Identifying the most at-risk age-group and longitudinal trends of drug allergy labeling amongst 7.3 million individuals in Hong Kong.

BACKGROUND: Incorrect drug 'allergy' labels remain a global public health concern. Identifying regional trends of drug allergy labeling can guide appropriate public health interventions, but longitudinal or population drug allergy studies remain scarce. We analysed the serial epidemiology of drug allergy labeling to identify specific subgroups at highest risk of drug allergy labeling for potential interventions. METHODS: Longitudinal, population-wide drug allergy labels and clinical data from over 7,337,778 individuals in Hong Kong between 2016 and 2021 were analysed. RESULTS: The absolute prevalence and incidence of documented drug allergy were 5.61% and 277/100,000 population, respectively. Annual incidence of new allergy labels was stable between 2016 and 2019, until a significant drop in 2020 (-16.3%) during the COVID19 pandemic. The most common allergy labels were anti-infectives (245,832 [44.5%]), non-steroidal anti-inflammatory (106,843 [19.3%]), and nervous system drugs (45,802 [8.3%]). The most common labeled culprits for the most severe immediate-type (anaphylaxis) and non-immediate-type (Stevens-Johnson syndrome) reactions were beta-lactams and nervous system drugs, respectively. For individuals at highest risk of labeling, there was significantly higher incidence of overall drug and beta-lactam allergy labeling amongst individuals aged > 40 years which contributed to the majority of newly labeled allergies (377,004, 68.2%). CONCLUSIONS: Contrary to traditional dogma, we identified disproportionately higher incidence of drug allergy labeling amongst older individuals, rather than the paediatric age group. We advocate for more population-wide drug allergy studies to investigate this phenomenon in other cohorts as well as future preventative and delabeling efforts focusing on the adult population.

Penicillin Allergy in China: Consequences of Inappropriate Skin Testing Practices and Policies.

Penicillins are the most frequently prescribed class of medications worldwide and first-line antibiotic of choice for most bacterial infections. They are also commonly labelled as the culprit of drug 'allergy'; leading to obligatory use of second-line antibiotics, suboptimal antibiotic therapy and increased antimicrobial resistance. However, the majority of reported penicillin 'allergy' labels are found to be incorrect after allergy testing, emphasising the importance of proper drug allergy testing and evaluation. Penicillin skin testing (PST) remains an important component of drug allergy diagnosis; however, its practice and policies significantly differ across the world. Inappropriate and non-evidence-based PST practices can lead to consequences associated with allergy mislabelling. Even within different regions of China, with a population exceeding 1.4 billion, there are marked differences in the implementation, execution and interpretation of PST. This review aims to examine the differences in PST between Mainland China, Hong Kong and the rest of the world. We critically analyse the current practice of 'pre-emptive' PST in Mainland China, which has a significant false-positive rate leading to high levels of penicillin allergy mislabelling. Non-evidence-based practices further compound the high false-positive rates of indiscriminatory PST. We postulate that inappropriate PST policies and practices may exacerbate the mislabelling of penicillin allergy, leading to unnecessary overuse of inappropriate second-line antibiotics, increasing antimicrobial resistance and healthcare costs. We advocate for the importance of more collaborative research to improve the contemporary workflow of penicillin allergy diagnosis, reduce mislabelling and promote the dissemination of evidence-based methods for allergy diagnosis.

Impact of a drug allergy education course for non-specialists: Findings from ADAPT-A randomized crossover trial.

