Longitudinal Characterization of Phagocytic and Neutralization Functions of Anti-Spike Antibodies in Plasma of Patients after Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

Phagocytic responses by effector cells to opsonized viruses have been recognized to play a key role in antiviral immunity. Limited data on coronavirus disease 2019 suggest that the role of Ab-dependent and -independent phagocytosis may contribute to the observed immunological and inflammatory responses; however, their development, duration, and role remain to be fully elucidated. In this study of 62 acute and convalescent patients, we found that patients with acute coronavirus disease 2019 can mount a phagocytic response to autologous plasma-opsonized Spike protein-coated microbeads as early as 10 d after symptom onset, while heat inactivation of this plasma caused 77-95% abrogation of the phagocytic response and preblocking of Fc receptors showed variable 18-60% inhibition. In convalescent patients, phagocytic response significantly correlated with anti-Spike IgG titers and older patients, while patients with severe disease had significantly higher phagocytosis and neutralization functions compared with patients with asymptomatic, mild, or moderate disease. A longitudinal subset of the convalescent patients over 12 mo showed an increase in plasma Ab affinity toward Spike Ag and preservation of phagocytic and neutralization functions, despite a decline in the anti-Spike IgG titers by >90%. Our data suggest that early phagocytosis is primarily driven by heat-liable components of the plasma, such as activated complements, while anti-Spike IgG titers account for the majority of observed phagocytosis at convalescence. Longitudinally, a significant increase in the affinity of the anti-Spike Abs was observed that correlated with the maintenance of both the phagocytic and neutralization functions, suggesting an improvement in the quality of the Abs.

Lymphopenia in sepsis-an acquired immunodeficiency?

Sepsis is a global health priority, yet effective host-directed targeted therapies have not been identified outside of the setting of coronavirus disease 2019 (COVID-19). Lymphopenia occurs in up to ~52% of patients with sepsis and is associated with a higher mortality at both 30 and 100 days. In COVID-19, the presence of lymphopenia correlates with intensive care unit admission, acute respiratory distress syndrome and death. The mechanisms underpinning lymphopenic sepsis remain unknown, and while high rates of lymphocyte apoptosis have been implicated, the relative contributions of cellular trafficking to inflamed tissues and reduction in lymphopoiesis require investigation. Further delineation of these underlying mechanisms holds the potential to open new avenues for the development of host-directed therapies in lymphopenic sepsis. These may include recombinant cytokines (e.g. interleukin-7), monoclonal antibodies (e.g. anti-interleukin-1, anti-programmed cell death protein 1) and small interfering RNA (e.g. targeting interleukin-10, transforming growth factor beta). Applying the frontier tools of translational cellular and genomic medicine to understand lymphopenia in the setting of critical infections holds the potential to significantly reduce the excessive global burden of sepsis.

High activation levels maintained in receptor-binding domain-specific memory B cells in people with severe coronavirus disease 2019.

The long-term health consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are still being understood. The molecular and phenotypic properties of SARS-CoV-2 antigen-specific T cells suggest a dysfunctional profile that persists in convalescence in those who were severely ill. By contrast, the antigen-specific memory B-cell (MBC) population has not yet been analyzed to the same degree, but phenotypic analysis suggests differences following recovery from mild or severe coronavirus disease 2019 (COVID-19). Here, we performed single-cell molecular analysis of the SARS-CoV-2 receptor-binding domain (RBD)-specific MBC population in three patients after severe COVID-19 and four patients after mild/moderate COVID-19. We analyzed the transcriptomic and B-cell receptor repertoire profiles at ~2 months and ~4 months after symptom onset. Transcriptomic analysis revealed a higher level of tumor necrosis factor-alpha (TNF-α) signaling via nuclear factor-kappa B in the severe group, involving CD80, FOS, CD83 and TNFAIP3 genes that was maintained over time. We demonstrated the presence of two distinct activated MBCs subsets based on expression of CD80hi TNFAIP3hi and CD11chi CD95hi at the transcriptome level. Both groups revealed an increase in somatic hypermutation over time, indicating progressive evolution of humoral memory. This study revealed distinct molecular signatures of long-term RBD-specific MBCs in convalescence, indicating that the longevity of these cells may differ depending on acute COVID-19 severity.

Mortality and costs related to severe acute pancreatitis in the intensive care units of Australia and New Zealand (ANZ), 2003-2020.

