Medicine (Austin & Northern Health) - Research Publications

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    Study protocol: Australasian Registry of Severe Cutaneous Adverse Reactions (AUS-SCAR)
    James, F ; Goh, MSY ; Mouhtouris, E ; Vogrin, S ; Chua, KYL ; Holmes, NE ; Awad, A ; Copaescu, A-M ; De Luca, JF ; Zubrinich, C ; Gin, D ; Cleland, H ; Douglas, A ; Kern, JS ; Katelaris, CH ; Thien, F ; Barnes, S ; Yun, J ; Tong, W ; Smith, WB ; Carr, A ; Anderson, T ; Legg, A ; Bourke, J ; Mackay, LK ; Aung, AK ; Phillips, EJ ; Trubiano, J (BMJ PUBLISHING GROUP, 2022-08)
    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).
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    Use of a penicillin allergy clinical decision rule to enable direct oral penicillin provocation: an international multicentre randomised control trial in an adult population (PALACE): study protocol
    Copaescu, A-M ; James, F ; Vogrin, S ; Rose, M ; Chua, K ; Holmes, NE ; Turner, NA ; Stone, C ; Phillips, E ; Trubiano, J (BMJ PUBLISHING GROUP, 2022-08)
    INTRODUCTION: Penicillin allergies are highly prevalent in the healthcare setting and associated with the prescription of second-line inferior antibiotics. More than 85% of all penicillin allergy labels can be removed by skin testing and 96%-99% of low-risk penicillin allergy labels can be removed by direct oral challenge. An internally and externally validated clinical assessment tool for penicillin allergy, PEN-FAST, can identify a low-risk penicillin allergy without the need for skin testing; a score of less than 3 has a negative predictive value of 96.3% (95% CI, 94.1 to 97.8) for the presence of a penicillin allergy. It is hypothesised that PEN-FAST is a safe and effective tool for assessing penicillin allergy in an outpatient clinic setting. METHODS AND ANALYSIS: This is an international, multicentre randomised control trial using the PEN-FAST tool to risk-stratify penicillin allergy labels in adult outpatients. The study's primary objective is to evaluate the non-inferiority of using PEN-FAST score-guided management with direct oral challenge compared with standard care (defined as prick and intradermal skin testing followed by oral penicillin challenge). Participants will be randomised 1:1 to the intervention arm (direct oral penicillin challenge) or standard of care arm (skin testing followed by oral penicillin challenge, if skin testing is negative). The sample size of 380 randomised patients (190 per treatment arm) is required to demonstrate non-inferiority. ETHICS AND DISSEMINATION: The study will be performed according to the guidelines of the Helsinki Declaration and is approved by the Austin Health Human Research Ethics Committee (HREC/62425/Austin-2020) in Melbourne Australia, Vanderbilt University Institutional Review Board (IRB #202174) in Tennessee, USA, Duke University Institutional Review Board (IRB #Pro00108461) in North Carolina, USA and McGill University Health Centre Research Ethics Board in Canada (PALACE/2022-7605). The results of this study will be published and presented in various scientific forums. TRIAL REGISTRATION NUMBER: NCT04454229.
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    Standards for practical intravenous rapid drug desensitization & delabeling: A WAO committee statement.
    Alvarez-Cuesta, E ; Madrigal-Burgaleta, R ; Broyles, AD ; Cuesta-Herranz, J ; Guzman-Melendez, MA ; Maciag, MC ; Phillips, EJ ; Trubiano, JA ; Wong, JT ; Ansotegui, I ; Steering Committee Authors, ; Review Panel Members, (Elsevier BV, 2022-06)
    Drug hypersensitivity reactions (DHRs) to intravenous drugs can be severe and might leave patients and doctors in a difficult position where an essential treatment or intervention has to be suspended. Even if virtually any intravenous medication can potentially trigger a life-threatening DHR, chemotherapeutics, biologics, and antibiotics are amongst the intravenous drugs most frequently involved in these reactions. Admittedly, suspending such treatments may negatively impact the survival outcomes or the quality of life of affected patients. Delabeling pathways and rapid drug desensitization (RDD) can help reactive patients stay on first-choice therapies instead of turning to less efficacious, less cost-effective, or more toxic alternatives. However, these are high-complexity and high-risk techniques, which usually need expert teams and allergy-specific techniques (skin testing, in vitro testing, drug provocation testing) to ensure safety, an accurate diagnosis, and personalized management. Unfortunately, there are significant inequalities within and among countries in access to allergy departments with the necessary expertise and resources to offer these techniques and tackle these DHRs optimally. The main objective of this consensus document is to create a great benefit for patients worldwide by aiding allergists to expand the scope of their practice and support them with evidence, data, and experience from leading groups from around the globe. This statement of the Drug Hypersensitivity Committee of the World Allergy Organization (WAO) aims to be a comprehensive practical guide on the technical aspects of implementing acute-onset intravenous hypersensitivity delabeling and RDD for a wide range of drugs. Thus, the manuscript does not only focus on clinical pathways. Instead, it also provides guidance on topics usually left unaddressed, namely, internal validation, continuous quality improvement, creating a healthy multidisciplinary environment, and redesigning care (including a specific supplemental section on a real-life example of how to design a dedicated space that can combine basic and complex diagnostic and therapeutic techniques in allergy).
