Diagnostic performance of type I hypersensitivity-specific markers combined with CRP and IL-6 in complicated acute appendicitis in pediatric patients.

OBJECTIVE: In this study, the diagnostic value of C-reactive protein (CRP), interleukin-6 (IL)-6, and specific markers for type I hypersensitivity were evaluated in pediatric patients with severe acute appendicitis. METHODS: A total of 140 pediatric patients with "acute appendicitis" who underwent surgery at the Department of General Surgery of the Anhui Provincial Pediatric Patients' Hospital between December 2022 and April 2023 were studied retrospectively. The data collected included the gender, age, onset time, white blood cell count (WBC), CRP, procalcitonin (PCT), serum IgE, serum IL-4, serum IL-5, serum IL-6, serum IL-9, and serum IL-13 levels. The pediatric patients were divided into two groups based on the intraoperative situation and postoperative pathology: the non-complicated acute appendicitis group (NCAA) and the complicated acute appendicitis group (CAA). We analyzed the data from both groups using univariate and multivariate logistic regression models and constructed an ROC curve. RESULTS: The CAA group outperformed the NCAA group in terms of onset time, WBC, CRP, PCT, IgE, IL-6, IL-9, and IL-13 levels (P < 0.05), but there was no statistically significant difference between the two groups in terms of gender, IL-4, or IL-5 levels (P > 0.05). Then, significant independent variables were incorporated into multivariate logistic regression. According to the results, CRP, IgE, IL-6, and IL-13 are all independent risk factors for CAA. The OR and 95% CI for each factor are as follows: CRP (OR = 1.073, 95%CI: 1.010-1.140, P = 0.022), IgE (OR = 0.975, 95%CI: 0.952-0.999, P = 0.038), IL-6 (OR = 1.494, 95%CI: 1.052-2.121, P = 0.025), and IL-13 (OR = 1.310, 95%CI: 1.036-1.657, P = 0.024). The receiving operator characteristics analysis yielded area under the curve (AUC) values of 0.8187, 0.9083, 0.8947, and 0.8394, respectively, for CRP, IgE, IL-6, and IL-13, confirming their significance in the diagnosis of CAA (P < 0.05). CONCLUSION: Risk factors for CAA include CRP, IgE, IL-6, and IL-13. The combination of these serological markers can be used to diagnose CAA.

Analysis of type I hypersensitivity-induced inflammatory response in children of different age groups with acute appendicitis.

OBJECTIVE: To explore the differences in type I hypersensitivity-induced inflammatory response among children of different age groups with acute appendicitis. METHODS: We selected children diagnosed with "acute appendicitis" who underwent surgery in the Department of General Surgery of Anhui Provincial Children's Hospital from January 2022 to June 2022 and collected their basic data. We divided them into two groups according to age: the infant group (less than 3 years old) and the pediatric group (3-14 years old). The gender, age, onset time, hospital stay, preoperative white blood cells, percentage of neutrophils, C-reactive protein (CRP), and enzyme-linked immunosorbent assay (ELISA) were collected to determine the levels of immunoglobulin E (IgE), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-6 (IL-6), and interleukin-9 (IL-9) in appendicular lavage fluid, and the differences between the two groups were compared. RESULTS: There were 15 children in the infant group and 15 in the pediatric group. There was no significant difference between the two groups with respect to onset time and gender. The hospitalization time in the pediatric group was (5.7 ± 2.1) d, the preoperative white blood cells were (14.3 ± 3.7) × 10^9/mL, neutrophil percentage was (84.5 ± 6.3)%, and CRP was (20.0 ± 17.9) mg/mL. The hospitalization time of the infant group was (8.0 ± 3.1) d, the preoperative white blood cells were (19.0 ± 3.8) × 10^9/mL, neutrophil percentage was (77.8 ± 10.4)%, and CRP was (42.5 ± 25.0) mg/mL. The differences between the two groups were significant. There was no significant difference in IL-5 concentration between the two groups in the appendicular lavage fluid. IgE (610.74 ± 72.56) ng/mL, IL-4 (30.80 ± 12.04) ng/mL, IL-6 (118.09 ± 14.29) ng/mL, IL-9 (133.94 ± 16.00) ng/mL were found in the infant group, and IgE (495.61 ± 95.09) ng/mL, IL-4 (22.68 ± 7.05) ng/mL, IL-6 (98.22 ± 22.18) ng/mL and IL-9 (107.86 ± 27.34) ng/mL were found in the pediatric group, and the differences between the two groups were statistically significant. CONCLUSIONS: The inflammatory response in children with acute appendicitis was associated with type I hypersensitivity-induced inflammatory responses, and the type I hypersensitivity was more intense in children in the lower age group.