BACKGROUND AND OBJECTIVE: Comprehensive data on the burden of severe acute pancreatitis (SAP) in global intensive care units (ICUs) and trends over time are lacking. Our objective was to compare trends in hospital and ICU mortality, in-hospital and ICU length of stay, and costs related to ICU admission in Australia and New Zealand (ANZ) for SAP. METHODS: We performed a retrospective, observational, cohort study of ICU admissions reported to the ANZ Intensive Care Society Adult Patient Database over three consecutive six-year time periods from 2003 to 2020. RESULTS: 12,635 patients with SAP from 189 ICUs in ANZ were analysed. No difference in adjusted hospital mortality (11.4% vs 11.5% vs 11.0%, p = 0.85) and ICU mortality rates (7.5% vs 8.0% vs 8.1%, p = 0.73) were noted over the study period. Median length of hospital admission reduced over time (13.9 days in 2003-08, 13.1 days in 2009-14 and 12.5 days in 2015-20; p < 0.01). No difference in length of ICU stay was noted over the study period (p = 0.13). The cost of managing SAP in ANZ ICUs remained constant over the three time periods. CONCLUSIONS: In critically-ill SAP patients in ANZ, no change in mortality has been noted over nearly two decades. There was a slight reduction in hospital stay (1 day), while the length of ICU stay remained unchanged. Given the significant costs related to care of patients with SAP in ICU, these findings highlight the need to prioritise resource allocation for healthcare delivery and targeted clinical research to identify treatments aimed at reducing mortality.

Patients with treated indolent lymphomas immunized with BNT162b2 have reduced anti-spike neutralizing IgG to SARS-CoV-2 variants, but preserved antigen-specific T cell responses.

Patients with indolent lymphoma undertaking recurrent or continuous B cell suppression are at risk of severe COVID-19. Patients and healthy controls (HC; N = 13) received two doses of BNT162b2: follicular lymphoma (FL; N = 35) who were treatment naïve (TN; N = 11) or received immunochemotherapy (ICT; N = 23) and Waldenström's macroglobulinemia (WM; N = 37) including TN (N = 9), ICT (N = 14), or treated with Bruton's tyrosine kinase inhibitors (BTKi; N = 12). Anti-spike immunoglobulin G (IgG) was determined by a high-sensitivity flow-cytometric assay, in addition to live-virus neutralization. Antigen-specific T cells were identified by coexpression of CD69/CD137 and CD25/CD134 on T cells. A subgroup (N = 29) were assessed for third mRNA vaccine response, including omicron neutralization. One month after second BNT162b2, median anti-spike IgG mean fluorescence intensity (MFI) in FL ICT patients (9977) was 25-fold lower than TN (245 898) and HC (228 255, p = .0002 for both). Anti-spike IgG correlated with lymphocyte count (r = .63; p = .002), and time from treatment (r = .56; p = .007), on univariate analysis, but only with lymphocyte count on multivariate analysis (p = .03). In the WM cohort, median anti-spike IgG MFI in BTKi patients (39 039) was reduced compared to TN (220 645, p = .0008) and HC (p < .0001). Anti-spike IgG correlated with neutralization of the delta variant (r = .62, p < .0001). Median neutralization titer for WM BTKi (0) was lower than HC (40, p < .0001) for early-clade and delta. All cohorts had functional T cell responses. Median anti-spike IgG decreased 4-fold from second to third dose (p = .004). Only 5 of 29 poor initial responders assessed after third vaccination demonstrated seroconversion and improvement in neutralization activity, including to the omicron variant.

Interferon-Gamma-Producing CD8+ Tissue Resident Memory T Cells Are a Targetable Hallmark of Immune Checkpoint Inhibitor-Colitis.

