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Introduction: Digital twins of patients are virtual models that can create a digital patient replica to test clinical interventions in silico without exposing real patients to risk. With the increasing availability of electronic health records and sensor-derived patient data, digital twins offer significant potential for applications in the healthcare sector. Methods: This article presents a scalable full-stack architecture for a patient simulation application driven by graph-based models. This patient simulation application enables medical practitioners and trainees to simulate the trajectory of critically ill patients with sepsis. Directed acyclic graphs are utilized to model the complex underlying causal pathways that focus on the physiological interactions and medication effects relevant to the first 6 h of critical illness. To realize the sepsis patient simulation at scale, we propose an application architecture with three core components, a cross-platform frontend application that clinicians and trainees use to run the simulation, a simulation engine hosted in the cloud on a serverless function that performs all of the computations, and a graph database that hosts the graph model utilized by the simulation engine to determine the progression of each simulation. Results: A short case study is presented to demonstrate the viability of the proposed simulation architecture. Discussion: The proposed patient simulation application could help train future generations of healthcare professionals and could be used to facilitate clinicians' bedside decision-making.
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Social media platforms have emerged as invaluable tools for remote training in resource-constrained countries. This study presents the development, implementation, and preliminary assessment of a remote intensive care unit (ICU) training program conducted in Libya utilizing social media platforms. This educational initiative was based on the Checklist for Early Recognition and Treatment of Acute Illness and iNjury (CERTAIN) program, targeting Libyan resident physicians. The initiative comprised a series of live-streamed pulmonary/critical care lectures and asynchronous discussion of clinical cases via a private messaging chat. Participant engagement, satisfaction, and learning outcomes were evaluated using social media analytics and surveys. A total of 323 learners joined the Libyan ICU training program chat group, and two tele-education sessions were broadcast, accumulating a total of 749 views. The majority (72.6%) of learners had graduated from medical school within the past five years and were in residency training. Clinical cases and learning materials were shared through 2,991 messages in the chat group. Learners' objective and subjective clinical knowledge improved after each tele-education session, and 88% of survey respondents rated the remote ICU training program as excellent. This study highlights the potential of using widely available social media platforms for remote ICU education in resource-limited settings.
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Diagnostic delay leads to poor outcomes in infections, and it occurs more often when the causative agent is unusual. Delays are attributable to failing to consider such diagnoses in a timely fashion. Using routinely collected electronic health record (EHR) data, we built a preliminary multivariable diagnostic model for early identification of unusual fungal infections and tuberculosis in hospitalized patients. We conducted a two-gate case-control study. Cases encompassed adult patients admitted to 19 Mayo Clinic enterprise hospitals between January 2010 and March 2023 diagnosed with blastomycosis, cryptococcosis, histoplasmosis, mucormycosis, pneumocystosis, or tuberculosis. Control groups were drawn from all admitted patients (random controls) and those with community-acquired infections (ID-controls). Development and validation datasets were created using randomization for dividing cases and controls (7:3), with a secondary validation using ID-controls. A logistic regression model was constructed using baseline and laboratory variables, with the unusual infections of interest outcome. The derivation dataset comprised 1043 cases and 7000 random controls, while the 451 cases were compared to 3000 random controls and 1990 ID-controls for validation. Within the derivation dataset, the model achieved an area under the curve (AUC) of 0.88 (95% confidence interval [CI]: 0.87-0.89) with a good calibration accuracy (Hosmer-Lemeshow P = 0.623). Comparable performance was observed in the primary (AUC = 0.88; 95% CI: 0.86-0.9) and secondary validation datasets (AUC = 0.84; 95% CI: 0.82-0.86). In this multicenter study, an EHR-based preliminary diagnostic model accurately identified five unusual fungal infections and tuberculosis in hospitalized patients. With further validation, this model could help decrease time to diagnosis.
