Search

Rationale: Genetic variation influences susceptibility to clinical tuberculosis (TB). Activation of the P2X(7) receptor on human macrophages induces killing of mycobacteria. We have identified polymorphisms in the P2X(7) gene that markedly reduce this killing. Objective: To determine if polymorphisms in P2X7 are associated with increased risk of TB, the prevalence of four polymorphisms was assessed in individuals from Southeast Asia, where the majority of patients with TB in our study originate. The association of these polymorphisms with clinical TB was subsequently investigated in two separate case-control cohorts and the function of P2X(7) was assessed in subjects from one cohort. Methods: Genotyping of P2X7 polymorphisms was performed from subjects in a nested case-control study of a longitudinal refugee cohort and a separate case-control study. The functional capacity of P2X(7) was investigated by measuring ATP-mediated mycobacterial killing and apoptosis. Results: Only the 1513A-C polymorphism was present in Southeast Asians and the allele was associated with reduced killing of Mycobacterium tuberculosis. The 1513C allele was strongly associated with extrapulmonary, but not pulmonary, TB in the first (odds ratio, 3.8; 95% confidence interval, 1.6-9.0) and second cohorts (odds ratio, 3.7; 95% confidence interval, 1.7-8.0). ATP-mediated killing of mycobacteria was ablated in macrophages from subjects homozygous for the 1513C allele and significantly impaired in macrophages from heterozygous subjects. There was strong correlation between the degree of mycobacterial killing and ATP-induced apoptosis. Conclusions: The 1513C allele increases susceptibility to extrapulmonary TB, and this defect is associated with the reduction in the capacity of macrophages to kill M. tuberculosis. [ABSTRACT FROM AUTHOR]

Coronavirus (COVID-19) vaccines have proved to be effective in the pandemic response but can cause adverse events such as delayed hypersensitivity reactions (DHRs). Delayed-reading intradermal tests (IDT) to vaccines are limited by false-positive results and may reflect a cell-mediated rather than IgE-mediated immune response. Lymphocyte transformation test (LTT), which has been utilized in the diagnosis of drug allergy, may be helpful in suspected COVID-19 vaccine and/or its excipient-related DHRs. To investigate the use of LTT in two suspected cases of COVID-19 vaccine-induced DHRs, two patients with suspected DHRs to COVID-19 vaccination were tested by delayed-reading IDT and LTT against vaccines and their excipients. A 47-year-old man developed acute mixed-pattern hepatitis after the second dose of ChAdOx1 vaccine. LTT performed at 2 months post-vaccination revealed reactivity to the ChAdOx1 vaccine, polysorbate 80 and mildly to PEG 2050 but not BNT162b2 vaccine. Delayed-reading IDT returned negative to both vaccines and excipients. He tolerated BNT162b2 vaccination with no adverse events. A 36-year-old woman presented with subacute morbilliform eruption and hepatitis after the first dose of BNT162b2 vaccine. LTT performed 3 months later revealed reactivity to the BNT162b2 but not PEG 2050. Repeat LTT following subsequent natural Severe Acute Respiratory Coronavirus-2 (SARS-CoV-2) infection revealed reactivity to ChAdOx1 and NVX-CoV2373 vaccines but not polysorbate 80. Delayed-reading IDT remained negative. She proceeded with NVX-CoV2373 vaccination with no symptom recurrence. LTT may be a useful tool in suspected COVID-19 vaccine-related DHRs. Further evaluation with a larger patient cohort is required.

Late-onset combined immunodeficiency (LOCID), considered now a subset of common variable immunodeficiency (CVID) disorders, is characterized by a predominantly T-cell immune defect. LOCID has a distinct phenotype from CVID with a greater risk of lymphoproliferative complications. As compared to the CVID cohort, LOCID patients also have increased rates of splenomegaly and granulomatous disease. We report a case of central nervous system (CNS) T-cell lymphoma in a 67-year-old male as the presenting manifestation of LOCID. The patient achieved a complete response to therapy after 4 cycles of MATRix (methotrexate, cytarabine, and thiotepa) and 2 cycles of ICE (etoposide, carboplatin, and ifosfamide) chemotherapy followed by CNS-directed autologous stem cell transplantation. Intravenous immunoglobulin replacement was commenced to address the underlying immunodeficiency. Pulmonary lesions consistent with a diagnosis of granulomatous and lymphocytic interstitial lung disease (GLILD) were identified as a second noninfectious complication of LOCID. The pulmonary lesions resolved after chemotherapy and immunoglobulin replacement. The patient remains well with no evidence of disease recurrence now more than 18 months after completion of therapy. This is the first reported case of T-cell lymphoma in an adult patient with LOCID. Further study is needed to elucidate the mechanisms of transformation of B- or T-cells to lymphoproliferation in primary immunodeficiency patients as well as research to inform evidence-based therapeutic strategies for this challenging cohort of patients., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2023 Anthony Jeffrey et al.)