BACKGROUND: The consequences of drug allergy remain a global health concern. Drug allergy is often a neglected topic and many non-specialists lack sufficient knowledge or confidence in evaluating or managing this common condition. Evidence-based interventions to better equip non-specialists to tackle drug allergy are needed. The aim of the study is to evaluate the effectiveness of an intensive educational course on drug allergy knowledge and practice of non-specialists. METHODS: A randomized crossover trial (NCT06399601) was conducted among practicing physicians and nurses participating in an intensive drug allergy course-Advances in Drug Allergy & Penicillin Testing (ADAPT). Participants' baseline knowledge and self-reported practices were assessed with standardized questionnaires (scored from 0 to 100, with "satisfactory" defined as ≥60/100). Participants were randomized into two cohorts and attended ADAPT at different time points. Serial responses before and after the course were compared within and between cohorts. RESULTS: Seventy participants (25 physicians, 45 nurses) randomized into two groups completed the course. Baseline drug allergy knowledge (58.0 ± 19.9) and self-reported practice (36.9 ± 24.3) were unsatisfactory among non-specialists, with significantly lower scores from nurses than physicians in both domains (knowledge: 49.0 ± 17.4 vs. 74.0 ± 12.7; practice: 32.1 ± 21.3 vs. 53.3 ± 23.1; all p < 0.001). Following completion of ADAPT, participants demonstrated significant improvements in knowledge (58.0 ± 19.9 vs. 77.7 ± 15.9, p < 0.001) and self-reported practice (36.9 ± 24.3 vs. 71.0 ± 20.2, p < 0.001). All participants (100%) and 99% of participants agreed that the course improved their clinical knowledge and practice, respectively. CONCLUSIONS: ADAPT, an intensive drug allergy educational course was effective in improving drug allergy knowledge and practice for non-specialists. Further longitudinal studies are required to evaluate long-term impact.

Beyond the classic players: Mas-related G protein-coupled receptor member X2 role in pruritus and skin diseases.

Chronic spontaneous urticaria (CSU), atopic dermatitis (AD), psoriasis and rosacea are highly prevalent inflammatory skin conditions which impose a significant burden on patients' quality of life. Their pathophysiology is likely multifactorial, involving genetic, immune and environmental factors. Recent advancements in the field have demonstrated the key role of mast cells (MC) in the pathophysiology of these conditions. The Mas-related G protein-coupled receptor X2 (MRGPRX2) has emerged as a promising non-IgE-mediated MC activation receptor. MRGPRX2 is predominately expressed on MC and activated by endogenous and exogenous ligands, leading to MC degranulation and release of various pro-inflammatory mediators. Mounting evidence on the presence of endogenous MRGPRX2 agonists (substance P, cortistatin-14, LL37, PAMP-12 and VIP) and its high expression among patients with CSU, AD, rosacea, psoriasis and chronic pruritus emphasizes the pathogenic role of MRGPRX2 in these conditions. Despite the currently available treatments, there remains a pressing need for novel drug targets and treatment options for these chronic inflammatory skin conditions. Here, we reviewed the pathogenic role of MRGPRX2 and its potential as a novel therapeutic target and provided an update on future research directions.

Evaluation of vaccine allergy safety track program to assess potential COVID-19 vaccine allergy: a cost-effectiveness analysis.

BACKGROUND: Concerns about new COVID-19 vaccines played a key role in vaccine hesitancy and hampered population uptake. Hong Kong initiated a Vaccine Allergy Safety Track (VAS-Track) program to assess potential COVID-19 vaccine-associated allergies. A 'Hub-and-Spoke' model of predominately non-specialists supported by the allergist hub was established to meet overwhelming demand despite limited specialists. OBJECTIVE: To assess the cost-effectiveness of VAS-Track as a pre- and post-vaccination assessment service for individuals potentially at high risk of COVID-19 vaccine-related allergy. METHODS: An individual-level decision-analytical model was constructed using data from VAS-Track participants supplemented by published estimates. Analyses were from a health service provider perspective over 12 months. We calculated the incremental cost-effectiveness ratio (ICER) to estimate the cost per quality-adjusted life years (QALYs) gained. Willingness-to-pay threshold was based on local GDP per capita (US$ 49,590). Sensitivity analyses examined robustness of findings. RESULTS: Cost-effectiveness varied widely across age groups. VAS-Track was cost-saving for older adults (dominant strategy for age ≥ 50) compared with standard practice across a range of sensitivity analyses. VAS-Track was not cost-effective for younger groups (age 18-49: ICER: US$ 410,914/QALY for pre-vaccination and US$ 213,786/QALY for post-vaccination assessments). Infection rate, cost of treating severe infection, and vaccination rate were most influential on cost-effectiveness estimates. CONCLUSION: VAS-Track was cost-effective both as a pre- and post-vaccination assessment service for adults over 50. The 'Hub-and-Spoke' model using non-specialists with limited allergy specialist resources to provide vaccine allergy assessment services would provide high economic value compared with usual care for adults aged 50 and over.

Ten-year outcomes of Perioperative Anaphylaxis Workup Study in Hong Kong (PAWS-HK): Performance of diagnostic modalities.

