Leukotriene receptor antagonists as add-on therapy to antihistamines for urticaria: Systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: The benefits and harms of adding antileukotrienes to H1 antihistamines (AHs) for the management of urticaria (hives, itch, and/or angioedema) remain unclear. OBJECTIVE: We sought to systematically synthesize the treatment outcomes of antileukotrienes in combination with AHs versus AHs alone for acute and chronic urticaria. METHODS: As part of updating American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma, and Immunology Joint Task Force on Practice Parameters urticaria guidelines, we searched Medline, Embase, Central, LILACS, WPRIM, IBECS, ICTRP, CBM, CNKI, VIP, Wanfang, US Food and Drug Administration, and European Medicines Agency databases from inception to December 18, 2023, for randomized controlled trials (RCTs) evaluating antileukotrienes and AHs versus AHs alone in patients with urticaria. Paired reviewers independently screened citations, extracted data, and assessed risk of bias. Random effects models pooled effect estimates for urticaria activity, itch, wheal, sleep, quality of life, and harms. The GRADE approach informed certainty of evidence ratings. The study was registered at the Open Science Framework (osf.io/h2bfx/). RESULTS: Thirty-four RCTs enrolled 3324 children and adults. Compared to AHs alone, the combination of a leukotriene receptor antagonist with AHs probably modestly reduces urticaria activity (mean difference, -5.04; 95% confidence interval, -6.36 to -3.71; 7-day urticaria activity score) with moderate certainty. We made similar findings for itch and wheal severity as well as quality of life. Adverse events were probably not different between groups (moderate certainty); however, no RCT reported on neuropsychiatric adverse events. CONCLUSION: Among patients with urticaria, adding leukotriene receptor antagonists to AHs probably modestly improves urticaria activity with little to no increase in overall adverse events. The added risk of neuropsychiatric adverse events in this population with leukotriene receptor antagonists is small and uncertain.

Topical corticosteroids for hives and itch (urticaria): Systematic review and Bayesian meta-analysis of randomized trials.

BACKGROUND: Topical corticosteroids are widely used as a treatment for itch and wheals (urticaria), but their benefits and harms are unclear. OBJECTIVE: To systematically synthesize the benefits and harms of topical corticosteroids for the treatment of urticaria. METHODS: We searched MEDLINE, EMBASE, and CENTRAL from database inception to March 23, 2024, for randomized trials comparing topical corticosteroids with placebo for patients with urticaria (either chronic spontaneous or inducible urticaria or acute urticaria elicited from skin/intradermal allergy testing). Paired reviewers independently screened records, extracted data, and assessed risk of bias. Random-effects meta-analyses addressed urticaria severity, itch severity (numeric rating scale; range 0-10; higher is worse), and adverse events. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach informed certainty of evidence ratings. PROSPERO registration: CRD42023455182. RESULTS: A total of 19 randomized controlled trials enrolled 379 participants with a median of mean age of 30.1 (range 21.1-44.0) years. Compared with placebo, topical corticosteroids may reduce wheal size (ratio of means 0.47, 95% CI 0.38-0.59; low certainty) and itch severity (mean difference -1.30, 95% CI -5.07 to 2.46; very low certainty). Topical corticosteroids result in little to no difference in overall adverse events (94 fewer patients per 1000, 95% credible intervals 172 fewer to 12 more; high certainty). CONCLUSION: Compared with placebo, topical corticosteroids may result in a reduction of wheal size and little to no difference in overall adverse events. Topical corticosteroids may reduce itch severity, but the evidence is very uncertain. Future large, randomized trials addressing the use of topical corticosteroids would further support optimal urticaria management.

The efficacy of omalizumab treatment in chronic spontaneous urticaria is associated with basophil phenotypes.

