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Kumar S, Petschner P, Gecse K, Torok D, Juhasz G. Acute neuroendocrine challenge elicits enhanced cortisol response and parallel transcriptomic changes in patients with migraine. Pain Rep 2025; 10:e1254. [PMID: 40322023 PMCID: PMC12047896 DOI: 10.1097/pr9.0000000000001254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 12/18/2024] [Accepted: 01/10/2025] [Indexed: 05/08/2025] Open
Abstract
Introduction Migraine is a neurological disorder with recurrent attacks characterized by headaches and sensitivity to stimuli. Stress is a significant trigger for attacks; however, molecular mechanisms of the connection are poorly understood. Objectives To better characterize such mechanisms, we performed a placebo-controlled, double-blind crossover study with 51 participants (21 patients with migraine without aura and 30 healthy controls). Methods Participants received a low-dose citalopram- or placebo challenge on 2 separate days. Prechallenge and postchallenge assessment of cortisol concentrations and transcriptomic changes using RNA-seq was performed from whole blood samples. Analysis of an accidental attack following the citalopram challenge was also conducted. Results Neuroendocrine challenge elicited elevated cortisol concentrations at 30 (P-value = 0.1355) and 70 minutes (P-value = 0.07292) postchallenge in patients with migraine compared with controls. Gene expression analysis showed 10 differentially expressed genes (2 down- and 8 upregulated, P-value ā¤ 0.005) and 10 dysregulated gene sets (P-value ā¤ 0.005). Among them, dysregulated IKBKGP1 and NKRF genes and upregulated protein synthesis and translation, carbohydrate metabolism, and, attack-related, glycosylation can be highlighted. Conclusion Patients with migraine without aura showed an enhanced cortisol response to a neuroendocrine challenge. This was accompanied by a probable suppression of NFĪŗB activity through dysregulation of NKRF and an altered immune function. Upregulated carbohydrate metabolism may reflect the elevated cortisol concentrations' stimulating effects on endothelial glycocalyx, playing a role in NO-induced vasodilation, a trigger for migraine attacks. The results suggest the elevated cortisol response may trigger migraine attacks through altered glycocalyx and immune functions.
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Affiliation(s)
- Sahel Kumar
- Department of Pharmacodynamics, Faculty of Pharmaceutical Sciences, Semmelweis University, Budapest, Hungary
| | - Peter Petschner
- Department of Pharmacodynamics, Faculty of Pharmaceutical Sciences, Semmelweis University, Budapest, Hungary
| | - Kinga Gecse
- Department of Pharmacodynamics, Faculty of Pharmaceutical Sciences, Semmelweis University, Budapest, Hungary
- NAP3.0-SE Neuropsychopharmacology Research Group, Hungarian Brain Research Program, Semmelweis University, Budapest, Hungary
| | - Dora Torok
- Department of Pharmacodynamics, Faculty of Pharmaceutical Sciences, Semmelweis University, Budapest, Hungary
| | - Gabriella Juhasz
- Department of Pharmacodynamics, Faculty of Pharmaceutical Sciences, Semmelweis University, Budapest, Hungary
- NAP3.0-SE Neuropsychopharmacology Research Group, Hungarian Brain Research Program, Semmelweis University, Budapest, Hungary
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Bhatt B, Franco LM. Endogenous glucocorticoids and human immunity: Time to revisit old dogmas. Semin Immunol 2025; 78:101949. [PMID: 40203674 DOI: 10.1016/j.smim.2025.101949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 02/24/2025] [Accepted: 03/22/2025] [Indexed: 04/11/2025]
Abstract
Glucocorticoids (GCs) are steroid hormones with diverse and important roles in the physiologic response to stress. These include permissive and suppressive effects on immunity, which help prepare the organism for future infectious stressors and control the immunological response to a recent stressor, preventing autoimmune damage. The ability of GCs to rapidly suppress an overactive immune system has been harnessed pharmacologically and synthetic GCs have played a central role in the treatment of inflammatory and autoimmune diseases for the past eight decades. Given their importance in clinical medicine, an emphasis on the anti-inflammatory and immunosuppressive effects of synthetic GCs has overshadowed the study of the physiologic roles of endogenous GCs in human immunity. The rising interest in the intersection between neurobiology and immunity, and the development of technologies that facilitate direct experimentation with human cells and tissues, make this an ideal time to critically review existing knowledge on this subject. In this review of the past 100 years of biomedical literature on the effects of endogenous glucocorticoids on human immunity, we summarize existing experimental evidence, reveal key knowledge gaps and misconceptions, and highlight specific areas of opportunity for new research.
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Affiliation(s)
- Brinda Bhatt
- Functional Immunogenomics Section. National Institute of Arthritis and Musculoskeletal and Skin Diseases. National Institutes of Health, Bethesda, MD 20902, USA
| | - Luis M Franco
- Functional Immunogenomics Section. National Institute of Arthritis and Musculoskeletal and Skin Diseases. National Institutes of Health, Bethesda, MD 20902, USA.
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3
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BraĆÆk R. Are corticosteroids in intensive care immunosuppressive? Reflections and hypotheses. Anaesth Crit Care Pain Med 2025; 44:101492. [PMID: 39956476 DOI: 10.1016/j.accpm.2025.101492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 10/18/2024] [Accepted: 11/07/2024] [Indexed: 02/18/2025]
Abstract
This review reconsiders the classification of corticosteroids as immunosuppressants in the management of acute inflammatory conditions in critical care. Despite their widespread use in ARDS and septic shock, the association between corticosteroid therapy and increased infection risk remains contentious. By exploring alternative mechanisms and presenting new hypotheses, this review suggests that the traditional view of corticosteroids as immunosuppressants may be overly simplistic and context dependent.
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Affiliation(s)
- Rayan BraĆÆk
- Service de rĆ©animation chirurgicale polyvalente, Sorbonne University, GRC 29, AP-HP, DMU DREAM and Department of Anaesthesiology and Critical Care, PitiĆ©-SalpĆŖtriĆØre Hospital, 47-83 Bd de l'HĆ“pital, 75013 Paris, France.
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MĆølgaard AK, Gasbjerg KS, Mathiesen O, HƤgi-Pedersen D, Gƶgenur I. Dexamethasone vs. placebo modulation of the perioperative blood immune proteome in patients undergoing total knee arthroplasty. BMC Anesthesiol 2025; 25:136. [PMID: 40119286 PMCID: PMC11927264 DOI: 10.1186/s12871-025-03003-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Accepted: 03/10/2025] [Indexed: 03/24/2025] Open
Abstract
BACKGROUND Pre- and post-operative immune status has gained interest in recent years, as it has been shown to be related to postoperative complications and recovery. The change in immune status has also been known to constitute a large part of the surgical stress response, and it has been speculated that immunomodulatory treatment by glucocorticoids may impact it. Profiling of the impact of specific surgeries and medications on immune status are therefore needed. METHODS We characterized the postoperative blood immune proteome in 83 patients receiving either placebo (nā=ā20) or IV 24 mg dexamethasone (nā=ā60) preoperative before total knee arthroplasty (TKA). The primary outcome was the effect of dexamethasone on total knee arthroplasty surgical stress by comparing postoperative immune proteome in the dexamethasone group and the placebo group. Secondary outcomes were the surgical stress by total knee arthroplasty by comparing pre- to postoperative immune proteome in the placebo group, and the combined effect of surgical stress and dexamethasone by comparing pre- to postoperative immune proteome in the dexamethasone group. Characterization was performed with the Olink Explorer Inflammation panel on blood samples from the biobank for future research collected during the randomized, clinical DEX-2-TKA Trial. Protein change was reported as log2-fold-change and p-values were corrected a.m. Benjamini-Hochberg. RESULTS The surgical stress (placebo) was characterized by a 4.7 log2-fold-change of IL6 (adjusted p-valueā<ā0.01) and up-regulation of central immune signaling pathways and bone marrow mobilization. The combined effect of surgery and dexamethasone showed a less pro-inflammatory profile: IL6 2.5 log2-fold-change (adjusted p-valueā<ā0.01), with decreased signaling for osteoclast activity and innate, immune cell reaction. The effect of dexamethasone showed upregulation of CSF3 (1.55 log2-fold-change, adjusted p-valueā<ā0.01) and an inhibitory effect on both innate and adaptive immune response, immune cell reactivity and formation of extracellular matrix. CONCLUSIONS Preoperative dexamethasone indicated anti-inflammatory properties on both innate and adaptive immune response, while surgery was pro-inflammatory. the combination of total knee arthroplasty and dexamethasone inhibited pathways for osteoclast-activity, indicating possible implications on aseptic prosthesis loosening. Dexamethasone showed strong modulation of the surgical stress response following total knee arthroplasty and future studies must explore the clinical associations of these findings. TRIAL REGISTRATION NCT03506789.