BACKGROUND: Studies on perioperative anaphylaxis (PA) in Asia are lacking. Furthermore, allergy workup for PA has largely been limited to the "silver standard" of skin tests (ST). Using in vitro tests as an adjunct to ST may improve and overcome these diagnostic challenges. OBJECTIVE: To evaluate the clinical characteristics and diagnostic tests of patients with suspected PA through the Perioperative Anaphylaxis Workup Study in Hong Kong cohort. METHODS: Patients with a diagnosis of PA over a 10-year period were recruited into the Perioperative Anaphylaxis Workup Study in Hong Kong. We reviewed the medical records, tryptase elevation, and diagnostic tests including ST, specific immunoglobulin E, and basophil activation tests (BAT). RESULTS: In 151 patients with PA, diagnosis was reached in three-fourths of the cases (113/151, 74.8%). The most common culprits identified were neuromuscular blocking agents (25.8%), ß lactams (17.2%) and chlorhexidine (13.9%). Severe anaphylaxis was associated with female sex, older age, elevated acute tryptase levels, and more cardiovascular manifestations during induction. Skin tests remained the most sensitive diagnostic modality overall (66.2%). BAT showed better performance for chlorhexidine and gelofusine anaphylaxis, with sensitivity of 80.0% and 79.6%, respectively. Specific Immunoglobulin E indicated even higher sensitivity (95.2%) than did ST (85.0%) and BAT (80.0%) for chlorhexidine anaphylaxis but performed poorly for other drugs. CONCLUSION: Neuromuscular blocking agents remain the most common culprit in PA. There was a higher prevalence of gelofusine anaphylaxis in our cohort than was seen in the literature. Skin tests remain the most sensitive testing modality. In vitro tests for chlorhexidine and gelofusine showed promising results, but more studies to further elucidate its use are warranted.

The Role of the Allergist in Coronavirus Disease 2019 Vaccine Allergy Safety: A Pilot Study on a "Hub-and-Spoke" Model for Population-Wide Allergy Service.

BACKGROUND: Hong Kong started its coronavirus disease 2019 (COVID-19) vaccination program in February 2021. A territory-wide Vaccine Allergy Safety (VAS) clinic was set up to assess individuals deemed at "higher risk" of COVID-19 vaccine-associated allergies. A novel "hub-and-spoke" model was piloted to tackle the overwhelming demand of services by allowing nonallergists to conduct assessment. OBJECTIVE: To evaluate the outcomes of the VAS hub-and-spoke model for allergy assessment. METHODS: Records of patients attending the VAS hub-and-spoke Clinics between March and August 2021 were reviewed (n = 2725). We studied the overall results between the Hub (allergist led) and Spoke (nonallergist led) Clinics. The Hub and the Hong Kong West Cluster Spoke Clinic were selected for subgroup analysis as they saw the largest number of patients (n = 1411). RESULTS: A total of 2725 patients were assessed under the VAS hub-and-spoke model. Overall, 2324 patients (85.3%) were recommended to proceed with vaccination. Allergists recommended significantly more patients for vaccination than nonallergists (odds ratio = 21.58; P < .001). Subgroup analysis revealed that 881 of 1055 (83.5%) patients received their first dose of COVID-19 vaccination safely after assessment. Among those recommended vaccination, more patients assessed by allergists received their first dose of vaccination (odds ratio = 4.18; P < .001). CONCLUSION: The hub-and-spoke model has proven to be successful for the vaccination campaign. This study has illustrated the crucial role of allergists in countering vaccine hesitancy. Results from the study revealed considerable differences in outcomes between allergist-led and nonallergist-led clinics. Precise reasons for these differences warrant further evaluation. We are hopeful that the hub-and-spoke model can be similarly adapted for other allergist-integrative services in the future.

Helper T cell subsets: Development, function and clinical role in hypersensitivity reactions in the modern perspective.