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BACKGROUND: Intensive care unit (ICU) clinicians encounter frequent challenges with managing vast amounts of fragmented data while caring for multiple critically ill patients simultaneously. This may lead to increased provider cognitive load that may jeopardize patient safety. OBJECTIVES: This systematic review assesses the impact of centralized multipatient dashboards on ICU clinician performance, perceptions regarding the use of these tools, and patient outcomes. METHODS: A literature search was conducted on February 9, 2023, using the EBSCO CINAHL, Cochrane Central Register of Controlled Trials, Embase, IEEE Xplore, MEDLINE, Scopus, and Web of Science Core Collection databases. Eligible studies that included ICU clinicians as participants and tested the effect of dashboards designed for use by multiple users to manage multiple patients on user performance and/or satisfaction compared with the standard practice. We narratively synthesized eligible studies following the SWiM (Synthesis Without Meta-analysis) guidelines. Studies were grouped based on dashboard type and outcomes assessed. RESULTS: The search yielded a total of 2,407 studies. Five studies met inclusion criteria and were included. Among these, three studies evaluated interactive displays in the ICU, one study assessed two dashboards in the pediatric ICU (PICU), and one study examined centralized monitor in the PICU. Most studies reported several positive outcomes, including reductions in data gathering time before rounds, a decrease in misrepresentations during multidisciplinary rounds, improved daily documentation compliance, faster decision-making, and user satisfaction. One study did not report any significant association. CONCLUSION: The multipatient dashboards were associated with improved ICU clinician performance and were positively perceived in most of the included studies. The risk of bias was high, and the certainty of evidence was very low, due to inconsistencies, imprecision, indirectness in the outcome measure, and methodological limitations. Designing and evaluating multipatient tools using robust research methodologies is an important focus for future research.
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Intensive Care Units , HumansABSTRACT
Idiopathic acute pancreatitis (IAP) presents a diagnostic challenge and refers to cases where the cause of acute pancreatitis remains uncertain despite a comprehensive diagnostic evaluation. Endoscopic ultrasound (EUS) has emerged as a valuable tool in the diagnostic workup of IAP. This review explores the pivotal role of EUS in detecting the actual cause of IAP and assessing its accuracy, timing, safety, and future technological improvement. In this review, we investigate the role of EUS in identifying the actual cause of IAP by examining the available literature. We aim to assess possible existing evidence regarding EUS accuracy, timing, and safety and explore potential trends of future technological improvements in EUS for diagnostic purposes. Following PRISMA guidelines, 60 pertinent studies were selected and analysed. EUS emerges as a crucial diagnostic tool, particularly when conventional imaging fails. It can offer intricate visualization of the pancreas, biliary system, and adjacent structures. Microlithiasis, biliary sludge, chronic pancreatitis, and small pancreatic tumors seem to be much more accurately identified with EUS in the setting of IAP. The optimal timing for EUS is post-resolution of the acute phase of the disease. With a low rate of complications, EUS poses minimal safety concerns. EUS-guided interventions, including fine-needle aspiration, collection drainage, and biopsies, aid in the cytological analysis. With high diagnostic accuracy, safety, and therapeutic potential, EUS is able to improve patient outcomes when managing IAP. Further refinement of EUS techniques and cost-effectiveness assessment of EUS-guided approaches need to be explored in multicentre prospective studies. This review underscores EUS as a transformative tool in unraveling IAP's enigma and advancing diagnostic and therapeutic strategies.