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Affiliation(s)
- Asger K MĆølgaard
- Department of Anaesthesiology, NƦstved, Slagelse and Ringsted Hospitals, Research Centre of Anaesthesiology and Intensive Care Medicine, Slagelse, Denmark.
| | - Kasper S Gasbjerg
- Department of Anaesthesiology, NƦstved, Slagelse and Ringsted Hospitals, Research Centre of Anaesthesiology and Intensive Care Medicine, Slagelse, Denmark
| | - Ole Mathiesen
- Department of Anaesthesiology, Centre of Anaesthesiological Research, Zealand University, KĆøge, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen N, Denmark
| | - Daniel HƤgi-Pedersen
- Department of Anaesthesiology, NƦstved, Slagelse and Ringsted Hospitals, Research Centre of Anaesthesiology and Intensive Care Medicine, Slagelse, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen N, Denmark
| | - Ismail Gƶgenur
- Department of Clinical Medicine, University of Copenhagen, Copenhagen N, Denmark
- Department of Gastrointestinal Surgery, Center of Surgical Science, Zealand University Hospital, KĆøge, Denmark
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Clarke SA, Eng PC, Comninos AN, Lazarus K, Choudhury S, Tsang C, Meeran K, Tan TM, Dhillo WS, Abbara A. Current Challenges and Future Directions in the Assessment of Glucocorticoid Status. Endocr Rev 2024; 45:795-817. [PMID: 38795365 PMCID: PMC11581704 DOI: 10.1210/endrev/bnae016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 05/07/2024] [Accepted: 05/23/2024] [Indexed: 05/27/2024]
Abstract
Glucocorticoid (GC) hormones are secreted in a circadian and ultradian rhythm and play a critical role in maintaining physiological homeostasis, with both excess and insufficient GC associated with adverse effects on health. Current assessment of GC status is primarily clinical, often in conjunction with serum cortisol values, which may be stimulated or suppressed depending on the GC disturbance being assessed. In the setting of extreme perturbations in cortisol levels ie, markedly low or high levels, symptoms and signs of GC dysfunction may be overt. However, when disturbances in cortisol GC status values are less extreme, such as when assessing optimization of a GC replacement regimen, signs and symptoms can be more subtle or nonspecific. Current tools for assessing GC status are best suited to identifying profound disturbances but may lack sensitivity for confirming optimal GC status. Moreover, single cortisol values do not necessarily reflect an individual's GC status, as they are subject to inter- and intraindividual variation and do not take into account the pulsatile nature of cortisol secretion, variation in binding proteins, or local tissue concentrations as dictated by 11beta-hydroxysteroid dehydrogenase activity, as well as GC receptor sensitivity. In the present review, we evaluate possible alternative methods for the assessment of GC status that do not solely rely on the measurement of circulating cortisol levels. We discuss the potential of changes in metabolomic profiles, micro RNA, gene expression, and epigenetic and other novel biomarkers such as growth differentiating factor 15 and osteocalcin, which could in the future aid in the objective classification of GC status.
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Affiliation(s)
- Sophie A Clarke
- Section of Investigative Medicine, Imperial College London, London W12 ONN, UK
- Department of Endocrinology, Imperial College Healthcare NHS Trust, London W6 8RF, UK
| | - Pei Chia Eng
- Section of Investigative Medicine, Imperial College London, London W12 ONN, UK
- Department of Endocrinology, Imperial College Healthcare NHS Trust, London W6 8RF, UK
- Department of Endocrinology, National University of Singapore, Singapore
| | - Alexander N Comninos
- Section of Investigative Medicine, Imperial College London, London W12 ONN, UK
- Department of Endocrinology, Imperial College Healthcare NHS Trust, London W6 8RF, UK
| | - Katharine Lazarus
- Section of Investigative Medicine, Imperial College London, London W12 ONN, UK
- Department of Endocrinology, Imperial College Healthcare NHS Trust, London W6 8RF, UK
| | - Sirazum Choudhury
- Section of Investigative Medicine, Imperial College London, London W12 ONN, UK
- Department of Endocrinology, Imperial College Healthcare NHS Trust, London W6 8RF, UK
| | - Christie Tsang
- Section of Investigative Medicine, Imperial College London, London W12 ONN, UK
| | - Karim Meeran
- Section of Investigative Medicine, Imperial College London, London W12 ONN, UK
- Department of Endocrinology, Imperial College Healthcare NHS Trust, London W6 8RF, UK
| | - Tricia M Tan
- Section of Investigative Medicine, Imperial College London, London W12 ONN, UK
- Department of Endocrinology, Imperial College Healthcare NHS Trust, London W6 8RF, UK
| | - Waljit S Dhillo
- Section of Investigative Medicine, Imperial College London, London W12 ONN, UK
- Department of Endocrinology, Imperial College Healthcare NHS Trust, London W6 8RF, UK
| | - Ali Abbara
- Section of Investigative Medicine, Imperial College London, London W12 ONN, UK
- Department of Endocrinology, Imperial College Healthcare NHS Trust, London W6 8RF, UK
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6
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Sejdic A, Hartling HJ, Gitz Holler J, Klingen GjƦrde L, Matovu Dungu A, Engel MĆøller ME, Svanberg Teglgaard R, Utoft Niemann CU, Brooks PT, Mogensen TH, Weis N, Podlekareva D, Baum JĆørgensen ML, Ortved Gang A, Stampe Hersby D, Hald A, Dam Nielsen S, Lebech AM, Helleberg M, Lundgren J, TrƦholt Franck K, Fischer TK, Harboe ZB, Marquart HV, Rye Ostrowski S, Lindegaard B. Deep immune cell phenotyping and induced immune cell responses at admission stratified by BMI in patients hospitalized with COVID-19: An observational multicenter cohort pilot study. Clin Immunol 2024; 267:110336. [PMID: 39117044 DOI: 10.1016/j.clim.2024.110336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Revised: 07/18/2024] [Accepted: 07/28/2024] [Indexed: 08/10/2024]
Abstract
INTRODUCTION Overweight and obesity are linked to increased hospitalization and mortality in COVID-19 patients. This study aimed to characterize induced immune responses and deep immune cell profiles stratified by BMI in hospitalized COVID-19 patients. METHODS AND RESULTS This observational multicenter cohort pilot study included 122 adult patients with PCR-confirmed COVID-19 in Denmark, stratified by BMI (normal weight, overweight, obese). Inflammation was assessed using TruCultureĀ® and immune cell profiles by flow cytometry with a customized antibody panel (DuraCloneĀ®). Patients with obesity had a more pro-inflammatory phenotype with increased TNF-Ī±, IL-8, IL-17, and IL-10 levels post-T cell stimulation, and altered B cell profiles. Patients with obesity showed higher concentrations of naĆÆve, transitional, and non-isotype switched memory B cells, and plasmablasts compared to normal weight patients and healthy controls. CONCLUSIONS Obesity in hospitalized COVID-19 patients may correlate with elevated pro-inflammatory cytokines, anti-inflammatory IL-10, and increased B cell subset activation, highlighting the need for further studies.
