Administration of BNT162b2 mRNA COVID-19 vaccine to subjects with various allergic backgrounds.

Background: The mRNA-based COVID-19 vaccine was introduced to the general public in December 2020. Shortly thereafter, safety concerns were raised due to the reporting of allergic reactions. Allergy-related disorders were suspected to be significant risk factors and the excipient polyethylene glycol was suggested to be a robust allergen. Methods: This is a retrospective study analysis. Subjects with putative risk factors for severe allergic reactions to the Pfizer-BioNTech BNT162b2 vaccine were referred for vaccination under observation at the Unit of Allergy and Clinical Immunology. Data was collected for each subject, including demographic details, medical history and previous reactions to any allergen. When appropriate, skin tests were done prior to vaccination. Results: A total of 346 subjects received 623 vaccine doses under observation. The study included patients with various allergy-related disorders (n=290) and those with allergy to a previous COVID-19 vaccine dose (n=56). Both groups showed female predominance (78% and 88%, p=NS). Patients without reactions to previous doses reported more drug allergy (80% vs. 39%, p<0.001) and previous anaphylaxis (64% vs. 14%, p<0.001). There was no difference in sensitivity to other allergens, including polyethylene glycol. Under observation, mild allergic reactions were noted in 13 individuals characterized by female gender (100%), a history of anaphylaxis (69%) and drug allergy (62%). In 7 subjects, allergy was treated with antihistamines while others recovered spontaneously. Conclusion: Our study demonstrates that vaccination under specialist-supervision is a powerful tool for reducing over-diagnosis of systemic reactions and for rapid and reliable collection of vaccine safety data.

Fast Acting, Dry Powder, Needle-Free, Intranasal Epinephrine Spray: A Promising Future Treatment for Anaphylaxis.

BACKGROUND: Epinephrine intramuscular (IM) autoinjector is a life-saving drug for the emergency treatment of immediate-type allergic reactions (type I). Nevertheless, it is sometimes applied incorrectly or underused because of short shelf life, high costs, fear of use, or inconvenience of carrying. FMXIN002, a nasal powder spray of epinephrine, was developed as a needle-free alternative. OBJECTIVE: To compare epinephrine pharmacokinetics, pharmacodynamics, and safety after the administration of the FMXIN002 nasal spray versus autoinjector. METHODS: An open-label trial was performed in 12 adults with seasonal allergic rhinitis without asthma. Epinephrine pharmacokinetics, pharmacodynamics, and safety were compared between FMXIN002 (1.6 mg and 3.2 mg) administered intranasally with/without a nasal allergen challenge and IM (0.3 mg) EpiPen. RESULTS: FMXIN002 3.2 mg, administered after a nasal allergen challenge, displayed a shorter Tmax than EpiPen (median: 2.5 minutes vs 9.0 minutes, statistically nonsignificant [NS]) and a significantly shorter time when the measured analyte concentration is 100 pg/mL during the absorption phase pg/mL (median: 1.0 minutes vs 3.0 minutes for FMXIN002, P < .02). Moreover, FMXIN002 3.2 mg administered after the challenge test has resulted in a doubling of the maximal measured plasma analyte concentration over the sampling period (1110 vs 551 pg/mL, NS); area under the curve from 0 to 8 hours was 56% higher (672 vs 431 hours pg/mL, compared with EpiPen, NS). Pharmacodynamic response was comparable at all treatments. FMXIN002 was well tolerated, and treatment-emergent adverse events (AEs) were mild, local, and resolved spontaneously. No AEs were reported after the administration of EpiPen in our study. FMXIN002 was stable for 2 years at room temperature conditions. However, variability in the pharmacokinetics (expressed in coefficient of variation) is high. Having a prior nasal allergen challenge results in a substantial increase and speed of absorption. CONCLUSIONS: Intranasal absorption of dry powder epinephrine is faster than EpiPen offering a clinical advantage in the short therapeutic window for the treatment of anaphylaxis. The FMXIN002 product offers a needle-free, pocket-size, safe, user-friendly, and stable alternative to epinephrine autoinjectors.

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.

Reporting of Allergic Reactions During Pfizer-BioNTech BNTT162B2 Vaccination in Israel.