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Background: Pneumocystis pneumonia (PCP) is a growing concern as the immunocompromised population expands. Current laboratory approaches are limited. This systematic review aimed to evaluate metagenomic next-generation sequencing (MNGS) tests' performance in detecting PCP. Methods: Five databases were searched through December 19, 2022, to identify original studies comparing MNGS with clinically diagnosed PCP. To assess the accuracy, symmetric hierarchical summary receiver operating characteristic models were used. Results: Eleven observational studies reporting 1442 patients (424 with PCP) were included. Six studies focused exclusively on recipients of biologic immunosuppression (none with HIV-associated immunosuppression). Six were exclusively on bronchoalveolar lavage, while 1 was on blood samples. The sensitivity of MGNS was 0.96 (95% CI, 0.90-0.99), and specificity was 0.96 (95% CI, 0.92-0.98), with negative and positive likelihood ratios of 0.02 (95% CI, 0.01-0.05) and 19.31 (95% CI, 10.26-36.36), respectively. A subgroup analysis of studies exclusively including bronchoalveolar lavage (BAL) and blood samples demonstrated a sensitivity of 0.94 (95% CI, 0.78-0.99) and 0.93 (95% CI, 0.80-0.98) and a specificity of 0.96 (95% CI, 0.88-0.99) and 0.98 (95% CI, 0.76-1.00), respectively. The sensitivity analysis on recipients of biologic immunosuppression showed a sensitivity and specificity of 0.96 (95% CI, 0.90-0.98) and 0.94 (95% CI, 0.84-0.98), respectively. The overall confidence in the estimates was low. Conclusions: Despite the low certainty of evidence, MNGS detects PCP with high sensitivity and specificity. This also applies to recipients of biologic immunosuppression and tests performed exclusively on blood samples without the need for BAL. Further studies are required in individuals with HIV-associated immunosuppression.
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ABSTRACT: Background: Although central venous oxygen saturation (ScvO 2 ) has been used as an endpoint for the treatment of circulatory shock, its role in guiding the evaluation and treatment of patients with severe hypoxemia remains to be assessed. The aim of this study was to assess the incidence of low ScvO 2 in a cohort of hypoxemic patients and the association of this finding with differences in clinical management and patient outcomes. Methods: Retrospective review of data from adult intensive care unit patients with hypoxemia who required invasive mechanical ventilation for over 24 h and had at least one ScvO 2 measured within 6 h of a PaO 2 /FiO 2 ratio <200. Results: Of 442 mechanically ventilated patients with severe hypoxemia, 249 (56%) had an ScvO 2 <70%. When compared with patients with ScvO 2 ≥70%, those with low ScvO 2 had worse systemic oxygenation and hemodynamic parameters and were more likely to receive red blood cell transfusions (31.7% vs. 18.1%, P = 0.001), epinephrine (27.3% vs. 16.6%, P = 0.007), and inodilators. Outcomes such as median intensive care unit length of stay (7.5 vs. 8.3 days, P = 0.337) and hospital mortality (39.8% vs. 35.7%, P = 0.389) were not different between groups. When stratified by the central venous-to-arterial CO 2 difference (∆PCO 2 ), patients with a low ScvO 2 and normal ∆PCO 2 had lower median PaO 2 and hemoglobin levels and received more red blood cell transfusions, whereas those with an increased ∆PCO 2 had a lower pulse pressure and cardiac index and were more likely to receive epinephrine and milrinone. Conclusion: Low ScvO 2 is frequently observed in mechanically ventilated patients with severe hypoxemia, and these patients receive different interventions. Clinicians often use therapies targeting systemic oxygen delivery to correct low ScvO 2 . Prospective research is needed to identify patients with severe hypoxemia that might benefit from interventions targeting systemic oxygen delivery.