AT9283, 1-Cyclopropyl-3-(3-(5-(Morpholinomethyl)-1H-Benzo[d]Imidazole-2-yl)-1H-Pyrazol-4-yl) Urea, Inhibits Syk to Suppress Mast Cell-Mediated Allergic Response.

Mast cells are an effector cell that plays a pivotal role in type I hypersensitive immune responses. Mast cells exist in connective tissues, such as skin and mucosal tissue, and contain granules which contain bioactive substances such as histamine and heparin in cells. The granules of mast cells are secreted by antigen stimulation to cause the type I allergic hypersensitivity. In addition, stimulated by antigen, mast cells synthesize and secrete various eicosanoids and cytokines. While AT9283 is known to have anticancer effects, the therapeutic effect of AT9283 on allergic disorders is completely unknown. In this study, it was found that AT9283 reversibly inhibited antigen-IgE binding-induced degranulation in mast cells (IC50, approx. 0.58 µM) and suppressed the secretion of the inflammatory cytokines IL-4 (IC50, approx. 0.09 µM) and TNF-α (IC50, approx. 0.19 µM). For a mechanism of mast cell inhibition, while not inhibiting Syk phosphorylation, AT9283 suppressed the activation of LAT, a downstream substrate protein of Syk, in a dose-dependent manner. As expected, AT9283 also inhibited the activation of PLCγ1 and Akt, downstream signaling molecules of Syk/LAT, and MAP kinases such as JNK, Erk1/2, and P38. In an in vitro protein tyrosine kinase assay, AT9283 directly inhibited Syk activity. Next, AT9283 dose-dependently inhibited passive cutaneous anaphylaxis (PCA), an IgE-mediated allergic acute response, in mice (ED50, approx. 34 mg/kg, p.o.). These findings suggest that AT9283 has potential to use as a new drug for alleviating the symptoms of IgE-mediated allergic disorders.

Clinical and Translational Significance of Basophils in Patients with Cancer.

Despite comprising a very small proportion of circulating blood leukocytes, basophils are potent immune effector cells. The high-affinity receptor for IgE (FcɛRI) is expressed on the basophil cell surface and powerful inflammatory mediators such as histamine, granzyme B, and cytokines are stored in dense cytoplasmic granules, ready to be secreted in response to a range of immune stimuli. Basophils play key roles in eliciting potent effector functions in allergic diseases and type 1 hypersensitivity. Beyond allergies, basophils can be recruited to tissues in chronic and autoimmune inflammation, and in response to parasitic, bacterial, and viral infections. While their activation states and functions can be influenced by Th2-biased inflammatory signals, which are also known features of several tumor types, basophils have received little attention in cancer. Here, we discuss the presence and functional significance of basophils in the circulation of cancer patients and in the tumor microenvironment (TME). Interrogating publicly available datasets, we conduct gene expression analyses to explore basophil signatures and associations with clinical outcomes in several cancers. Furthermore, we assess how basophils can be harnessed to predict hypersensitivity to cancer treatments and to monitor the desensitization of patients to oncology drugs, using assays such as the basophil activation test (BAT).

Molecular Insights of Nickel Binding to Therapeutic Antibodies as a Possible New Antibody Superantigen.

The binding of nickel by immune proteins can manifest as Type IV contact dermatitis (Ni-specific T cells mediated) and less frequently as Type I hypersensitivity with both mechanisms remaining unknown to date. Since there are reports of patients co-manifesting the two hypersensitivities, a common mechanism may underlie both the TCR and IgE nickel binding. Focusing on Trastuzumab and Pertuzumab IgE variants as serendipitous investigation models, we found Ni-NTA interactions independent of Her2 binding to be due to glutamine stretches. These stretches are both Ni-inducible and in fixed pockets at the antibody complementarity-determining regions (CDRs) and framework regions (FWRs) of both the antibody heavy and light chains with influence from the heavy chain constant region. Comparisons with TCRs structures revealed similar interactions, demonstrating the possible underlying mechanism in selecting for Ni-binding IgEs and TCRs respectively. With the elucidation of the interaction, future therapeutic antibodies could also be sagaciously engineered to utilize such nickel binding for biotechnological purposes.

