Iodinated contrast media allergy is rare in patients undergoing sialography.

BACKGROUND: Iodinated contrast media allergy is considered as a strong contra-indication for performing sialography. There is little evidence to support this approach. OBJECTIVE: To evaluate the rate of iodinated contrast media (ICM) allergy in subjects undergoing sialography and to assess the risk for allergic responses in patients with a previous diagnosis of allergy. METHODS: We retrospectively reviewed sialo-CBCT studies performed from 2014 to 2019. During the study period we implemented a protocol for performing sialo-CBCT in patients with a prior diagnosis of allergy: 1) Clinical data were collected from a questionnaire and medical records. 2) No premedication was administered but, instead, oxygen, epinephrine and a resuscitation cart were accessible. 3) Following the procedure, each patient was observed for one hour and contacted by telephone 24 hrs later. RESULTS: No allergic responses were documented in the medical records of 1515 subjects following sialo-CBCT studies, including 13 individuals previously diagnosed with ICM allergy. Investigation of the subgroup with prior allergy disclosed that the range of injected volume was between 2 ml to 6.2 ml per patient and that complete secretion of ICM was detected in 7 of 13 patients. In the remainder of subjects, retention rates of 5-50% were observed. CONCLUSIONS: Allergic reactions are exceedingly rare following sialo-CBCT studies regardless of a previous diagnosis of allergy. Pre-medication with corticosteroids and antihistamines is usually not warranted.

Epidemiological, clinical and economic burden of severe eosinophilic asthma in Taiwan: Results from a large tertiary care hospital.

BACKGROUND: Burden of severe eosinophilic asthma (SEA) data in Asia are limited. OBJECTIVE: This retrospective, observational study characterized SEA epidemiology, healthcare resource use (HCRU) and costs for adult patients in Taiwan. METHODS: Data from Taichung Veterans General Hospital electronic medical record database, between 2013 to 2016, were extracted. Eligible general asthma patients were ≥ 18 years at index date, with ≥ 1 medical claim with an asthma diagnosis after the index date. Patients with SEA (meeting additional criteria: Global Initiative for Asthma Step 4/5 treatment guidelines [within 3 months preceding index date], ≥ 2 clinically significant exacerbations, and eosinophil counts ≥ 300 cells/µL [within 12 months preceding index date] or ≥ 150 cells/µL [on index date]) and SEA patients using high-dose inhaled corticosteroids (HD ICS) were also identified. Twelve months' pre-index data were used to evaluate exacerbation frequency, treatment patterns, HCRU, and costs (2016 US Dollars). RESULTS: Of 2,601 eligible general asthmatic patients, 162 (6.2%) met predefined criteria for SEA; of SEA patients, 72/162 (44.4%) had used HD ICS. SEA and HD ICS SEA patients experienced more clinically significant exacerbations than general asthma patients (1.6 ± 3.3 and 1.5 ± 2.6 vs 0.6 ± 2.0, p < 0.01). HD ICS SEA and SEA patients incurred at least 2-2.5-fold higher total asthma-related and all-cause costs than general asthma patients and had significantly greater HCRU. CONCLUSIONS: Of eligible Taiwanese general asthma patients, 6.2% met predefined SEA criteria. Compared with general asthma patients, SEA and HD ICS SEA patients used more respiratory medications, experienced more exacerbations, and incurred greater HCRU and higher costs.

Allergic-like disorders and asthma in patients with common variable immunodeficiency: a multi-center experience.

OBJECTIVE: Common variable immune deficiency (CVID) encompasses a variety of diseases characterized by disturbed immunoglobulin (Ig) production and various immune dysregulations. Scarce data are available regarding relationships between CVID and allergic diseases. Here we examined possible associations between allergies and CVID. METHODS: For this multicenter study, we prospectively enrolled 79 adult CVID patients (≥18 years) who were diagnosed and treated between 2002-2017 at the Hadassah-Hebrew University and Shaare Zedek Medical Centers, Jerusalem, Israel. These patients were examined for allergic manifestations. Patient evaluation comprised medical history, physical examination, skin allergen testing, complete blood count, serum immunoglobulins, IgE levels, and pulmonary function tests. RESULTS: After implementing exclusion criteria, 29 patients were included in the final analysis. Allergic-like disorders were diagnosed in 65% of CVID patients with non-elevated serum IgE levels. Moreover, allergic CVID patients exhibited a higher prevalence of bronchiectasis on chest CT. Autoimmunity was diagnosed in 41.3% of CVID subjects. The type I allergy detected in our study was non-IgE mediated. CONCLUSIONS: Timely diagnosis and stratification of allergy in CVID patients is expected to improve their outcome and quality of life, as well as promote appropriate treatment and better management of pulmonary exacerbations.