Forty-four of 50 immunology patients with primary or secondary immunodeficiency receiving intravenous immunoglobulin at a hospital in New South Wales, Australia, were rapidly enrolled in the subcutaneous immunoglobulin (SCIg) programme at the onset of the 2020 COVID-19 pandemic. Health and economic outcomes demonstrated that SCIg provides clinical efficacy as evidenced by the number of infections and maintenance of IgG levels, and also facilitates cost reduction in immunoglobulin maintenance programmes., (© 2023 Royal Australasian College of Physicians.)

Successful vaccination has been the decisive factor in the overall decline of SARS-CoV2 infection related morbidity and mortality. However, global effects of the COVID-19 pandemic are ongoing, with reports of glomerular disease occurring in relation to both infection and vaccination. A particular rise in anti-GBM disease has been identified. Information is still emerging regarding the optimal management of such cases. We reviewed anti-GBM antibody detection rates at our test center over the past 5 years. We followed three patients with biopsy confirmed glomerular disease temporally related to COVID-19 vaccination. Each patient proceeded to receive subsequent COVID-19 vaccination as per immunologist recommendations. Further assessment included COVID-19 antibody testing in each case. A three-fold increase in significant anti-GBM antibody results noted at our center was associated with COVID infection in 10% of cases, and COVID vaccination in 25% of cases. We demonstrated that subsequent vaccination did not appear to lead to adverse effects including relapse in our three cases of COVID-19 vaccine-associated GN. We also identified positive COVID-19 antibody levels in two out of three cases, despite immunosuppression. We report a rise in anti-GBM antibody disease incidence. Our small study suggests that COVID-19 antibody testing can help determine COVID prophylaxis requirements, and subsequent vaccination with an alternative vaccine type appears safe.

Aim: Oral food challenges (OFC) are an important tool in the assessment of food allergy. We sought to identify factors available at initial assessment visit which were associated with successful outcome or challenge failure in Australian children., Methods: We conducted a retrospective review of all paediatric patients who underwent OFC in our allergy service over a 5-year period. Clinical data comprising patient demographics, co-morbidities, skin prick test (SPT) results, nature of previous reactions, elapsed time since previous reactions and outcome at OFC were recorded., Results: Four hundred and fifty-six OFCs were conducted, with 56 cases (12.3%) resulting in a reaction. Likelihood of reaction at OFC was significantly increased for patients with atopic dermatitis (odds ratio 1.99). When stratified by food substance, atopic dermatitis had the strongest association with reaction within the peanut group (odds ratio 3.2), and no association was demonstrated for soy or prawn. Increasing SPT wheal size (P < 0.001) and previous history of anaphylaxis to the challenge food (P < 0.001) correlated with failure at OFC. A low-risk group was identified, of patients with no clear history of prior reaction to the challenge food, and SPT result <3 mm., Conclusions: Factors identified at assessment visit which correlated with reaction at OFC are atopic dermatitis, prior history of anaphylaxis, and increasing SPT wheal size. Domiciliary OFC could be considered in a select low-risk group of patients undergoing food challenge. This study was performed at a single centre with limited sample size, further large-scale and multicentre study verification of our data will provide more accurate representation of the Australian demographic., (© 2023 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Introduction: Increasing implementation of the highly efficacious immune checkpoint inhibitors (ICIs) has raised awareness of their various complications in the form of immune-related adverse events (irAEs). Transverse myelitis following ICIs is thought to be a rare but serious neurologic irAE and knowledge is limited about this distinct clinical entity., Cases: We describe four patients across three tertiary centers in Australia with ICI-induced transverse myelitis. Three patients had a diagnosis of stage III-IV melanoma treated with nivolumab and one patient had stage IV non-small cell lung cancer treated with pembrolizumab. All patients had longitudinally extensive transverse myelitis on magnetic resonance imaging (MRI) spine and clinical presentation was accompanied by inflammatory cerebrospinal fluid (CSF) findings. Half of our cohort had received spinal radiotherapy, with the areas of transverse myelitis extending beyond the level of previous radiation field. Inflammatory changes on neuroimaging did not extend to the brain parenchyma or caudal nerve roots, except for one case involving the conus medullaris. All patients received high dose glucocorticoids as first-line therapy, however the majority relapsed or had a refractory state (3/4) despite this, requiring escalation of their immunomodulation, with either induction intravenous immunoglobulin (IVIg) or plasmapheresis. Patients in our cohort who relapsed had a poorer outcome with more severe disability and reduced functional independence following resolution of their myelitis. Two patients had no progression of their malignancy and two patients had malignancy progression. Of the three patients who survived, two had resolution of their neurological symptoms and one remained symptomatic., Conclusion: We propose that prompt intensive immunomodulation is favored for patients with ICI-transverse myelitis in an attempt to reduce associated significant morbidity and mortality. Furthermore, there is a significant risk of relapse following cessation of immunomodulatory therapy. We suggest one treatment approach of IVMP and induction IVIg for all patients presenting with ICI-induced transverse myelitis based on such findings. With the increasing use of ICIs across oncology, further studies are required to explore this neurological phenomenon in greater detail to help establish management consensus guidelines., Competing Interests: AM has served on advisory boards for BMS, MSD, Novartis, Roche, Pierre-Fabre, and OBiotics. GVL is a consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA, Mercke Sharp & Dohme, Novartis, OncoSec, PHMR Ltd, Pierre Fabre, Provectus, Qbiotics, and Regeneron. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chatterton, Xi, Jia, Krause, Long, Atkinson, Menzies, Fernando, Boyle, Kwok, Duggins, Karikios and Parratt.)