BACKGROUND & AIMS: The pathogenesis of immune checkpoint inhibitor (ICI)-colitis remains incompletely understood. We sought to identify key cellular drivers of ICI-colitis and their similarities to idiopathic ulcerative colitis, and to determine potential novel therapeutic targets. METHODS: We used a cross-sectional approach to study patients with ICI-colitis, those receiving ICI without the development of colitis, idiopathic ulcerative colitis, and healthy controls. A subset of patients with ICI-colitis were studied longitudinally. We applied a range of methods, including multiparameter and spectral flow cytometry, spectral immunofluorescence microscopy, targeted gene panels, and bulk and single-cell RNA sequencing. RESULTS: We demonstrate CD8+ tissue resident memory T (TRM) cells are the dominant activated T cell subset in ICI-colitis. The pattern of gastrointestinal immunopathology is distinct from ulcerative colitis at both the immune and epithelial-signaling levels. CD8+ TRM cell activation correlates with clinical and endoscopic ICI-colitis severity. Single-cell RNA sequencing analysis confirms activated CD8+ TRM cells express high levels of transcripts for checkpoint inhibitors and interferon-gamma in ICI-colitis. We demonstrate similar findings in both anti-CTLA-4/PD-1 combination therapy and in anti-PD-1 inhibitor-associated colitis. On the basis of our data, we successfully targeted this pathway in a patient with refractory ICI-colitis, using the JAK inhibitor tofacitinib. CONCLUSIONS: Interferon gamma-producing CD8+ TRM cells are a pathological hallmark of ICI-colitis and a novel target for therapy.

Decreased ATM Function Causes Delayed DNA Repair and Apoptosis in Common Variable Immunodeficiency Disorders.

PURPOSE: Common variable immunodeficiency disorders (CVID) is characterized by low/absent serum immunoglobulins and susceptibility to bacterial infection. Patients can develop an infections-only phenotype or a complex disease course with inflammatory, autoimmune, and/or malignant complications. We hypothesized that deficient DNA repair mechanisms may be responsible for the antibody deficiency and susceptibility to inflammation and cancer in some patients. METHODS: Germline variants were identified following targeted sequencing of n = 252 genes related to DNA repair in n = 38 patients. NanoString nCounter PlexSet assay measured gene expression in n = 20 CVID patients and n = 7 controls. DNA damage and apoptosis were assessed by flow cytometry in n = 34 CVID patients and n = 11 controls. RESULTS: Targeted sequencing supported enrichment of rare genetic variants in genes related to DNA repair pathways with novel and rare likely pathogenic variants identified and an altered gene expression signature that distinguished patients from controls and complex patients from those with an infections-only phenotype. Consistent with this, flow cytometric analyses of lymphocytes following DNA damage revealed a subset of CVID patients whose immune cells have downregulated ATM, impairing the recruitment of other repair factors, delaying repair and promoting apoptosis. CONCLUSION: These data suggest that germline genetics and altered gene expression predispose a subset of CVID patients to increased sensitivity to DNA damage and reduced DNA repair capacity.

Immune checkpoint inhibitor-related colitis assessment and prognosis: can IBD scoring point the way?

BACKGROUND: Immune checkpoint inhibitors (ICI) improve survival but cause immune-related adverse events (irAE). We sought to determine if CTCAE classification, IBD biomarkers/endoscopic/histological scores correlate with irAE colitis outcomes. METHODS: A dual-centre retrospective study was performed on patients receiving ICI for melanoma, NSCLC or urothelial cancer from 2012 to 2018. Demographics, clinical data, endoscopies (reanalysed using Mayo/Ulcerative Colitis Endoscopic Index of Severity (UCEIS) scores), histology (scored with Nancy Index) and treatment outcomes were analysed. RESULTS: In all, 1074 patients were analysed. Twelve percent (134) developed irAE colitis. Median patient age was 66, 59% were male. CTCAE diarrhoea grade does not correlate with steroid/ infliximab use. G3/4 colitis patients are more likely to need infliximab (p < 0.0001) but colitis grade does not correlate with steroid duration. CRP, albumin and haemoglobin do not correlate with severity. The UCEIS (p = 0.008) and Mayo (p = 0.016) scores correlate with severity/infliximab requirement. Patients with higher Nancy indices (3/4) are more likely to require infliximab (p = 0.03). CONCLUSIONS: CTCAE assessment does not accurately reflect colitis severity and our data do not support its use in isolation, as this may negatively impact timely management. Our data support utilising endoscopic scoring for patients with >grade 1 CTCAE disease, and demonstrate the potential prognostic utility of objective histologic scoring.

Cerebral toxoplasmosis in a patient with myasthenia gravis and thymoma with immunodeficiency/Good's syndrome: a case report.