BACKGROUND: In December 2020, the Israeli Ministry of Health launched a national vaccination campaign against SARS-CoV-2. Concomitant sporadic reports on anaphylactic responses in other countries raised safety concerns at the outset of this operation. OBJECTIVE: To characterize reports on allergic reactions to coronavirus disease 2019 vaccines. METHODS: Allergy events were reported by health care professionals throughout the country to Israeli Ministry of Health Division of Epidemiology via a Web-based computerized national vaccine registry. The study period was from December 19, 2020 to September 13, 2021, during which 14,475,979 injections were administered. RESULTS: Allergic reactions were reported in 463 subjects, 99.3% of whom received Pfizer-BioNTech BNTT162B2. The reporting rate was 106 per million in December 2020. From January to May 2021, a reduction was observed to 66, 18, 14, eight, and zero per million, and reporting remained low until September. Mean age of subjects was 48.9 ± 16.7 years (range, 15-96 years) with a female preponderance of 78%. Epinephrine was administered in 34 subjects. Validated immediate allergy was observed in only 37 cases (8%), suggesting 2.5 to 3.3 bona fide reactions per million. In subjects with reactions classified as severe (n = 46), plausible allergy was identified in 36% to 41% of cases. A history of allergy was associated with high false reporting of immediate reactions (83%). Allergic events after the first dose did not compromise adherence to subsequent doses. CONCLUSIONS: Excessive reporting of allergy declined over time and did not affect adherence to vaccination. The existence of previous allergy may affect reporting profiles, but not the occurrence of vaccine allergy.

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.

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.

Mean platelet volume and clinical outcomes of patients with chest pain discharged from internal medicine wards.

BACKGROUND: Currently, there are no clinical scores for risk stratification of low-risk patients with chest pain. We aimed to examine the association between mean platelet volume (MPV) and risk for adverse clinical outcomes in patients with chest pain discharged from internal medicine wards following acute coronary syndrome (ACS) rule-out. PATIENTS AND METHODS: Included were patients who were admitted to internal medicine wards and were discharged following an ACS-rule-out during 2010-2016. The primary endpoint was the composite of all-cause mortality and hospital admission due to ACS at 30-days following hospital discharge. RESULTS: Included in the study were12 440 patients who were divided into three groups according to MPV. The composite endpoint of 30-day all-cause mortality and hospital admission for ACS occurred more frequently among patients with high MPV. Each one-point increase in MPV was associated with an 18% increase in the risk for the composite endpoint (P = 0.02). Considering patients with MPV less than 7.8 fl as the reference group yielded adjusted hazard ratios for the composite endpoint that was significantly higher in patients in the high MPV tertile ( > 8.8 fl) (hazard ratio 1.6; 95% confidence interval = 1.1-2.5; P = 0.04). Each one-point increase in MPV was associated with an 11% increase in the risk for 1-year all-cause mortality (P = 0.01) and a 10% increase in the risk for 1-year ACS (P = 0.04). CONCLUSION: We found an independent association between high MPV and the risk of death and ACS among patients with chest pain who were discharged from internal medicine wards following an ACS-rule-out. MPV may be combined in the risk stratification of patients with chest pain.

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.

A practical approach to infarction of the spleen as a rare manifestation of multiple common diseases.

INTRODUCTION: There are insufficient data on the aetiologic factors underlying splenic infarction (SI). Therefore, there is no consensus regarding the appropriate diagnostic approach. METHODS: We conducted a retrospective analysis of all patients admitted with SI from January 2004 to December 2014. Medical records were screened for the clinical presentation, underlying causes, associated medical conditions and methods of patient evaluation. RESULTS: We found 89 subjects with 90 episodes of SI. Presentation of SI was characterized by abdominal, flank and chest pain (82.2%, 18.9%, 7.8%, respectively); leukocytosis (in 67% of tested subjects); elevated LDH (72%), CRP (97.5%) and D-Dimer (100%). The main underlying mechanisms were cardioembolic (54.4%), vascular (20%), haematologic disorders (15.6%) and multiple causes (21.1%). Atrial fibrillation and atherosclerosis were common in older patients (age > 70 years) while antiphospholipid syndrome occurred exclusively in younger individuals. SI was the presentation of previously unknown medical conditions in 38% of patients. Abdominal CT, ECG, echocardiography and blood cultures demonstrated the highest diagnostic yield. CONCLUSIONS: Contributing factors are identified in the majority of SI patients. We recommend CT, ECG, echocardiography and blood cultures in all cases. Atrial fibrillation should be sought in older patients, while APLS and haematologic disorders should be suspected in younger ones. KEY MESSAGES There is no consensus regarding the diagnostic approach and management of splenic infarction. Cardiovascular disease and atrial fibrillation are the main causes for SI in elderly subjects while hematological, infectious and other causes are more prevalent in younger ones. Our data strongly suggests a high diagnostic yield for CT scan, ECG, blood culture and echocardiogram in every patient with SI.