Helper T cells are traditionally classified into T helper 1 (TH1) and T helper 2 (TH2). The more recent discoveries of T helper 17 (TH17), follicular helper T cells (TFH) and regulatory T cells (Treg) enhanced our understanding on the mechanisms of immune function and hypersensitivity reactions, which shaped the modern perspective on the function and role of these different subsets of helper T cells in hypersensitivity reactions. Each subset of helper T cells has characteristic roles in different types of hypersensitivity reactions, hence giving rise to the respective characteristic clinical manifestations. The roles of helper T cells in allergic contact dermatitis (TH1-mediated), drug rash with eosinophilia and systemic symptoms (DRESS) syndrome (TH2-mediated), and acute generalised exanthematous pustulosis (AGEP) (TH17-mediated) are summarised in this article, demonstrating the correlation between the type of helper T cell involved and the clinical features. TFH plays crucial roles in antibody class-switch recombination; they may be implicated in antibody-mediated hypersensitivity reactions, but further research is warranted to delineate their exact pathogenic roles. The helper T cell subsets and their specific cytokine profiles implicated in different hypersensitivity reactions could be potential treatment targets by biologics, but more clinical trials are warranted to establish their clinical effectiveness.

MRGPRX2 antagonist GE1111 attenuated DNFB-induced atopic dermatitis in mice by reducing inflammatory cytokines and restoring skin integrity.

Introduction: Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterised by itching, erythema, and epidermal barrier dysfunction. The pathogenesis of AD is complex and multifactorial; however,mast cell (MC) activation has been reported to be one of the crucial mechanisms in the pathogenesis of AD. The MC receptor Mas related G protein-coupled receptor-X2 (MRGPRX2) has been identified as a prominent alternative receptor to the IgE receptor in causing MC activation and the subsequent release of inflammatory mediators. The current study aimed to evaluate the therapeutic effect of a novel small molecule MRGPRX2 antagonist GE1111 in AD using in vitro and in vivo approaches. Methods: We developed an in vitro cell culture disease model by using LAD-2 MC, HaCaT keratinocytes and RAW 264.7 macrophage cell lines. We challenged keratinocytes and macrophage cells with CST-14 treated MC supernatant in the presence and absence of GE1111 and measured the expression of tight junction protein claudin 1, inflammatory cytokines and macrophage phagocytosis activity through immunohistochemistry, western blotting, RT-qPCR and fluorescence imaging techniques. In addition to this, we developed a DFNB-induced AD model in mice and evaluated the protective effect and underlying mechanism of GE1111. Results and Discussion: Our in vitro findings demonstrated a potential therapeutic effect of GE1111, which inhibits the expression of TSLP, IL-13, MCP-1, TNF-a, and IL-1ß in MC and keratinocytes. In addition to this, GE1111 was able to preserve the expression of claudin 1 in keratinocytes and the phagocytotic activity of macrophage cells. The in vivo results demonstrated that GE1111 treatment significantly reduced phenotypic changes associated with AD (skin thickening, scaling, erythema and epidermal thickness). Furthermore, immunohistochemical analysis demonstrated that GE1111 treatment preserved the expression of the tight junction protein Involucrin and reduced the expression of the inflammatory mediator periostin in the mouse model of AD. These findings were supported by gene and protein expression analysis, where GE1111 treatment reduced the expression of TSLP, IL-13, and IL-1ß, as well as downstream signalling pathways of MRGPRX2 in AD skin lesions. In conclusion, our findings provide compelling in vitro and in vivo evidence supporting the contribution of MRGPRX2-MC interaction with keratinocytes and macrophages in the pathogenesis of AD.

Bibliometric analysis of the trends and evolution in ß-lactam allergy research.

Background: ß-Lactams remain the most reported drug allergy globally, with the volume and diversity of related drug allergy research continuing to accumulate. Recognizing evolving research trends can help inform future directions and encourage synergistic collaborations. Objective: We conducted a comprehensive bibliometric analysis of all publications relevant to ß-lactam allergy, with a focus on longitudinal publication rates, international collaborations, and key word/trend analysis. Methods: Meta-data from all original articles, letters, and reviews relevant to ß-lactam allergy on the Web of Science Core Collection up until December 31, 2023, were analyzed. Results: From 1966 to 2023, there were 4451 records (3536 articles, 631 reviews, and 284 letters) from 78 countries. There was an exponential increase in publications, especially during the past decade, with half of all publications on ß-lactam allergy published during this time (50.6% [2252 of 4452]). Overall, 18.1% of the publications (805 of 4452) involved international coauthorships, with a significant increase since the previous decade (12.7% vs 23.3% [P < .001]). The most frequent key words in the first published half of articles were skin testing (84 of 1919), IgE (57 of 1919), and anaphylaxis (49 of 1919); in contrast to the key word skin testing (137 of 3351), the key words drug provocation test (121 of 3351), antimicrobial resistance (120 of 3351), and antimicrobial stewardship (118 of 3351) were the most frequent key words in the latter half. Conclusion: There has been a surge in publications, international collaboration, and shifting paradigms in ß-lactam allergy research. The field has evolved beyond focusing on in vitro tests or desensitization toward antimicrobial stewardship. However, there still seems to be relatively fewer collaborations with non-Western countries. Further international collaborations to harmonize delabeling strategies against the threat of mislabeled ß-lactam allergy should be encouraged.