Mast cell interleukin-2 production contributes to suppression of chronic allergic dermatitis.

The incidence of chronic allergic dermatitis is rapidly increasing. Regulatory control of this disease has not been adequately explored. Here we report that mast cell-derived interleukin-2 (IL-2) contributes to the suppression of chronic allergic dermatitis. Mice deficient in IL-2 production, or deficient in mast cells (Kit(W-sh/W-sh)), showed exacerbated dermatitis upon repeated oxazolone challenge when compared to their wild-type counterparts. Adoptive transfer of wild-type, but not Il2(-/-), mast cells into Kit(W-sh/W-sh) mice dampened the inflammatory response. During the course of disease, mast cell expansion occurred at the site of inflammation and also in the spleen, where production of IL-2 by mast cells was markedly enhanced. In the absence of mast cell IL-2 production, the ratio of activated to regulatory T cells at the site of inflammation was increased. Thus, MC-derived IL-2 contributes to the maintenance of suppression in chronic allergic skin inflammation.

A Novel Tool for Nasal Polyp Investigation: An Ex vivo Organ Culture System.

BACKGROUND: Nasal polyps are three-dimensional structures arising from the mucosa of the upper airway. Due to their complexity, the reliability of single-layer cell cultures and animal systems as research models is limited. OBJECTIVES: To evaluate the feasibility of an ex vivo organ culture of human polyps, preserving tissue structure and function. METHODS: Nasal polyps were excised during routine endoscopic sinus surgery for chronic rhinosinusitis and polyposis. Fresh tissue samples were used for pathological evaluation and for the preparation of 250-500 µm sections, which were incubated in culture media. Tissue viability was assessed by visualisation of cilia motility, measurement of glucose uptake, and an infectivity assay. Cytokine secretion was evaluated by enzyme-linked immunosorbent assay and real-time polymerase chain reaction before and after the introduction of steroids. RESULTS: Polyp tissue viability was retained for 2-3 days as demonstrated by cilia motility, glucose uptake and preserved cellular composition. Tissue samples maintained their capacity to respond to infection by herpes simplex virus 1 and adenovirus. Introduction of dexamethasone to cultured tissue samples led to suppression of interferon-g production. CONCLUSIONS: The ex vivo nasal polyp organ culture reproduces the physiological, metabolic, and cellular features of nasal polyps. Furthermore, it shows a preserved capacity for viral infection and response to drugs. This system is a useful tool for the investigation nasal-polyps and for the development of novel therapies.

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

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

MicroRNA-4443 regulates mast cell activation by T cell-derived microvesicles.

BACKGROUND: The mechanism by which mast cells (MCs) are activated in T cell-mediated inflammatory processes remains elusive. Recently, we have shown that microvesicles derived from activated T cells (mvT*s) can stimulate MCs to degranulate and release several cytokines. OBJECTIVE: The aim of this study was to characterize the contribution of microRNAs (miRs) delivered by microvesicles to MC activation. METHODS: miR profiling was performed with NanoString technology and validated by using real-time PCR. The biological role of mvT* miR was verified by overexpression of miRs in MCs using mimic or inhibitory molecules and analyzing the effect on their predicted targets. RESULTS: mvT*s were found to downregulate the expression of the tyrosine phosphatase protein tyrosine phosphatase receptor type J (PTPRJ), a known extracellular signal-regulated kinase inhibitor. Bioinformatics analysis predicted that miR-4443 regulates the PTPRJ gene expression. Indeed, miR-4443, which was present in mvT*s, was also found to be overexpressed in human MCs stimulated with these MVs. α-Amanitin insensitivity confirmed that overexpression of miR-4443 was not due to transcriptional activation. The luciferase reporter assay indicated that the 3' untranslated region of PTPRJ was targeted by this miR. Transfection of MCs with mimic or inhibitor of miR-4443 resulted in decreased or enhanced PTPRJ expression, respectively. Furthermore, miR-4443 regulated extracellular signal-regulated kinase phosphorylation and IL-8 release in MCs activated by mvT*s. CONCLUSION: These results support a scenario by which T cell-derived microvesicles act as intercellular carriers of functional miR-4443, which might exert heterotypic regulation of PTPRJ gene expression in MCs, leading to their activation in the context of T cell-mediated inflammatory processes.