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Oxygen , Respiration, Artificial , Adult , Humans , Oxygen/therapeutic use , Prospective Studies , Oxygen Saturation , Hypoxia/therapy , EpinephrineABSTRACT
Importance: The conflict in Ukraine has forced civilian hospitals with limited trauma and battlefield medicine experience to care for casualties of war, placing significant strain on the health care system. Using the Checklist for Early Recognition and Treatment of Acute Illness and Injury (CERTAIN) program, a multimodal trauma critical care knowledge-exchange platform was created for clinicians practicing in these institutions. Objectives: To describe the development and implementation of the CERTAIN for Ukraine program and to evaluate the reach of this intervention, together with participant engagement and satisfaction. Design, Setting, and Participants: This quality improvement study included clinicians caring for critically ill patients during the ongoing Ukrainian conflict who were part of a community developed using a messaging app. The program was implemented by a group of international trauma and critical care experts in collaboration with critical care leaders from the Shupyk National Healthcare University in Kyiv, Ukraine. This study evaluates data collected from the CERTAIN for Ukraine program from its launch on April 9, 2022, to August 31, 2022. Interventions: The initiative comprised a longitudinal series of interactive tele-education sessions, a webpage containing the CERTAIN approach and current trauma critical care guidelines translated into Ukrainian and Russian, and a private messaging chat for asynchronous discussion. Main Outcomes and Measures: Participant engagement and satisfaction were tracked using multimedia analytics and a post-session survey. Results: Since program launch, 838 participants have joined the messaging group, and 6 tele-education sessions have been delivered, with 1835 total views. The CERTAIN website has had 3527 visits, mainly from Ukraine (1378 [39%]) and the United States (1060 [30%]). Of the 74 completed postsession surveys, 65 respondents (88%) rated the course content excellent or very good, and 73 (99%) recommended it to others. Conclusions and Relevance: The findings of this quality improvement study indicate that, using widely available and low-cost platforms, knowledge was shared rapidly and efficiently to a large community of clinicians practicing in a wartime environment with broad-based engagement and a high level of learner satisfaction.
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Critical Care , Hospitals , Humans , United States , Ukraine , Quality Improvement , Longitudinal StudiesABSTRACT
Background: Digital twins are computerized patient replicas that allow clinical interventions testing in silico to minimize preventable patient harm. Our group has developed a novel application software utilizing a digital twin patient model based on electronic health record (EHR) variables to simulate clinical trajectories during the initial 6 h of critical illness. This study aimed to assess the usability, workload, and acceptance of the digital twin application as an educational tool in critical care. Methods: A mixed methods study was conducted during seven user testing sessions of the digital twin application with thirty-five first-year internal medicine residents. Qualitative data were collected using a think-aloud and semi-structured interview format, while quantitative measurements included the System Usability Scale (SUS), NASA Task Load Index (NASA-TLX), and a short survey. Results: Median SUS scores and NASA-TLX were 70 (IQR 62.5-82.5) and 29.2 (IQR 22.5-34.2), consistent with good software usability and low to moderate workload, respectively. Residents expressed interest in using the digital twin application for ICU rotations and identified five themes for software improvement: clinical fidelity, interface organization, learning experience, serious gaming, and implementation strategies. Conclusion: A digital twin application based on EHR clinical variables showed good usability and high acceptance for critical care education.
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OBJECTIVES: IgG4-related disease (IgG4-RD) is a systemic fibro-inflammatory disorder characterized by a dysregulated resolution of inflammation and wound healing response that might develop after an apoptotic insult induced by cytotoxic T lymphocytes (CTLs). Mer receptor tyrosine kinase (MerTK) and its ligand, protein S (ProS1), have a pivotal role in the resolution of inflammation, being implicated in the clearance of apoptotic cells, quenching of the immune response and development of tissue fibrosis. In the present work we aimed to investigate a possible involvement of the MerTK signalling pathway in the pathogenesis of IgG4-RD and development of tissue fibrosis. METHODS: MerTK and ProS1 expression patterns in IgG4-RD lesions were evaluated by immunohistochemistry and immunofluorescence studies. Circulating MerTK+ monocytes, soluble Mer and MerTK ligands were measured in the peripheral blood of IgG4-RD patients and healthy controls by flow cytometry and ELISA, respectively. RESULTS: MerTK was highly expressed by macrophages infiltrating IgG4-RD lesions. MerTK+ macrophages were more abundant in IgG4-RD than in Sjögren's syndrome and interacted with apoptotic cells and ProS1-expressing T and B lymphocytes. Moreover, they expressed the pro-fibrotic cytokine TGF-ß and their numbers declined following rituximab-induced disease remission. Circulating MerTK+ monocytes, soluble Mer and MerTK ligands were not increased in the peripheral blood of patients with IgG4-RD. CONCLUSIONS: The MerTK-ProS1 axis is activated in IgG4-RD lesions, possibly leading to persistent stimulation of processes involved in the resolution of inflammation and tissue fibrosis.