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Affiliation(s)
- Adin Sejdic
- Department of Pulmonary and Infectious Diseases, Copenhagen University Hospital - North Zealand, HillerĆød, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
| | - Hans Jakob Hartling
- Department of Clinical Immunology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Jon Gitz Holler
- Department of Pulmonary and Infectious Diseases, Copenhagen University Hospital - North Zealand, HillerĆød, Denmark
| | - Lars Klingen GjƦrde
- Department of Haematology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Arnold Matovu Dungu
- Department of Pulmonary and Infectious Diseases, Copenhagen University Hospital - North Zealand, HillerĆød, Denmark
| | | | | | - Carsten Utoft Utoft Niemann
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Haematology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Patrick Terrence Brooks
- Department of Clinical Immunology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Trine H Mogensen
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark; Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Nina Weis
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Infectious Diseases, Copenhagen University Hospital - Hvidovre, Copenhagen, Denmark
| | - Daria Podlekareva
- Department of Respiratory Medicine and Infectious Disease, Copenhagen University Hospital - Bispebjerg, Denmark
| | | | - Anne Ortved Gang
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Haematology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Ditte Stampe Hersby
- Department of Haematology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Annemette Hald
- Department of Infectious Diseases, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Susanne Dam Nielsen
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Infectious Diseases, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Anne-Mette Lebech
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Infectious Diseases, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Marie Helleberg
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Infectious Diseases, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Jens Lundgren
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Infectious Diseases, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | | | - Thea K Fischer
- Department of Clinical Research, Copenhagen University Hospital - North Zealand, HillerĆød, Denmark; Department of Public Health, University of Copenhagen, Copenhagen, Denmark
| | - Zitta Barrella Harboe
- Department of Pulmonary and Infectious Diseases, Copenhagen University Hospital - North Zealand, HillerĆød, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Hanne Vibeke Marquart
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Immunology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Sisse Rye Ostrowski
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Immunology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Birgitte Lindegaard
- Department of Pulmonary and Infectious Diseases, Copenhagen University Hospital - North Zealand, HillerĆød, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Braik R, Germain Y, Flet T, Chaba A, Guinot PG, Garreau L, Bar S, Diouf M, Abou-Arab O, Mahjoub Y, Berna P, Dupont H. Intraoperative dexamethasone is associated with a lower risk of respiratory failure in thoracic surgery: Observational cohort study (SURTHODEX). Anaesth Crit Care Pain Med 2024; 43:101386. [PMID: 38710322 DOI: 10.1016/j.accpm.2024.101386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 04/10/2024] [Accepted: 04/12/2024] [Indexed: 05/08/2024]
Abstract
BACKGROUND Postoperative complications, particularly respiratory complications, are of significant clinical concern in patients undergoing elective thoracic surgery. Dexamethasone (DXM), commonly administered to prevent postoperative nausea and vomiting (PONV), has potential anti-inflammatory effects that might be beneficial in reducing these complications. We aimed to investigate whether intraoperative DXM administration could mitigate the occurrence of respiratory complications following elective thoracic surgery. METHODS We conducted a single-center observational study, including patients who underwent elective thoracic surgery from 2012 to 2020. The primary outcome was the onset of acute respiratory failure within 7 days post-surgery. Secondary outcomes encompassed other postoperative complications, duration of hospital stay, and mortality within 30 days post-surgery. An overlap propensity score analysis was employed to estimate the treatment effect. RESULTS We included 1,247 adult patients, 897 who received dexamethasone (DXM) and 350 who served as controls. Intraoperative dexamethasone administration was associated with a significant reduction in respiratory complications with an adjusted relative risk (RR) of 0.65 (95% CI: 0.43-0.97). There was also a significant decline in composite infectious criteria with an adjusted RR of 0.76 (95% CI: 0.63-0.93). Cardiac complications were also assessed as a composite criterion, and a significant reduction was observed (adjusted RR, 0.68; 95% CI, 0.51-0.9). However, there were no association with mechanical complications, mortality within 30 days (adjusted RR of 0.43, 95% CI: 0.17-1.09) or in the length of hospital stay (adjusted RR of 0.85, 95% CI: 0.71-1.02). CONCLUSIONS Dexamethasone administration was associated with a reduction in postoperative respiratory complications. Further prospective studies are needed to confirm these findings.
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Affiliation(s)
- Rayan Braik
- Sorbonne University, GRC 29, AP-HP, DMU DREAM and Department of Anaesthesiology and Critical Care, PitiĆ©-SalpĆŖtriĆØre Hospital, Paris, France.
| | - Yohan Germain
- Poly clinique Saint CĆ“me, Service d'anesthĆ©sie-rĆ©animation, CompiĆØgne, France
| | - Thomas Flet
- Centre hospitalier universitaire d'Amiens, DƩpartement d'anesthƩsie-rƩanimation, Amiens, France
| | - Anis Chaba
- Department of Intensive Care, Austin Hospital, Melbourne, Australia
| | - Piere-GrƩgoire Guinot
- Centre hospitalier universitaire de Dijon, DƩpartement d'anesthƩsie-rƩanimation, Dijon, France
| | - Leo Garreau
- Centre hospitalier universitaire de Bordeaux, DƩpartement d'anesthƩsie-rƩanimation, Bordeaux, France
| | - Stephane Bar
- Centre hospitalier universitaire d'Amiens, DƩpartement d'anesthƩsie-rƩanimation, Amiens, France
| | - Momar Diouf
- Centre hospitalier universitaire d'Amiens, DƩpartement d'anesthƩsie-rƩanimation, Amiens, France
| | - Osama Abou-Arab
- Centre hospitalier universitaire d'Amiens, DƩpartement d'anesthƩsie-rƩanimation, Amiens, France
| | - Yazine Mahjoub
- Centre hospitalier universitaire d'Amiens, DƩpartement d'anesthƩsie-rƩanimation, Amiens, France
| | - Pascal Berna
- Clinique Victor Pauchet, Service de chirurgie thoracique, Amiens France
| | - HervƩ Dupont
- Centre hospitalier universitaire d'Amiens, DƩpartement d'anesthƩsie-rƩanimation, Amiens, France
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8
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Mun SJ, Cho E, Kim HK, Gil WJ, Yang CS. Enhancing acute inflammatory and sepsis treatment: superiority of membrane receptor blockade. Front Immunol 2024; 15:1424768. [PMID: 39081318 PMCID: PMC11286478 DOI: 10.3389/fimmu.2024.1424768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Accepted: 07/03/2024] [Indexed: 08/02/2024] Open
Abstract
Conditions such as acute pancreatitis, ulcerative colitis, delayed graft function and infections caused by a variety of microorganisms, including gram-positive and gram-negative organisms, increase the risk of sepsis and therefore mortality. Immune dysfunction is a characterization of sepsis, so timely and effective treatment strategies are needed. The conventional approaches, such as antibiotic-based treatments, face challenges such as antibiotic resistance, and cytokine-based treatments have shown limited efficacy. To address these limitations, a novel approach focusing on membrane receptors, the initiators of the inflammatory cascade, is proposed. Membrane receptors such as Toll-like receptors, interleukin-1 receptor, endothelial protein C receptor, Ī¼-opioid receptor, triggering receptor expressed on myeloid cells 1, and G-protein coupled receptors play pivotal roles in the inflammatory response, offering opportunities for rapid regulation. Various membrane receptor blockade strategies have demonstrated efficacy in both preclinical and clinical studies. These membrane receptor blockades act as early stage inflammation modulators, providing faster responses compared to conventional therapies. Importantly, these blockers exhibit immunomodulatory capabilities without inducing complete immunosuppression. Finally, this review underscores the critical need for early intervention in acute inflammatory and infectious diseases, particularly those posing a risk of progressing to sepsis. And, exploring membrane receptor blockade as an adjunctive treatment for acute inflammatory and infectious diseases presents a promising avenue. These novel approaches, when combined with antibiotics, have the potential to enhance patient outcomes, particularly in conditions prone to sepsis, while minimizing risks associated with antibiotic resistance and immune suppression.