CD300f associates with IL-4 receptor α and amplifies IL-4-induced immune cell responses.

IL-4 receptor (R) α, the common receptor chain for IL-4 and IL-13, is a critical component in IL-4- and IL-13-mediated signaling and subsequent effector functions such as those observed in type 2 inflammatory responses. Nonetheless, the existence of intrinsic pathways capable of amplifying IL-4Rα-induced responses remains unknown. In this study, we identified the myeloid-associated Ig receptor CD300f as an IL-4-induced molecule in macrophages. Subsequent analyses demonstrated that CD300f was colocalized and physically associated with IL-4Rα. Using Cd300f(-/-) cells and receptor cross-linking experiments, we established that CD300f amplified IL-4Rα-induced responses by augmenting IL-4/IL-13-induced signaling, mediator release, and priming. Consistently, IL-4- and aeroallergen-treated Cd300f(-/-) mice displayed decreased IgE production, chemokine expression, and inflammatory cell recruitment. Impaired responses in Cd300f(-/-) mice were not due to the inability to generate a proper Th2 response, because IL-4/IL-13 levels were markedly increased in allergen-challenged Cd300f(-/-) mice, a finding that is consistent with decreased cytokine consumption. Finally, CD300f expression was increased in monocytes and eosinophils obtained from allergic rhinitis patients. Collectively, our data highlight a previously unidentified role for CD300f in IL-4Rα-induced immune cell responses. These data provide new insights into the molecular mechanisms governing IL-4Rα-induced responses, and may provide new therapeutic tools to target IL-4 in allergy and asthma.

Physical Training in a Medical Fitness Room for Patients with Chronic Diseases: Functional and Metabolic Outcomes.

BACKGROUND: Physical inactivity is a pivotal factor in the development and progression of various chronic diseases. However, most fitness facilities exclude unhealthy individuals. Therefore, an exercise program that admits such patients is imperative. OBJECTIVES: To evaluate the effectiveness of a fitness facility that admits adult subjects with multiple chronic diseases. METHODS: We conducted a retrospective screening of patient records from the Medical Fitness Facility at Meir Medical Center, Israel. Intake of subjects was done by a multidisciplinary team. For each individual, personalized diet and exercise plans were developed and patients attended the facility twice a week. Each participant was evaluated at enrolment and after 4 months for well-being, metabolic parameters, exercise capacity, and laboratory blood tests. RESULTS: A total of 838 individuals were enrolled, mean age 57 years. Their medical conditions included dyslipidemia (48.8%), hypertension (37.6%), and diabetes mellitus (24.9%), followed by musculoskeletal problems (arthropathy 19%, lower back pain 16.1%) and ischemic heart disease (13.4%). Less common diagnoses were vascular diseases, pulmonary diseases, and malignancy. Only 40.5% of participants adhered to the regimen with advanced age being the best predictor for adherence. At the follow-up visit, body mass index was lower (31.2 vs. 30.2 kg/m2, P <0.0001), exercise capacity increased (measured as maximal MET; 7.1 vs. 8.1, P < 0.0001), and well-being improved (measured by Short Form Survey [SF-36]; 69.3 vs. 76.0, P <0.0001). CONCLUSIONS: We show that a fitness program for patients with multiple chronic diseases is feasible and effective in improving prognostic parameters, albeit significantly challenged by adherence limitations.

The Involvement of Protein Kinase D in T Cell-Induced Mast Cell Activation.

BACKGROUND: It has recently been reported that mast cells (MC) can be activated to degranulate and release certain cytokines in response to direct physical contact with activated but not resting T cells or their membranes. The MAPK family members ERK and p38 were found to participate. In this work, we further characterize the signaling events involved in this novel pathway of activation. METHODS: Human MC were stimulated by activated T cell membranes (T*m). Phosphorylation of kinases was assessed by Western blotting. Protein kinase D (PKD) translocation was visualized by confocal microscopy. Degranulation was assessed by ß-hexosaminidase release and cytokine production by ELISA. RESULTS: Stimulation of human MC by activated T*m resulted in the activation of PKD. PKD inhibition by the specific pharmacological inhibitor Gö6976 resulted in a reduction in the phosphorylation of p38 but not ERK. Gö6976 also inhibited degranulation and cytokine release. CONCLUSIONS: MC stimulation by physical contact with T cells results in PKD activation, leading to the phosphorylation of p38, degranulation and release of cytokines. Understanding the molecular events associated with T cell-induced MC activation might lead to therapeutic approaches for controlling T cell-mediated inflammatory processes in which MC participate.