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    The assessment of severe cutaneous adverse drug reactions
    Copaescu, AM ; Trubiano, JA (NATL PRESCRIBING SERVICE LTD, 2022-04)
    Severe cutaneous adverse drug reactions include Stevens-Johnson syndrome, toxic epidermal necrolysis and acute generalised exanthematous pustulosis. These eruptions are a type of delayed hypersensitivity reaction and can be life-threatening. The assessment of a severe cutaneous drug reaction requires a detailed clinical history and examination to identify the culprit drug and evaluate the allergy. Allopurinol, antibiotics and anticonvulsants are often implicated. Patch testing and delayed intradermal testing can assist in determining if the reaction was allergic, however there is limited evidence about the sensitivity and specificity of skin testing in severe cutaneous adverse drug reactions. If the testing is non-conclusive or negative, it is recommended to avoid the suspected culprit drug and any structurally similar drug in future. Any decision to reintroduce a drug should be made after considering the harm-benefit ratio. Caution is also needed if considering a possibly cross-reactive drug in a patient with a history of severe cutaneous adverse drug reactions.
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    Editorial: The Immunology of Adverse Drug Reactions
    Illing, PT ; Mifsud, NA ; Ardern-Jones, MR ; Trubiano, J (FRONTIERS MEDIA SA, 2022-02-18)
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    Testing Strategies and Predictors for Evaluating Immediate and Delayed Reactions to Cephalosporins
    Stone, CA ; Trubiano, JA ; Phillips, EJ (ELSEVIER, 2021-01)
    BACKGROUND: Although 1% to 2% of the general population carries a cephalosporin allergy label (CAL), we lack validated testing strategies and predictors of true allergy. OBJECTIVE: To identify cross-reactivity patterns and predictors of skin test positive (STP) in geographically disparate patients with a CAL. METHODS: A total of 780 adult patients labeled with a CAL or penicillin allergy label (PAL) with unknown tolerance of cephalosporins identified from the Austin Hospital (Melbourne, Australia) (n = 410) and Vanderbilt University Medical Center (Nashville, TN) (n = 370) between 2014 and 2018 underwent a standardized skin testing. RESULTS: Of 328 patients with a CAL, 29 (8.8%) tested STP to ≥1 cephalosporin(s). There were no cefazolin or ceftriaxone STP, 0 of 452 (0%), in patients with a PAL only. Of 328 patients with a CAL, 16 (4.8%) were ampicillin STP. Eleven of 16 of these patients had an initial allergy label to cephalexin. Twenty of 29 cephalosporin STP patients demonstrated tolerance to a cephalosporin with a different R1 side chain, and 8 of 14 ampicillin STP patients demonstrated tolerance to ≥1 non-amino R1 group cephalosporin. Eleven of 13 patients STP to cefazolin were skin and ingestion challenge negative to all other penicillins and cephalosporins predicted by its distinct R1/R2 groups. Seven of 15 ceftriaxone STP patients demonstrated cross-reactivity with R1-similar cephalosporins. Time since the original reaction predicted STP testing to both penicillins, adjusted odds ratio (aOR) per year 0.93 (95% confidence interval [CI]: 0.90, 0.97), and cephalosporins, aOR per year 0.71 (95% CI: 0.56, 0.90). CONCLUSIONS: Cephalosporin cross-reactivity is based on shared R1 groupings. Increasing time since the original reaction and the presence of a PAL with unknown cephalosporin tolerance predict a lower likelihood of cephalosporin STP.