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Affiliation(s)
- Seok-Jun Mun
- Department of Bionano Engineering, Hanyang University, Seoul, Republic of Korea
- Center for Bionano Intelligence Education and Research, Hanyang University, Ansan, Republic of Korea
| | - Euni Cho
- Department of Bionano Engineering, Hanyang University, Seoul, Republic of Korea
- Center for Bionano Intelligence Education and Research, Hanyang University, Ansan, Republic of Korea
| | - Hyo Keun Kim
- Center for Bionano Intelligence Education and Research, Hanyang University, Ansan, Republic of Korea
- Department of Molecular and Life Science, Hanyang University, Ansan, Republic of Korea
| | - Woo Jin Gil
- Center for Bionano Intelligence Education and Research, Hanyang University, Ansan, Republic of Korea
- Department of Molecular and Life Science, Hanyang University, Ansan, Republic of Korea
| | - Chul-Su Yang
- Center for Bionano Intelligence Education and Research, Hanyang University, Ansan, Republic of Korea
- Department of Molecular and Life Science, Hanyang University, Ansan, Republic of Korea
- Department of Medicinal and Life Science, Hanyang University, Ansan, Republic of Korea
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9
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Heemelaar JC, Louisa M, Neilan TG. Treatment of Immune Checkpoint Inhibitor-associated Myocarditis. J Cardiovasc Pharmacol 2024; 83:384-391. [PMID: 37506676 PMCID: PMC10830893 DOI: 10.1097/fjc.0000000000001456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 07/08/2023] [Indexed: 07/30/2023]
Abstract
ABSTRACT Immune checkpoint inhibitors (ICIs) are a form immunotherapy where the negative regulators of host immunity are targeted, thereby leveraging the own immune system. ICIs have significantly improved cancer survival in several advanced malignancies, and there are currently more than 90 different cancer indications for ICIs. Most patients develop immune-related adverse events during ICI therapy. Most are mild, but a small subset of patients will develop severe and potentially fatal immune-related adverse events. A serious cardiovascular complication of ICI therapy is myocarditis. Although the incidence of myocarditis is low, mortality rates of up to 50% have been reported. The mainstay of ICI-associated myocarditis treatment is high-dose corticosteroids. Unfortunately, half of patients with myocarditis do not show clinical improvement after corticosteroid treatment. Also, high doses of corticosteroids may adversely impact cancer outcomes. There is an evidence gap in the optimal second-line treatment strategy. Currently, there is a paradigm shift in second-line treatment taking place from empirical corticosteroid-only strategies to either intensified initial immunosuppression where corticosteroids are combined with another immunosuppressant or targeted therapies directed at the pathophysiology of ICI myocarditis. However, the available evidence to support these novel strategies is limited to observational studies and case reports. The aim of this review is to summarize the literature, guidelines, and future directions on the pharmacological treatment of ICI myocarditis.
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Affiliation(s)
- Julius C Heemelaar
- Cardiovascular Imaging Research Center (CIRC), Department of Cardiology and Radiology, Massachusetts General Hospital, Boston, MA; and
- Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Maria Louisa
- Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Tomas G Neilan
- Cardiovascular Imaging Research Center (CIRC), Department of Cardiology and Radiology, Massachusetts General Hospital, Boston, MA; and
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10
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Quiroga-Garza ME, Ruiz-Lozano RE, Rodriguez-Gutierrez LA, Khodor A, Ma S, Komai S, Mohamed-Noriega K, Perez VL. Lessons Learned From Ocular Graft versus Host Disease: An Ocular Surface Inflammatory Disease of Known Time of Onset. Eye Contact Lens 2024; 50:212-221. [PMID: 38518064 DOI: 10.1097/icl.0000000000001082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/03/2024] [Indexed: 03/24/2024]
Abstract
ABSTRACT The ocular surface inflammatory disorders (OSIDs) comprise a group of conditions characterized by persistent inflammation of the ocular surface and adnexal tissues. Systemic autoimmune diseases and hypersensitivity reactions cause them, and, if left untreated, can result in severe inflammatory dry eye, corneal damage, and vision loss. Ocular graft-versus-host disease (oGVHD) forms part of the ocular surface inflammatory disease umbrella. It is a condition occurring after allogeneic hematopoietic stem cell or bone marrow transplantation, usually in chronic graft-versus-host disease. oGVHD can virtually affect any ocular adnexal tissue, especially the meibomian glands, and cause persistent inflammation, tissue fibrosis, and subsequent chronic, severe dry eye disease. Among the OSIDs, oGVHD has the particularity that it has a "time zero," meaning we know when the disease started. As such, preclinical models have leveraged this to investigate the molecular mechanisms involved in the damage oGVHD causes to the ocular surface. In oGVHD, establishing a "time zero" allows for predicting the clinical course and establishing adequate treatment. This is also possible because the inflammatory infiltration occurs in ocular surface tissues, which are readily accessible. Using oGVHD, we might be able to understand the immune response mechanisms in other OSIDs better (i.e., Sjƶgren syndrome, Stevens-Johnson syndrome, among others). This review presents an up-to-date overview of the pathogenesis, clinical presentation, and treatment of oGVHD. In addition, we will discuss the value of the "time zero" concept in the study of oGVHD.
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Affiliation(s)
- Manuel E Quiroga-Garza
- Department of Ophthalmology (M.E.Q.-G., R.E.R.-L., S.M., S.K., V.L.P.), Foster Center for Ocular Immunology at Duke Eye Center, Duke University School of Medicine, Durham, NC; Bascom Palmer Eye Institute (M.E.Q.-G., R.E.R.-L., L.A.R.-G., A.K., S.M., S.K., V.L.P.), University of Miami, Miami, FL; and Department of Ophthalmology (K.M.-N.), University Hospital and Faculty of Medicine, Autonomous University of Nuevo LeĆ³n (UANL), Monterrey, Mexico
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11
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Escoe B, Fogleman BM, Sherertz R. Epiglottitis Strikes Twice: A Case of Adult Recurrent Epiglottitis. Cureus 2024; 16:e56940. [PMID: 38665746 PMCID: PMC11044190 DOI: 10.7759/cureus.56940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 03/26/2024] [Indexed: 04/28/2024] Open
Abstract
Epiglottitis is an uncommon condition in adults, and recurrent episodes are rare. We report a 58-year-old male who had a second episode of epiglottitis nine years after his first. Our patient's immunologic profile obtained during his hospitalization revealed a significantly low absolute cluster of differentiation 4+ (CD4+) T lymphocyte count of 77 cells/mcL and a low immunoglobulin G (IgG) level of 635 mg/dL. Our patient was successfully managed with broad-spectrum antibiotics and corticosteroids. Given the known ability of short-term corticosteroids and acute inflammation's effect on lymphocyte populations, the significance of these laboratory values remains unclear due to our patient's unwillingness to undergo further diagnostic testing following discharge from our facility. We have considered multiple underlying etiologies for our patient's predisposition to developing this rare, recurrent, infectious manifestation; however, the exact cause is yet to be fully elucidated.
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Affiliation(s)
- Brooke Escoe
- Department of Internal Medicine, Grand Strand Regional Medical Center, Myrtle Beach, USA
| | - Brody M Fogleman
- Department of Internal Medicine, Edward Via College of Osteopathic Medicine - Carolinas, Spartanburg, USA
| | - Robert Sherertz
- Department of Internal Medicine, Grand Strand Regional Medical Center, Myrtle Beach, USA
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12
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de FrƩminville A, Saad M, Sage E, Pricopi C, Fischler M, Trillat B, Salze B, Pascreau T, Vasse M, VallƩe A, Guen ML, Fessler J. Relationship Between Preoperative Inflammation Ratios Derived From Preoperative Blood Cell Count and Postoperative Pulmonary Complications in Patients Undergoing Lobectomy: A Single-Center Observational Study. J Cardiothorac Vasc Anesth 2024; 38:482-489. [PMID: 38016820 DOI: 10.1053/j.jvca.2023.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 10/19/2023] [Accepted: 11/01/2023] [Indexed: 11/30/2023]
Abstract
OBJECTIVE Evaluation of the association of inflammatory cell ratios, especially neutrophil-to-lymphocyte ratio (NLR), based on preoperative complete blood counts, with postoperative complications in lobectomy surgery. DESIGN This was a retrospective monocentric cohort study. SETTING The study was conducted at Foch University Hospital in Suresnes, France. PARTICIPANTS Patients having undergone a scheduled lobectomy from January 2018 to September 2021. INTERVENTIONS There were no interventions. MEASUREMENTS AND MAIN RESULTS The authors studied 208 consecutive patients. Preoperative NLR, monocyte-to-lymphocyte ratio, platelet-to-lymphocyte ratio, systemic inflammation index, systemic inflammation response index, and aggregate inflammation systemic index were calculated. Median and (IQR) of NLR was 2.67 (1.92-3.69). No statistically significant association was observed between any index and the occurrence of at least one major postoperative complication, which occurred in 37% of the patients. Median postoperative length of stay was 7 (5-10) days. None of the ratios was associated with prolonged length of stay (LOS), defined as a LOS above the 75th percentile. CONCLUSIONS The results suggested that simple available inflammatory ratios are not useful for the preoperative identification of patients at risk of postoperative major complications in elective lobectomy surgery.