Background: Tumefactive demyelinating lesions (TDLs) are defined as lesions >2 cm on MRI of the brain. They are identified in a range of demyelinating diseases including massive demyelination due to Marburg's acute MS, Schilder's Disease, Balo's concentric sclerosis, and Tumefactive MS. Apart from the rare demyelinating variants which are often diagnosed histologically, there are no detailed data to phenotype TDLs., Methods: We describe the clinical and radiological features of four similar patients with very large TDLs (>4 cm), that are not consistent with the rare demyelinating variants and may represent a distinct phenotype., Results: All patients presented with hemiplegia and apraxia. The mean age at onset was 37 years with an equal sex distribution. All patients were diagnosed with Tumefactive demyelination based on MRI and CSF analysis, precluding the need for brain biopsy. All responded to potent immunotherapy (including high dose corticosteroids, plasma exchange, rituximab, and/or cyclophosphamide). The mean lag from diagnosis to treatment was 1 day. The median EDSS at presentation was six and recovery to a median EDSS of two occurred over 6 months., Conclusion: We propose that Tumefactive lesions larger than 4 cm are termed "Giant demyelinating lesions" (GDLs) not only on the basis of size, but a rapid and fulminant demyelinating presentation leading to acute, severe neurological disability that is, nonetheless, responsive to immunotherapy. Further clinical studies are required to ratify this proposed phenotype, establish the immunological profile and best treatment for such patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Boyle, Fernando, Drummond, Fontes and Parratt.)

Background: The mechanism of immediate reactions to drugs or vaccines containing polyethylene glycol (PEG) and PEG derivatives is not fully elucidated. It is considered in many instances to be IgE-mediated. Diagnosis and management of PEG allergy is topical, as BNT162b and mRNA-1273 contain PEG (2[PEG-2000]-N), and ChAdOx1-S and NVX-CoV2373 contain polysorbate 80. mRNA vaccines contain PEG 2000, which encapsulates the mRNA to impair its degradation. This PEG MW is specific to mRNA vaccines and is not used in other drugs and vaccines. PEG 2000 allergy is not well studied, as higher PEG molecular weights are implicated in most of the PEG allergy published in the literature., Methods: We performed a literature review on PEG allergy and sought to evaluate the safety and effectiveness of our protocol for assessment of PEG 2000 and polysorbate 80 reactions in an outpatient clinic setting. All patients referred to our drug allergy service between 1 July 2021 and 31 December 2021 with suspected immediate allergy to PEG or its derivatives were eligible for the study. Skin testing (ST) and basophil activation testing (BAT) were performed for all patients to multiple PEG molecular weights (MWs)., Results: We reviewed twenty patients during the study period. Five patients were allergic. Fifteen patients had a masquerade of allergy and were enrolled as control patients. PEG 2000, polysorbate 80, BNT162b, and ChAdOx1-S had excellent performance characteristics on skin testing. BAT showed high specificity for all vaccines and PEG MWs., Discussion: In our small study, we found ST and BAT to add useful information, particularly for PEG 2000 allergy. Further study of our protocol in larger patient cohorts will provide more information on its performance characteristics and usefulness.