BACKGROUND: The mechanisms underlying disease pathogenesis in chronic spontaneous urticaria (CSU) and improvement with omalizumab are incompletely understood. OBJECTIVES: This study sought to examine whether the rate of clinical remission is concordant with baseline basophil features or the rate of change of IgE-dependent functions of basophils and/or plasmacytoid dendritic cells during omalizumab therapy. METHODS: Adults (n = 18) with refractory CSU were treated with omalizumab 300 mg monthly for 90 days. Subjects recorded daily urticaria activity scores, and clinical assessments with blood sampling occurred at baseline and on days 1, 3, 6, 10, 20, 30, 60, and 90 following omalizumab. At baseline, subjects were categorized by basophil functional phenotypes, determined by in vitro histamine release (HR) responses to anti-IgE antibody, as CSU-responder (CSU-R) or CSU-non-responder (CSU-NR), as well as basopenic (B) or nonbasopenic (NB). RESULTS: CSU-R/NB subjects demonstrated the most rapid and complete symptom improvement. By day 6, CSU-R/NB and CSU-NR/NB had increased anti-IgE-mediated basophil HR relative to baseline, and these shifts did not correlate with symptom improvement. In contrast, CSU-NR/B basophil HR did not change during therapy. The kinetics of the decrease in surface IgE/FcεRI was similar in all 3 phenotypic groups and independent of the timing of the clinical response. Likewise, plasmacytoid dendritic cells' surface IgE/FcεRI decline and TLR9-induced IFN-α responses did not reflect clinical change. CONCLUSIONS: Changes in basophil IgE-based HR, surface IgE, or FcεRI bear no relationship to the kinetics in the change in clinical symptoms. Baseline basophil count and basophil functional phenotype, as determined by HR, may be predictive of responsiveness to omalizumab.

Effects of an Oral CRTh2 Antagonist (AZD1981) on Eosinophil Activity and Symptoms in Chronic Spontaneous Urticaria.

BACKGROUND: Approximately 50% of patients with chronic spontaneous urticaria (CSU) experience symptoms that are not fully controlled by antihistamines, indicating an unmet clinical need. OBJECTIVE: To evaluate the effects of the selective CRTh2 antagonist AZD1981 on symptoms and targeted leukocytes in adults with persistent CSU despite treatment with H1-antihistamines. METHODS: We performed a single-center, randomized, placebo-controlled study involving adult CSU subjects with symptoms despite daily antihistamines. The subjects underwent a 2-week placebo run-in and 4 weeks of double-blinded therapy with either AZD1981 40 mg TID or placebo, followed by a 2-week placebo washout. The primary objective was to assess the effect of AZD1981 on CSU signs and symptoms. Secondary objectives included the effects of AZD1981 on prostaglandin D2 (PGD2)-induced eosinophil shape change, circulating leukocyte subsets, CRTh2 expression on blood leukocytes, and total blood leukocyte histamine content. RESULTS: Twenty-eight subjects were randomized to AZD1981 or placebo, with 26 subjects completing the study. The urticaria activity scores declined during the treatment phase in both groups, and they were significantly reduced in the AZD1981 group at the end of washout. AZD1981 treatment increased circulating eosinophils and significantly impaired PGD2-mediated eosinophil shape change. CRTh2 surface expression rose significantly on blood basophils during active treatment. No serious adverse events were observed. CONCLUSIONS: This is the first study to examine the efficacy of a CRTh2 antagonist in antihistamine-refractory CSU. AZD1981 treatment was well tolerated, effectively inhibited PGD2-mediated eosinophil shape change, shifted numbers of circulating eosinophils, and reduced weekly itch scores more than hives during treatment and into washout. Further studies are needed to determine whether inhibition of the PGD2/CRTh2 pathway will be an -effective treatment for CSU.

Chronic Spontaneous Urticaria: Etiology and Pathogenesis.

Urticaria, also known as hives, is a common condition thought to affect up to 20% of individuals worldwide in their lifetime. This skin condition is characterized by the appearance of pruritic, erythematous papules or plaques with superficial swelling of the dermis. The major complaint is the symptom of pruritus. Angioedema, which involves a deeper swelling of dermal or mucosal tissues, may accompany urticaria. Urticaria can be classified by both time course of symptoms and the underlying etiology.

