in vitro (dexamethasone, DEX) effect on basophil histamine release in mild and steroid-dependent asthmatics. Methods Histamine release from basophils to anti-IgE and anti-IgE + IL3 was evaluated following live days of prednisone given 20 mg twice daily in eight subjects with mild disease and 2 h following their daily prednisone ingestion in eight subjects with severe disease, as well as after in vitro DEX was added to the cells. Results Histamine release from basophils was seen following anti- IgE as well as anti-IgE + IL-3. The same amount of release was seen in the mild and severe asthmatics. In vivo prednisone suppressed histamine release to both stimuli and DEX added to the suppression in the mild asthmatics. In the severe ones. DEX showed no inhibitory effect on histamine release. Conclusion Oral and in-vitro CST suppressed histamine release from basophils of mild but not severe CST-dependent asthmatics. Suppression of basophil releasability can be a reflection of asthma severity.

Background: The For Angioedema Subcutaneous Treatment (FAST)-2, a phase III, double-blind, randomized, multicenter, placebo-controlled study (ClinicalTri als.gov identifier: NCT00500656), established the efficacy and safety of single injections of icatibant, a bradykinin B2 receptor antagonist, in the treatment of hereditary angioedema (HAE) attacks. Here, we evaluate the efficacy and safety of repeated treatment with icatibant in adult patients experiencing HAE attacks during the FAST-2 open-label extension (OLE) phase. Methods: Patients completing the controlled phase were eligible to participate in the OLE phase and receive open-label icatibant (30 mg subcutaneously) for the treatment of cutaneous, abdominal, and/or laryngeal HAE attack(s) severe enough to warrant treatment. Time to onset of symptom relief was calculated for each attack. Descriptive analyses (median, 95% CIs) were performed for all attacks; post hoc analyses were conducted in patients with at least five icatibanttreated attacks throughout the FAST-2 OLE phase. Safety was also monitored. Results: Fifty-four patients received icatibant for 374 attacks (176 cutaneous, 168 abdominal, and 30 laryngeal). For cutaneous and/or abdominal attacks (attacks 2–5), the median times to onset of symptom relief ranged between 2.0 and 2.5 h. For all laryngeal attacks, the median times to regression (start of improvement) of symptoms ranged between 0.3 and 4.0 h. Post hoc analyses showed that the overall median time to onset of symptom relief was 2.0 h. Overall, 89.8% of attacks resolved with a single icatibant injection. No drug-related serious adverse events were reported. Conclusions: These findings have demonstrated the efficacy and safety of repeated icatibant treatment for HAE attacks.

Lung inflammation from exposure to airborne particulate matter (PM) may be responsible for morbidity in asthma, but several studies using environmental monitoring data showed inconsistent results. Thus, the aim of this study was to evaluate the capability of induced sputum (IS) technology in order to biologically monitor PM in the lungs of urban asthmatic children.We collected clinical, demographic, biological and environmental monitoring data on 136 children referred for asthma evaluations. The study participants were divided into two groups according to IS eosinophil counts of3% (non-eosinophilic inflammation, n = 52) and ≥3% (eosinophilic inflammation, n = 84).The eosinophilic group displays significantly higher levels of fractional exhaled nitric oxide than the non-eosinophilic one (58.8 ± 47.5 vs 28.9 ± 34.2 ppm, p = 0.007). Particles (0-2.5 and 0-5 µm) comprised a strong risk factor for eosinophilic inflammation in IS (≥3%). Children with80% of particles (0-2.5 µm) out of the total PM accumulated in the airways displayed the highest OR 10.7 (CI 2.052-56.4 p = 0.005) for an existing eosinophilic inflammation. Heme oxygenase-1 (HO-1) enzyme levels in IS positively correlated with % eosinophils and with particles in IS ranging between 2 and 3 μm. The level of HO-1 enzyme activity and FEV1/FVC in children with3% eosinophils, but not ≥3%, was positively and significantly correlated, showing a protective effect of HO-1.Accumulation of PM involves oxidative stress pathways and is a risk factor for developing eosinophilic inflammation in asthmatic children. IS can biologically monitor this process.

Metachromatic cells are increased in the airways of asthmatic patients. We obtained metachromatic cells from asthmatic airways using an induced sputum technique. The histamine release following ConA, anti-IgE and anti-IgE + IL3 from those cells were evaluated before and following the addition of cromoline Na and nedocromil Na. Metachromatic cells had a higher rate of spontaneous histamine release when compared to peripheral basophils. Cromoline Na and nedocromil Na inhibited histamine release from triggered metachromatic cells but not from peripheral basophils. It is concluded that airway metachromatic cells from asthmatics behave differently than peripheral basophils.

A total of 107, 636 subjects of both sexes who were drafted into the Israeli Defense Forces during 1986 to 1988 were analyzed for the presence of asthma based on questionnaire responses and the results of pulmonary function tests. Most patients (79%) had either mild or inactive disease. Lifetime prevalence increased by 21.7% from 5.3% in 1986 to 6.5% in 1988. The results of a follow-up carried out over 5 to 7 years showed no major change in severity in most patients. The incidence rate remained stable throughout 1987 to 1989 (275, 245, and 243 per 100,000, respectively), without there being any major change in the severity of the asthma during the subsequent 3 to 5 years. It was also revealed that the more physically demanding jobs were associated with a higher prevalence of job transfer. The results of this study suggest that the factors causally associated with asthma are relatively more active during early childhood.

Defective immunological suppression can be a cause of the inflammation that leads to an allergic condition such as asthma. Suppressor regulatory T cells (Tregs) are essential for inducing and maintaining immunological tolerance to foreign and self-antigens, including allergens. Tregs are apparently altered in number and function in allergic asthmatic patients. Some treatments that ameliorate asthma symptoms lead to an increase in the number and functional impairment of Tregs, indicating that these cells play an important role in the anti-inflammatory effect of those medications.

The prevalence of food allergy is increasing in both the pediatric and adult populations. While symptom onset occurs mostly during childhood, there are a considerable number of patients whose symptoms first begin to appear after the age of 18 years. The majority of patients with adult-onset food allergy suffer from the pollen-plant allergy syndromes. Many of them manifest their allergy after exercise and consuming food to which they are allergic. Eosinophilic esophagitis, an eosinophilic inflammation of the esophagus affecting individuals of all ages, recently emerged as another allergic manifestation, with both immediate and late response to the ingested food. This review provides a condensed update of the current data in the literature on adult-onset allergy.