Background: Penicillin allergy delabeling confers many benefits, including reduced patient morbidity and mortality and improved health economics. Reports suggest that both patients and clinicians often remain hesitant to take and prescribe penicillins, respectively, after penicillin delabeling. However, follow-up of an individual's penicillin allergy label and incorporation of this into relevant health care records after delabeling have not been well studied in the Australian population., Objective: To evaluate the status of penicillin allergy labels in the community 1 year after penicillin delabeling at a tertiary hospital in Australia., Methods: A cross-sectional study was performed using follow-up interviews with patients and community primary care providers after 1 year from the date of patients' penicillin delabeling at a tertiary hospital in New South Wales, Australia. The main outcome measures that were evaluated included patient willingness to accept penicillin for future infections, patient self-reported receipt of penicillin-based antibiotics after delabeling, accuracy of penicillin allergy labels in the records of the primary care provider, and prescription of penicillin-based antibiotics by the general practitioner., Results: A total of 86 patients were included in this study. The percentage of patients with a correct penicillin allergy status at 1-year follow-up was 94% in the hospital electronic medical record but only 37% in primary care records. At 1-year follow-up, 14% of delabeled patients continued to reject penicillin prescriptions., Conclusion: Better strategies are required to increase patient confidence in receiving penicillins after penicillin delabeling and to ensure that penicillin allergy labels are translated into the medical records at the primary care level., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The lymphocyte transformation test (LTT) is an in vitro assay used to diagnose drug induced hypersensitivity reactions by detecting the activation and expansion of drug-specific memory T cells to the suspected implicated drug. Traditionally radiolabelled thymidine (3H-thymidine) has been used but requires the handling and disposal of radioactive materials., Objective: To examine safe alternatives to 3H-thymidine, test assay modifications for improved assay sensitivity and evaluate the modified LTT in patients with DRESS and AGEP., Methods: Four proliferation detection assays (BRDU, CyQUANT™, MTT and XTT) were screened for LTT sensitivity. XTT the most sensitive and practical was selected for further evaluation Modifications like autologous serum (AS) and regulatory T cell depletion (T-REG) were tested for improved assay sensitivity. Finally, an initial evaluation of the XTT-LTT was performed in 8 patients with DRESS and 2 with AGEP including cytokine testing., Results: Of the non-radioactive alternatives we tested, XTT a colorimetric assay was the most sensitive and practical to move to evaluation. The addition of AS increased background signal. Depletion of T-REGs improved sensitivity but cell sorting time and risk of contamination limited benefit. Of eight patients diagnosed with DRESS and 2 with AGEP tested with XTT-LTT assay results showed our assay matched clinical findings of implicated drugs in 8/10 patients when using a stimulation index (SI) ≥ 2 and 8/10 with analysis by ANOVA. All ten patients were correctly diagnosed by either analysis., Conclusion: XTT appears to be a safe, viable alternative to 3H-thymidine, with high sensitivity and allowing direct cytokine quantification on specific patient cells., (© 2022. The Author(s).)