Analysis of risk factors for immune-related adverse events in various solid tumors using real-world data.

The aim of this study was to determine the risk factors for immune-related adverse events (irAEs) induced by immune checkpoint inhibitors. The authors conducted a retrospective study in which patients with malignant melanoma, non-small-cell lung cancer, gastric cancer or renal cell carcinoma who received anti-PD-1/PD-L1 antibodies were included. Of 247 patients, 118 developed a total of 182 irAEs. In the multivariate Fine-Gray regression analysis, serum albumin level ≥3.6 g/dl (hazard ratio: 1.62; 95% CI: 1.10-2.39; p = 0.015) and history of Type I hypersensitivity reactions (hazard ratio: 1.48; 95% CI: 1.02-2.14; p = 0.037) were significantly associated with the development of irAEs. High serum albumin levels and history of Type I hypersensitivity reactions are risk factors for irAEs.

IgE Antibodies against Cancer: Efficacy and Safety.

Immunoglobulin E (IgE) antibodies are well known for their role in allergic diseases and for contributions to antiparasitic immune responses. Properties of this antibody class that mediate powerful effector functions may be redirected for the treatment of solid tumours. This has led to the rise of a new class of therapeutic antibodies to complement the armamentarium of approved tumour targeting antibodies, which to date are all IgG class. The perceived risk of type I hypersensitivity reactions following administration of IgE has necessitated particular consideration in the development of these therapeutic agents. Here, we bring together the properties of IgE antibodies pivotal to the hypothesis for superior antitumour activity compared to IgG, observations of in vitro and in vivo efficacy and mechanisms of action, and a focus on the safety considerations for this novel class of therapeutic agent. These include in vitro studies of potential hypersensitivity, selection of and observations from appropriate in vivo animal models and possible implications of the high degree of glycosylation of IgE. We also discuss the use of ex vivo predictive and monitoring clinical tools, as well as the risk mitigation steps employed in, and the preliminary outcomes from, the first-in-human clinical trial of a candidate anticancer IgE therapeutic.

Dasatinib Inhibits Lyn and Fyn Src-Family Kinases in Mast Cells to Suppress Type I Hypersensitivity in Mice.

Mast cells (MCs) are systemically distributed and secrete several allergic mediators such as histamine and leukotrienes to cause type I hypersensitivity. Dasatinib is a type of anti-cancer agent and it has also been reported to inhibit human basophils. However, dasatinib has not been reported for its inhibitory effects on MCs or type I hypersensitivity in mice. In this study, we examined the inhibitory effect of dasatinib on MCs and MC-mediated allergic response in vitro and in vivo. in vitro, dasatinib inhibited the degranulation of MCs by antigen stimulation in a dose-dependent manner (IC50, ~34 nM for RBL-2H3 cells; ~52 nM for BMMCs) without any cytotoxicity. It also suppressed the secretion of inflammatory cytokines IL-4 and TNF-α by antigen stimulation. Furthermore, dasatinib inhibited MC-mediated passive cutaneous anaphylaxis (PCA) in mice (ED50, ~29 mg/kg). Notably, dasatinib significantly suppressed the degranulation of MCs in the ear tissue. As the mechanism of its effect, dasatinib inhibited the activation of Syk and Syk-mediated downstream signaling proteins, LAT, PLCγ1, and three typical MAP kinases (Erk1/2, JNK, and p38), which are essential for the activation of MCs. Interestingly, in vitro tyrosine kinase assay, dasatinib directly inhibited the activities of Lyn and Fyn, the upstream tyrosine kinases of Syk in MCs. Taken together, dasatinib suppresses MCs and PCA in vitro and in vivo through the inhibition of Lyn and Fyn Src-family kinases. Therefore, we suggest the possibility of repositioning the anti-cancer drug dasatinib as a treatment for various MC-mediated type I hypersensitive diseases.