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Affiliation(s)
- Amaury de FrƩminville
- Department of Anesthesiology, HƓpital Foch, Suresnes, France, and UniversitƩ Versailles-Saint-Quentin-en-Yvelines, Versailles, France
| | - Mary Saad
- Department of Anesthesia, Institut Curie, PSL Research University, Saint Cloud, France, and PSL Research University, INSERM, Institut Curies, Saint Cloud, France
| | - Edouard Sage
- Department of Thoracic Surgery and Lung Transplantation, HƓpital Foch, Suresnes, France, and UniversitƩ Versailles-Saint-Quentin-en-Yvelines, Versailles, France
| | - Ciprian Pricopi
- Department of Thoracic Surgery and Lung Transplantation, HƓpital Foch, Suresnes, France, and UniversitƩ Versailles-Saint-Quentin-en-Yvelines, Versailles, France
| | - Marc Fischler
- Department of Anesthesiology, HƓpital Foch, Suresnes, France, and UniversitƩ Versailles-Saint-Quentin-en-Yvelines, Versailles, France.
| | - Bernard Trillat
- Department of Information Systems, HĆ“pital Foch, Suresnes, France
| | - Benjamin Salze
- Department of Anesthesiology, HƓpital Foch, Suresnes, France, and UniversitƩ Versailles-Saint-Quentin-en-Yvelines, Versailles, France
| | - Tiffany Pascreau
- Department of Clinical Biology, HĆ“pital Foch, Suresnes, France, and Department of Epidemiology-Data-Biostatistics, Delegation of Clinical Research and Innovation, HĆ“pital Foch, Suresnes, France
| | - Marc Vasse
- Department of Clinical Biology, HĆ“pital Foch, Suresnes, France, and Department of Epidemiology-Data-Biostatistics, Delegation of Clinical Research and Innovation, HĆ“pital Foch, Suresnes, France
| | - Alexandre VallƩe
- Department of Epidemiology and Public Health, HĆ“pital Foch, Suresnes, France
| | - Morgan Le Guen
- Department of Anesthesiology, HƓpital Foch, Suresnes, France, and UniversitƩ Versailles-Saint-Quentin-en-Yvelines, Versailles, France
| | - Julien Fessler
- Department of Anesthesiology, HƓpital Foch, Suresnes, France, and UniversitƩ Versailles-Saint-Quentin-en-Yvelines, Versailles, France
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13
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Suda K, Shimizu T, Ishizuka M, Miyashita S, Niki M, Shibuya N, Hachiya H, Shiraki T, Matsumoto T, Sakuraoka Y, Mori S, Iso Y, Takagi K, Aoki T, Kubota K. Total Steroid Intake is Associated With Hospital Mortality in Patients With Pan-Peritonitis due to Colorectal Perforation. Am Surg 2023; 89:4764-4771. [PMID: 36301856 DOI: 10.1177/00031348221136576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/06/2023]
Abstract
BACKGROUND Patients with pan-peritonitis (PP) due to colorectal perforation have high mortality rate because colorectal perforation causes septic shock. The association between total steroid intake (TSI) and hospital mortality of such patients is not clear. METHODS One hundred forty-two patients who underwent surgery for PP due to colorectal perforation were reviewed. Patients were divided into two groups by 8000 mg of TSI. The cut-off value of TSI was determined using a receiver operating characteristic curve for hospital mortality. RESULTS The cut-off value of TSI for hospital mortality was 8000 mg. Patients with TSI>8000 mg had high rate of hemodialysis, hospital mortality, and elevated neutrophil ratio (>95%) compared with those with TSIā¤8000 mg. Multivariate analyses revealed that TSI (>8000/ā¤8000, mg) (OR, 9.669; 95% CI, 1.011-92.49; P = .049) was significantly associated with hospital mortality as well as bleeding volume (>1000/ā¤1000, mL) (OR, 26.08; 95% CI, 3.566-190.4; P = .001), lymphocyte ratio (ā¤4/>4, %) (OR, 7.988; 95% CI, 1.498-42.58; P = .015) and C-reactive protein (ā¤7.5/>7.5, mg/dL) (OR, 41.66; 95% CI, 4.784-33.33; P = .001). DISCUSSION There was a significant association between TSI and hospital mortality in patients with PP due to colorectal perforation as well as intraoperative bleeding and systemic inflammatory markers.
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Affiliation(s)
- Kotaro Suda
- Second Department of Surgery, Dokkyo Medical University, Tochigi, Japan
| | - Takayuki Shimizu
- Second Department of Surgery, Dokkyo Medical University, Tochigi, Japan
| | - Mitsuru Ishizuka
- Second Department of Surgery, Dokkyo Medical University, Tochigi, Japan
| | - Shotaro Miyashita
- Second Department of Surgery, Dokkyo Medical University, Tochigi, Japan
| | - Maiko Niki
- Second Department of Surgery, Dokkyo Medical University, Tochigi, Japan
| | - Norisuke Shibuya
- Second Department of Surgery, Dokkyo Medical University, Tochigi, Japan
| | - Hiroyuki Hachiya
- Second Department of Surgery, Dokkyo Medical University, Tochigi, Japan
| | - Takayuki Shiraki
- Second Department of Surgery, Dokkyo Medical University, Tochigi, Japan
| | | | - Yuhki Sakuraoka
- Second Department of Surgery, Dokkyo Medical University, Tochigi, Japan
| | - Shozo Mori
- Second Department of Surgery, Dokkyo Medical University, Tochigi, Japan
| | - Yukihiro Iso
- Second Department of Surgery, Dokkyo Medical University, Tochigi, Japan
| | - Kazutoshi Takagi
- Second Department of Surgery, Dokkyo Medical University, Tochigi, Japan
| | - Taku Aoki
- Second Department of Surgery, Dokkyo Medical University, Tochigi, Japan
| | - Keiichi Kubota
- Second Department of Surgery, Dokkyo Medical University, Tochigi, Japan
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14
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Jovanovic M, Sabovic M. Refractory drug-induced systemic small-vessel vasculitis with two varied extracutaneous manifestations: a case report and review of the literature. J Med Case Rep 2023; 17:470. [PMID: 37885023 PMCID: PMC10605860 DOI: 10.1186/s13256-023-04174-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 09/11/2023] [Indexed: 10/28/2023] Open
Abstract
BACKGROUND Clopidogrel and ticagrelor are rarely reported to cause vasculitis via drug hypersensitivity reaction, largely mediated by T cells and immunoglobulin E (IgE). Despite therapeutic advances, the etiology of refractory vasculitides remains incompletely understood. Recently, (non)immunological mechanisms bypassing T cells and IgE have been proposed to explain resistance to standard immunosuppressants. Herein, we report a case of refractory drug-induced systemic small-vessel vasculitis with varied extracutaneous manifestations and incorporate multiple sources of data to provide detailed accounts of complex (non)immunological phenomena involved in this case. Study objectives are to provide an insight about rare presentations of commonly used drugs, upgrade the pathophysiological concepts of drug-induced vasculitis, raise need for further investigation to define causes and risk factors for refractory vasculitis, and discuss most of the current knowledge suggesting novel therapeutic approaches to treat this vasculitis. To our knowledge, this is the first case of the two flares of systemic small-vessel vasculitis in a single patient in response to clopidogrel and ticagrelor exposure, respectively. However, this report is limited by attribution/observer bias. CASE PRESENTATION We herein report a 24-year-old Caucasian male student with a medical history of mild seasonal allergic rhinoconjunctivitis, tension-type headaches, posttraumatic arterial stenosis, and previous exposure to ibuprofen, acetylsalicylic acid, and mRNA coronavirus disease 2019 (COVID-19) vaccine who suffered largely from acute urticaria and dyspnea after 20 days of acetylsalicylic acid and clopidogrel introduction. A skin punch biopsy confirmed leukocytoclastic vasculitis. Serologic antibody testing, complement analysis, microbiologic testing, and cancer biomarkers revealed no abnormalities. Regarding the patient's medical history, both acetylsalicylic acid and clopidogrel were exchanged for ticagrelor. Furthermore, the addition of naproxen, cyclosporine, bilastine, prednisolone, and montelukast resulted in complete recovery. After 7 days, diarrhea and hematuria occurred. Urinalysis and computed tomography showed reversible proteinuria with gross hematuria and hypodense changes in kidney medulla, respectively, associated with discontinuation of ticagrelor and naproxen. In addition, the patient recovered completely without any immunosuppression up-titration. CONCLUSIONS This case highlights the role of clopidogrel and ticagrelor as possible triggering agents for systemic small-vessel vasculitis and offers an insight into novel therapeutic strategies for refractory vasculitides. Further research is needed to build on the findings of a current report.
