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.

A case of persistent IgE sensitisation almost two decades following ampicillin anaphylaxis.

BACKGROUND: Although most immunoglobulin E (IgE)-mediated penicillin allergy wanes with time, sensitisation may occasionally persist for many years. Previous reports on the loss of penicillin-specific IgE sensitisation were based on non-anaphylaxis cases and, although uncommon, persistent sensitisation may still be possible in the minority of cases. OBJECTIVE: This case highlights that irrespective of the elapsed duration since the index reaction, it is important to remain vigilant when approaching patients with a history of severe reactions. MATERIAL AND METHODS: We described a case of persistent IgE sensitisation almost two decades following ampicillin anaphylaxis. RESULTS: A 78-year-old male with a history of perioperative penicillin anaphylaxis in 2003 was referred for allergy workup in 2022 before his knee joint replacement surgery. The patient had strictly avoided all beta-lactams since the index reaction. However, his penicillin-specific sensitisation persisted, evidenced by positive skin tests (with generalised urticaria after intradermal testing) and basophil activation tests. CONCLUSION: To our knowledge, this was the first case of positive BAT tested around two decades following the index reaction. This case illustrates that a cautious approach may still be warranted in patients with a history of severe reaction to penicillin regardless of the duration since the reported index reaction.

Prospective Assessment of Penicillin Allergy (PAPA): Evaluating the performance of penicillin allergy testing and post-delabelling outcomes among Hong Kong Chinese.

BACKGROUND: Incorrect penicillin 'allergy' labels predispose patients to adverse outcomes but are under-recognised in many Asian countries. Studies on performance and post-delabelling outcomes of penicillin allergy evaluation among Chinese remain scarce. OBJECTIVE: To evaluate the diagnostic performance of allergy testing and post-delabelling outcomes among Chinese patients in a prospective penicillin allergy cohort - Prospective Assessment of Penicillin Allergy (PAPA). METHODS: All adult patients (age ≥ 18 years) who underwent penicillin allergy evaluation between January 2020 to December 2021 were recruited and prospectively reviewed by both medical records and individual interviews at least 6 months after delabelling or allergy confirmation. RESULTS: Out of 372 patients who completed penicillin allergy evaluation, 335 (90%) patients were delabelled. The overall negative predictive value of penicillin skin testing was 95%, but lower for patients with non-immediate type reactions (88%). History of non-immediate symptom onset (OR = 4.501 [95%CI = 2.085-9.716], p < 0.001) and duration since index reaction (OR = 0.942 [95%CI = 0.899-0.987], p = 0.012) were associated with positive skin testing. After at least 6 months, 60 (18%) of de-labelled patients had received penicillins again without any adverse reactions. Fluoroquinolone-use was significantly lower among delabelled patients compared to those with penicillin allergy (38[11%] vs 11[30%], p = 0.004). CONCLUSIONS: After at least 6 months, one in six delabelled patients already received penicillins again safely, with significantly lower fluoroquinolone usage. None experienced adverse reactions. History of non-immediate onset and shorter duration since index reaction were associated with genuine allergy. In patients with severe non-immediate reactions, skin tests should be supplemented with thorough clinical history and adjunct diagnostic evaluations.

COVID-19 Vaccine Allergy Safety Track (VAS-Track) pathway: real-world outcomes on vaccination rates and antibody protection.