BACKGROUND: Patients with thymoma with immunodeficiency (TWI)/Good's syndrome characteristically have evidence of combined immunodeficiency including low or absent B-cells, hypogammaglobulinemia and defects in T-cell mediated immunity. These patients can present with common or opportunistic infections. CASE PRESENTATION: A 54-year-old female was diagnosed with cerebral toxoplasmosis. This occurred on a background of metastatic thymoma previously treated with chemotherapy and myasthenia gravis (MG) treated with mycophenolate mofetil, monthly intravenous immunoglobulin (IVIG) and pyridostigmine. She reported recurrent herpes zoster infection. The patient had clinical and radiological progression of cerebral infection despite completing standard induction and maintenance therapy with sulfadiazine and pyrimethamine. Investigations found a complete absence of B-cells and evidence for hypogammaglobulinemia which, together with evidence of defects in T-cell mediated immunity and thymoma, lead to a diagnosis of TWI/Good's Syndrome. The patient has undergone prolonged high-dose therapy for toxoplasmosis and a reduction in immunosuppression with no evidence of recurrent toxoplasmosis or flare of MG. CONCLUSIONS: TWI/Good's Syndrome should be suspected in patients with thymoma and recurrent, persistent or unusual infections. If suspected serum immunoglobulins and lymphocyte subsets should be measured. These patients may need closer monitoring, higher dose and prolonged treatment of infections, and weaning of concurrent immunosuppression may be considered.

Episodic fevers and vasodilatory shock mimicking urosepsis in a patient with HIV-associated multicentric Castleman's Disease: a case report.

BACKGROUND: Multicentric Castleman's disease (MCD) is a pre-malignancy that presents with lymphadenopathy and features of systemic inflammation. Human immunodeficiency virus (HIV)-associated MCD is associated with human herpesvirus-8 (HHV-8) infection. If untreated MCD has a relapsing and remitting course that is eventually fatal. CASE PRESENTATION: A 67-year-old man had six hospital admissions over 20 months characterised by fever, urinary frequency and CRP >100 mg/L. The final admission was complicated by hypotension requiring intensive care unit admission and ionotropic support. His history included HIV and Hepatitis B virus (HBV) co-infection on suppressive therapy. Each presentation was managed as presumed urosepsis with use of empirical antibiotics, however numerous blood and urine cultures failed to identify a pathogen. A bone-marrow aspirate and trephine found no evidence of haematological malignancy. A positron emission tomography scan found active lymph nodes, one of which was biopsied and found to contain the plasma-cell variant of Castleman's disease. Ultimately the cause for the recurrent presentations was attributed to progressive MCD. The patient received rituximab monotherapy and has had no further related admissions. CONCLUSIONS: MCD should be considered in patients with chronic HIV infection presenting with recurrent sepsis-like episodes and/or vasodilatory shock, particularly if no pathogen is identified or lymphadenopathy is evident.

Defining the correlates of lymphopenia and independent predictors of poor clinical outcome in adults hospitalized with COVID-19 in Australia.

Lymphopenia is a common feature of acute COVID-19 and is associated with increased disease severity and 30-day mortality. Here we aim to define the demographic and clinical characteristics that correlate with lymphopenia in COVID-19 and determine if lymphopenia is an independent predictor of poor clinical outcome. We analysed the ENTER-COVID (Epidemiology of hospitalized in-patient admissions following planned introduction of Epidemic SARS-CoV-2 to highly vaccinated COVID-19 naïve population) dataset of adults (N = 811) admitted for COVID-19 treatment in South Australia in a retrospective registry study, categorizing them as (a) lymphopenic (lymphocyte count < 1 × 109/L) or (b) non-lymphopenic at hospital admission. Comorbidities and laboratory parameters were compared between groups. Multiple regression analysis was performed using a linear or logistic model. Intensive care unit (ICU) patients and non-survivors exhibited lower median lymphocyte counts than non-ICU patients and survivors respectively. Univariate analysis revealed that low lymphocyte counts associated with hypertension and correlated with haemoglobin, platelet count and negatively correlated with urea, creatinine, bilirubin, and aspartate aminotransferase (AST). Multivariate analysis identified age, male, haemoglobin, platelet count, diabetes, creatinine, bilirubin, alanine transaminase, c-reactive protein (CRP) and lactate dehydrogenase (LDH) as independent predictors of poor clinical outcome in COVID-19, while lymphopenia did not emerge as a significant predictor.

Checkpoint Inhibitor-Associated Autoimmune Diabetes Mellitus Is Characterized by C-peptide Loss and Pancreatic Atrophy.