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Affiliation(s)
- Mark Jovanovic
- Department of Internal Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia.
| | - Miso Sabovic
- Department of Angiology, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
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15
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Kaba K, Purnell B, Liu Y, Royall PG, Alhnan MA. Computer numerical control (CNC) carving as an on-demand point-of-care manufacturing of solid dosage form: A digital alternative method for 3D printing. Int J Pharm 2023; 645:123390. [PMID: 37683980 DOI: 10.1016/j.ijpharm.2023.123390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 09/03/2023] [Accepted: 09/05/2023] [Indexed: 09/10/2023]
Abstract
Computer numerical control (CNC) carving is a widely used method of industrial subtractive manufacturing of wood, plastics, and metal products. However, there have been no previous reports of applying this approach to manufacture medicines. In this work, the novel method of tablet production using CNC carving is introduced for the first time. This report provides a proof-of-concept for applying subtractive manufacturing as an alternative to formative (powder compression) and additive (3D printing) manufacturing for the on-demand production of solid dosage forms. This exemplar manufacturing approach was employed to produce patient-specific hydrocortisone (HC) tablets for the treatment of children with congenital adrenal hyperplasia. A specially made drug-polymer cast based on polyethene glycol (PEG 6,000) and hydroxypropyl cellulose was produced using thermal casting. The cast was used as a workpiece and digitally carved using a small-scale 3-dimensional (3D) CNC carving. To establish the ability of this new approach to provide an accurate dose of HC, four different sizes of CNC carved tablet were manufactured to achieve HC doses of 2.5, 5, 7.5 and 10 mg with a relative standard deviation of the tablet weight in the range of 3.69-4.79%. In addition, batches of 2.5 and 5 mg HC tablets met the British Pharmacopeia standards for weight uniformity. Thermal analysis and X-ray powder diffraction indicated that the model drug was in amorphous form. In addition, HPLC analysis indicated a level of purity of 96.5 Ā± 1.1% of HC. In addition, the process yielded mechanically strong cylindrical tablets with tensile strength ranging from 0.49 to 1.6 MPa and friability values of <1%, whilst maintaining an aesthetic look. In vitro, HC release from the CNC-carved tablets was slower with larger tablet sizes and higher binder contents. This is the first report on applying CNC carving in the pharmaceutical context of producing solid dosage forms. The work showed the potential of this technology as an alternative method for the on-demand manufacturing of patient-specific dosage forms.
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Affiliation(s)
- Kazim Kaba
- Centre for Pharmaceutical Medicine Research, Institute of Pharmaceutical Science, King's College London, London SE1 9NH, United Kingdom
| | - Bryn Purnell
- Centre for Pharmaceutical Medicine Research, Institute of Pharmaceutical Science, King's College London, London SE1 9NH, United Kingdom
| | - Yujing Liu
- Centre for Pharmaceutical Medicine Research, Institute of Pharmaceutical Science, King's College London, London SE1 9NH, United Kingdom
| | - Paul G Royall
- Centre for Pharmaceutical Medicine Research, Institute of Pharmaceutical Science, King's College London, London SE1 9NH, United Kingdom
| | - Mohamed A Alhnan
- Centre for Pharmaceutical Medicine Research, Institute of Pharmaceutical Science, King's College London, London SE1 9NH, United Kingdom.
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16
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Zhong H, Huan X, Zhao R, Su M, Yan C, Song J, Xi J, Zhao C, Luo F, Luo S. Peripheral immune landscape for hypercytokinemia in myasthenic crisis utilizing single-cell transcriptomics. J Transl Med 2023; 21:564. [PMID: 37620910 PMCID: PMC10464341 DOI: 10.1186/s12967-023-04421-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 08/07/2023] [Indexed: 08/26/2023] Open
Abstract
BACKGROUND Myasthenia gravis (MG) is the most prevalent autoimmune disorder affecting the neuromuscular junction. A rapid deterioration in respiratory muscle can lead to a myasthenic crisis (MC), which represents a life-threatening condition with high mortality in MG. Multiple CD4+ T subsets and hypercytokinemia have been identified in the peripheral pro-inflammatory milieu during the crisis. However, the pathogenesis is complicated due to the many types of cells involved, leaving the underlying mechanism largely unexplored. METHODS We conducted single-cell transcriptomic and immune repertoire sequencing on 33,577 peripheral blood mononuclear cells (PBMCs) from two acetylcholine receptor antibody-positive (AChRā+) MG patients during MC and again three months post-MC. We followed the Scanpy workflow for quality control, dimension reduction, and clustering of the single-cell data. Subsequently, we annotated high-resolution cell types utilizing transfer-learning models derived from publicly available single-cell immune datasets. RNA velocity calculations from unspliced and spliced mRNAs were applied to infer cellular state progression. We analyzed cell communication and MG-relevant cytokines and chemokines to identify potential inflammation initiators. RESULTS We identified a unique subset of monocytes, termed monocytes 3 (FCGR3B+ monocytes), which exhibited significant differential expression of pro-inflammatory signaling pathways during and after the crisis. In line with the activated innate immune state indicated by MC, a high neutrophil-lymphocyte ratio (NLR) was confirmed in an additional 22 AChRā+āMC patients in subsequent hemogram analysis and was associated with MG-relevant clinical scores. Furthermore, oligoclonal expansions were identified in age-associated B cells exhibiting high autoimmune activity, and in CD4+ and CD8+ T cells demonstrating persistent T exhaustion. CONCLUSIONS In summary, our integrated analysis of single-cell transcriptomics and TCR/BCR sequencing has underscored the role of innate immune activation which is associated with hypercytokinemia in MC. The identification of a specific monocyte cluster that dominates the peripheral immune profile may provide some hints into the etiology and pathology of MC. However, future functional studies are required to explore causality.
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Affiliation(s)
- Huahua Zhong
- Huashan Rare Disease Center and Department of Neurology, Huashan Hospital, Shanghai Medical College, National Center for Neurological Disorders, Fudan University, Shanghai, 200040, China
| | - Xiao Huan
- Huashan Rare Disease Center and Department of Neurology, Huashan Hospital, Shanghai Medical College, National Center for Neurological Disorders, Fudan University, Shanghai, 200040, China
| | - Rui Zhao
- Huashan Rare Disease Center and Department of Neurology, Huashan Hospital, Shanghai Medical College, National Center for Neurological Disorders, Fudan University, Shanghai, 200040, China
| | - Manqiqige Su
- Huashan Rare Disease Center and Department of Neurology, Huashan Hospital, Shanghai Medical College, National Center for Neurological Disorders, Fudan University, Shanghai, 200040, China
| | - Chong Yan
- Huashan Rare Disease Center and Department of Neurology, Huashan Hospital, Shanghai Medical College, National Center for Neurological Disorders, Fudan University, Shanghai, 200040, China
| | - Jie Song
- Huashan Rare Disease Center and Department of Neurology, Huashan Hospital, Shanghai Medical College, National Center for Neurological Disorders, Fudan University, Shanghai, 200040, China
| | - Jianying Xi
- Huashan Rare Disease Center and Department of Neurology, Huashan Hospital, Shanghai Medical College, National Center for Neurological Disorders, Fudan University, Shanghai, 200040, China
| | - Chongbo Zhao
- Huashan Rare Disease Center and Department of Neurology, Huashan Hospital, Shanghai Medical College, National Center for Neurological Disorders, Fudan University, Shanghai, 200040, China
| | - Feifei Luo
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China.
| | - Sushan Luo
- Huashan Rare Disease Center and Department of Neurology, Huashan Hospital, Shanghai Medical College, National Center for Neurological Disorders, Fudan University, Shanghai, 200040, China.
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17
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Miyase T, Mochizuki K, Kokuzawa S, Shiraki I, Murata K, Sakaguchi H. Vitreous Humor Positive for DNA of Human Herpesvirus 7 in Eye With Ocular Toxoplasmosis. Cureus 2023; 15:e41237. [PMID: 37529513 PMCID: PMC10387729 DOI: 10.7759/cureus.41237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/29/2023] [Indexed: 08/03/2023] Open
Abstract
The aim of this article was to report our findings in a case of infectious uveitis in which the DNAs of both Toxoplasma gondii and human herpesvirus 7 (HHV-7) were detected in the vitreous fluid. A 31-year-old Brazilian man was examined in our hospital with a one-month history of blurred vision (20/40) in the right eye. He had been diagnosed with ocular toxoplasmosis of the right eye at nine years of age and has had repeated relapses. Because of the persistent vitreous opacities and refractoriness to acetylspiramycin and betamethasone, pars plana vitrectomy was performed. Multiplex PCR of the vitreous sample demonstrated the DNAs for both T. gondii and HHV-7. Trimethoprim/sulfamethoxazole with prednisone was prescribed. Six months after the beginning of the therapy, a resolution of the retinochoroiditis was found and the vision recovered to 20/25. Two months later, we performed a pars plana vitrectomy for an epiretinal membrane. The DNAs of both T. gondii and HHV-7 were not detected in the vitreous fluid and the epiretinal membrane. After continued treatment, the best-corrected visual acuity (BCVA) in the right eye improved to 20/16 and the metamorphopsia was reduced. It is inferred from this work that HHV-7 reactivation can activate refractory infectious uveitis in patients with chronic ocular toxoplasmosis.