Background: Chlorhexidine is an antiseptic widely used in healthcare settings. There are increasing reports of significant hypersensitivity reactions associated with its use. Development of chlorhexidine allergy has been identified as an important occupational risk to healthcare workers (HCWs)., Aims: To evaluate the prevalence of sensitization to chlorhexidine amongst HCWs at a large tertiary hospital to assess the potential allergic safety risks associated with chlorhexidine exposure to staff., Methods: Sensitization to chlorhexidine was evaluated by measurement of serum-specific immunoglobulin E (IgE) in samples collected from staff assessed after a sharps-injury incident and laboratory staff collected for quality assurance procedures. This test method has been shown to have high sensitivity and specificity in the diagnosis of chlorhexidine allergy. Prevalence of sensitization was additionally evaluated with reference to changes in exposure to chlorhexidine-based hand hygiene products because of infection control procedures and the coronavirus disease 2019 pandemic., Results: A total of 320 samples were examined. The prevalence of positive chlorhexidine-specific IgE was 2%. Prevalence of sensitization in samples collected before and after increased chlorhexidine exposure was 1% and 3%. This did not represent a statistically significant difference., Conclusions: The prevalence figures for chlorhexidine sensitization in this study are higher than have been estimated previously for similar HCW cohorts. Increased exposure to chlorhexidine-based hand hygiene products was not demonstrated to increase sensitization in this group. Given the risk of severe reactions in sensitized individuals, this study indicates that evaluation of chlorhexidine allergy is important when investigating occupational allergy in HCWs., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Screening for HLA-A*31:01/HLA-B*15:02, HLA-B*57:01 and HLA-B*58:01 is recommended in selected populations for prevention of carbamazepine, abacavir, and allopurinol-induced severe cutaneous adverse reactions (SCARs). Compared to conventional methods for detection of HLA alleles, PCR using a tag single nucleotide polymorphism (SNP) can be cost-effective, particularly where the surrogate marker SNP is in absolute linkage disequilibrium with the relevant HLA allele., Objective: To determine guidelines for prevention of SCARs though predictive screening for the Australian Vietnamese population, the prevalence of four HLA alleles (HLA-A*31:01, HLA-B*15:02, HLA-B*57:01 and HLA-B*58:01) was examined. The utility of surrogate markers, rs2395029 and rs9263726, was investigated to predict for the presence of HLA-B*57:01 and HLA-B*58:01, respectively., Methods: Genotyping for specific HLA alleles was performed in 152 healthy Vietnamese living in Sydney using validated and established PCR-based methods. SNP genotyping was conducted using restriction-fragment-length-polymorphism analysis., Results: rs2395029 and rs9263726 strongly correlated with HLA-B*57:01 (κ = 1, p < 0.001) and HLA-B*58:01 (Κ = 0.9, p < 0.001) with 100% sensitivity and 100% negative predictive value for predicting the HLA-B*57:01 and HLA-B*58:01 carriers, respectively. A high prevalence of carriers of HLA-A*31:01 (3.29%), HLA-B*15:02 (14.47%), HLA-B*57:01 (6.58%) and HLA-B*58:01 (9.21%) was revealed., Conclusions: Screening is recommended for these alleles in Australian Vietnamese prior to introducing relevant therapies. SNPs, rs2395029 and rs9263726, can be successfully used as surrogate markers for HLA-B*57:01 and HLA-B*58:01 in this population.

Background: Endovascular procedures are standard of care for an increasing range of cerebrovascular diseases. Many endovascular devices contain plastic and are coated with a hydrophilic polymer which has been rarely described to embolize, resulting in distal granulomatous inflammatory lesions within the vascular territory., Methods: We reviewed three cases of cerebral granulomatous reactions that occurred after endovascular intervention for internal carotid aneurysms. The patient procedure details, presentation, relevant investigations, and treatment course are described. We also provide a literature review on endovascular granulomatous reactions., Results: These three cases represent the largest biopsy proven series of cerebral granulomatosis following endovascular intervention. We highlight the variable clinical presentation, with two of the three cases having an unusually delayed onset of up to 4 years following the intervention. We show the characteristic histological findings of granulomatous lesions with foreign body material consistent with a type IV reaction, radiological abnormalities of enhancing lesions within the vascular territory of the intervention, and the requirement of prolonged immunosuppression for maintenance of clinical remission, with two of the three patients requiring a corticosteroid sparing agent. In comparison with the available literature, in addition to hydrophilic gel polymer, we discuss that plastic from the lining of the envoy catheter may be a source of embolic material. We also discuss the recommendations of the Food and Drug Administration and the implementation of novel biomaterials for the prevention of these reactions in the future., Conclusions: There is a need for increased awareness of this severe complication of cerebral endovascular procedures and further longitudinal studies of its prevalence, optimal management and preventative measures., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Common variable immunodeficiency (CVID) is established as a heterogeneous collection of disorders of immune dysregulation rather than an infectious complication of antibody deficiency. Approximately 70% of patients have one or more of the non-infectious complications of autoimmunity, enteropathy, polyclonal lymphocytic and malignancy. The CVID-disorders represent a particular challenge as they fall under an umbrella diagnosis governed currently by non-universal diagnostic criteria. The rubric of CVID is shrinking as next generation sequencing is progressively and rapidly identifying the genetic basis for many of its disorders. Although identification of monogenic cause of CVID allows for naming of separate or specific entities, it still provides valuable insight into the immune dysregulation of these disorders along with recognition of a polygenic basis of disease and cellular changes observed in innate and adaptive immune pathways. Cellular abnormalities in the T-cell (reduced regulatory T cells (Tregs) and increased T follicular helper cells), and B-cell compartments (reduced switched memory B-cells and increased peripheral CD21 low cells) along with an increase in innate lymphoid cells type 3 promote a milieu for inflammation. Immune dysregulation also results from increased microbial translocation from impaired gastrointestinal barrier function in CVID-patients with loss of Tregs. An understanding of the manifestations and mechanisms of immune dysregulation allows for improved vigilance in screening for the diagnosis, monitoring for complications of disease and the continued development and introduction of targeted therapies for non-infectious phenotypes., (Crown Copyright © 2020. Published by Elsevier B.V. All rights reserved.)