Validity, reliability, and sensitivity to change of the traditional Chinese Urticaria Control Test (UCT) in Hong Kong.

Background: Uncontrolled chronic urticaria (CU) can severely affect physical and psychosocial health as well as quality of life. Patient-reported outcome measures are crucial for measuring disease control. The Urticaria Control Test (UCT) is recommended by guidelines to monitor CU and guide clinical management. However, the traditional Chinese version of the UCT has not yet been validated. Objective: We sought to validate the traditional Chinese UCT among Chinese CU patients in Hong Kong. Methods: Patients with CU were enrolled at a Urticaria Centre of Reference and Excellence (aka UCARE) in Hong Kong and completed the traditional Chinese UCT. The internal consistency, test-retest reliability, construct validity, convergent validity, known-group validity, and sensitivity to change of the traditional Chinese UCT were evaluated. Results: We recruited 162 CU patients (80.9% female; age 50 ± 14 years) with a mean (median) ± standard deviation baseline UCT score of 8.8 (8) ± 4.7. Overall, Chinese UCT showed excellent internal consistency (Cronbach α and McDonald ω = 0.948), as well as test-retest reliability (intraclass correlation coefficient = 0.916 [95% confidence interval = 0.866-0.953]). Exploratory factor analysis revealed a unidimensional structure and confirmed its construct validity. Strong correlation between UCT and the 7-day urticaria activity score (UAS7) attested to its convergent validity (ρ = -0.699, P < .001). Its known-group validity was supported by significantly different UCT scores among patient subgroups with different disease activity. The Chinese UCT also demonstrated good sensitivity to change, as reflected by the significant correlation between changes in UCT and UAS7 scores (ρ = 0.491, P < .001). Conclusion: The traditional Chinese UCT is a valid, reliable, and sensitive-to-change instrument among Hong Kong Chinese with CU.

Validation and correlations of the Angioedema Activity Score (AAS), Angioedema Quality of Life (AE-QoL) questionnaire, and Angioedema Control Test (AECT) in Chinese patients with angioedema.

Background: The impact of recurrent angioedema can be severely debilitating and remains difficult to quantify. Several standardized patient-reported outcome measures (PROMs), including the Angioedema Activity Score (AAS), Angioedema Quality of Life (AE-QoL) questionnaire, and Angioedema Control Test (AECT), have been developed and translated into different languages. However, these PROMs have yet to be validated in Chinese individuals, and their correlations in the Chinese population remain unknown. Objective: Our aim was to validate the Chinese versions of the AAS, AE-QoL questionnaire, and AECT and assess their intercorrelations. Methods: A prospective cohort of 118 Chinese patients with recurrent angioedema at the Angioedema and Urticaria Centre of Reference and Excellence in Hong Kong completed the traditional Chinese versions of the AAS, AE-QoL questionnaire, and AECT. We analyzed the reliability and validity of these PROMs and their correlations with each other as well as with generic PROMs. Results: The Chinese AAS, AE-QoL questionnaire, and AECT demonstrated excellent internal consistency (Cronbach α = 0.920, 0.976, and 0.832, respectively; McDonald ω = 0.972, 0.977, and 0.901, respectively). Confirmatory factor analysis for the AE-QoL questionnaire showed an acceptable fit with the 4-dimensional model (comparative fit index = 0.869; Tucker-Lewis index = 0.842). The AECT showed significant correlations with both the AAS and AE-QoL questionnaire (ρ = -0.750 and -0.456 respectively [both P < .05]). The AE-QoL questionnaire was moderately correlated with certain domains of generic PROMs such as the Work Productivity and Activity Impairment Questionnaire: General Health, version 2.0, and the Short Form 12-Item Health Survey, version 2 (all ρ < 0.60). Conclusion: The Chinese AE-QoL questionnaire, AAS, and AECT are valid and reliable tools for use with Chinese patients. More validated tools should be made available to improve patient care and research for all patients with angioedema globally.