Development and application of Adverse drug reactions reports QUality Algorithm (AQUA-12) score: a single-centre quality improvement initiative.

PURPOSE: To develop a reliable assessment tool to monitor the quality of adverse drug reaction (ADR) reports and evaluate its performance within a quaternary hospital setting. METHODS: Adverse drug reactions report QUality Algorithm (AQUA-12) was developed by a multidisciplinary team with the expertise in the management of ADRs. The design was based on data elements required to establish medication causality. Inter-rater reliability of AQUA-12 was evaluated over three rounds in two phases: development and prospective evaluation phases, by independent assessors both internal and external to the institutional ADR review processes. The characteristics and quality of ADR reports were subsequently assessed, and potential factors contributing to low-quality reports were identified. RESULTS: A total of 70 ADR reports were assessed, 20 in development and 50 in evaluation phases. The inter-rater reliability of AQUA-12 was found to be excellent in all three rounds (Cronbach's alpha of  ≥ 0.9, p < 0.001 for all). Approximately one in five reports concerned immediate hypersensitivity reactions while delayed hypersensitivity reactions constituted 60% of all reactions. AQUA-12 identified 18 (25.7%) reports as 'low-quality' with a score of  < 10. Identification of suspected medications (37.1%), description of index ADR (27.1%), and key events (ADR narrative, 35.7%) were the top data elements incomplete or missing from all reports. Univariable analyses identified the severity of the reaction as a factor associated with low quality of reports (p = 0.008). CONCLUSIONS: AQUA-12 is a practical and highly reliable assessment tool that can be utilised in hospital settings to regularly monitor the completeness of ADR reports to guide quality improvement initiatives.

Diagnostic value of a medical algorithm for investigation of perioperative hypersensitivity reactions.

BACKGROUND: Evaluation of perioperative hypersensitivity (POH) is challenging, and accurate screening tools are needed to optimize the diagnostic process. We aimed to assess and validate the diagnostic value of a published algorithm (using tryptase and clinical presentation) to identify appropriate individuals for further testing for IgE-mediated POH. METHODS: We analysed the clinical presentation (tryptase elevation, cardiovascular, respiratory, skin involvement) of patients proceeding to testing for possible IgE-mediated POH at a single tertiary referral centre, relative to subsequent skin testing and specific IgE results. Clinical presentations by drug class were also determined. RESULTS: In 293 consecutive patients, the use of a published algorithm based on one or more of; (i) defined increase in serum tryptase, (ii) involvement of at least two-organ systems, or (iii) presentation with new urticaria and/or angioedema; was highly sensitive [98.8% (CI95: 95.7-99.9%)] but less specific [34.6% (CI95: 25.7-44.4%)] in identifying patients testing positive on skin testing and/or specific IgE. Presentation with cardiovascular symptoms was also sensitive [89.8%(CI95: 84.2-94.0%)], while the combination of respiratory symptoms and increased tryptase was most specific [85.9%(CI95:76.6-92.5%)]. Respiratory involvement was more common in neuromuscular blocking agent allergy, while urticaria/angioedema was more common in antibiotic allergy. CONCLUSION: The published algorithm (of tryptase rise, two-organ involvement or new urticaria/angioedema) is highly sensitive, and appropriate as a screening tool to identify patients suitable for testing for IgE-mediated POH.

Phenotypic Distinctions Between Omega-5-Gliadin Allergy and Peanut Allergy: Clinical Profile, Reaction Rates and Triggers, and Quality of Life.

Background: Different phenotypes of food allergy may exist, exhibiting distinct clinical features, and driven by different pathogenic mechanisms. We compared omega-5-gliadin (O5G) allergy to peanut allergy, focusing on clinical features, reaction rates and triggers, and quality of life (QOL). Methods: We surveyed adults with O5G allergy and peanut allergy regarding their diagnosis, co-morbidities, allergic reactions, and QOL measured by the FAQLQ-AF. Results: We received responses from 43/80 (54%) individuals with O5G allergy and 43/130 (33%) with peanut allergy. Compared to peanut allergic individuals, those with O5G allergy were older at age of onset (37.2 vs 2.5 years, p < 0.001), had fewer additional atopic conditions (0.88 vs 2.93, p < 0.001) or food allergies (0.15 vs 1.86, p < 0.001), and more frequent reactions before diagnosis (1.085 vs 0.29 per month, p < 0.05) Reaction rates improved in both groups following diagnosis. Reactions to peanut were more often triggered by accidental exposure (84% vs 26%, p < 0.001) and being away from home (65% vs 28%, p < 0.001), while reactions to O5G were more often due to deliberate ingestion (30% vs 9%, p < 0.05) or unexpected exercise (35% vs 2%, p < 0.001). Overall QOL score was similar between groups (4.2 in O5G allergy, 4.7 in peanut allergy, p = 0.12), but worse among women and those with additional food allergies. Conclusion: Phenotypic differences between O5G and peanut allergy support the development of different clinical approaches and the possibility of targeting distinct pathogenic mechanisms for prevention and treatment. Quality of life was impaired to a similar degree between groups.