BACKGROUND: Misdiagnosed vaccine-related "allergies" lead to unnecessary vaccine deferrals and incomplete vaccinations, leaving patients unprotected against COVID-19. To overcome limitations and queues for Allergist assessment, the "VAS-Track" pathway was developed to evaluate patients via a multi-disciplinary triage model including nurses, non-specialists, and Allergists. OBJECTIVE: We assessed the effectiveness and safety of VAS-Track and evaluate its real-world impact in terms of vaccination rates and COVID-19 protection. METHODS: Patients referred to VAS-Track between September 2021 and March 2022 were recruited. Subgroup analysis was performed with prospective pre- and post-clinic antibody levels. RESULTS: Nurse-assisted screening identified 10,412 (76%) referrals as inappropriate. 369 patients were assessed by VAS-Track. Overall, 100% of patients were recommended to complete vaccination and 332 (90%) completed their primary series. No patients reported any significant allergic reactions following subsequent vaccination. Vaccination completion rates between patients seen by non-specialists and additional Allergist review were similar (90% vs. 89%, p = 0.617). Vaccination rates were higher among patients with prior history of immediate-type reactions (odds ratio: 2.43, p = 0.025). Subgroup analysis revealed that only 20% (56/284) of patients had seropositive COVID-19 neutralizing antibody levels (≥ 15 AU/mL) prior to VAS-Track, which increased to 92% after vaccine completion (pre-clinic antibody level 6.0 ± 13.5 AU/mL vs. post-clinic antibody level 778.8 ± 337.4 AU/mL, p > 0.001). CONCLUSIONS: A multi-disciplinary allergy team was able to streamline our COVID-19 VAS services, enabling almost all patients to complete their primary series, significantly boosting antibody levels and real-world COVID-19 protection. We propose similar multidisciplinary models to be further utilized, especially in the settings with limited allergy services.

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.

Clinical characteristics, densitometric parameters and outcomes of patients with atypical femoral fractures related to bisphosphonate treatment for osteoporosis.

PURPOSE: We described the clinical and densitometric characteristics and treatment outcomes of patients who developed atypical femoral fractures (AFF) while on bisphosphonate for osteoporosis. METHODS: We performed a retrospective cohort study including all adults aged ≥50 years who developed AFF while on bisphosphonates between 1 January 2008 and 31 December 2020, and subsequently managed in the Osteoporosis Centre at Queen Mary Hospital in Hong Kong. A control group of patients who developed fragility hip fractures while on bisphosphonates in the same period was included for comparison. We compared the clinical and densitometric characteristics between the two groups, and described the clinical outcomes for the AFF group. RESULTS: In total, 75 patients were included (AFF: n = 35; fragility hip fracture: n = 40). All were related to oral bisphosphonates. The AFF group was characterised by a longer duration of bisphosphonate use (median of 5 years), higher bone mineral density (BMD) and more acute neck-shaft angle (all p < 0.05). Following AFF, 8 patients (22.9%) did not receive any subsequent bone-active agents: due to refusal to use an injectable, or BMD out of osteoporotic range. Most of those who received bone-active agents were given teriparatide, followed by raloxifene, and achieved stable BMD. However, subsequent fragility risk remained high. Nonetheless, AFF did not confer excess morbidity and mortality. CONCLUSION: AFF was characterised by usually long duration of bisphosphonate use, higher BMD and more acute neck-shaft angle. AFF did not confer significant impairment in mobility or mortality. Nonetheless, further research work is necessary to optimise bone health among patients who develop AFF.

Inactivated COVID-19 vaccines: potential concerns of antibody-dependent enhancement and original antigenic sin.

Inactivated vaccine is one of the platforms employed in COVID-19 vaccines. Inactivated vaccines have been associated with concerns of antibody-dependent enhancement (ADE) and original antigenic sin (OAS), which are related to non-neutralising or poorly neutralising antibodies against the pathogen. Since inactivated COVID-19 vaccines use whole-SARS-CoV-2 virus as the immunogen, they are expected to generate antibodies against non-spike structural proteins, which are highly conservative across variants of SARS-CoV-2. These antibodies against non-spike structural proteins have found to be largely non-neutralising or poorly neutralising in nature. Hence, inactivated COVID-19 vaccines could possibly be associated with ADE and OAS, especially as novel variants emerge. This article explores the potential concern of ADE and OAS in the context of inactivated COVID-19 vaccine, and outlines the future research directions.

Chronic Spontaneous Urticaria in Hong Kong: Clinical Characteristics, Real-World Practice and Implications for COVID-19 Vaccination.

