Loss of the TRPM4 channel in humans causes immune dysregulation with defective monocyte migration.

BACKGROUND: TRPM4 is a broadly expressed, calcium-activated, monovalent cation channel that regulates immune cell function in mice and cell lines. Clinically, however, partial loss- or gain-of-function mutations in TRPM4 lead to arrhythmia and heart disease, with no documentation of immunologic disorders. OBJECTIVE: To characterize functional cellular mechanisms underlying the immune dysregulation phenotype in a proband with a mutated TRPM4 gene. METHODS: We employed a combination of biochemical, cell biological, imaging, omics analyses, flow cytometry, and gene editing approaches. RESULTS: We report the first human cases to our knowledge with complete loss of the TRPM4 channel, leading to immune dysregulation with frequent bacterial and fungal infections. Single-cell and bulk RNA sequencing point to altered expression of genes affecting cell migration, specifically in monocytes. Inhibition of TRPM4 in T cells and the THP-1 monocyte cell line reduces migration. More importantly, primary T cells and monocytes from TRPM4 patients migrate poorly. Finally, CRISPR knockout of TRPM4 in THP-1 cells greatly reduces their migration potential. CONCLUSION: Our results demonstrate that TRPM4 plays a critical role in regulating immune cell migration, leading to increased susceptibility to infections.

Urticaria exacerbations and adverse reactions in patients with chronic urticaria receiving COVID-19 vaccination: Results of the UCARE COVAC-CU study.

BACKGROUND: Concern about disease exacerbations and fear of reactions after coronavirus disease 2019 (COVID-19) vaccinations are common in chronic urticaria (CU) patients and may lead to vaccine hesitancy. OBJECTIVE: We assessed the frequency and risk factors of CU exacerbation and adverse reactions in CU patients after COVID-19 vaccination. METHODS: COVAC-CU is an international multicenter study of Urticaria Centers of Reference and Excellence (UCAREs) that retrospectively evaluated the effects of COVID-19 vaccination in CU patients aged ≥18 years and vaccinated with ≥1 dose of any COVID-19 vaccine. We evaluated CU exacerbations and severe allergic reactions as well as other adverse events associated with COVID-19 vaccinations and their association with various CU parameters. RESULTS: Across 2769 COVID-19-vaccinated CU patients, most (90%) received at least 2 COVID-19 vaccine doses, and most patients received CU treatment and had well-controlled disease. The rate of COVID-19 vaccination-induced CU exacerbation was 9%. Of 223 patients with CU exacerbation after the first dose, 53.4% experienced recurrence of CU exacerbation after the second dose. CU exacerbation most often started <48 hours after vaccination (59.2%), lasted for a few weeks or less (70%), and was treated mainly with antihistamines (70.3%). Factors that increased the risk for COVID-19 vaccination-induced CU exacerbation included female sex, disease duration shorter than 24 months, having chronic spontaneous versus inducible urticaria, receipt of adenovirus viral vector vaccine, having nonsteroidal anti-inflammatory drug/aspirin intolerance, and having concerns about getting vaccinated; receiving omalizumab treatment and Latino/Hispanic ethnicity lowered the risk. First-dose vaccine-related adverse effects, most commonly local reactions, fever, fatigue, and muscle pain, were reported by 43.5% of CU patients. Seven patients reported severe allergic reactions. CONCLUSIONS: COVID-19 vaccination leads to disease exacerbation in only a small number of CU patients and is generally well tolerated.

Chronic urticaria and COVID-19 vaccination: Qatar data (preliminary report of COVAC-CU-international).

BACKGROUND: It is a well-known fact that patients with chronic urticaria (CU) are not at a higher risk for a serious allergic reaction such as anaphylaxis from medications. However, there is a fear and some misconceptions regarding allergic reactions to the COVID-19 vaccine among patients and physicians, which might result in resistance to vaccination. Data about the incidence and severity of COVID-19 vaccine reactions in the CU population are scarce. In this study, we aimed to evaluate the real-world (Qatar) experience of the effects of COVID-19 vaccination on patients with CU and analyze the rates of vaccine-associated reactions and risk factors associated. METHODS: This is a cross-sectional questionnaire-based study conducted as a part of COVAC-CU international under the GALEN UCARE program. Adult patients with CU who received one or more doses of COVID-19 vaccination were administered a questionnaire regarding their demographic characteristics and any potential unfavorable effect of the vaccination from the November 03 to December 31, 2021. RESULTS: These are preliminary results from an ongoing study. The data were collected from 91 patients with CU, of whom 79.12% had chronic spontaneous urticaria, 15.3% had chronic inducible urticaria, and the remaining had both. Of these patients, 74.7% were women. The average age of the patients was 39.3 (range 15-68) years. The majority (84.6%) of them received 2 vaccine doses, 13.1% received 3 doses, and the remaining received 1 dose. Most (70.3%) of these patients did not experience any worsening in CU after vaccination. A total of 62.6% patients reported some type of side effects to the vaccine (16.4% had CU exacerbation and 46.1% other types of reactions, such as fever and muscle pain). None of the patients reported anaphylaxis. Two patients reported improvement in their symptoms. CONCLUSION: Our local data suggest that patients with CU in Qatar can safely take the COVID-19 vaccine. Most patients with CU did not experience any worsening in symptoms, and there were no reports of a severe reaction (anaphylaxis). We recommend maximizing symptom control prior to vaccination to minimize the risk of worsening urticarial symptoms.