Functional human skin explants as tools for assessing mast cell activation and inhibition.

Mast cells are activated through a variety of different receptors to release preformed granules and mediators synthesized de novo. However, the physiology and function of mast cells are not fully understood. Traditional studies of mast cell activation in humans have utilized cultures of tissue-derived mast cells including CD34+ progenitor cells or well-characterized commercially available cell lines. One limitation of these methods is that mast cells are no longer in a natural state. Therefore, their applicability to human skin disorders may be limited. Human skin explant models have been utilized to investigate the short-term effects of cell mediators, drugs, and irritants on skin while avoiding the ethical concerns surrounding in vivo stimulation studies with non-approved agents. Nonetheless, few studies have utilized intact human tissue to study mast cell degranulation. This "Methods" paper describes the development and application of an intact skin explant model to study human mast cell activation. In this manuscript, we share our protocol for setting up ex vivo human skin explants and describe the results of stimulation experiments and techniques to minimize trauma-induced histamine release. Skin explants were generated using de-identified, full-thickness, non-diseased skin specimens from plastic and reconstructive surgeries. Results were reproducible and demonstrated FcɛRI- and MRGPRX2-induced mediator release which was inhibited with the use of a BTK inhibitor and QWF, respectively. Thus, this explant model provides a quick and accessible method of assessing human skin mast cell activation and inhibition.

A Skin Testing Strategy for Non-IgE-Mediated Reactions Associated With Vancomycin.

BACKGROUND: Vancomycin infusion reaction (VIR), reportedly mediated through Mas-Related G Protein-Coupled Receptor-X2, is the primary vancomycin-induced immediate drug reaction. Clinically, distinguishing the underlying drug-induced immediate drug reaction mechanisms is crucial for future treatment strategies, including drug restriction, re-administration, and pretreatment considerations. However, the lack of validated diagnostic tests makes this challenging, often leading to unnecessary drug restriction. OBJECTIVE: To determine whether intradermal tests (IDTs) and, separately, the basophil activation test (BAT) differentiate VIR from vancomycin-tolerant subjects. METHODS: This was a cross-sectional study of vancomycin-exposed adults with and without a history of VIR. Data on demographics, allergy-related comorbidities, history of vancomycin exposures, and VIR characteristics were collected. IDT with vancomycin was performed. IDT dose-response EC50, IDT-related local symptoms, and BAT results were compared between groups. RESULTS: A total of 11 VIR and 10 vancomycin-tolerant subjects were enrolled. The most reported VIR symptoms were pruritus (82%), flushing (82%), hives (46%), angioedema (27%), and dyspnea (19%). The IDT dose-response mean EC50 was 328 µg/mL (95% CI, 296-367) in the VIR versus 1166 µg/mL (95% CI, 1029-1379) in the tolerant group (P < .0001). All VIR subjects reported IDT-related local pruritus compared with 60% of tolerant subjects (P = .0185). The %CD63+ basophils were consistently less than 2%, without significant differences between groups (P < .54). CONCLUSIONS: Variations in skin test methodologies could help identify other immediate drug reaction mechanisms beyond IgE. This skin test protocol holds the potential for identifying VIR, particularly in cases where patients have received multiple drugs while BAT is insufficient. Future studies will validate and delineate its predictive value, assessing the risk of VIR.