PURPOSE: The real-world management and clinical characteristics of chronic spontaneous urticaria (CSU) in Hong Kong and its implications for coronavirus disease 2019 (COVID-19) vaccination are unknown. We investigated the clinical characteristics of patients with CSU and the role of an immunologist-led Urticaria Clinic as well as the impact of CSU on COVID-19 vaccine uptake in Hong Kong. METHODS: Longitudinal clinical data of 257 CSU patients were collected and analyzed. Association analyses were performed to identify the relationships between variables and factors associated with COVID-19 vaccine uptake. RESULTS: After the immunologist review, the Weekly Urticaria Activity Score (UAS7) was significantly lower than baseline (median: 0.00 vs. 12.0, P < 0.001). Changes in UAS7 were significantly greater among patients with baseline UAS7 ≥ 16 compared to those with UAS7 < 16 (median: -24.0 vs. -2.00, P < 0.001). CSU patients had lower COVID-19 vaccination rates than the general population with only 176 (68.5%) and 165 (65.0%) receiving at least one dose and 2 doses of vaccination, respectively. The presence of concomitant suspected drug allergy was associated with lower COVID-19 vaccine uptake (odds ratio [OR], 0.47; P = 0.010), while regular pharmacological treatment was associated with higher COVID-19 vaccine uptake among CSU patients (OR, 3.79; P = 0.010). CONCLUSIONS: A dedicated immunologist-led Urticaria Clinic may effectively improve CSU management and outcomes in Hong Kong.

Feasibility of a drug allergy registry-based excipient allergy database and call for universal mandatory drug ingredient disclosure: the case of PEG.

Background: Excipient allergy is a rare, but potentially lethal, form of drug allergy. Diagnosing excipient allergy remains difficult in regions without mandatory drug ingredient disclosure and is a significant barrier to drug safety. Objective: To investigate the feasibility of a drug allergy registry-based excipient database to identify potential excipient culprits in patients with history of drug allergy, using polyethylene glycol (PEG) as an example. Methods: An excipient registry was created by compiling the excipient lists pertaining to all available formulations of the top 50 most reported drug allergy culprits in Hong Kong. Availability of excipient information, and its relationship with total number of formulations of individual drugs were analysed. All formulations were checked for the presence or absence of PEG. Results: Complete excipient information was available for 36.5% (729/2,000) of all formulations of the top 50 reported drug allergy culprits in Hong Kong. The number of formulations for each drug was associated with proportion of available excipient information (ρ = 0.466, p = 0.001). Out of 729 formulations, 109 (15.0%) and 620 (85.0%) were confirmed to contain and not contain PEG, respectively. Excipient information was not available for the other 1,271 (63.6%) formulations. We were unable to confirm the presence or absence of PEG in any of the top 50 drug allergy culprits in Hong Kong. Conclusion: In countries without mandatory drug ingredient disclosure, excipient databases are unlikely able to identify potential excipient allergy in drug allergy patients. Legislations to enforce mandatory and universal ingredient disclosure are urgently needed.

Ten-year population trends of immunoglobulin use, burden of adult antibody deficiency and feasibility of subcutaneous immunoglobulin (SCIg) replacement in Hong Kong Chinese.