Real-world experience of the clinical effectiveness of omalizumab use in Qatar - a study protocol.

Omalizumab (XOLAIR®) is a recombinant DNA-derived humanized IgG1κ monoclonal antibody that binds to IgE and was first introduced in Qatar in 2009. Omalizumab is used to treat moderate-to-severe allergic asthma (SAA), chronic idiopathic urticaria (CIU), and chronic rhinosinusitis with nasal polyposis (CRSwNP). In this study, we have described a proposal to investigate the outcomes and impact of the clinical use of omalizumab for the labeled indications (SAA, CIU, and CRSwNP) and other off-label indications (food allergy, dermatitis, and others) in clinical practice in Qatar. This is a mixed-design study in which the first stage included a chart review of all the patients from the Allergy and Immunology Division registry who received omalizumab since May 2009. The second stage was a cross-sectional questionnaire to review all (previous and current) patients and identify their current health status and treatment outcomes. The third stage was a proof of concept and consisted of selecting a cohort to investigate the omalizumab mechanism for patients before and after administration. Patients with a physician diagnosis of asthma and/or urticaria fulfilling the diagnostic criteria for omalizumab administration and patients with off-label indications were recruited. Expected outcomes included identifying the real-life effectiveness and the experience of using omalizumab in Qatar and reporting all potential adverse effects that might have been missed during early trials or other published studies. This study was essential to observe Qatar's local clinical practice regarding the use of omalizumab; and in addition, we could gather data about the risk factors contributing to disease recovery or progression and those resulting in favorable or unfavorable outcomes. We expect the results to augment the current knowledge about understanding diseases and the global experience on the use of omalizumab.

Polypharmacy and drug interactions amongst cirrhotic patients discharged from a tertiary center: Results from a national quality improvement audit.

BACKGROUND AND STUDY AIMS: Auditing of polypharmacy is particularly essential in patients with cirrhosis because of the crucial role of liver in drug metabolism. The aim of this study was to audit the drug prescribed in this group of patients and analyzed the quantity and severity of potential drug-drug interaction. PATIENTS AND METHODS: In this cross-sectional study we analyzed the last prescription as recorded in the Electronic Medical Record at the time of discharge for cirrhotic patients who were hospitalized during 24-months study period. Data were also collected for age, gender, and diagnoses. The drugs were analyzed for cross interactions using the Lexicomp-online e-formulary. The drug interactions are classified as: class A: no known interaction, class B: no action needed, Class C: monitor therapy, class D: consider therapy modification, and Class X: the drug should be avoided. RESULTS: A total of 333 patients with cirrhosis were audited, whereas complete and relevant data were available for 181 patients (134 males, 74%) with a mean age ± SD 59.7 ± 10.1. Out of these, 168 (92.8%) patients were using at least one medicine and the total number of medications used was 808 drugs. The observed average of utilization was 7.8 ± 3.1 drugs (range = 1-17) and 102 (56.3%) patients used polypharmacy. A total of 198 (24.5%) consumed drugs were related to cirrhosis and its complications. Six (3.3%), 30 (16.6%) and 65 (35.9%) patients had Class-X, Class D, and Class C, respectively. Utilization of polypharmacy was statistical significant in patients with class X (83.3%, p = 0.03), class D (16.6%, p = 0.01), and class C (35.9%, p = 0.02). CONCLUSION: The findings highlight the importance of auditing for polypharmacy to recognize and prevent potential drug-related problems in patients with cirrhosis. Implementation of strategies to optimize medication use in patients with cirrhosis should be considered necessary as it can have a bearing on length of stay and morbidity.

Acute Myeloid Leukemia Presenting with Numb Chin Syndrome: A Case Report and Review of Literature.

BACKGROUND Numb chin syndrome is a rare and under diagnosed neuropathy of the inferior alveolar branch of the trigeminal nerve usually causing a lower lip and chin anesthesia or paresthesia. The syndrome is commonly associated with broad-spectrum malignant and non-malignant conditions. CASE REPORT Here we report a case of a 30-year-old male who presented with numb chin syndrome in the form of jaw pain, paresthesia, and hypoesthesia of the mental area as the presenting symptoms of acute of myeloid leukemia with t(8;21) treated with (3+7) protocol (3 days anthracycline+7 days cytarabine). The pain and paresthesia improved but hypothesia persisted. CONCLUSIONS Acute myeloid leukemia is one of the most serious causes of numb chin syndrome which should not be overlooked.

A Novel STAT3 Mutation in a Qatari Patient With Hyper-IgE Syndrome.

Autosomal dominant hyper-IgE syndrome caused by mutations in the transcription factor STAT3 (AD-HIES) is characterized by a collection of immunologic and non-immune features including eczema, recurrent infections, elevated IgE levels, and connective tissue anomalies. We report the case of a Qatari child with a history of recurrent staphylococcal skin infections since infancy, who was found to have a novel, de novo mutation in STAT3 (c.1934T>A, p.L645Q). The absence of mucocutaneous candidiasis and undetectable IgE levels until the age of 7 years prolonged the time to molecular confirmation of the cause for the patient's immune deficiency. STAT3 p.L645Q was found to have decreased transcriptional capacity. The patient also had low levels of Th17 cells and STAT3 phosphorylation was impaired in patient-derived cells. Nearly 100 unique mutations in STAT3 have been reported in association with AD-HIES.