Oral Administration of Fucoidan Can Exert Anti-Allergic Activity after Allergen Sensitization by Enhancement of Galectin-9 Secretion in Blood.

A previous study revealed that fucoidan inhibited mast cell degranulation through the upregulation of galectin-9 in blood. The purpose of this study is to elucidate its mechanism using ovalbumin (OVA) induced anaphylaxis model mice (BALB/c, Female, 5-week-old) and mast cell line (RBL-2H3 cells). Oral administration of fucoidan after sensitization with OVA/Al(OH)3 inhibited reduction of rectal temperature induced by activation of mast cells. Fucoidan increased galectin-9 mRNA expression only in colonic epithelial cells. These results suggested that fucoidan could suppress the allergic symptoms in sensitized mice by inducing galectin-9 production from colonic epithelial cells. In addition, to check the influence of galectin 9 on the degranulation of mast cells, RBL-2H3 cell lines were treated directly with recombinant galectin-9. As expected, galectin-9 inhibited degranulation of RBL-2H3 cells pre-bound with IgE. Moreover, the residual amounts of IgE on RBL-2H3 cells were decreased by an addition of galectin-9. It was demonstrated that galectin-9 could remove IgE even if IgE was already bound to mast cells and suppress the mast cells degranulation induced by antigen. This study shows that fucoidan might become an effective therapeutic agent for patients already developed type I allergic diseases.

Occupational disease due to Anisakis simplex in fish handlers.

BACKGROUND: Anisakis is a marine nematode. Its larvae can be found encysted in several species, both in the abdominal cavity and in the adjacent musculature. The most commonly affected commercial species are hake, whiting, cod, and mackerel. The prevalence in fish varies according to the fishing area and the size of the host. MATERIALS AND METHODS: Until now only three species have been confirmed to be involved in human anisakiasis, the most common ones being A. simplex sensu stricto (s.s.) and A. pegreffii, and anecdotally, A. physeteris. Infestation in humans occurs when they eat raw or undercooked parasitized fish or cephalopods (pickled, cold-smoked, salted, semi-preserved, prepared in certain Asian styles like sushi or sashimi, ceviche). RESULTS: The majority of anisakiasis cases have been described by Japanese authors. However, over the last few years there has been an increase in the number of cases reported in other countries including Italy and Spain. It is estimated that its incidence in the European Union is 0.32/100,000, and in the Basque Country (Spain), this parasite is responsible for 10% of anaphylaxis cases and 32% of urticaria cases in adults aged 40-60 years, around 300 cases/year. Anisakis-related disease in the work environment (occupational disease) is less common. CONCLUSIONS: We present three cases of the occupational disease in Spain due to a type I hypersensitivity to Anisakis simplex in individuals who handle fish (one fishmonger, one supermarket employee, and one chef).

Investigation of possible risk factors in the development of seasonal allergic conjunctivitis.

AIM: To analyze the possible risk factors in the development of seasonal allergic conjunctivitis (SAC) through an evaluation of skin allergy tests and data obtained from questionnaires. METHODS: The study included a total of 75 SAC patients and 71 control subjects without SAC diagnosis who were admitted to the Abant Izzet Baysal University Medical Faculty Ophthalmology Clinic between March 2016 and December 2016. Skin prick tests were performed for all participants. Serum levels of total IgE and 25-OH vitamin D were also measured. In the tear, total IgE levels were measured. Moreover, possible risk factors for the onset of SAC (smoking, paracetamol exposure, vitamin D supplementation and environmental factors etc.) were examined for all patients by both prenatal and postnatal aspects. RESULTS: The patients with SAC were found to have a history of maternal paracetamol exposure during the prenatal period. Likewise, in the same patient group, the duration of postnatal vitamin D supplementation was shorter (P<0.001). However, no significant correlation was found between SAC and maternal antibiotic exposure, maternal smoking, the mode of delivery and birth weight, as well as presence of pets. Moreover, patients with SAC were more likely to have asthma, allergic rhinitis and oral allergy syndrome. We have also found that SAC patients' mothers and siblings were more likely to have allergic conjunctivitis. Likewise, their fathers were more likely to have allergic rhinitis. CONCLUSION: Prenatal maternal paracetamol exposure and shorter duration of vitamin D supplementation in the postnatal period may play a role in development of SAC. Therefore prevention of unnecessary gestational paracetamol intake and vitamin D supplementation during infancy could potentially reduce the onset and development of SAC.