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Immunoglobulin G4-Related Disease/enzymology , Inflammation/enzymology , c-Mer Tyrosine Kinase/metabolism , Case-Control Studies , Enzyme-Linked Immunosorbent Assay , Female , Fibrosis , Flow Cytometry , Fluorescent Antibody Technique , Humans , Immunoglobulin G4-Related Disease/pathology , Inflammation/pathology , Leukocytes, Mononuclear/enzymology , Leukocytes, Mononuclear/metabolism , Leukocytes, Mononuclear/pathology , Macrophages/pathology , MaleABSTRACT
The COVID-19 pandemic has caused the destruction of routine hospital services globally, leading to an increase in the backlog of elective surgery cases. The aim of the study was to retrospectively investigate the pandemic's impact on the urologic oncology surgical activity of a high-volume center located in Milan, Italy. The number and type of procedures performed in 2020 during the COVID-19 pandemic was evaluated using 2019 data as control. Waiting times for each surgical procedure were compared, on a bimonthly basis, between the two different years. Overall, a 26.7% reduction in the number of urologic oncology surgeries between 2019 and 2020 was observed (2019: 720, 2020: 528). Both the main indication for surgery and the type of procedure performed significantly differed between 2019 and 2020 (all p < 0.0001), with a decrease in the number of radical prostatectomies and an increase in the number of radical cystectomies and radical nephrectomies/nephroureterectomies performed in 2020. Waiting time decreased by 20% between 2019 and 2020, with the most significant reduction seen after the first wave of the COVID-19 pandemic (July-October 2020), in particular for partial nephrectomy and radical prostatectomy, possibly due to the underdiagnosis of cases. In conclusion, in accordance with recommendations by international urological societies on prioritization strategies for oncological procedures, a higher proportion of surgeries for high-risk tumors was performed in 2020 at our center at the expense of procedures for lower risk diseases; however, future implications for patients' prognosis still need to be determined.
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Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent stromal reaction that has been variably implicated in both tumor growth and tumor suppression. B-lymphocytes have been recently implicated in PDAC progression but their contribution to the characteristic stromal desmoplasia has never been assessed before. In the present work, we aimed to verify whether B-lymphocytes contribute to stromal cell activation in PDAC. CD19+ B-lymphocytes purified from peripheral blood of patients with PDAC were cultivated in the presence of human pancreatic fibroblasts and cancer-associated fibroblasts. Released pro-fibrotic soluble factors and collagen production were assessed by ELISA and Luminex assays. Quantitative RT-PCR was used to assess fibroblast activation in the presence of B cells. The expression of selected pro-fibrotic and inflammatory molecules was confirmed on PDAC tissue sections by multi-color immunofluorescence studies. We herein demonstrate that B-cells from PDAC patients (i) produce the pro-fibrotic molecule PDGF-B and stimulate collagen production by fibroblasts; (ii) express enzymes implicated in extracellular matrix remodeling including LOXL2; and (iii) produce the chemotactic factors CCL-4, CCL-5, and CCL-11. In addition we demonstrate that circulating plasmablasts are expanded in the peripheral blood of patients with PDAC, stimulate collagen production by fibroblasts, and infiltrate pancreatic lesions. Our results indicate that PDAC is characterized by perturbations of the B-cell compartment with expansion of B-lymphocyte subsets that directly contribute to the stromal reaction observed at disease site. These findings provide an additional rationale for modulating B-cell activity in patients with pancreatic cancer.