Study protocol: Australasian Registry of Severe Cutaneous Adverse Reactions (AUS-SCAR).

INTRODUCTION: Severe cutaneous adverse reactions (SCAR) are a group of T cell-mediated hypersensitivities associated with significant morbidity, mortality and hospital costs. Clinical phenotypes include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalised exanthematous pustulosis (AGEP). In this Australasian, multicentre, prospective registry, we plan to examine the clinical presentation, drug causality, genomic predictors, potential diagnostic approaches, treatments and long-term outcomes of SCAR in Australia and New Zealand. METHODS AND ANALYSIS: Adult and adolescent patients with SCAR including SJS, TEN, DRESS, AGEP and another T cell-mediated hypersensitivity, generalised bullous fixed drug eruption, will be prospectively recruited. A waiver of consent has been granted for some sites to retrospectively include cases which result in early mortality. DNA will be collected for all prospective cases. Blood, blister fluid and skin biopsy sampling is optional and subject to patient consent and site capacity. To develop culprit drug identification and prevention, genomic testing will be performed to confirm human leukocyte antigen (HLA) type and ex vivo testing will be performed via interferon-γ release enzyme linked immunospot assay using collected peripheral blood mononuclear cells. The long-term outcomes of SCAR will be investigated with a 12-month quality of life survey and examination of prescribing and mortality data. ETHICS AND DISSEMINATION: This study was reviewed and approved by the Austin Health Human Research Ethics Committee (HREC/50791/Austin-19). Results will be published in peer-reviewed journals and presented at relevant conferences. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12619000241134).

Mast Cell Diseases in Practice and Research: Issues and Perspectives Raised by Patients and Their Recommendations to the Scientific Community and Beyond.

BACKGROUND: Since 2010, patients and physicians have collaborated to understand unmet needs of patients with mast cell diseases, incorporating mastocytosis and mast cell activation disorders, which include mast cell activation syndromes. OBJECTIVE: This Open Innovation in Science project aims to expand understanding of the needs of patients affected by mast cell diseases, and encourage global communication among patient advocacy groups, physicians, researchers, industry, and government. A major aim is to support the scientific community's efforts to improve diagnosis, management, therapy, and patients' quality of life by addressing unmet needs. METHODS: In collaboration with mast cell disease specialists, 13 patient advocacy groups from 12 countries and regions developed lists of top patient needs. A core team of leaders from patient advocacy groups collected and analyzed the data and proposed possible actions to address patient needs. RESULTS: Findings identified similarities and differences among participating countries in unmet needs between patients with mastocytosis and those with mast cell activation syndromes. Issues emphasized struggles relating to the nature and rarity of mast cell diseases, their impact on quality of life, the diagnostic process, access to appropriate care, more effective treatment, and the need for research. CONCLUSIONS: Solutions vary across countries because situations differ, in particular regarding the existence of and access to centers of excellence and reference centers. Multifaceted mast cell activation syndrome barriers necessitate innovative approaches to improve access to appropriate care. The outcomes of this project should greatly support scientists and clinicians in their efforts to improve diagnosis, management, and treatment of patients with mastocytosis and mast cell activation disorders.

Combination treatment with monoclonal antibodies: Secukinumab, benralizumab and dupilumab for the combined management of psoriasis and severe asthma.

Biological disease-modifying agents have increasingly become available for the effective treatment of both cutaneous and non-cutaneous inflammatory conditions. We report a case of a woman treated successfully for psoriasis and psoriatic arthritis with the IL-17 inhibitor secukinumab whilst simultaneously being treated for severe asthma and nasal polyps, initially with the IL-5 inhibitor benralizumab, followed by dupilumab, a monoclonal antibody that targets the IL-4 receptor alpha subunit which blocks signalling from both IL-4 and IL-13.