Anaphylaxis in dogs and cats.

OBJECTIVE: To review and summarize current information regarding the pathophysiology and clinical manifestations associated with anaphylaxis in dogs and cats. The etiology, diagnosis, treatment, and prognosis is discussed. ETIOLOGY: Anaphylaxis is a systemic, type I hypersensitivity reaction that often has fatal consequences. Many of the principal clinical manifestations involve organs where mast cell concentrations are highest: the skin, the lungs, and the gastrointestinal tract. Histamine and other deleterious inflammatory mediators promote vascular permeability and smooth muscle contraction; they are readily released from sensitized mast cells and basophils challenged with antigen. Anaphylaxis may be triggered by a variety of antigens including insect and reptile venom, a variety of drugs, vaccines, and food. DIAGNOSIS: Anaphylaxis is a clinical diagnosis made from a collection of signs and symptoms. It is most commonly based on pattern recognition. Differential diagnoses include severe asthma, pheocromocytoma, and mastocytosis. THERAPY: Epinephrine is considered the drug of choice for the treatment of anaphylaxis. It acts primarily as a vasopressor in improving hemodynamic recovery. Adjunctive treatments include fluid therapy, H1 and H2 antihistamines, corticosteroids, and bronchodilators; however, these do not substitute for epinephrine. PROGNOSIS: Prognosis depends on the severity of the clinical signs. The clinical signs will vary among species and route of exposure. The most severe clinical reactions are associated when the antigen is administered parenterally.

Dermatite alérgica sazonal em ovinos deslanados no nordeste do Brasil / Sazonal allergic dermatitis in hair sheep from northeastern Brazil

Dermatite alérgica sazonal foi diagnosticada em um rebanho de 40 ovinos da raça Santa Inês no município de Jucurutú, Estado de Rio Grande do Norte. Para o estudo epidemiológico e observação dos sinais clínicos a propriedade foi visitada periodicamente entre 2007 e 2010. Os ovinos eram criados extensivamente em campo nativo cortado pelo rio Piranhas e com um açude permanente. Entre 2007 e 2009 adoeceram 13 (32,5%) ovinos de um total de 40. As lesões eram observadas durante a época da chuva e regrediam total ou parcialmente durante a seca, reaparecendo no próximo período chuvoso. Os animais que foram retirados da área se recuperaram. No final de 2009 foram eliminados os animais susceptíveis e três novos casos apareceram em 2010. A pele apresentava lesões alopécicas, crostosas, enrugadas, esbranquiçadas e com intenso prurido, localizados na região da cabeça (orelhas, ao redor dos olhos e região frontal), região dorsal do corpo e garupa. Histologicamente, a epiderme apresentou hiperqueratose, acantose, hipergranulose e moderada espongiose. Na derme havia infiltrado inflamatório, principalmente perivascular, composto por eosinófilos, macrófagos e plasmócitos. Observou-se queratose de folículos pilosos e dilatação das glândulas sudoríparas. No hemograma, os valores de todos os animais estavam dentro dos valores normais. Em abril e junho de 2010 foram realizadas capturas de insetos com armadilhas luminosas CDC, sendo 110 dípteros capturados, dos quais 43 foram identificados como Culicoides insignis Lutz. Considerando que esta espécie tem sido associada à dermatite alérgica em outras regiões conclui-se que a doença é uma dermatite alérgica sazonal associada à picada de C. insignis.