Aims: To determine genetic susceptibility markers for carbamazepine (CBZ) and allopurinol-induced severe cutaneous adverse reactions (SCARs) in Vietnamese. Methods: A case-control study was performed involving 122 patients with CBZ or allopurinol-induced SCARs and 120 drug tolerant controls. Results: HLA-B*58:01 was strongly associated with allopurinol-induced SCARs and strongly correlated with SNP rs9263726. HLA-B*15:02 was associated with CBZ-induced Stevens-Johnson syndrome/toxic epidermal necrolysis but not with drug-induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms. No association was found between HLA-A*31:01 and CBZ-induced SCARs. HLA-B*58:01 and rs3909184 allele A with renal insufficiency were shown to increase the risk of allopurinol-induced SCARs. Conclusion: HLA-B*58:01 and HLA-B*15:02 confer susceptibility to allopurinol-induced SCARs and CBZ-induced SJS/TEN in Vietnamese. SNP rs9263726 can be used as a surrogate marker in identifying HLA-B*58:01 .

Background: Chlorhexidine (CHX) is a widely utilized disinfectant that can cause IgE-mediated urticaria/anaphylaxis. The cross-reactivity of patients with IgE-mediated CHX allergy with other disinfectants, which share structural similarities with CHX like polyhexanide (polyhexamethylene biguanide; PHMB), alexidine (ALX), or octenidine (OCT), is unknown., Methods: Forty-four patients with anaphylaxis or urticaria upon CHX exposure and positive skin prick test (SPT) and/or positive CHX ImmunoCAP test (Phadia TFS, Uppsala, Sweden) were recruited. IgE to the biguanide and/or hexamethylene structure was investigated with PHMB ImmunoCAP (n = 32) and by basophil activation tests (BAT) with CHX and ALX (n = 37). Inhibition tests of CHX and PHMB ImmunoCAPs by CHX, ALX, PHMB, and OCT were performed., Results: IgE reactivity to PHMB as surrogate marker for biguanide/hexamethylene reactivity was detected in 5/32 sera. Seven of 37 patients showed a positive BAT with ALX, but only under optimized conditions. Binding to CHX ImmunoCAP was inhibited by ALX in 1/32 sera, and binding to PHMB was blocked by ALX (1/5) and by OCT in another (1/5). In SPT, 9/10 patients were positive for CHX and 3 of them with ALX (only at highest concentration at 5 mg/mL). A further patient reacted primarily with OCT and showed IgE cross-reactivity with CHX, ALX, and PHMB., Conclusion: The IgE response to CHX seems polyclonal. The chloroguanide ending of CHX is the main epitope for the IgE and is suitable as screening assay to detect CHX reactivity. IgE-reactivities with the biguanide or hexamethylene components of other disinfectants (ALX, PHMB) can be detected by SPT, PHMB ImmunoCAP, and ALX-BAT in 15%-33% of CHX-allergic patients., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: Immune checkpoint inhibitors (ICI) have become the standard of care in many oncological conditions but are associated with a spectrum of renal immune-related adverse events (IrAEs). We aimed to describe the spectrum, histology, management and outcomes of renal IrAE in patients with metastatic melanoma undergoing ICI therapy., Methods: We conducted a retrospective review of 23 patients with a diagnosis of metastatic melanoma treated with ICI between January 2017 and April 2019 who developed a renal IrAE. Baseline demographic data, biochemical and histopathological results, management and outcomes were analyzed., Results: The majority of patients who developed renal irAE were male and received combination immunotherapy. The median time of onset from initiation of ICI therapy to renal IrAE was 4 months. 52% of the treated renal IrAE had histopathologically confirmed renal IrAE. The most common histological pattern of injury was acute tubulo-interstitial nephritis (92%). One patient developed anti-GBM disease with non-dialysis dependent stage 5 CKD. In tubulointerstitial injury, there was no association between peak creatinine, renal recovery and histologically reported inflammation or fibrosis. Patients with renal IrAE demonstrated persisting renal dysfunction at 3, 6 and 12 months with a mean baseline, 3 and 12 month creatinine of 90.0 μmol/L, 127.0 μmol/L and 107.5 μmol/L respectively., Conclusion: Renal IrAE is most commonly attributable to steroid responsive acute tubulointerstitial nephritis. The outcome of rarer pathologies such as anti-GBM disease may be adversely affected by a delayed diagnosis. There is persisting renal dysfunction following an episode of renal IrAE that may have impact on future renal and overall survival outcomes.