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Affiliation(s)
- Taishi Miyase
- Ophthalmology, Gifu University, Gifu, JPN
- Ophthalmology, Ogaki Municipal Hospital, Ogaki, JPN
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18
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Greenstein AE, Hunt HJ. The glucocorticoid receptor modulator relacorilant reverses the immunosuppressive effects of cortisol. Int Immunopharmacol 2023; 120:110312. [PMID: 37230031 DOI: 10.1016/j.intimp.2023.110312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 04/26/2023] [Accepted: 05/07/2023] [Indexed: 05/27/2023]
Abstract
Cortisol, an endogenous glucocorticoid receptor (GR) agonist, controls a broad transcriptional program that affects T-cell activation, pro-inflammatory cytokine secretion, apoptosis, and immune-cell trafficking. The degree to which endogenous cortisol blunts the anti-tumor immune response checkpoint inhibitors stimulate had not been assessed. We addressed this question using relacorilant, a selective GR modulator (SGRM) that competitively antagonizes the effects of cortisol activity. GR expression in human tumor and immune cells positively correlated with PD-L1 expression and tumor infiltration of Th2 and Treg cells, and negatively correlated with Th1-cell infiltration. In vitro, cortisol inhibited, and relacorilant restored, T-cell activation and pro-inflammatory cytokine secretion in human peripheral blood mononuclear cells. In the ovalbumin-expressing EG7 and MC38 immune-competent tumor models, relacorilant significantly improved anti-PD-1 antibody efficacy and showed favorable effects on antigen-specific T-cells and systemic TNFĪ± and IL-10. These data characterize the broad immunosuppressive effects of endogenous cortisol and highlight the potential of combining an SGRM with an immune checkpoint inhibitor.
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Affiliation(s)
| | - Hazel J Hunt
- Corcept Therapeutics, 149 Commonwealth Dr, Menlo Park, CA 94025, USA.
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19
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Desai N, Pradhan V, Chougule D, Tiwari S, Mandke C, Yadav RM, Athvale A, Kawle J, Pai V, Pawaskar S, Kharkar H, Bhosale S, Parab A, Ansari S, Kumar KH, Mhashal S, Redkar N, Madkaikar M. Perturbations of immune landscape in COVID-19 associated mucormycosis. Mycoses 2023; 66:226-236. [PMID: 36380699 DOI: 10.1111/myc.13546] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 11/11/2022] [Indexed: 11/17/2022]
Abstract
BACKGROUND A rise in secondary fungal infections during the COVID-19 pandemic necessitates a deeper understanding of the associated immunological perturbations. OBJECTIVES To evaluate the clinical and immunological characteristics observed in patients with COVID-19 associated mucormycosis (CAM) infection. PATIENTS/ METHODS Cases of mucormycosis with or post-COVID-19 infection were compared with cases of acute COVID-19 and convalescent COVID-19. Lymphocyte subsets, cytokines and other laboratory markers were compared between the groups. RESULTS The frequency of proposed risk factors for CAM was diabetes mellitus (77%), recent history of steroid use (69%) and hypoxia during COVID-19 infection (52%). Iron metabolism was dysregulated in CAM patients with low TIBC and total iron. Further, CAM was accompanied with lymphopenia with drastic reduction in B cell counts; however, plasmablasts were not altered. Further, CAM patients had low immunoglobulin levels and antibodies specific to mucor peptide did not increase in CAM suggesting dysfunction in B-cell response. There was increase in activated effector cytotoxic CD8 T cells and NK cells in CAM compared with COVID-19 infection and healthy controls. Among T helper cells, Tregs were reduced and Th-1 frequency was increased in CAM compared with COVID-19 infection. A distinct cytokine signature was evident in CAM with increase in IL-1Ī², IFN-Ī³, IL-6, IL-22, IL-17A, IL-10, IL-2, IL-8, IL-7, IL-21 and GM-CSF. CONCLUSION This is the first study on immunophenotyping in CAM suggesting the need for long-term monitoring of B-cell function after SARS-CoV-2 in patients with dysregulated glycaemic control and the possible benefit of therapeutic supplementation with intravenous immunoglobulins in CAM.
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Affiliation(s)
- Nidhi Desai
- Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research- National Institute of Immunohaematology, Mumbai, India
| | - Vandana Pradhan
- Department of Clinical & Experimental Immunology, Indian Council of Medical Research- National Institute of Immunohaematology, Mumbai, India
| | - Durga Chougule
- Department of Clinical & Experimental Immunology, Indian Council of Medical Research- National Institute of Immunohaematology, Mumbai, India
| | - Smrati Tiwari
- Department of Medicine, G.S. Medical College, King Edward Memorial Hospital, Mumbai, India
| | - Charuta Mandke
- Department of Ophthalmology, HBT Medical College and Dr R N Cooper Hospital, Mumbai, India
| | - Reetika Malik Yadav
- Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research- National Institute of Immunohaematology, Mumbai, India
| | - Amita Athvale
- Department of Pulmonary Medicine, G.S. Medical College, King Edward Memorial Hospital, Mumbai, India
| | - Juhi Kawle
- Department of Medicine, G.S. Medical College, King Edward Memorial Hospital, Mumbai, India
| | - Vinayak Pai
- Department of Medicine, G.S. Medical College, King Edward Memorial Hospital, Mumbai, India
| | - Swapnal Pawaskar
- Department of Clinical & Experimental Immunology, Indian Council of Medical Research- National Institute of Immunohaematology, Mumbai, India
| | - Harshada Kharkar
- Department of Clinical & Experimental Immunology, Indian Council of Medical Research- National Institute of Immunohaematology, Mumbai, India
| | - Snehal Bhosale
- Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research- National Institute of Immunohaematology, Mumbai, India
| | - Ankita Parab
- Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research- National Institute of Immunohaematology, Mumbai, India
| | - Shazia Ansari
- Department of Ophthalmology, HBT Medical College and Dr R N Cooper Hospital, Mumbai, India
| | - Kinnera Harish Kumar
- Department of Otorhinolaryngology, HBT Medical College and Dr R N Cooper Hospital, Mumbai, India
| | - Shashikant Mhashal
- Department of Otolaryngology, HBT Medical College and Dr R N Cooper Hospital, Mumbai, India
| | - Neelam Redkar
- Department of Medicine, HBT Medical College and Dr R N Cooper Hospital, Mumbai, India
| | - Manisha Madkaikar
- Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research- National Institute of Immunohaematology, Mumbai, India
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20
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Mustafa SS. Steroid-induced secondary immune deficiency. Ann Allergy Asthma Immunol 2023:S1081-1206(23)00011-X. [PMID: 36681272 DOI: 10.1016/j.anai.2023.01.010] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/29/2022] [Accepted: 01/06/2023] [Indexed: 01/19/2023]
Abstract
Despite their widespread clinical use, oral corticosteroids (OCSs) are well known to be associated with a myriad of adverse effects, including immunosuppression. By inhibiting transcription factors and affecting leukocyte function, prolonged OCS use leads to significant CD4 lymphopenia and often a decrease in serum immunoglobulin (Ig)G. Conversely, OCS use has minimal impact on circulating B cell, serum IgM, or serum IgA levels. Although there is a paucity of literature, individuals treated with prolonged OCS seem to typically maintain humoral response to various vaccinations despite hypogammaglobinemia, but this area warrants additional research, especially in the setting of the coronavirus disease 2019 pandemic. Individuals treated with prolonged OCS use are most at risk for opportunistic infections, especially those with underlying malignancy and history of bone marrow transplant. Risk mitigation strategies to decrease infectious complication with OCS use include limiting the dose and duration of therapy, appropriately completing a full vaccination series, consideration for passive immunization, and prophylaxis against opportunistic infections.
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Affiliation(s)
- S Shahzad Mustafa
- Rochester Regional Health, Rochester, New York; University of Rochester School of Medicine & Dentistry, Rochester, New York.