Seasonal allergic dermatitis is reported in a flock of 40 hair sheep of the Santa Inês breed, in the county of Jucurutú, State of Rio Grande do Norte, in the semiarid region of Northeastern Brazil. For the epidemiologic and clinical observations the farm was visited periodically from 2007 to 2010. The flock was raised extensively in a Paddock crossed by the Piranhas river, and had also a permanent pond. Between 2007 and 2009, 13 (32.5%) sheep out of 40 were affected. The lesions were observed during the raining season, regressed total or partially during the dry season, and reappeared in the next raining period. Sheep removed to other region recovered. At the end of 2009, all affected sheep were removed from the flock. Three new cases appeared in 2010. The skin of the affected sheep was whitish, irregularly thickened, with alopecia, crusts, and intense pruritus. Those lesions were localized more frequently in the head (ears and periocular and frontal regions) but in some animals the dorsum and croup were also affected. Histologic lesions of the epidermis were hyperkeratosis, acanthosis, hypergranulosis, and moderate spongiosis. The dermis showed infiltration by eosinophils, macrophages and plasma cells, mainly perivascular. The hair follicles showed keratosis and the sudoriparous glands were dilated. No changes were observed in the differential blood count. In April and June 2010 insects were captured by the use of CDC light trap. Forty three out of 110 dipterous captured were identified as Culicoides insignis Lutz. It is concluded that the disease is a seasonal allergic dermatitis associated with C. insignis bites.

Hipersensibilidade a inalantes e alimentos nos distúrbios do equilíbrio corporal / Hypersensitivity to inhalants and foods in corporal equilibrium disturbs

Introdução: O saco endolinfático tem sido apontado como o alvo das reações imuno-alérgicas da orelha interna. A prevalência de alergia em pacientes com Doença de Ménière foi estabelecida em torno de 41,6% para inalantes e 26,6% para alimentos, por Derebery em 2000, dados aumentados em relação à prevalência de alergia na população em geral, que, no Brasil, varia de 9% a 30% para inalantes e de 1% a 3% para alimentos. Objetivos: Avaliar a prevalência de reações de hipersensibilidade tipo I a inalantes e alimentos na população do setor de Otoneurologia do Hospital das Clínicas da Faculdade de Medicina de São Paulo e descrever os sintomas vestibulares dos pacientes. Casuística e método: Setenta e cinco pacientes com distúrbios do equilíbrio de origem periférica foram submetidos a questionário de caracterização clínica de sintomas cócleo-vestibulares e teste cutâneo (prick test) para 13 inalantes e 5 alimentos. Resultados: Vinte e cinco (33,3%) pacientes apresentaram prick test positivo a pelo menos um alérgeno inalante e 6 (8%) a pelo menos um alérgeno alimentar. Quatro pacientes apresentaram prick test positivo na ausência de sintomas alérgicos. Prevaleceu a queixa de tontura de caráter rotatório em proporções semelhantes entre os pacientes com prick test positivo e negativo. Conclusão: A prevalência de reações de hipersensibilidade tipo I a inalantes e a alimentos na população avaliada foi maior do que na população em geral. Os sintomas vestibulares não diferiram entre os pacientes da amostra, com prick test positivo ou negativo. No entanto, deve-se obter maior número de amostra para que os dados sejam confiáveis.

Introduction: The endolymphatic sac has been pointed out as the target of immuno-allergic reactions in the inner ear. The prevalence of allergy in patients with Ménières disease was established as approximately 41,6% for inhalants and 26,6% for food by Derebery in 2000, an increase in the data in relation to that of the prevalence of allergy in the general population, which in Brazil varies from 9% to 30% for inhalants and from 1% to 3% for food. Objectives: To evaluate the prevalence of reactions to type I hypersensitivity to inhalants and food in the population of the Otoneurological Section of the Clinics Hospital of the University of São Paulo Medicine School and to describe the vestibular symptoms of the patients. Method: Seventy-five patients with peripheral equilibrium disturbances who had answered a questionnaire of clinical characterization regarding cochlear-vestibular symptoms and undergone prick test for 13 inhalants and 5 types of food. Results: Twenty-five (33,3%) of the patients were positive for the prick test and for at least one allergen inhalant and 6 (8%) for at least one food allergen. Four patients were positive for the prick test in the absence of allergy symptoms. There was a prevalence of the complaint of rotatory dizziness in similar proportions among the patients with positive and negative prick test. Conclusion: The presence of type I hypersensitivity reactions to inhalants and food in the population evaluated was greater than in the general population. The vestibular symptoms did not differ among the patients in the sample, neither with positive or negative prick test results. However, a sample of greater number should be obtained for a higher confidence level of data results.