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.

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.

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.

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.

Disparities in chronic spontaneous urticaria: Eligibility for drug reimbursement associated with clinical outcomes.

Background: Chronic spontaneous urticaria (CSU) is an immunologic condition with an estimated prevalence of 0.1%. For CSU that is poorly controlled despite the use of antihistamines, omalizumab is the only treatment approved and recommended by international guidelines. Objective: Our aim was to outline the impact of treatment accessibility on CSU outcomes in the real world. Methods: Serial data on adult patients with CSU receiving care for at least 6 months at a dedicated, immunologist-led urticaria clinic at Grantham Hospital in Hong Kong between 2018 and 2023 were analyzed. Patients' clinicodemographic data, drug eligibility status (eligible for reimbursement or not), treatment step, and disease activity (weekly Urticaria Activity Score [UAS7]) were collected and compared according to drug eligibility status. Results: This study included 238 patients, 80 (33.6%) of whom were eligible for reimbursement and 158 of whom were not. No significant clinicodemographic differences, including disease activity, were found at baseline. At latest follow-up, significantly more patients in the eligible group were receiving omalizumab (28.7% vs 5.7% [P < .001]), which is equivalent to a multivariate odds ratio of 9.35 (95% CI = 3.689-23.703 [P < .001]). The discrepancy persisted even in patients with moderate-to-severe CSU whose UAS7 was 16 or higher (40.6% [13 of 32] vs 10.2% [6 of 59]; P < .001). In addition, there was significantly less dose reduction (<300 mg every 4 weeks) in the eligible omalizumab users (4.3% vs 44.4% [P = .015]). Clinically, significantly greater improvements in UAS7 were reported by the eligible group (median change -8.0 vs -5.0 [P = .021]). Conclusion: Patterns of management varied largely among patients with different drug eligibility statuses and led to disparities in health outcomes. More efforts to secure equitable access to guideline-based CSU care are warranted.

Prospective, Multicenter, Head-to-Head Comparison Between Allergists Versus Nonallergists in Low-Risk Penicillin Allergy Delabeling: Effectiveness, Safety, and Quality of Life (HK-DADI2).

BACKGROUND: Penicillin "allergy" labels are prevalent but frequently misdiagnosed. Mislabelled allergies are associated with adverse outcomes and increased antimicrobial resistance. With an urgent need to delabel the overwhelming number of mislabeled allergies, nonallergist evaluations have been advocated for low-risk individuals. Despite growing interest in non-allergist-led initiatives, evidence on their effectiveness, safety, and impact by direct comparisons is lacking. OBJECTIVE: To assess the comparative outcomes of penicillin allergy evaluations conducted by allergists versus nonallergists. METHODS: A prospective, multicenter, pragmatic study was conducted at 4 tertiary hospitals (1 allergist- vs 3 non-allergist-led) for low-risk penicillin allergy patients in Hong Kong-the Hong Kong Drug Allergy Delabelling Initiative 2 (HK-DADI2). RESULTS: Among 228 low-risk patients who underwent testing (32.9% by allergists, 67.1% by nonallergists), only 14 (6.1%) had positive penicillin allergy testing results. Delabeling rates (94.1% vs 93.3%; P = .777), positive skin test results (2.6% vs 2.7%; P > .99), and drug provocation test results (3.3% vs 2.7%; P = 1.000) were similar between allergists and nonallergists. There were no systemic reactions in either cohort. All patients had significant improvements in health-related quality of life (Drug Hypersensitivity Quality of Life Questionnaire scores -5.00 vs -8.33; P = .072). Nonallergist evaluations had shorter waiting times (0.57 vs 15.7 months; P < .001), whereas allergists required fewer consultations with higher rate of completing evaluations within a single visit (odds ratio, 0.04; P < .001). CONCLUSIONS: With training and support, nonallergists can independently evaluate low-risk penicillin allergies. Compared with allergists, evaluation of low-risk penicillin allergy by nonallergists can be comparably effective, safe, and impactful on quality of life. More multidisciplinary partnerships to empower nonallergists to conduct allergy evaluations should be encouraged.

Clinical utility of and correlation between Sniffin' Sticks and TIB smell identification test (TIBSIT) among Hong Kong Chinese with or without chronic rhinosinusitis.

Introduction: Olfactory dysfunction (OD) is common among patients with chronic rhinosinusitis (CRS). Validated and culturally specific tests, such as the "Sniffin' Sticks" test (SST) and the TIB Smell Identification Test (TIBSIT), are crucial for the diagnosis and monitoring of OD. However, they have not been utilised in Hong Kong Chinese and their correlations are unknown. Methods: Twelve CRS patients and twenty healthy volunteers were prospectively recruited from a joint allergy-otorhinolaryngology clinic in Hong Kong and performed both SST and TIBSIT. Demographics, baseline characteristics and all test results were compared and analysed. Results: Patients with CRS demonstrated significantly lower test scores than healthy controls (all p < 0.001). Significant and strong correlations were observed between all composite and subtest scores, particularly between the composite SST and TIBSIT scores (ρ = 0.789, p < 0.001). Multivariate analysis demonstrated that the presence of CRS and increasing age were significantly associated with OD. Conclusion: Both SST and TIBSIT are useful olfactory tests and are strongly correlated among Hong Kong Chinese. We advocate that either test can be used for measuring OD among CRS patients.

Enhancing Patient-Reported Outcome Measures for Drug Hypersensitivity: A Validated 6-Item Quality-of-Life Questionnaire for Patients With Drug Hypersensitivity.

BACKGROUND: Drug hypersensitivity reactions (DHRs) can significantly impair patients' health-related quality of life (HRQoL). However, tools for HRQoL assessment for patients with DHR are time-consuming and remain underutilized. OBJECTIVE: To develop and validate an optimized version of the Drug Hypersensitivity Quality-of-Life Questionnaire (DrHy-Q) designed for everyday clinical use. METHODS: Item response theory (IRT), a statistical framework for psychometric measurement, was used to evaluate the 15 questions from the original DrHy-Q for their respective item difficulty, discrimination, and information using prospective data from 243 patients with histories of suspected/confirmed DHR before allergy workup. Accordingly, the best-performing items were identified to develop a 6-item optimized version (DrHy-Q6), which was subsequently validated with another prospective cohort of 156 patients. RESULTS: All 15 items of the original DrHy-Q demonstrated satisfactory parameters in IRT analysis, including very high discrimination (>1.7), appropriate difficulty (in between -1.5 and 1.5), and good information (a high and broad peak in the information curve). Six items with top-ranked IRT parameters were identified to construct an optimized version, which we named the DrHy-Q6. The DrHy-Q6 demonstrated a 1-factor structure with an improved fit compared with the original DrHy-Q (comparative fit index = 0.985, Tucker-Lewis index = 0.974), excellent convergent validity (unadjusted Pearson correlation with the full version = 0.955; adjusted = 0.894, P < .001), reliability (Cronbach's α and McDonald's ω = 0.93), divergent validity (Pearson correlation with all Short Form 12-item Health Survey Version 2 subscales <0.60, P < .001), and discriminant validity (significantly higher scores with multiple DHR labels [42.45 ± 27.26 vs 32.93 ± 26.66], P = .013). CONCLUSIONS: From an IRT perspective, the DrHy-Q and all its constituent items are psychometrically valid for HRQoL assessment. We propose an optimized 6-item version (DrHy-Q6) as an abbreviated alternative for assessing HRQoL in patients with DHR, especially for routine use in clinical practice. Patients and physicians may benefit from its streamlined length and simpler scoring algorithm.