Susac's syndrome is a rare and debilitating disease characterized by the triad of encephalopathy, branch retinal artery occlusions, and sensorineural hearing loss. All manifestations may not be clinically apparent at presentation resulting in delayed diagnosis. Early recognition of the syndrome may prevent disease sequelae such as permanent cognitive, visual, and hearing loss. We present such a case of Susac's syndrome that was also refractory to conventionally prescribed combination of immunosuppressive treatments including high-dose potent corticosteroids, intravenous cyclophosphamide, methotrexate, plasma exchange, rituximab, and mycophenolate. His disease was stabilized with infliximab in combination with a tapering course of low-dose prednisone. After 2 years of remission with TNF treatment, consideration is being given to ceasing therapy. He has the sequelae of bilateral sensorineural hearing loss but no visual impairment or cognitive deficits on follow-up with neuropsychometric testing. This is the first case report to our knowledge of the successful use of infliximab for a patient with Susac's syndrome that was necessary following treatment with cyclophosphamide and then rituximab., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Suran L. Fernando et al.)

The advent of immune checkpoint inhibitors (ICIs) for cancer therapy has heralded increasing frequency of immune-related adverse events including endocrinopathies, hepatitis, colitis and rarely myocarditis and myasthenia gravis (MG). The heterogeneity in clinical presentations regardless of organ-specific involvement can lead to delayed recognition and management of these events and adverse health outcomes. We describe a case of ICI-induced subclinical focal myocarditis that was recognised and treated in the broader context of MG. It is essential that patients with ICI-induced MG should be screened and monitored for myocarditis, a potentially fatal complication., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

HLA-B27 is a risk marker for ankylosing spondylitis and other associated seronegative spondyloarthropathies. We compared three methods of HLA-B*27 typing in a New South Wales (NSW) population: flow cytometry, rs4349859 single nucleotide polymorphism (SNP) detection assay, and allele-specific real-time polymerase chain reaction (RT-PCR) analysis of exons 2 and 3. Over a 5-month period, 543 samples underwent flow cytometric testing and RT-PCR high-resolution melt analysis of rs4349859 SNP and of exon 2 (5' fragment) and exon 3. In the third method, positive samples were further analysed with fluorescent resonance emission transfer (FRET) RT-PCR of exon 2 fragments, 2a and 2b. HLA-B*27 and other genotypes were confirmed by Sanger sequencing of a 600 base pair fragment of exons 2 and 3. In our cohort, the rs4349859 SNP method had 78.6% sensitivity and 98.7% specificity. Screening with exon 2 (5' fragment) and exon 3 RT-PCR provided 100% sensitivity. Further testing with exon 2a and 2b FRET RT-PCR produced 100% specificity. This cascade approach with allele-specific RT-PCR assays was able to differentiate all samples into HLA-B*27 subtypes. HLA-B*27 genotyping with allele-specific RT-PCR assays, to screen for and confirm HLA-B27 positive samples, was more sensitive and specific than flow cytometry and rs4349859 SNP assays. It is a potentially cost-effective method for differentiating HLA-B27 subtypes. Our cascade genetic testing approach is suitable for replacing the current flow cytometric HLA-B27 assay for the heterogeneous NSW population., (Copyright © 2019 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Background: Microscopic polyangiitis (MPA) can manifest with atypical features such as pulmonary fibrosis and chronic obstructive pulmonary disease (COPD), which are atypical and unusual features of small vessel vasculitis., Case Presentation: This paper presents two patients with microscopic polyangiitis and respiratory symptoms attributable to atypical pulmonary manifestations. Pulmonary fibrosis was present in both cases, with COPD also present in one patient. Management involved methylprednisone, prednisone, and cyclophosphamide. The second patient also received azathioprine. Both patients responded well to immunosuppressive treatment; however, pulmonary fibrosis and COPD were refractory to immunosuppression., Conclusion: Pulmonary manifestations including pulmonary fibrosis, emphysema, and bronchiectasis are observed in MPA. Evaluation of MPA in unexplained cases should be performed to avoid delays in diagnosis and management. Patients who present with MPA with pulmonary manifestations may respond to treatment, but their pulmonary features demonstrate a refractory nature to such management., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2019 Liam M. Clifford et al.)