OBJECTIVE: To conduct a multicenter case series characterizing the clinical characteristics at presentation and pancreatic volume changes of patients with checkpoint inhibitor-associated autoimmune diabetes (CIADM). RESEARCH DESIGN AND METHODS: Electronic medical records were reviewed with 36 consecutive patients identified with CIADM, as defined by (1) previous immune checkpoint inhibitor (ICI) therapy, (2) new-onset hyperglycemia (blood glucose level ≥ 11.1 mmol/L and/or glycosylated hemoglobin ≥ 6.5%), and (3) insulin deficiency [C-peptide <0.4 nmol/L or diabetic ketoacidosis (DKA)] within 1 month of presentation. Pancreatic volume was available and measured using computed tomography volumetry for 17 patients with CIADM and 3 sets of control patients: 7 with ICI-related pancreatitis, 13 with asymptomatic ICI-related lipase elevation, and 11 ICI-treated controls for comparison. RESULTS: All patients had either anti-programmed cell death protein 1 or anti-programmed cell death ligand 1 therapy. Median time from ICI commencement to CIADM diagnosis was 15 weeks. At presentation, 25 (69%) had DKA, 27 (84%) had low C-peptide, and, by 1 month, 100% had low C-peptide. Traditional type 1 diabetes autoantibodies were positive in 15/35 (43%). Lipase was elevated in 13/27 (48%) at presentation. In 4 patients with longitudinal lipase testing, elevated levels peaked 1 month prior to CIADM diagnosis. Pancreatic volume was lower pre-ICI in CIADM patients compared with controls and demonstrated a mean decline of 41% from pretreatment to 6 months post-CIADM diagnosis. CONCLUSION: Pronounced biochemical and radiologic changes occur during CIADM pathogenesis. Rapid loss of C-peptide is a distinct characteristic that can be used to aid diagnosis as autoantibodies are often negative.

Indeterminate measurable residual disease by multiparameter flow cytometry is associated with an intermediate risk of clinical relapse in adult patients with acute leukaemia.

Measurable residual disease (MRD) is useful for prognostication and for monitoring response to treatment in patients with acute leukaemia. MRD by multiparametric flow cytometry (MFC-MRD) utilises the leukaemia-associated immunophenotype (LAIP) and difference from normal (DfN) strategies to identify the leukaemic clone. Difficulties arise when the LAIP overlaps with normal regeneration, there is clonal evolution, or when the abnormal clone population is exceptionally small e.g., <0.01% of CD45+ cells. Such cases are reported as 'indeterminate'; however, there is little international consensus on this reporting. The relationship between clinical outcomes and indeterminate MFC-MRD is unknown. Here we determine the rate of indeterminate MFC-MRD reporting, its relationship to concurrent molecular MRD results when available, and to clinical outcomes to 12 months. We performed an internal audit of all adult testing for MFC-MRD between January and December 2021. A total of 153 consecutive patients with a diagnosis of acute leukaemia were included. Successive MFC-MRD results and clinical outcomes were recorded over a 12-month period from time of inclusion into the study. In total, 460 MFC-MRD tests from 153 patients were reviewed and 73 (16%) MFC-MRD tests from 54 (35%) patients were reported as indeterminate. The majority (70%) were at low levels between 0.01-0.1% of CD45+ cells. Compared to patients with a negative result, acute myeloid leukaemia (AML) was more frequent in patients who had an indeterminate MFC-MRD (70% vs 36%), and B-cell acute lymphoblastic leukaemia was less common (20% vs 55%). In patients with indeterminate MFC-MRD results, one-third had received either chemotherapy or allogeneic haemopoietic stem cell transplant (aHSCT) within the preceding 3 months. Agreement between MFC and molecular MRD testing was low. Patients with indeterminate MFC-MRD had leukaemia relapse rates below patients with a positive MFC-MRD, but greater than those with negative MFC-MRD (positive 33% vs indeterminate 21% vs negative 8%, p = 0.038). Overall, these findings indicate that indeterminate MFC-MRD results are more common in adults with AML and also in those who have received chemotherapy or aHSCT within the previous 3 months. We report for the first time that indeterminate MFC-MRD is a finding of potential clinical significance, which associates with a numerically higher median relapse rate within 12 months when compared to a negative MFC-MRD result.

Tracking in situ checkpoint inhibitor-bound target T cells in patients with checkpoint-induced colitis.