Seasonal Exacerbation of Asthma Is Frequently Associated with Recurrent Episodes of Acute Urticaria.

BACKGROUND: Asthma and urticaria are both partially mediated by an increased release of histamine from highly activated mast cells. They are pathophysiologically different, as mast cell degranulation in these 2 disorders results from different mechanisms. OBJECTIVE: To assess the incidence of urticaria in patients with asthma, and of asthma in patients with chronic spontaneous urticaria (CSU). PATIENTS AND METHODS: Over 1 year of follow-up, asthma patients (n = 110) were assessed for the incidence and characteristics of urticaria, and a link, if it existed, to seasonal exacerbations and the severity of asthma was traced. We also prospectively assessed CSU patients (n = 95) during the same period of time for the incidence of asthma. Healthy individuals (n = 100), serving as a control group, were also assessed. RESULTS: Episodes of urticaria occurred in 26/110 asthma patients (23.6%), but in only 2/100 healthy control subjects (2%) (p < 0.0001). During the 1-year observation period, episodes of urticaria were significantly more frequent in asthma patients with positive skin-prick test reactions (mainly seasonal pollens), and consequently occurred mostly during seasonal asthma exacerbation, i.e. during acute episodes of urticaria. The incidence of asthma in CSU patients was recorded in 10.5% of the group, similar to that in the healthy control population. DISCUSSION: Our study demonstrates, for the first time, that asthma patients frequently develop acute urticaria, mainly during seasonal exacerbations. In contrast, CSU patients do not show an increased incidence of asthma.

Colchicine-clarithromycin-induced rhabdomyolysis in Familial Mediterranean Fever patients under treatment for Helicobacter pylori.

Chronic administration of colchicine remains a mainstay of therapy for patients with Familial Mediterranean Fever (FMF). As this medication is a strong CYP3A4 inhibitor, it has the potential to interact with many routinely used medications. One such medication is clarithromycin, itself a strong inhibitor of the same enzyme, and a typical choice for triple therapy eradication of H. pylori. Various sequelae of colchicine-clarithromycin interaction have been documented and can be expected by prescribing physicians, with rhabdomyolysis, though rare, being among the most serious. Review of cases from a tertiary academic medical center and full PubMed/MEDLINE literature review. Despite the prevalence of diseases treated with clarithromycin and the expected drug interaction with colchicine, only two cases in the literature document clinical rhabdomyolysis due to colchicine-clarithromycin interaction. In neither case, however, were patients undergoing treatment for FMF. Herein, we describe the first two cases in the literature of clinical rhabdomyolysis in FMF patients under colchicine therapy after administration of clarithromycin as part of therapy treating H. pylori infection.

T cell-derived microvesicles induce mast cell production of IL-24: relevance to inflammatory skin diseases.

BACKGROUND: It has recently been shown that microvesicles derived from activated T cells can stimulate human mast cells (MCs) to degranulate and release several cytokines. OBJECTIVE: The aim of this study was to characterize microvesicle-induced MC expression patterns. Through identification of unique cytokine and chemokine expression, we attempted to reveal pathogenetic roles for this pathway of MC activation. METHODS: T cell-derived microvesicles were labeled with PKH67 to allow visualization of their interaction with human MCs. Consequent gene expression profiling was studied by using a whole-genome microarray and analyzed for identification of cellular pathway clusters. Expression of 3 selected genes, chemokine (C-C motif) ligand 3 (CCL3), chemokine (C-C motif) ligand 7 (CCL7), and IL24, was validated by means of quantitative RT-PCR and specific ELISA. IL24, which has not been recognized heretofore in MCs, was also tested for its effect on keratinocyte signal transducer and activator of transcription 3 phosphorylation and for its presence in MCs in psoriatic skin lesions. RESULTS: Uptake and internalization of activated T cell-derived microvesicles into human MCs occurred within 24 hours. Microvesicles induced the upregulation of several clusters of genes, notably those that are cytokine related. Among these, IL24 appeared to be a hallmark of microvesicle-induced activation. MC-derived IL-24, in turn, activates keratinocytes in vitro, as manifested by signal transducer and activator of transcription 3 (STAT3) phosphorylation, and is produced in MCs within psoriatic lesions. CONCLUSION: Production of IL-24 is a unique feature of microvesicle-induced MC activation because its production by these cells has not been recognized thus far. We propose that this MC-derived cytokine might contribute to the pathologic findings in T cell-mediated skin inflammation.