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    SARS-CoV-2 infection results in immune responses in the respiratory tract and peripheral blood that suggest mechanisms of disease severity
    Zhang, W ; Chua, BY ; Selva, KJ ; Kedzierski, L ; Ashhurst, TM ; Haycroft, ER ; Shoffner-Beck, SK ; Hensen, L ; Boyd, DF ; James, F ; Mouhtouris, E ; Kwong, JC ; Chua, KYL ; Drewett, G ; Copaescu, A ; Dobson, JE ; Rowntree, LC ; Habel, JR ; Allen, LF ; Koay, H-F ; Neil, JA ; Gartner, MJ ; Lee, CY ; Andersson, P ; Khan, SF ; Blakeway, L ; Wisniewski, J ; McMahon, JH ; Vine, EE ; Cunningham, AL ; Audsley, J ; Thevarajan, I ; Seemann, T ; Sherry, NL ; Amanat, F ; Krammer, F ; Londrigan, SL ; Wakim, LM ; King, NJC ; Godfrey, DI ; Mackay, LK ; Thomas, PG ; Nicholson, S ; Arnold, KB ; Chung, AW ; Holmes, NE ; Smibert, OC ; Trubiano, JA ; Gordon, CL ; Nguyen, THO ; Kedzierska, K (NATURE PORTFOLIO, 2022-05-19)
    Respiratory tract infection with SARS-CoV-2 results in varying immunopathology underlying COVID-19. We examine cellular, humoral and cytokine responses covering 382 immune components in longitudinal blood and respiratory samples from hospitalized COVID-19 patients. SARS-CoV-2-specific IgM, IgG, IgA are detected in respiratory tract and blood, however, receptor-binding domain (RBD)-specific IgM and IgG seroconversion is enhanced in respiratory specimens. SARS-CoV-2 neutralization activity in respiratory samples correlates with RBD-specific IgM and IgG levels. Cytokines/chemokines vary between respiratory samples and plasma, indicating that inflammation should be assessed in respiratory specimens to understand immunopathology. IFN-α2 and IL-12p70 in endotracheal aspirate and neutralization in sputum negatively correlate with duration of hospital stay. Diverse immune subsets are detected in respiratory samples, dominated by neutrophils. Importantly, dexamethasone treatment does not affect humoral responses in blood of COVID-19 patients. Our study unveils differential immune responses between respiratory samples and blood, and shows how drug therapy affects immune responses during COVID-19.
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    Blister fluid as a cellular input for ex vivo diagnostics in drug-induced severe cutaneous adverse reactions improves sensitivity and explores immunopathogenesis.
    Awad, A ; Mouhtouris, E ; Nguyen-Robertson, CV ; Holmes, N ; Chua, KYL ; Copaescu, A ; James, F ; Goh, MS ; Aung, AK ; Godfrey, DI ; Philips, EJ ; Gibson, A ; Almeida, CF ; Trubiano, JA ; Australian Registry of Severe Cutaneous Adverse Reactions (AUS-SCAR), (Elsevier BV, 2022-02)
    BACKGROUND: Drug-induced severe cutaneous adverse reactions (SCARs) are presumed T-cell-mediated hypersensitivities associated with significant morbidity and mortality. Traditional in vivo testing methods, such as patch or intradermal testing, are limited by a lack of standardization and poor sensitivity. Modern approaches to testing include measurement of IFN-γ release from patient PBMCs stimulated with the suspected causative drug. OBJECTIVE: We sought to improve ex vivo diagnostics for drug-induced SCARs by comparing enzyme-linked immunospot (ELISpot) sensitivities and flow cytometry-based intracellular cytokine staining and determination of the cellular composition of separate samples (PBMCs or blister fluid cells [BFCs]) from the same donor. METHODS: ELISpot and flow cytometry analyses of IFN-γ release were performed on donor-matched PBMC and BFC samples from 4 patients with SCARs with distinct drug hypersensitivity. RESULTS: Immune responses to suspected drugs were detected in both the PBMC and BFC samples of 2 donors (donor patient 1 in response to ceftriaxone and case patient 4 in response to oxypurinol), with BFCs eliciting stronger responses. For the other 2 donors, only BFC samples showed a response to meloxicam (case patient 2) or sulfamethoxazole and its 4-nitro metabolite (case patient 3). Consistently, flow cytometry revealed a greater proportion of IFN-γ-secreting cells in the BFCs than in the PBMCs. The BFCs from case patient 3 were also enriched for memory, activation, and/or tissue recruitment markers over the PBMCs. CONCLUSION: Analysis of BFC samples for drug hypersensitivity diagnostics offers a higher sensitivity for detecting positive responses than does analysis of PBMC samples. This is consistent with recruitment (and enrichment) of cytokine-secreting cells with a memory/activated phenotype into blisters.