Long-term safety and effectiveness of berotralstat for hereditary angioedema: The open-label APeX-S study.

BACKGROUND: Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein recently approved for prevention of angioedema attacks in adults and adolescents with hereditary angioedema (HAE). The objective of this report is to summarize results from an interim analysis of an ongoing long-term safety study of berotralstat in patients with HAE. METHODS: APeX-S is an ongoing, phase 2, open-label study conducted in 22 countries (ClinicalTrials.gov, NCT03472040). Eligible patients with a clinical diagnosis of HAE due to C1 inhibitor deficiency (HAE-C1-INH) were centrally allocated to receive berotralstat 150 or 110 mg once daily. The primary objective was to determine long-term safety and the secondary objective was to evaluate effectiveness. RESULTS: Enrolled patients (N = 227) received berotralstat 150 mg (n = 127) or 110 mg (n = 100) once daily. The median (range) duration of exposure was 342 (11-540) and 307 (14-429) days for the 150-mg and 110-mg groups, respectively. Treatment-emergent adverse events (TEAEs) occurred in 91% (n = 206) of patients. The most common TEAEs across treatment groups were upper respiratory tract infection (n = 91, 40%), abdominal pain (n = 57, 25%), headache (n = 40, 18%), and diarrhea (n = 31, 14%) and were mostly mild to moderate. Fifty percent (n = 113) of patients had at least one drug-related adverse event (AE; 150 mg, n = 57 [45%]; 110 mg, n = 56 [56%]), and discontinuations due to AEs occurred in 19 (8%) patients (150 mg, n = 13 [10%]; 110 mg, n = 6 [6%]). Three (1.3%) patients experienced a drug-related serious TEAE. Among patients who received berotralstat through 48 weeks (150 mg, n = 73; 110 mg, n = 30), median HAE attack rates were low in month 1 (150 mg, 1.0 attacks/month; 110 mg, 0.5 attacks/month) and remained low through 12 months (0 attacks/month in both dose groups). Mean HAE attack rates followed a similar trend, and no evidence for patient tolerance to berotralstat emerged. In both dose groups, angioedema quality of life scores showed clinically meaningful changes from baseline. CONCLUSIONS: In this analysis, both berotralstat doses, 150  and 110 mg once daily, were generally well tolerated. Effectiveness results support the durability and robustness of berotralstat as prophylactic therapy in patients with HAE. TRIAL REGISTRATION: The study is registered with ClinicalTrials.gov (NCT03472040).

Evaluation of Diagnosis and Management of Omega-5-Gliadin Allergy: A Retrospective Survey.

BACKGROUND: Allergy to the omega-5-gliadin component of gluten (O-5-G allergy) often manifests when wheat ingestion is followed by a co-factor, usually exercise. There is no established best approach to management. OBJECTIVE: We sought to identify the beneficial effects, firstly of establishing a firm diagnosis, and secondly of stringent management, either by avoiding gluten ingestion altogether or separating it temporally from exercise by at least 4 hours. We also determined how frequently patients adhered to their physicians' clinical recommendations. METHODS: We undertook a survey of individuals diagnosed with O-5-G allergy at our institution over 8 years, who had a consistent clinical history and confirmatory laboratory evidence. RESULTS: Of 80 eligible individuals, 43 responded (54%). Symptoms began in adulthood for all bar one, and concurrent asthma and eczema was uncommon (9% prevalence, respectively). Median time to diagnosis was 2 years. Achieving a diagnosis reduced the rate of reactions (0.35 per month vs 1.085 reactions per month, p=0.029). Many patients (10/43) did not adhere to the recommended stringent approach, to either avoid wheat/gluten or separate food and exercise by 4 hours. However, those adopting a stringent approach had a substantially lower risk of recurrent allergic reaction (0.22 per month vs 0.74 per month, p=0.004). CONCLUSION: The epidemiology of O-5-G allergy implies pathogenic mechanisms potentially distinct from those of childhood-onset food allergy. Accurate diagnosis improves the clinical trajectory, primarily through the adoption of a stringent management approach.

The Role of In Vivo and Ex Vivo Diagnostic Tools in Severe Delayed Immune-Mediated Adverse Antibiotic Drug Reactions.

