Improving prescribing: a feasibility study of pharmacogenetic testing with clinical decision support in primary healthcare in Singapore.

BACKGROUND: The study of genetic variation as a factor influencing drug safety, efficacy, and effectiveness has brought about significant breakthroughs in understanding the clinical application of gene-drug interactions to better manage drug therapy. OBJECTIVE: This study was designed to assess the feasibility of collecting buccal samples by general practitioners (GPs) at private practices in Singapore within a usual consultation, incorporating use of a pharmacogenetics-based medical decision support system to guide subsequent drug dosing. METHODS: We used a prospective cohort study design, with GPs recruiting 189 patients between October 2020 and March 2021. The genotypes of 51 biallelic SNPs were determined using Illumina Infinium Global Screening Array. RESULTS: Seven GPs from 6 private practices recruited and obtained buccal samples from a total of 189 patients. All patients had at least one actionable variant. The prevalence of patients having 2, 3, or 4 variants was 37.0%, 32.8%, and 12.7%, respectively. Potential alterations to medications were identified using the Clinical Decision Support System. Patients were accepting and the GPs were enthusiastic about the potential of pharmacogenetics to personalize medicine for their patients. CONCLUSION: This is the first study in Singapore to demonstrate the feasibility of pharmacogenetic testing in primary care. The high prevalence of genetic variants underscores the potential use of pharmacogenetics in this setting.

Delayed symptoms and orthostatic intolerance following peanut challenge.

BACKGROUND: Clinical reactions to Oral Food Challenge (OFC) in peanut-allergic individuals have been well-characterised, but rates and phenotypes of symptom recurrence beyond the first hour after objective symptoms are less well-characterised. OBJECTIVE: To evaluate the rate of new-onset symptoms occurring at least 1 h after stopping OFC in peanut-allergic children and adults undergoing peanut-OFC. METHODS: We prospectively collected data relating to adverse events following positive reactions at double-blind, placebo-controlled food challenges (DBPCFC) to peanut in children and adults evaluated for eligibility to participate in two clinical trials (NCT02149719, NCT02665793). The trials included people aged 8 to 45 with primary, IgE-mediated peanut allergy at DBPCFC. The challenge protocol included consumption of a light meal 1 h after reaction. RESULTS: A total of 121 participants (64 children, 57 adults) had immediate, objective symptoms at DBPCFC, 25 (17 children, 8 adults) with anaphylaxis. Thirty-three (27%) had progression or recurrence of symptoms ≥ 1 h after objective clinical reaction, of whom 8 developed anaphylaxis. In 23 cases, the onset of new symptoms was associated with consumption of a light meal. In eight cases, symptoms were limited to a symptomatic postural fall in blood pressure noted in preparation for discharge, without any other new features of an allergic reaction. CONCLUSIONS & CLINICAL RELEVANCE: Progressive or new-onset symptoms ≥1 h following initial allergic reaction at OFC are common and can include orthostatic hypotension. Recurrent symptoms may be temporally associated with food consumption.

Self-administration of adrenaline for anaphylaxis during in-hospital food challenges improves health-related quality of life.

OBJECTIVE: To assess the impact of anaphylaxis on health-related quality of life (HRQL) and self-efficacy in food-allergic patients undergoing in-hospital food challenge. DESIGN: Secondary analysis of a randomised controlled trial. SETTING: Specialist allergy centre. PATIENTS: Peanut-allergic young people aged 8-16 years. INTERVENTIONS: Double-blind, placebo-controlled food challenge to peanut, with HRQL and self-efficacy assessed using validated questionnaire, approximately 2 weeks prior to and 2 weeks after challenge. Where possible, anaphylaxis was treated with self-injected adrenaline (epinephrine). MAIN OUTCOME MEASURES: Change in HRQL and self-efficacy. RESULTS: 56 participants had reactions at food challenge, of whom 16 (29%) had anaphylaxis. Overall, there was an improvement in HRQL (mean 2.6 points (95% CI 0.3 to 4.8); p=0.030) and self-efficacy (mean 4.1 points (95% CI 2.4 to 5.9); p<0.0001), independent of whether anaphylaxis occurred. Parents also reported improved HRQL (mean 10.3 points (95% CI 5.9 to 14.7); p<0.0001). We found evidence of discordance between the improvement in HRQL and self-efficacy as reported by young people and that perceived by parents in their child. CONCLUSIONS: Anaphylaxis at food challenge, followed by self-administration of injected adrenaline, was associated with an increase in HRQL and self-efficacy in young people with peanut allergy. We found no evidence that the occurrence of anaphylaxis had a detrimental effect. Young people should be encouraged to self-administer adrenaline using their autoinjector device to treat anaphylaxis at in-hospital challenge. TRIAL REGISTRATION NUMBER: NCT02149719.

Anaphylaxis Refractory to intramuscular adrenaline during in-hospital food challenges: A case series and proposed management.

BACKGROUND: Anaphylaxis is a severe, systemic hypersensitivity reaction that can be potentially life-threatening. Anaphylaxis during oral food challenge is not uncommon and can usually be effectively managed with intramuscular adrenaline as first line treatment. Although very rare, fatal anaphylaxis during in-hospital food challenge has been reported. OBJECTIVE: We describe our experience of cases of refractory anaphylaxis at in-hospital challenge and propose a framework for escalation of treatment in such cases using intravenous infusion of adrenaline which has been adopted for widespread use elsewhere. METHODS: We present four patients who all experienced severe life-threatening anaphylaxis, refractory to intramuscular adrenaline treatment, during supervised oral food challenges. Patient data were collected from contemporaneous notes, and patient consent was obtained. RESULTS: In all four cases, the anaphylaxis reactions were amenable to treatment with low-dose intravenous adrenaline, with no reported adverse effects. CONCLUSION AND CLINICAL RELEVANCE: These cases demonstrate the need for clinicians undertaking higher risk allergen challenges to be able to manage cases of severe anaphylaxis refractory to intramuscular adrenaline, and to consider a framework for managing these reactions. While peripheral intravenous adrenaline infusions should always be initiated only in conjunction with expert input, the protocol suggested is simple enough to be undertaken within the hospital environment while more experienced support is obtained.

Comparison of four distinct detection platforms using multiple ligand binding assay formats.

Several detection platforms are available for ligand binding assays (LBA), each claiming superiority in sensitivity and dynamic range. However, little information exists in the literature directly comparing the various LBA platforms for quantitation. We have tested four common platforms to evaluate and compare the interchangeability of detection platforms by comparing sensitivity and dynamic range to a colorimetric LBA. The detection platforms compared are: colorimetric, chemiluminescence, time-resolved fluorescence (TRF) and electrochemiluminescence (ECL). Five different LBA protocols were tested with each of the detection endpoints. The assay protocols include the following ligand binding assay formats: direct binding, sandwich ELISA, competitive and cell based ELISA. We found that no detection platform consistently performed better than all the others and it was not possible to predict which platform would perform best for a given assay protocol. We also found surprising differences in assays (plate coating efficiency, low signal) which add to difficulty in choosing the best platform ad hoc. We propose here that in developing new assay protocols for detection of biotherapeutic agents, multiple detection platforms should be tested in order to forward the best assays possible and for the right reasons.