Case Report: The Use of In Vivo Confocal Microscopy for Diagnosis and Monitoring in a Rare Case of Ancaliia algerae Microsporidial Keratitis in New South Wales, Australia.

We describe the successful management of Ancaliia Algerae microsporidial keratitis in an immunosuppressed 54-year-old woman with refractory linear IgA disease. The case highlights the challenges in diagnosis and management of this infection in immunocompromised individuals and emphasizes the usefulness of in vivo confocal microscopy as a novel, noninvasive tool to aid in the diagnosis and monitoring of microsporidial keratitis. We also discuss the possible mode of acquisition of this rare infection.

Central Nervous System (CNS) T-Cell Lymphoma as the Presenting Manifestation of Late-Onset Combined Immunodeficiency.

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.

Subsequent COVID-19 Prophylaxis in COVID-19 Associated Glomerulopathies.

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.

A retrospective review of immunology patients with primary and/or secondary immunodeficiency, demonstrating the benefits of the rapid transitioning from intravenous immunoglobulin to subcutaneous immunoglobulin at the onset of the COVID-19 pandemic.

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.

Oral food challenge outcomes in children and adolescents in a tertiary centre: A 5-year experience.

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.

Case series: Immune checkpoint inhibitor-induced transverse myelitis.

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.

The role of lymphocyte transformation tests (LTT) in suspected severe delayed hypersensitivity reactions following COVID-19 vaccination.

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.

Phenotyping variants of tumefactive demyelinating lesions according to clinical and radiological features-A case series.

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.

Skin Testing and Basophil Activation Testing Is Useful for Assessing Immediate Reactions to Polyethylene Glycol-Containing Vaccines.

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.

Follow-up of penicillin allergy labels 1 year after successful penicillin delabeling.

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.

Development and initial validation of a modified lymphocyte transformation test (LTT) assay in patients with DRESS and AGEP.

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.

The utility of surrogate markers in predicting HLA alleles associated with adverse drug reactions in Vietnamese.

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.

Medical treatment of polymeric cerebral granulomatous reactions following endovascular procedures.

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.

Genetic susceptibilities and prediction modeling of carbamazepine and allopurinol-induced severe cutaneous adverse reactions in Vietnamese.

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.