Background: Adult antibody deficiency remains under-recognised and under-studied - especially among Asian populations. Patterns of immunoglobulin use and the feasibility of subcutaneous immunoglobulin (SCIg) replacement among Chinese patients remains unclear. Objective: To investigate the trends of immunoglobulin use, burden of adult antibody deficiency and the outcomes of patients on SCIg compared to intravenous immunoglobulin (IVIg) replacement in Hong Kong through a retrospective observational study. Methods: Population-wide data of immunoglobulin recipients in Hong Kong between 2012 and 2021, and longitudinal clinical data of adult immunodeficiency patients at Queen Mary Hospital were collected and analysed. Results: Total immunoglobulin consumption and recurrent immunoglobulin recipients increased continuously from 175,512g to 298,514g (ρ=0.99, p<0.001) and 886 to 1,508 (ρ=0.89, p=0.001) between 2012-21 in Hong Kong. Among 469 immunoglobulin recipients at Queen Mary Hospital in 2021, 344 (73.3%) were indicated for replacement. Compared to those on IVIg (n=14), patients on SCIg replacement (n=8) had fewer immunodeficiency-related hospitalisations (IRR=0.11) and shorter duration of hospitalisation stay (IRR=0.10) per year, as well as better quality of life (SF-36v2 Health Survey and Life Quality Index). Estimated annual healthcare cost of SCIg replacement per patient was lower than that of IVIg (HKD196,850 [USD25,096] vs HKD222,136 [USD28,319]). Conclusion: There was a significantly increasing burden of adult antibody deficiency and immunoglobulin consumption in Hong Kong. SCIg was feasible and more cost-effective when compared to IVIg, with SCIg patients experiencing better clinical outcomes and quality of life. Future prospective studies to confirm the long-term efficacy and superiority of SCIg are required.

Prospective association of serum adipocyte fatty acid-binding protein with heart failure hospitalization in diabetes.

AIMS: Adipocyte fatty acid-binding protein (AFABP) is associated with cardiovascular diseases in type 2 diabetes. Whether circulating AFABP levels are associated with the risk of heart failure (HF) in type 2 diabetes remains undefined. We investigated the prospective association of circulating AFABP levels with incident HF hospitalization in type 2 diabetes, and its relationship to the use of sodium glucose co-transporter 2 inhibitors (SGLT2i) which reduce HF risk. METHODS AND RESULTS: Baseline serum AFABP level was measured in 3322 Chinese participants without known history of cardiovascular diseases or hospitalization for HF, recruited from the Hong Kong West Diabetes Registry. Its association with incident HF hospitalization was evaluated using multivariable Cox regression analysis. Use of SGLT2i was included as a time-dependent covariate. Among these 3322 participants (52.9% men; mean age 60.0 ± 12.6), 176 (5.3%) developed HF hospitalization over a median follow-up of 8 years. Seven hundred and thirty-one (22%) were started on SGLT2i during the study period (empagliflozin 55.1%, dapagliflozin 44.2%, canagliflozin 0.4%, and ertugliflozin 0.3%). Serum AFABP levels were significantly higher in participants who developed HF hospitalization than those who did not (men: 14.8 vs. 8.3 ng/mL; women: 21.5 vs. 14.6 ng/mL; all: 18.6 vs. 10.9 ng/mL, P < 0.001). In multivariable Cox regression analysis, baseline serum AFABP level was significantly associated with incident HF hospitalization [hazard ratio (HR) 1.38, 95% confidence interval (CI) 1.06-1.80, P = 0.019] independent of the use of SGLT2i, in a model also consisting of age; sex; body mass index; smoking status; duration of diabetes; hypertension, dyslipidaemia; atrial fibrillation; presence of chronic kidney disease and albuminuria; glycated haemoglobin and high-sensitivity C-reactive protein levels; and use of metformin, insulin, aspirin, furosemide, and beta-blockers at baseline. High cumulative defined daily dose (cDDD) of SGLT2i was protective of incident HF hospitalization (HR 0.10, 95% CI 0.01-0.68, P = 0.019). The addition of circulating AFABP level to a clinical model of conventional HF risk factors provided significant improvement in the category-free net reclassification index (11.5%, 95% CI 1.6-22.1, P = 0.02) and integrated discrimination improvement (0.3%, 95% CI 0.1-1.7, P = 0.04). A dose-dependent reduction in cumulative incidence of HF hospitalization in response to SGLT2i, based on cDDD, was more clearly observed in participants with a higher baseline AFABP level above the sex-specific median (P for trend <0.01). CONCLUSIONS: Circulating AFABP level is independently associated with incident HF hospitalization in type 2 diabetes and is potentially helpful in risk stratification for the prevention of HF hospitalization.