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    COVID-Care - a safe and successful digital self-assessment tool for outpatients with proven and suspected coronavirus-2019
    Drewett, GP ; Holmes, NE ; Trubiano, JA ; Vogrin, S ; Feldman, J ; Rose, M (SAGE PUBLICATIONS LTD, 2021-09)
    INTRODUCTION: The coronavirus-2019 (COVID-19) pandemic and restrictions placed on movement to prevent its transmission have led to a surge in demand for remote medical care. We investigated whether COVID-Care, a patient-reported, telehealth, symptom monitoring system, was successful at delivering safe monitoring and care for these patients leading to decreased hospital presentations. METHODS: We performed a single centre, prospective, interventional cohort study with symptomatic outpatients who presented for COVID-19 screening at Austin Health, Australia. Participants were invited to take part in the COVID-Care programme, entering common COVID-19 symptoms on a purpose-built, online survey monitored by infectious diseases physicians, and matched with clinical data including date of symptom onset, hospital admission, and screening clinic presentations. RESULTS: 42,158 COVID-19 swabs were performed in 31,626 patients from March to October 2020, with 414 positive cases. 20,768 people used the COVID-Care survey at least once. COVID-Care users were significantly younger than non-users. Of the 414 positive cases, 254 (61.3%) used COVID-Care, with 160 (38.6%) non-users. Excluding presentations on the same day or prior to the COVID-19 swab, of the positive cases there were 56 hospital presentations. 4.3% (11) of COVID-Care users and 28.1% (45) non-users were admitted to hospital or the emergency department (p < 0.001), with 3.9% (10) versus 22.5% (36) requiring inpatient admission (p < 0.001). There were no deaths in COVID-Care users versus 2 deaths in non-users. CONCLUSION: COVID-Care, a digitally integrated, outpatient, symptom tracking and telemedical service for patients with COVID-19, was safe and successful at reducing hospital and emergency department admissions, suggesting a strong role for telemedicine for future healthcare delivery in this logistically challenging setting.
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    Staff to staff transmission as a driver of healthcare worker infections with COVID-19
    Gordon, CL ; Trubiano, JA ; Holmes, NE ; Chua, KYL ; Feldman, J ; Young, G ; Sherry, NL ; Grayson, ML ; Kwong, JC (ELSEVIER INC, 2021-11)
    BACKGROUND: High rates of healthcare worker (HCW) infections due to COVID-19 have been attributed to several factors, including inadequate personal protective equipment (PPE), exposure to a high density of patients with COVID-19, and poor building ventilation. We investigated an increase in the number of staff COVID-19 infections at our hospital to determine the factors contributing to infection and to implement the interventions required to prevent subsequent infections. METHODS: We conducted a single-centre retrospective cohort study of staff working at a tertiary referral hospital who tested positive for SARS-CoV-2 between 25 January 2020 and 25 November 2020. The primary outcome was the source of COVID-19 infection. RESULTS: Of 45 staff who returned a positive test result for SARS-CoV-2, 19 were determined to be acquired at our hospital. Fifteen (15/19; 79% [95% CI: 54-94%]) of these were identified through contact tracing and testing following exposures to other infected staff and were presumed to be staff-to-staff transmission, including an outbreak in 10 healthcare workers (HCWs) linked to a single ward that cared for COVID-19 patients. The staff tearoom was identified as the likely location for transmission, with subsequent reduction in HCW infections and resolution of the outbreak following implementation of enhanced control measures in tearoom facilities. No HCW contacts (0/204; 0% [95% CI: 0-2%]) developed COVID-19 infection following exposure to unrecognised patients with COVID-19. CONCLUSION: Unrecognised infections among staff may be a significant driver of HCW infections in healthcare settings. Control measures should be implemented to prevent acquisition from other staff as well as patient-staff transmission.