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Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , B-Lymphocytes , Humans , Pancreas , Stromal CellsABSTRACT
BACKGROUND: IgG4-related disease (IgG4-RD) is a fibroinflammatory condition marked by rapid clinical improvement after selective depletion of B lymphocytes with rituximab. This feature suggests that B cells might participate in fibrogenesis and wound healing. OBJECTIVE: In the present work we aimed to demonstrate that B lymphocytes contribute directly to tissue fibrosis in patients with IgG4-RD. METHODS: Total circulating CD19+ B lymphocytes, naive B cells, memory B cells, or plasmablasts from patients with IgG4-RD were cultivated with human fibroblasts. Profibrotic soluble factors and collagen production in cocultures were assessed by using ELISAs and Luminex assays. RNA sequencing and quantitative RT-PCR were used to assess fibroblast activation in the presence of B cells, as well as induction of profibrotic pathways in B-cell subsets. Relevant profibrotic and inflammatory molecules were confirmed in vitro by using functional experiments and on IgG4-RD tissue sections by using multicolor immunofluorescence studies. RESULTS: B cells from patients with IgG4-RD (1) produced the profibrotic molecule platelet-derived growth factor B and stimulated collagen production by fibroblasts; (2) expressed enzymes implicated in extracellular matrix remodeling, such as lysyl oxidase homolog 2; (3) produced the chemotactic factors CCL4, CCL5, and CCL11; and (4) induced production of these same chemokines by activated fibroblasts. Plasmablasts expressed sets of genes implicated in fibroblast activation and proliferation and therefore represent cells with intrinsic profibrotic properties. CONCLUSION: We have demonstrated that B cells contribute directly to tissue fibrosis in patients with IgG4-RD. These unanticipated profibrotic properties of B lymphocytes, particularly plasmablasts, might be relevant for fibrogenesis in patients with other fibroinflammatory disorders and for wound-healing processes in physiologic conditions.
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B-Lymphocytes/pathology , Fibroblasts/pathology , Immunoglobulin G4-Related Disease/pathology , Pancreas/pathology , B-Lymphocytes/immunology , Cells, Cultured , Coculture Techniques , Collagen/biosynthesis , Fibrosis/immunology , Fibrosis/pathology , Humans , Immunoglobulin G4-Related Disease/immunologySubject(s)
Autoimmune Pancreatitis/diagnostic imaging , Autoimmune Pancreatitis/drug therapy , Methotrexate/administration & dosage , Positron Emission Tomography Computed Tomography/methods , Aged , Autoimmune Pancreatitis/pathology , Female , Follow-Up Studies , Glucocorticoids/administration & dosage , Humans , Immunoglobulin G/immunology , Immunosuppressive Agents/administration & dosage , Injections, Subcutaneous , Male , Remission Induction , Sampling Studies , Treatment OutcomeABSTRACT
Dendritic cells (DCs) initiate adaptive immune responses after their migration to secondary lymphoid organs. The LXR ligands/oxysterols and the RXR ligand 9-cis Retinoic Acid (9-cis RA) were shown to dampen DC migration to lymphoid organs through the inhibition of CCR7 expression. We performed transcriptomics of DCs undergoing maturation in the presence of the LXR ligand 22R-Hydroxycholesterol (22R-HC). The analysis highlighted more than 1500 genes modulated by 22R-HC treatment, including the triggering receptor expressed on myeloid cells (TREM)-1, which was found markedly up-regulated. We tested the effect of other nuclear receptor ligands (NRL) and we reported the induction of TREM-1 following RXR, RAR and VDR activation. From a functional point of view, triggering of TREM-1 induced by retinoids increased TNFα and IL-1ß release, suggesting an active role of NRL-activated TREM-1+ DCs in inflammation-driven diseases, including cancer. Consistently with this hypothesis we detected DCs expressing TREM-1 in pleural effusions and ascites of cancer patients, an observation validated by the induction of TREM-1, LXR and RAR target genes when monocyte-DCs were activated in the presence of tumor-conditioned fluids. Finally, we observed a better control of LLC tumor growth in Trem-1-/- bone marrow chimera mice as compared to wild type chimera mice. Future studies will be necessary to shed light on the mechanism of TREM-1 induction by distinct NRL, and to characterize the role of TREM-1+ DCs in tumor growth.