Iodinated Contrast Media Allergy in Patients Hospitalized for Investigation of Chest Pain.

BACKGROUND: Iodinated contrast media (ICM) allergy may entail severe adverse events in patients who undergo percutaneous coronary intervention (PCI). Premedication protocols and low-osmolality contrast media have been thought to improve the outcomes of these individuals. OBJECTIVE: The objective of this study was to assess the prevalence and severity of allergic reactions during PCI in patients admitted for investigation of chest pain. METHODS: This is a retrospective analysis of 13,652 patients who were hospitalized with chest pain during the years 2010-2016, at the Department of Internal Medicine, Meir Medical Center. Patient records were screened for diagnosis of prior ICM allergy. Primary outcomes were: (1) records of previous allergy to ICM, (2) administration of antiallergic premedication, and (3) allergic reactions to the ICM during the procedure. RESULTS: Nine hundred thirty-one individuals without prior ICM allergy were referred for PCI, of whom 2 had minor allergic reactions. Previously diagnosed ICM allergy was recorded for 216 subjects (mean age 65.5 ± 10 years, 42% males). Of these, 32 were referred to in-hospital PCI. Premedication was administered in 10 cases only with no documented rationale for not treating the other 22. Only one of the pretreated patients experienced a reaction attributed to allergy, showing no statistical advantage for premedication. No mortality was documented in the 30 days after PCI among the patients with known ICM allergy. CONCLUSIONS: PCI did not induce substantial allergic reactions to ICM in patients with a previously diagnosed allergy. This study did not demonstrate an advantage for premedication.

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.

Impaired renal function is associated with adverse outcomes in patients with chest pain discharged from internal medicine wards.

BACKGROUND: Assessment of chest pain is one of the most common reasons for hospital admissions in internal medicine wards. However, little is known regarding predictors for poor prognosis in patients discharged from internal medicine wards after acute coronary syndrome (ACS) rule-out. OBJECTIVE: To assess the association of kidney function with mortality and hospital admissions due to ACS in patients with chest pain who were discharged from internal medicine wards following ACS rule-out. METHODS: Included were patients admitted to an internal medicine ward who were subsequently discharged following an ACSrule-out during 2010-2016. The primary endpoint was the composite of all-cause mortality and hospital admission due to ACS at 30-days following hospital discharge. RESULTS: Included in the study were12,337 patients who were divided into 3 groups according to renal function. Considering patients with an eGFR ≥ 60 ml/min/1.73m2 as the reference group yielded adjusted hazard ratios for the composite of 30-day all-cause mortality and hospital admission for ACS that increased with reduced eGFR (HR = 2, 95%CI = 1.3-3.3, HR = 4.8, 95%CI = 3-7.6, for patients with eGFR of 45 to 59.9 or <45 ml/min/1.73m2, respectively, p < 0.001). Similarly, reduced renal function was associated with increased 1-year all-cause mortality (HR = 1.6, 95%CI = 1.2-2.2, HR = 4.5, 95%CI = 3.4-5.9, for patients with eGFR of 45-59.9 or <45 ml/min/1.73m2, respectively, p < 0.001). CONCLUSION: We found an independent graded association between lower eGFR and the risk of death and ACS among patients with chest pain who were discharged from internal medicine wards following an ACS rule-out. The eGFR may be combined in the risk stratification of patients with chest pain.

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.