BACKGROUND: The use of in vivo and ex vivo diagnostic tools for delayed immune-mediated adverse drug reactions is currently ill defined. OBJECTIVE: To determine whether the combination of skin testing and/or IFN-γ enzyme-linked immunoSpot assay (ELISpot) can aid diagnosis of these allergy phenotypes. METHODS: Patients with antibiotic-associated severe delayed immune-mediated adverse drug reaction hypersensitivity, including Stevens-Johnson syndrome and toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis, generalized bullous fixed drug eruption, and severe maculopapular exanthema, were prospectively recruited. In vivo testing was completed to the implicated drug(s), and ex vivo testing was performed with the patient's PBMCs stimulated with the relevant antibiotic concentrations for IFN-γ release ELISpot measurement. RESULTS: Eighty-one patients met the inclusion criteria, with DRESS (42; 51.9%) accounting for most cases. Among the 63 (78%) who had an ELISpot assay performed, 34 (54%) were positive to at least 1 implicated antibiotic (median spot-forming units/million cells, 99.5; interquartile range, 68-187), with glycopeptide being a strong predictor of positivity (adjusted odds ratio, 6.11; 95% CI, 1.74-21.42). In combination (in vivo and ex vivo), 51 (63%) of those tested were positive to an implicated antibiotic. For DRESS and severe maculopapular exanthema associated with penicillins and cephalosporins, this combination confirmed the culprit agent in 11 of the 12 cases and in 6 of 7 for DRESS associated with glycopeptides. CONCLUSIONS: This study demonstrates that using in vivo in combination with ex vivo testing can enhance the diagnostic approach in these severe phenotypes by assisting with the identification of possible culprit antibiotics.

A Survey on Knowledge Gaps in Assessment and Management of Severe Drug Hypersensitivity Reactions: Multicenter Cross-Sectional Study of Australian Health Care Providers.

Severe drug hypersensitivity reactions (DHRs) are often encountered by health care professionals (HCPs). We evaluated knowledge of doctors and pharmacists in the assessment and management of severe DHRs using a structured questionnaire. A cross-sectional study was conducted in 4 metropolitan hospital networks in Melbourne, Australia. A 13-question, scenario-based multiple-choice questionnaire to assess specific knowledge domains in drug hypersensitivity syndrome recognition, causality attribution, cross-reactivity patterns, appropriate diagnostic tests, and therapy was administered to HCPs of various vocation and specialty groups. Data were analyzed according to profession, self-reported experience, and preparedness in managing severe DHRs. Two hundred thirty-eight participants (45.0% senior doctors, 24.4% junior doctors, and 30.7% pharmacists) across a range of subspecialties achieved an overall median score of 7 (IQR, 5-8)-overall 55.6% correct responses to all questions-with senior doctors outperforming junior doctors and pharmacists (P < .001). The best performance by all participants was in DHR syndrome recognition (60.9%), and the poorest was in diagnostics/therapy (52.0%). HCP group and experience level were significantly associated with better performance in the knowledge domains of cross-reactivity and diagnostics/therapy (P = .003 and < .001, respectively), but not in the domains of syndrome recognition and causality attribution (P > .05). Levels of self-reported preparedness in DHR management were not associated with performance rates in any of the knowledge domains. This study demonstrated significant knowledge gaps in the recognition and management of severe drug hypersensitivity reactions. Targeted multidisciplinary education of staff caring for these patients is needed to improve knowledge gaps.

Safety of Intravenous Iron Following Infusion Reactions.

BACKGROUND: Where an ongoing requirement for intravenous iron replacement exists after an index infusion reaction, current recommendations are limited to expert opinion and isolated case reports. OBJECTIVE: To evaluate the safety of recommencing an infusion or subsequent rechallenge following an infusion reaction to intravenous iron. METHODS: Infusion reactions to intravenous iron occurring between January 1, 2010, and December 31, 2019, at a metropolitan health network were identified. Patient characteristics, reaction type (mild, moderate, or severe hypersensitivity, delayed, or Fishbane: transient flushing and truncal myalgias), and outcomes of recommencing the index infusion or subsequent rechallenge were examined. RESULTS: Among 13,509 iron infusions, 195 infusion reactions occurred in 195 patients (1.4% of infusions). Recommencement of the index infusion (generally with a reduced infusion rate and premedication) was tolerated in 33 of 33 patients with Fishbane (20 of 20) or mild (9 of 9) and moderate (4 of 4) hypersensitivity reactions. Subsequent rechallenge (generally at standard infusion rates to an alternative formulation, ferric carboxymaltose) was successful in 68 of 69 patients with Fishbane (23 of 23), mild (26 of 26), moderate (16 of 17), and severe (3 of 3) hypersensitivity, or delayed (2 of 2) reactions. All 9 patients rechallenged to the original formulation (iron polymaltose) completed the infusion. CONCLUSIONS: Following an infusion reaction to intravenous iron infusion, recommencement of the index infusion is safe for Fishbane or mild and moderate hypersensitivity reactions. Subsequent rechallenge to an alternative formulation is tolerated, including in severe hypersensitivity reactions (albeit based on limited numbers). Where alternative formulations are not available, rechallenge to the same formulation could be considered, depending on the risk-benefit profile.