Efficacy and Safety of Systemic Corticosteroids for Urticaria: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

BACKGROUND: Short courses of adjunctive systemic corticosteroids are commonly used to treat acute urticaria and chronic urticaria flares (both with and without mast cell-mediated angioedema), but their benefits and harms are unclear. OBJECTIVE: To evaluate the efficacy and safety of treating acute urticaria or chronic urticaria flares with versus without systemic corticosteroids. METHODS: We searched the MEDLINE, EMBASE, CENTRAL, CNKI, VIP, Wanfang, and CBM databases from inception to July 8, 2023, for randomized controlled trials of treating urticaria with versus without systemic corticosteroids. Paired reviewers independently screened records, extracted data, and appraised risk of bias with the Cochrane 2.0 tool. We performed random-effects meta-analyses of urticaria activity, itch severity, and adverse events. We assessed certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluations (GRADE) approach. RESULTS: We identified 12 randomized trials enrolling 944 patients. For patients with low or moderate probability (17.5%-64%) to improve with antihistamines alone, add-on systemic corticosteroids likely improve urticaria activity by a 14% to 15% absolute difference (odds ratio [OR], 2.17, 95% confidence interval [CI]: 1.43-3.31; number needed to treat [NNT], 7; moderate certainty). Among patients with a high chance (95.8%) for urticaria to improve with antihistamines alone, add-on systemic corticosteroids likely improved urticaria activity by a 2.2% absolute difference (NNT, 45; moderate certainty). Corticosteroids may improve itch severity (OR, 2.44; 95% CI: 0.87-6.83; risk difference, 9%; NNT, 11; low certainty). Systemic corticosteroids also likely increase adverse events (OR, 2.76; 95% CI: 1.00-7.62; risk difference, 15%; number needed to harm, 9; moderate certainty). CONCLUSIONS: Systemic corticosteroids for acute urticaria or chronic urticaria exacerbations likely improve urticaria, depending on antihistamine responsiveness, but also likely increase adverse effects in approximately 15% more.

Efficacy of Antimicrobial Interventions Used in Meat Processing Plants against Antimicrobial Tolerant Non-Antibiotic-Resistant and Antibiotic-Resistant Salmonella on Fresh Beef.

ABSTRACT: Salmonella is a common cause of foodborne illness in the United States, and several strains of Salmonella have been identified as resistant to antibiotics. It is not known whether strains that are antibiotic resistant (ABR) and that have some tolerance to antimicrobial compounds are also able to resist the inactivation effects of antimicrobial interventions used in fresh meat processing. Sixty-eight Salmonella isolates (non-ABR and ABR strains) were treated with half concentrations of lactic acid (LA), peracetic acid (PAA), and cetylpyridinium chloride (CPC), which are used in beef processing plants to screen for tolerant strains. Six strains each from non-ABR and ABR Salmonella that were most tolerant of LA (2%), PAA (200 ppm), and CPC (0.4%) were selected. Selected strains were inoculated on surfaces of fresh beef and subjected to spray wash treatment with 4% LA, 400 ppm PAA, or 0.8% CPC for the challenge study. Tissue samples were collected before and after each antimicrobial treatment for enumeration of survivors. Spray treatment with LA, PAA, or CPC significantly reduced non-ABR Salmonella and ABR Salmonella on surfaces of fresh beef by 1.95, 1.22, and 1.33 log CFU/cm2, and 2.14, 1.45, and 1.43 log CFU/cm2, respectively. The order of effectiveness was LA > PAA = CPC. The findings also indicated that LA, PAA, and CPC were equally (P ≤ 0.05) effective against non-ABR and ABR Salmonella on surfaces of fresh beef. These data contribute to the body of work that indicates that foodborne pathogens that have acquired both antibiotic resistance and antimicrobial tolerance are still equally susceptible to meat processing antimicrobial intervention treatments.

Marine Heatwaves.

Ocean temperature variability is a fundamental component of the Earth's climate system, and extremes in this variability affect the health of marine ecosystems around the world. The study of marine heatwaves has emerged as a rapidly growing field of research, given notable extreme warm-water events that have occurred against a background trend of global ocean warming. This review summarizes the latest physical and statistical understanding of marine heatwaves based on how they are identified, defined, characterized, and monitored through remotely sensed and in situ data sets. We describe the physical mechanisms that cause marine heatwaves, along with their global distribution, variability, and trends. Finally, we discuss current issues in this developing research area, including considerations related to thechoice of climatological baseline periods in defining extremes and how to communicate findings in the context of societal needs.

