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JAMA Pediatrics Oct 2023Proton pump inhibitor (PPI) use may lead to infections through alteration of the microbiota or direct action on the immune system. However, only a few studies were...
IMPORTANCE
Proton pump inhibitor (PPI) use may lead to infections through alteration of the microbiota or direct action on the immune system. However, only a few studies were conducted in children, with conflicting results.
OBJECTIVE
To assess the associations between PPI use and serious infections in children, overall and by infection site and pathogen.
DESIGN, SETTING, AND PARTICIPANTS
This nationwide cohort study was based on the Mother-Child EPI-MERES Register built from the French Health Data System (SNDS). We included all children born between January 1, 2010, and December 31, 2018, who received a treatment for gastroesophageal reflux disease or other gastric acid-related disorders, namely PPIs, histamine 2 receptor antagonists, or antacids/alginate. The index date was defined as the first date any of these medications was dispensed. Children were followed up until admission to the hospital for serious infection, loss of follow-up, death, or December 31, 2019.
EXPOSURE
PPI exposure over time.
MAIN OUTCOMES AND MEASURES
Associations between serious infections and PPI use were estimated by adjusted hazard ratios (aHRs) and 95% CIs using Cox models. PPI use was introduced as time-varying. A 30-day lag was applied to minimize reverse causality. Models were adjusted for sociodemographic data, pregnancy characteristics, child comorbidities, and health care utilization.
RESULTS
The study population comprised 1 262 424 children (median [IQR] follow-up, 3.8 [1.8-6.2] years), including 606 645 who received PPI (323 852 male [53.4%]; median [IQR] age at index date, 88 [44-282] days) and 655 779 who did not receive PPI (342 454 male [52.2%]; median [IQR] age, 82 [44-172] days). PPI exposure was associated with an increased risk of serious infections overall (aHR, 1.34; 95% CI, 1.32-1.36). Increased risks were also observed for infections in the digestive tract (aHR, 1.52; 95% CI, 1.48-1.55); ear, nose, and throat sphere (aHR, 1.47; 95% CI, 1.41-1.52); lower respiratory tract (aHR, 1.22; 95% CI, 1.19-1.25); kidneys or urinary tract (aHR, 1.20; 95% CI, 1.15-1.25); and nervous system (aHR, 1.31; 95% CI, 1.11-1.54) and for both bacterial (aHR, 1.56; 95% CI, 1.50-1.63) and viral infections (aHR, 1.30; 95% CI, 1.28-1.33).
CONCLUSIONS AND RELEVANCE
In this study, PPI use was associated with increased risks of serious infections in young children. Proton pump inhibitors should not be used without a clear indication in this population.
Topics: Humans; Male; Child, Preschool; Aged, 80 and over; Proton Pump Inhibitors; Cohort Studies; Risk Factors; Gastroesophageal Reflux; Hospitalization
PubMed: 37578761
DOI: 10.1001/jamapediatrics.2023.2900 -
The Journal of Allergy and Clinical... May 2024Chronic spontaneous urticaria (CSU) is an inflammatory skin disorder that manifests with itchy wheals, angioedema, or both for more than 6 weeks. Mast cells and... (Review)
Review
Chronic spontaneous urticaria (CSU) is an inflammatory skin disorder that manifests with itchy wheals, angioedema, or both for more than 6 weeks. Mast cells and basophils are the key pathogenic drivers of CSU; their activation results in histamine and cytokine release with subsequent dermal inflammation. Two overlapping mechanisms of mast cell and basophil activation have been proposed in CSU: type I autoimmunity, also called autoallergy, which is mediated via IgE against various autoallergens, and type IIb autoimmunity, which is mediated predominantly via IgG directed against the IgE receptor FcεRI or FcεRI-bound IgE. Both mechanisms involve cross-linking of FcεRI and activation of downstream signaling pathways, and they may co-occur in the same patient. In addition, B-cell receptor signaling has been postulated to play a key role in CSU by generating autoreactive B cells and autoantibody production. A cornerstone of FcεRI and B-cell receptor signaling is Bruton tyrosine kinase (BTK), making BTK inhibition a clear therapeutic target in CSU. The potential application of early-generation BTK inhibitors, including ibrutinib, in allergic and autoimmune diseases is limited owing to their unfavorable benefit-risk profile. However, novel BTK inhibitors with improved selectivity and safety profiles have been developed and are under clinical investigation in autoimmune diseases, including CSU. In phase 2 trials, the BTK inhibitors remibrutinib and fenebrutinib have demonstrated rapid and sustained improvements in CSU disease activity. With phase 3 studies of remibrutinib ongoing, it is hoped that BTK inhibitors will present an effective, well-tolerated option for patients with antihistamine-refractory CSU, a phenotype that presents a considerable clinical challenge.
Topics: Humans; Agammaglobulinaemia Tyrosine Kinase; Chronic Urticaria; Signal Transduction; Mast Cells; Animals; Receptors, IgE; Basophils; Protein Kinase Inhibitors
PubMed: 38141832
DOI: 10.1016/j.jaci.2023.12.008 -
Frontiers in Immunology 2023Basophils are rare cells in the peripheral blood which have the capability to infiltrate into the skin. Invasion of basophils has been detected in pruritic skin... (Review)
Review
Basophils are rare cells in the peripheral blood which have the capability to infiltrate into the skin. Invasion of basophils has been detected in pruritic skin diseases, including atopic dermatitis, bullous pemphigoid, chronic spontaneous urticaria and contact dermatitis. In the skin, basophils are important players of the inflammatory immune response, as they release Th2 cytokines, including interleukin (IL)-4 and IL-13, subsequently inducing the early activation of T-cells. Further, basophils release a multitude of mediators, such as histamine and IL-31, which both play an important role in the initiation of the pruritic response activation of sensory nerves. Chronic pruritus significantly affects the quality of life and the working capability of patients, though its mechanisms are not fully elucidated yet. Since basophils and neurons share many receptors and channels, bidirectional interaction mechanisms, which drive the sensation of itch, are highlighted in this review.
Topics: Humans; Basophils; Quality of Life; Pruritus; Skin; Skin Diseases
PubMed: 37465674
DOI: 10.3389/fimmu.2023.1213138