The success of checkpoint inhibitors (CPIs) for cancer has been tempered by immune-related adverse effects including colitis. CPI-induced colitis is hallmarked by expansion of resident mucosal IFNγ cytotoxic CD8+ T cells, but how these arise is unclear. Here, we track CPI-bound T cells in intestinal tissue using multimodal single-cell and subcellular spatial transcriptomics (ST). Target occupancy was increased in inflamed tissue, with drug-bound T cells located in distinct microdomains distinguished by specific intercellular signaling and transcriptional gradients. CPI-bound cells were largely CD4+ T cells, including enrichment in CPI-bound peripheral helper, follicular helper, and regulatory T cells. IFNγ CD8+ T cells emerged from both tissue-resident memory (TRM) and peripheral populations, displayed more restricted target occupancy profiles, and co-localized with damaged epithelial microdomains lacking effective regulatory cues. Our multimodal analysis identifies causal pathways and constitutes a resource to inform novel preventive strategies.

Posterior reversible encephalopathy syndrome (PRES) in an HIV-1 infected patient with disseminated varicella zoster virus: a case report.

BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is an uncommon pathology characterized by the acute onset of headache, vomiting, altered consciousness, seizures and focal neurological deficits. It was initially described in the setting of hypertension, uremia and immunosuppression. In the last decade there have been emerging reports of PRES in patients with advanced human immunodeficiency virus (HIV)-infection in the presence of hypertension, dialysis, hypercalcaemia and two opportunistic infections: blastomycosis and tuberculosis (TB). CASE PRESENTATION: Here we present the case of a 54 year old male being treated for disseminated varicella zoster virus (VZV) and vasculopathy in the setting of HIV infection who acutely deteriorated to the point of requiring intubation. His clinicoradiological diagnosis was of PRES and he subsequently improved within 72 h with supportive management. Serial neuroimaging correlated with the clinical findings. The pathogenesis of PRES is poorly understood but is thought to stem from vasogenic oedema either as a result of loss of endothelial integrity and transudate of fluid across the blood-brain barrier, or secondary to vasospasm resulting in tissue oedema in the absence of infarction. How HIV infection impacts on this model is unclear. It is possible the HIV infection causes endothelial dysfunction and disruption of the blood-brain barrier that may be further exacerbated by infections in the central nervous system. CONCLUSION: The phenomenon of PRES in advanced HIV is an important clinical entity for both physicians and critical care doctors to recognize firstly given its potential mortality but also because of its favourable prognosis and reversibility with supportive care and treatment of underlying causes.

Human papillomavirus in the setting of immunodeficiency: Pathogenesis and the emergence of next-generation therapies to reduce the high associated cancer risk.

Human papillomavirus (HPV), a common sexually transmitted virus infecting mucosal or cutaneous stratified epithelia, is implicated in the rising of associated cancers worldwide. While HPV infection can be cleared by an adequate immune response, immunocompromised individuals can develop persistent, treatment-refractory, and progressive disease. Primary immunodeficiencies (PIDs) associated with HPV-related disease include inborn errors of GATA, EVER1/2, and CXCR4 mutations, resulting in defective cellular function. People living with secondary immunodeficiency (e.g. solid-organ transplants recipients of immunosuppression) and acquired immunodeficiency (e.g. concurrent human immunodeficiency virus (HIV) infection) are also at significant risk of HPV-related disease. Immunocompromised people are highly susceptible to the development of cutaneous and mucosal warts, and cervical, anogenital and oropharyngeal carcinomas. The specific mechanisms underlying high-risk HPV-driven cancer development in immunocompromised hosts are not well understood. Current treatments for HPV-related cancers include surgery with adjuvant chemotherapy and/or radiotherapy, with clinical trials underway to investigate the use of anti-PD-1 therapy. In the setting of HIV co-infection, persistent high-grade anal intraepithelial neoplasia can occur despite suppressive antiretroviral therapy, resulting in an ongoing risk for transformation to overt malignancy. Although therapeutic vaccines against HPV are under development, the efficacy of these in the setting of PID, secondary- or acquired- immunodeficiencies remains unclear. RNA-based therapeutic targeting of the HPV genome or mRNA transcript has become a promising next-generation therapeutic avenue. In this review, we summarise the current understanding of HPV pathogenesis, immune evasion, and malignant transformation, with a focus on key PIDs, secondary immunodeficiencies, and HIV infection. Current management and vaccine regimes are outlined in relation to HPV-driven cancer, and specifically, the need for more effective therapeutic strategies for immunocompromised hosts. The recent advances in RNA-based gene targeting including CRISPR and short interfering RNA (siRNA), and the potential application to HPV infection are of great interest. An increased understanding of both the dysregulated immune responses in immunocompromised hosts and of viral persistence is essential for the design of next-generation therapies to eliminate HPV persistence and cancer development in the most at-risk populations.