Drivers and impacts of the most extreme marine heatwaves events.

Prolonged high-temperature extreme events in the ocean, marine heatwaves, can have severe and long-lasting impacts on marine ecosystems, fisheries and associated services. This study applies a marine heatwave framework to analyse a global sea surface temperature product and identify the most extreme events, based on their intensity, duration and spatial extent. Many of these events have yet to be described in terms of their physical attributes, generation mechanisms, or ecological impacts. Our synthesis identifies commonalities between marine heatwave characteristics and seasonality, links to the El Niño-Southern Oscillation, triggering processes and impacts on ocean productivity. The most intense events preferentially occur in summer, when climatological oceanic mixed layers are shallow and winds are weak, but at a time preceding climatological maximum sea surface temperatures. Most subtropical extreme marine heatwaves were triggered by persistent atmospheric high-pressure systems and anomalously weak wind speeds, associated with increased insolation, and reduced ocean heat losses. Furthermore, the most extreme events tended to coincide with reduced chlorophyll-a concentration at low and mid-latitudes. Understanding the importance of the oceanic background state, local and remote drivers and the ocean productivity response from past events are critical steps toward improving predictions of future marine heatwaves and their impacts.

Environmental drivers of unprecedented Alexandrium catenella dinoflagellate blooms off eastern Tasmania, 2012-2018.

Blooms of the highly toxic dinoflagellate Alexandrium catenella (previously referred to as tamarense group 1) were first detected off eastern Tasmania in 2012 and have since been responsible for incidences of human paralytic shellfish poisoning and extended closures (up to 25 weeks) of mussel, oyster, scallop, abalone and rock lobster industries (up to 150 mg/kg PST in mussels). Investigation of meteorological and oceanographic influences indicate that the annually recurrent winter-spring blooms (June-Oct) occur within a narrow water temperature window (10-15 °C) under two distinct sets of conditions: (1) following high rainfall and land run-off, under relatively light winds; and (2) following periods of anomalously low air temperatures and associated cooling of shallow coastal waters, again under relatively light winds. The common driver of blooms appears to be the development of stratification in coastal waters, via salinity and/or temperature gradients. We propose a framework for evaluating the risk of Alexandrium with the aim of developing a forecasting capability, and compare these environmental conditions with historic data to understand the recent advent of these blooms.

A global assessment of marine heatwaves and their drivers.

Marine heatwaves (MHWs) can cause devastating impacts to marine life. Despite the serious consequences of MHWs, our understanding of their drivers is largely based on isolated case studies rather than any systematic unifying assessment. Here we provide the first global assessment under a consistent framework by combining a confidence assessment of the historical refereed literature from 1950 to February 2016, together with the analysis of MHWs determined from daily satellite sea surface temperatures from 1982-2016, to identify the important local processes, large-scale climate modes and teleconnections that are associated with MHWs regionally. Clear patterns emerge, including coherent relationships between enhanced or suppressed MHW occurrences with the dominant climate modes across most regions of the globe - an important exception being western boundary current regions where reports of MHW events are few and ocean-climate relationships are complex. These results provide a global baseline for future MHW process and prediction studies.

Longer and more frequent marine heatwaves over the past century.

Heatwaves are important climatic extremes in atmospheric and oceanic systems that can have devastating and long-term impacts on ecosystems, with subsequent socioeconomic consequences. Recent prominent marine heatwaves have attracted considerable scientific and public interest. Despite this, a comprehensive assessment of how these ocean temperature extremes have been changing globally is missing. Using a range of ocean temperature data including global records of daily satellite observations, daily in situ measurements and gridded monthly in situ-based data sets, we identify significant increases in marine heatwaves over the past century. We find that from 1925 to 2016, global average marine heatwave frequency and duration increased by 34% and 17%, respectively, resulting in a 54% increase in annual marine heatwave days globally. Importantly, these trends can largely be explained by increases in mean ocean temperatures, suggesting that we can expect further increases in marine heatwave days under continued global warming.