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OBJECTIVES: Glucocorticoids induce prompt clinical improvement in patients with IgG4-related disease (IgG4-RD) but their mechanisms of action in this specific condition are not fully understood. B lymphocytes appear central to IgG4-RD pathogenesis because B-cell depletion with rituximab leads to swift clinical responses. In the present work we aim to assess the effects of glucocorticoids on B-cell subpopulations in patients with IgG4-RD. METHODS: Fifty patients with active untreated IgG4-RD and 20 healthy controls were enrolled in the present study. Flow cytometry analysis for total circulating CD19+ and CD20+ cells, naïve B cells, memory B cells, plasmablasts, and plasma cells was performed at baseline in all patients, and after 6 months of glucocorticoid treatment in 30 patients. Correlation studies with biomarkers of disease activity were also performed. RESULTS: At baseline, patients with IgG4-RD showed reduced CD19+ and CD20+ B cells compared to healthy controls, but increased circulating plasmablasts and plasma cells. Circulating plasmablasts and plasma cells correlated with clinical and serological biomarkers of IgG4-RD activity. Glucocorticoid-induced disease remission was accompanied by a reduction of naïve B cell count, an increase of memory B cells, and by a depletion of circulating plasmablasts and plasma cells. CD19+ and CD20+ B cells, were not affected by glucocorticoids. CONCLUSIONS: The efficacy of glucocorticoids in IgG4-RD is associated with selective effects on different B-cell subpopulations. Further studies are warranted to fully understand possible perturbations of the naïve and memory B-cell compartments in patients with IgG4-RD.
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B-Lymphocytes/drug effects , Glucocorticoids , Immunoglobulin G4-Related Disease , Glucocorticoids/pharmacology , Glucocorticoids/therapeutic use , Humans , Immunoglobulin G , Immunoglobulin G4-Related Disease/blood , Immunoglobulin G4-Related Disease/drug therapy , Immunoglobulin G4-Related Disease/immunology , Plasma Cells , Remission InductionABSTRACT
BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) promptly responds to glucocorticoids but relapses in a considerable fraction of patients. Reliable biomarkers of flare are currently lacking because the pathophysiology of IgG4-RD remains largely elusive. In the present work, we aimed to identify perturbations of B-cell subpopulations that might predict IgG4-RD relapse. METHODS: Thirty patients were treated with glucocorticoids according to international guidelines. Circulating CD19+ and CD20+ cells, naive B cells, memory B cells, plasmablasts, and plasma cells were measured by flow cytometry at baseline and every 6 months for 2 years after the initiation of corticosteroid therapy. RESULTS: Patients with active untreated IgG4-RD showed significantly reduced CD19+ B cells, CD20+ B cells, and naive B cells compared with healthy subjects (p < 0.05), but significantly expanded plasmablasts and plasma cells (p < 0.01). After 6 months of corticosteroid treatment, all patients achieved clinical improvement. Naive B cells, plasmablasts, and plasma cells significantly decreased compared with disease onset, whereas memory B cells significantly increased compared with baseline (p < 0.01). Increase of memory B cells was observed only in patients who relapsed within 2 years of follow-up, however (HR, 12.24; 2.99 to 50.2; p = 0.0005). In these patients, the relapse rates at 12 and 24 months were 30% and 100%, respectively. No abnormalities of other B-cell subpopulations at disease onset or after 6 months of glucocorticoid treatment were found to predict IgG4-RD relapse at 2 years. CONCLUSIONS: Increase of circulating memory B cells after 6 months of glucocorticoid treatment might predict IgG4-RD relapse.