Measurable residual disease in adult acute myeloid leukaemia: evaluation of a multidimensional 'radar' flow cytometric plot analysis method.

Measurable residual disease (MRD) monitoring in acute myeloid leukaemia (AML) is becoming increasingly important and is predominantly performed by multiparameter flow cytometry (MFC) or quantitative polymerase chain reactions (RT-qPCR). We investigated the use of multidimensional plots (MD-MFC) for AML MRD monitoring in an adult cohort. AML MRD was determined using a novel MD-MFC method for 115 MRD samples. Results were correlated with traditional two-dimensional MFC (2D-MFC) and molecular methods. Using the standard cut-off of 0.1% CD45+ cells, concordance was 99/115 (p=0.332). Eighty-four of 115 were concordant using a very low reporting limit of 0.01% (p=0.216). MRD <0.1% by either method was present in 40 of 115 samples. Fifteen of 40 were MD-MFC positive and 2D-MFC negative. Of these two of 15 had a molecular MRD marker and both were positive. Molecular MRD markers were available in 36 of 115 cases. Twenty-one of 36 (58%) were concordant with MD-MFC. Eight of 36 had detectable molecular MRD only and eight of 36 had positive MD-MFC only. There was no correlation between either the MFC method and the molecular results. In summary, there is good correlation between MD- and 2D-MFC-MRD and no correlation between the MFC and molecular methods.

Immune response to COVID-19 vaccination in patients with Waldenström macroglobulinaemia who pause their BTKi therapy.

Patients with Waldenström macroglobulinaemia (WM) are at increased risk of severe COVID-19 infection and have poor immune responses to COVID-19 vaccination. This study assessed whether a closely monitored pause in Bruton's Tyrosine Kinase inhibitor (BTKi) therapy might result in an improved humoral response to a 3rd COVID-19 vaccine dose. Improved response was observed in WM patients who paused their BTKi, compared to a group who did not pause their BTKi. However, the response was attenuated after BTKi recommencement. This data contributes to our understanding of vaccination strategies in this patient group and may help inform consensus approaches in the future.

Risk Factors and Characteristics of Checkpoint Inhibitor-Associated Autoimmune Diabetes Mellitus (CIADM): A Systematic Review and Delineation From Type 1 Diabetes.

BACKGROUND: Checkpoint inhibitor-associated autoimmune diabetes mellitus (CIADM) is a distinct form of autoimmune diabetes that is a rare complication of immune checkpoint inhibitor therapy. Data regarding CIADM are limited. PURPOSE: To systematically review available evidence to identify presentation characteristics and risk factors for early or severe presentations of adult patients with CIADM. DATA SOURCES: MEDLINE and PubMed databases were reviewed. STUDY SELECTION: English full text articles from 2014 to April 2022 were identified with a predefined search strategy. Patients meeting diagnostic criteria for CIADM with evidence of hyperglycemia (blood glucose level >11 mmol/L or HbA1c ≥6.5%) and insulin deficiency (C-peptide <0.4 nmol/L and/or diabetic ketoacidosis [DKA]) were included for analysis. DATA EXTRACTION: With the search strategy we identified 1,206 articles. From 146 articles, 278 patients were labeled with "CIADM," with 192 patients meeting our diagnostic criteria and included in analysis. DATA SYNTHESIS: Mean ± SD age was 63.4 ± 12.4 years. All but one patient (99.5%) had prior exposure to either anti-PD1 or anti-PD-L1 therapy. Of the 91 patients tested (47.3%), 59.3% had susceptibility haplotypes for type 1 diabetes (T1D). Median time to CIADM onset was 12 weeks (interquartile range 6-24). DKA occurred in 69.7%, and initial C-peptide was low in 91.6%. T1D autoantibodies were present in 40.4% (73 of 179) and were significantly associated with DKA (P = 0.0009) and earlier time to CIADM onset (P = 0.02). LIMITATIONS: Reporting of follow-up data, lipase, and HLA haplotyping was limited. CONCLUSIONS: CIADM commonly presents in DKA. While T1D autoantibodies are only positive in 40.4%, they associate with earlier, more severe presentations.