Background: Nonprescription of penicillin-containing antibiotics in patients diagnosed with penicillin allergy is associated with morbidity and mortality. Adverse reactions to penicillins comprise type A and B reactions., Objective: To assess the feasibility of penicillin allergy evaluation without penicillin skin testing (PST) for adult patients with type B reactions and the health and economic benefits of this process., Methods: Inpatients at an Australian tertiary hospital between April 1, 2017, and April 30, 2018, with a diagnosis of type B penicillin allergy, requiring a penicillin-containing antibiotic for treatment, were included. All patients underwent clinical history review, PST, and drug provocation testing (DPT)., Results: Seventy-one patients were enrolled. Sixty-three reported a history of type B or unknown adverse reactions. No patients had a history of anaphylaxis requiring intubation or epinephrine within the last 10 years or a history suggesting Gell and Coombs type 2, 3, or 4 (severe) hypersensitivity reaction. Seven did not complete DPT because the treating team used a β-lactam antibiotic other than amoxicillin. Fifty-four of 56 remaining patients (96%) completed 3-day DPT to amoxicillin with no adverse reaction. Two experienced mild cutaneous reactions. Penicillin allergy evaluation was significantly associated with reduced length of stay, reduced hospital expenditure on bed and second-line antibiotics, and reduced readmission rates., Conclusion: Penicillin allergy evaluation with DPT without PST may be feasible for all adult patients with a reported history of type B reactions to penicillins who do not have a history of anaphylaxis within the last 10 years or a type 2, 3, or 4 (severe) hypersensitivity reaction., (Copyright © 2019 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Neuromuscular blocking agents (NMBAs) remain the leading cause of perioperative anaphylaxis in Australia. Standard evaluation comprises history, skin tests, and in vitro specific immunoglobulin E tests. Drug provocation tests to suspected NMBA culprits are associated with a significant risk. Basophil activation testing (BAT) is a potentially useful in vitro test that is not commercially available in Australia or as part of standard evaluation., Methods: All patients attending the Anaesthetic Allergy Clinic in Sydney, Australia between May 2017 and July 2018 exposed to an NMBA before the onset of anaphylaxis during their anaesthetic qualified for the study. We recruited 120 patients sequentially who received standard evaluation plus BAT using CD63, CD203c, and CD300a as surface activation markers., Results: BAT results were expressed as % upregulation above the negative control and stimulation index (mean fluorescence index of stimulated sample divided by the negative control). We calculated cut-offs of 4.45% and 1.44 for CD63, and 8.80% and 1.49 for CD203c, respectively. Sensitivity was 77% with specificity of 76%. A subgroup of 10 patients with NMBA anaphylaxis had no sensitisation on skin tests. BAT using CD63 and CD203c showed sensitisation in six of these 10, and adding CD300a identified sensitisation in nine patients. BAT was positive in seven of nine patients with anaphylaxis of unknown aetiology., Conclusions: BAT may be a useful supplement to the standard evaluation in diagnosing NMBA anaphylaxis in patients with suggestive histories, but no sensitisation on skin tests. Ongoing study of this specific group of patients is required to clarify its utility in clinical practice., (Copyright © 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)