Percutaneous versus surgical tracheotomy: an updated meta-analysis.

OBJECTIVE: Perform an updated meta-analysis investigating differences in complication rates, procedure times, and costs between percutaneous dilational tracheotomy (PDT), operating room surgical tracheotomy (ST), and bedside surgical tracheotomy (BST). METHODS: Meta-analysis using the Mantel-Haenszel fixed effects model. Prospective and randomized trials comparing ST with PDT from 1999 to present were identified through two independent searches. Outcome measures analyzed included mortality, early complications, late complications, procedure times, and cost. RESULTS: Fourteen studies were identified (1,273 patients) that satisfied the search criteria. Analysis of randomized studies demonstrated significantly more minor early complications with PDT compared with ST (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.01-2.66). Randomized studies comparing PDT with BST demonstrated significantly more early complications with PDT (OR, 4.66; 95% CI, 1.46-14.91). There was no significant difference in late serious complications in studies that randomized patients to ST or PDT (OR, 1.39; 95% CI, 0-16,000). PDT is significantly faster to perform than ST (OR, 0.51; 95% CI, 95% 0.49-0.53). BST and PDT have similar costs, and both are less expensive than ST. CONCLUSIONS: Although significantly faster than ST, PDT has more early complications compared with open tracheotomy in the operating room or at the bedside. The long-term complications of the two techniques appear comparable but have not been thoroughly investigated. These findings suggest that a team approach between surgeons and critical care specialists is essential to select the appropriate tracheotomy technique for a given patient.

High resolution T2 MRI in the diagnosis of cerebellopontine angle and internal auditory canal lesions.

High resolution T2 magnetic resonance imaging (MRI) can provide exquisite detail of internal auditory canal (IAC) and cerebellopontine angle (CPA) lesions. In this retrospective case series, blinded imaging sequences were delivered to three radiologists and compared with previously archived clinical reads that were non-blinded and incorporated both T1+C and T2 sequences together. This article demonstrates high sensitivity and specificity for high resolution T2 MRI particularly with lesions >5mm. This suggests a role for high resolution T2 MRI as an initial screening sequence or as a surveillance sequence.

Chronic Idiopathic Urticaria: Systemic Complaints and Their Relationship with Disease and Immune Measures.

BACKGROUND: Patients with chronic idiopathic urticaria (CIU)/chronic spontaneous urticaria sometimes report systemic complaints (SCs). OBJECTIVE: We sought to determine the frequency and characteristics of SCs among patients with CIU, as well as the association of SCs with disease measures, basophil histamine release, and serum tryptase. METHODS: Adult patients with CIU were recruited from a university allergy clinic. Patients completed a disease symptom survey and underwent blood sampling for subsequent basophil histamine release and serum tryptase measurement. RESULTS: A total of 155 patients with CIU were surveyed, with 103 reporting SCs with concomitant hives as follows: joint pain or swelling (55.3%), headache/fatigue (47.6%), flushing (42.7%), wheezing (30.1%), gastrointestinal complaints (26.2%), and palpitations (9.7%). Patients with SCs (CIU-SC) were compared with those with no SCs (CIU-NSC). Both groups had similar demographic characteristics (average age in 40s, majority female and white) and basophil histamine release profiles. CIU-SC had significantly greater disease duration (51.5% CIU-SC vs 30.8% CIU-NSC had >4 years duration), emergency department visits (41.7% vs 23.1% had >1 visit in the last year), CIU-related work absences (65% vs 27.5% had >1 day), oral corticosteroid use (84.5% vs 59.6%), quality-of-life impairment (76.1 vs 59.2 SkinDex score), and serum tryptase levels (5.1 ng/mL vs 3.9 ng/mL). CONCLUSIONS: Despite similar demographic characteristics and basophil profiles as patients with CIU-NSC, patients with CIU-SC have features of greater disease burden (work absences, emergency department visits, and corticosteroid use), quality-of-life impairment, and baseline serum tryptase levels.