Subject(s)
B-Lymphocytes/metabolism , Glucocorticoids/therapeutic use , Immunoglobulin G4-Related Disease/blood , Immunoglobulin G4-Related Disease/drug therapy , Aged , B-Lymphocytes/drug effects , Biomarkers/blood , Female , Glucocorticoids/pharmacology , Humans , Immunoglobulin G4-Related Disease/diagnosis , Male , Middle Aged , Prospective Studies , Recurrence , Remission Induction/methods , Risk FactorsABSTRACT
Immunoglobulin G4-related disease (IgG4-RD) is an uncommon disorder that demonstrates characteristic clinicopathologic features including sclerosing lesions with storiform fibrosis, increased IgG4+ plasma cells with an increased IgG4+/IgG+ plasma cell ratio, obliterative phlebitis, and often an increased serum IgG4 level. This review summarizes the characteristic histopathologic and clinical features of IgG4-RD with detailed discussion of the histopathologic characteristics of the most commonly involved anatomic sites. We also present recent advances in our understanding of the pathophysiologic mechanisms of IgG4-RD and discuss updates on the treatment, prognosis, and outcomes of this rare disease, including discussion of the possible association between IgG4-RD and malignancy.
Subject(s)
Autoimmune Diseases/blood , Autoimmune Diseases/diagnosis , Immunoglobulin G/blood , Plasma Cells/cytology , Cholangitis, Sclerosing/blood , Cholangitis, Sclerosing/diagnosis , Dacryocystitis/blood , Dacryocystitis/diagnosis , Diagnosis, Differential , Humans , Kidney Diseases/blood , Kidney Diseases/diagnosis , Lung Diseases/blood , Lung Diseases/diagnosis , Lymphadenopathy/blood , Lymphadenopathy/diagnosis , Pancreatitis/blood , Pancreatitis/diagnosisABSTRACT
OBJECTIVE: An unconventional population of CD4+ signaling lymphocytic activation molecule family member 7-positive (SLAMF7+) cytotoxic effector memory T (TEM ) cells (CD4+ cytotoxic T lymphocytes [CTLs]) has been linked causally to IgG4-related disease (IgG4-RD). Glucocorticoids represent the first-line therapeutic approach in patients with IgG4-RD, but their mechanism of action in this specific condition remains unknown. We undertook this study to determine the impact of glucocorticoids on CD4+ CTLs in IgG4-RD. METHODS: Expression of CD8α, granzyme A, perforin, and SLAMF7 within the effector memory compartment of CD45RO+ (TEM ) and CD45RA+ effector memory T (TEMRA ) CD4+ cells was quantified by flow cytometry in 18 patients with active IgG4-RD, both at baseline and after 6 months of glucocorticoid treatment. Eighteen healthy subjects were studied as controls. Next-generation sequencing of the T cell receptor α- and ß-chain gene was performed on circulating CD4+ CTLs from patients with IgG4-RD before and after treatment and in affected tissues. RESULTS: Circulating CD4+ TEM and TEMRA cells were not expanded in IgG4-RD patients compared to healthy controls. CD4+SLAMF7+ TEM cells (but not TEMRA cells) were significantly increased among IgG4-RD patients. Within CD4+SLAMF7+ TEM cells, CD8α- cells but not CD8αlow cells were elevated in IgG4-RD patients. The same dominant clones of CD8α-CD4+SLAMF7+ TEM cells found in peripheral blood were also identified in affected tissue. CD8α- and CD8αlow CD4+SLAMF7+ TEM cells both expressed cytolytic molecules. Clonally expanded CD8α- but not CD8αlow CD4+SLAMF7+ TEM cells decreased following glucocorticoid-induced disease remission. CONCLUSION: A subset of CD8α-CD4+SLAMF7+ cytotoxic TEM cells is oligoclonally expanded in patients with active IgG4-RD. This TEM cell population contracts following glucocorticoid-induced remission. Further characterization of this cell population may provide prognostic information and targets for therapeutic intervention.