Increased Prevalence of Diabetes Mellitus in a Non-Obese Adult Population: HIV-Infected Ethiopians.

BACKGROUND: Diabetes mellitus (DM) is a metabolic sequel in people infected with HIV, especially following the advent of HAART. This may be a particular concern in immigrants due to lifestyle changes. OBJECTIVES: To characterize the prevalence of DM in HIV-infected Ethiopians in Israel, and to define the risk factors. METHODS: We retrospectively screened the records of 173 HIV-infected Ethiopians and 69 HIV-infected non-Ethiopian HIV patients currently registered at the HIV Clinic of Meir Medical Center. Data were also retrieved from 1323 non-HIV Ethiopians treated in the hospital between 2007 and 2012. The presence of DM was determined by family physician diagnosis as recorded in the hospital database or by the presence of one or more of the following: fasting glucose > 127 mg/dl, hA1C > 6.5% (> 48 mmol/mol), or blood glucose > 200 mg/dl. Population data and risk factors for DM were analyzed by univariate and multivariate analyses. RESULTS: Among HIV-infected Ethiopian subjects, the prevalence of DM was 31% (54/173) compared to 4% (3/69) in HIV-infected non-Ethiopians and 8% (102/1323) in non-HIV-infected Ethiopians (P < 0.0001). The relatively increased prevalence of DM was age independent, but most noticeable in those under the median age (< 42 years). Body mass index (BMI) was a predictor for DM (OR 1.263, CI 1.104-1.444, P = 0.001), although its values did not vary between the two ethnic groups. CONCLUSIONS: HIV-infected Ethiopians are more likely to develop DM at low BMI values compared to non-Ethiopians. This observation questions the relevance of accepted BMI values in this population and suggests that preventive measures against DM be routinely taken in these subjects.

Cutting edge: persistence of increased mast cell numbers in tissues links dermatitis to enhanced airway disease in a mouse model of atopy.

The development of chronic allergic dermatitis in early life has been associated with increased onset and severity of allergic asthma later in life. However, the mechanisms linking these two diseases are poorly understood. In this study, we report that the development of oxazolone-induced chronic allergic dermatitis, in a mouse model, caused enhanced OVA-induced allergic asthma after the resolution of the former disease. Our findings show that oxazolone-induced dermatitis caused a marked increase in tissue mast cells, which persisted long after the resolution of this disease. Subsequent OVA sensitization and airway challenge of mice that had recovered from dermatitis resulted in increased allergic airway hyperreactivity. The findings demonstrate that the accumulation of mast cells during dermatitis has the detrimental effect of increasing allergic airway hypersensitivity. Importantly, our findings also show that exposure to a given allergen can modify the immune response to an unrelated allergen.

Cyclosporin A impairs the secretion and activity of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeat).

The protease ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeat) cleaves multimers of von Willebrand factor, thus regulating platelet aggregation. ADAMTS13 deficiency leads to the fatal disorder thrombotic thrombocytopenic purpura (TTP). It has been observed that cyclosporin A (CsA) treatment, particularly in transplant patients, may sometimes be linked to the development of TTP. Until now, the reason for such a link was unclear. Here we provide evidence demonstrating that cyclophilin B (CypB) activity plays an important role in the secretion of active ADAMTS13. We found that CsA, an inhibitor of CypB, reduces the secretion of ADAMTS13 and leads to conformational changes in the protein resulting in diminished ADAMTS13 proteolytic activity. A direct, functional interaction between CypB (which possesses peptidyl-prolyl cis-trans isomerase (PPIase) and chaperone functions) and ADAMTS13 is demonstrated using immunoprecipitation and siRNA knockdown of CypB. Finally, CypB knock-out mice were found to have reduced ADAMTS13 levels. Taken together, our findings indicate that cyclophilin-mediated activity is an important factor affecting secretion and activity of ADAMTS13. The large number of proline residues in ADAMTS13 is consistent with the important role of cis-trans isomerization in the proper folding of this protein. These results altogether provide a novel mechanistic explanation for CsA-induced TTP in transplant patients.