Strongyloides infection as a reversible cause of chronic urticaria.

Recurrent urticaria is a frequent presenting complaint in the Allergy Clinic, despite the fact that chronic urticaria is not an IgE-mediated (atopic) condition in most cases. We present four cases assessed over 5 years in our allergy service who were found to have evidence of strongyloidiasis and whose clinical features resolved with standard anti-helminth treatment.

Medication-related anaphylaxis treated in hospital: Agents implicated, patient outcomes, and management lessons.

PURPOSE: On background of increasing medication-related anaphylaxis rates in Australia, our aim was to determine epidemiology, outcomes, adverse drug reaction (ADR) reporting rates, and accuracy of coding in patients treated for nonantimicrobial medication-related anaphylaxis in our hospital network. METHODS: From January 2010 to December 2015 patients treated in our hospital network for medication-related anaphylaxis were identified using International Classification of Diseases, 10th Edition diagnosis code T88.6. Cases were also extracted from the hospital ADR database. Medical records were reviewed to ensure consistent diagnosis and to extract clinical, documentation, and outcome data. RESULTS: Of 1110 patients coded as T88.6, 177 (15.9%) met the medication-related anaphylaxis definition. Eighty (40.8%) had anaphylaxis due to nonantimicrobial agents. Thirteen of these (16.3%) had a previous reaction to the same medication/group. In 51 (63.8%) patients, anaphylaxis occurred during inpatient stay, with 31 reactions occurring during surgery. Eighty-five medications were implicated, most commonly neuromuscular blocking agents (31, 36.5%) and nonsteroidal anti-inflammatory drugs. No trends were noted over the 6-year period, and there was no anaphylaxis-related mortality. Fifty-three (66.3%) patients were assessed in allergy clinics. One in 10 cases did not have the reaction documented in the discharge summary. Adverse drug reaction reports were received for 38 patients (47.5%). CONCLUSIONS: Although acute patient outcomes were excellent, gaps in practice were noted regarding ADR coding accuracy and reporting rates. One in 6 patients had a prior hypersensitivity reaction to a similar medication, so we recommend accurate documentation, ADR review with allergy follow-up, and patient held information to decrease re-exposure risk.

Adverse Drug Reactions Reported by Healthcare Professionals: Reaction Characteristics and Time to Reporting.

We describe adverse drug reaction (ADR) reporting characteristics and factors contributing to length of time to report by healthcare professionals. This is a retrospective study of voluntary reports to an Australian healthcare ADR Review Committee over a 2-year period (2015-2016). Descriptive and univariate models were used for outcomes, employing standardized ADR definitions. Hospital pharmacists reported 84.8% of the 555 ADRs: 70.3% were hospital onset reactions, and 71.7% were at least of moderate severity. Immunologically mediated reactions were most commonly reported (409, 73.7%). The median time to submit an ADR report was 3 (interquartile range 1-10) days. Longer median times to reporting were associated with multiple implicated agents and delayed hypersensitivity reactions, especially severe cutaneous adverse reactions. A total of 650 medications were implicated that involved multiple agents in 165/555 (29.7%) reports. Antimicrobials were the most commonly implicated agents. Immunologically mediated reactions were most commonly associated with antimicrobials and radiocontrast agents (P < .0001, odds ratio [OR] 3.6, 95%CI 2.4-5.5, and P = .04, OR 4.2, 95%CI 1.2-18.2, respectively). Opioids and psychoactive medications were more commonly implicated in nonimmunological reported ADRs (P = .0002, OR 3.9, 95%CI 1.9-7.9, and P < .0001, OR 11.4, 95%CI 4.6-27.8, respectively). Due to the predominant reporting of immunologically mediated reactions, a targeted education program is being planned to improve identification and accuracy of ADR reports, with the overall aim of improved management to ensure quality service provision and patient safety.