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21
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CardosoāVigueros C, von Blumenthal T, RĆ¼ckert B, Rinaldi AO, Tan G, Dreher A, Radzikowska U, Menz G, SchmidāGrendelmeier P, Akdis CA, Sokolowska M. Leukocyte redistribution as immunological biomarker of corticosteroid resistance in severe asthma. Clin Exp Allergy 2022; 52:1183-1194. [PMID: 35305052 PMCID: PMC9790739 DOI: 10.1111/cea.14128] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 02/15/2022] [Accepted: 03/07/2022] [Indexed: 01/26/2023]
Abstract
BACKGROUND Earlier studies have suggested that the leukocyte redistribution can be considered as an immunological marker of the clinical response to corticosteroids (CS), representing an easy measurable potential biomarker in severe asthma. OBJECTIVE The aim of this study was to determinate the utility of the leukocyte redistribution as a biomarker of disease heterogeneity in patients with severe asthma and as a bioindicator of potential CS resistance. METHODS We developed an unbiased clustering approach based on the clinical data and the flow cytometry results of peripheral blood leukocyte phenotypes of 142 patients with severe asthma before and after systemic CS administration. RESULTS Based on the differences in the blood count eosinophils, neutrophils and lymphocytes, together with the flow cytometry measurements of basic T cell, B cell and NK cell subpopulations before and after systemic CS administration, we identified two severe asthma clusters, which differed in the cell frequencies, response to CS and atopy status. Patients in cluster 1 had higher frequency of blood eosinophils at baseline, were sensitized to less allergens and had better steroid responsiveness, measured as the pronounced leukocyte redistribution after the administration of systemic CS. Patients in cluster 2 were determined by the higher frequency of B-cells and stronger IgE sensitization status to the multiple allergens. They also displayed higher steroid resistance, as the clinical correlate for the lower leukocyte redistribution after administration of systemic CS. CONCLUSION The flow cytometry-based profiling of the basic populations of immune cells in the blood and its analysis before and after systemic corticosteroid administration could improve personalized treatment approaches in patients with severe asthma.
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Affiliation(s)
| | - Tobias von Blumenthal
- Swiss Institute of Allergy and Asthma Research (SIAF)University of ZurichDavosSwitzerland
| | - Beate RĆ¼ckert
- Swiss Institute of Allergy and Asthma Research (SIAF)University of ZurichDavosSwitzerland
| | - Arturo O. Rinaldi
- Swiss Institute of Allergy and Asthma Research (SIAF)University of ZurichDavosSwitzerland
| | - Ge Tan
- Swiss Institute of Allergy and Asthma Research (SIAF)University of ZurichDavosSwitzerland
| | - Anita Dreher
- Christine KĆ¼hne ā Center for Allergy Research and Education (CKāCARE)DavosSwitzerland
| | - Urszula Radzikowska
- Swiss Institute of Allergy and Asthma Research (SIAF)University of ZurichDavosSwitzerland,Christine KĆ¼hne ā Center for Allergy Research and Education (CKāCARE)DavosSwitzerland
| | | | - Peter SchmidāGrendelmeier
- Department of AllergyUniversity Hospital of ZurichZurichSwitzerland,Christine KĆ¼hne ā Center for Allergy Research and Education (CKāCARE)DavosSwitzerland
| | - Cezmi A. Akdis
- Swiss Institute of Allergy and Asthma Research (SIAF)University of ZurichDavosSwitzerland,Christine KĆ¼hne ā Center for Allergy Research and Education (CKāCARE)DavosSwitzerland
| | - Milena Sokolowska
- Swiss Institute of Allergy and Asthma Research (SIAF)University of ZurichDavosSwitzerland,Christine KĆ¼hne ā Center for Allergy Research and Education (CKāCARE)DavosSwitzerland
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22
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Ishii N, Hatakeyama S, Yoneyama T, Tanaka R, Narita T, Fujita N, Okamoto T, Yamamoto H, Yoneyama T, Hashimoto Y, Ohyama C. Humoral response after SARS-CoV-2 mRNA vaccination in patients with prostate cancer using steroids. Urol Oncol 2022; 40:451.e1-451.e8. [PMID: 36008254 PMCID: PMC9339980 DOI: 10.1016/j.urolonc.2022.07.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 07/18/2022] [Accepted: 07/25/2022] [Indexed: 01/13/2023]
Abstract
OBJECTIVES The effect of concomitant steroid use on the antibody response to a SARS-CoV-2 vaccine in patients with prostate cancer (PC) remains unknown. We aimed to evaluate the rates of antispike immunoglobulin G (IgG) antibody response to the BNT162b2 mRNA vaccine in patients with PC using steroids. METHODS This cross-sectional study conducted from June 21, 2021 to January 5, 2022 included 215 patients with PC who received the second dose of the BNT162b2 mRNA vaccine at least 7 days before the measurement of titers of IgG antibodies against the receptor-binding domain of SARS-CoV-2 spike (S) protein. We compared the rate of anti-SARS-CoV-2 S IgG ā„15 U/mL between patients with or without concomitant steroid use. RESULTS Of 215, we identified 33 patients who had concomitant steroid use. Of these, 12 and 21 patients were metastatic castration-sensitive PC and castration-resistant PC (CRPC), respectively. Patients with concomitant steroid use had a significantly lower rate of antibody titer ā„15 U/mL than those without steroid use (82% vs. 95%, PāÆ=āÆ0.021). Patients with CRPC with concomitant steroid use (n =21) also had a lower rate of antibody titer ā„15 U/mL (71%) than those without steroid use (93%, PāÆ=āÆ0.051), although this was not statistically different. Increased number of systemic treatments administered after diagnosis of CRPC (3 lines or more) were significantly associated with antibody titers <15 U/mL (97% vs. 77%, P <0.001). CONCLUSION The humoral response to the BNT162b2 mRNA vaccine was significantly lower in patients with concomitant steroid use. Anti-SARS-CoV-2 S antibody titers were affected by CRPC status, the accumulation of post-CRPC treatments, and steroid use.
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Affiliation(s)
- Noritaka Ishii
- Department of Urology, Hirosaki University School of Medicine, Hirosaki, Aomori, Japan
| | - Shingo Hatakeyama
- Department of Advanced Blood Purification Therapy, Hirosaki University School of Medicine, Hirosaki, Aomori,, Japan.
| | - Tohru Yoneyama
- Department of Glycotechnology, Center for Advanced Medical Research, Hirosaki University School of Medicine, Hirosaki, Aomori Japan
| | - Ryuma Tanaka
- Department of Urology, Hirosaki University School of Medicine, Hirosaki, Aomori, Japan
| | - Takuma Narita
- Department of Urology, Hirosaki University School of Medicine, Hirosaki, Aomori, Japan
| | - Naoki Fujita
- Department of Urology, Hirosaki University School of Medicine, Hirosaki, Aomori, Japan
| | - Teppei Okamoto
- Department of Urology, Hirosaki University School of Medicine, Hirosaki, Aomori, Japan
| | - Hayato Yamamoto
- Department of Urology, Hirosaki University School of Medicine, Hirosaki, Aomori, Japan
| | - Takahiro Yoneyama
- Department of Advanced Transplant and Regenerative Medicine, Hirosaki University School of Medicine, Hirosaki, Aomori, Japan
| | - Yasuhiro Hashimoto
- Department of Urology, Hirosaki University School of Medicine, Hirosaki, Aomori, Japan
| | - Chikara Ohyama
- Department of Urology, Hirosaki University School of Medicine, Hirosaki, Aomori, Japan; Department of Advanced Blood Purification Therapy, Hirosaki University School of Medicine, Hirosaki, Aomori,, Japan; Department of Advanced Transplant and Regenerative Medicine, Hirosaki University School of Medicine, Hirosaki, Aomori, Japan
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23
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Zinellu A, Mangoni AA. A systematic review and meta-analysis of the association between the neutrophil, lymphocyte, and platelet count, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio and COVID-19 progression and mortality. Expert Rev Clin Immunol 2022; 18:1187-1202. [PMID: 36047369 DOI: 10.1080/1744666x.2022.2120472] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS Severe manifestations of coronavirus disease 2019 (COVID-19) are associated with alterations in blood cells that regulate immunity, inflammation, and hemostasis. We conducted an updated systematic review and meta-analysis of the association between the neutrophil, lymphocyte, and platelet count, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR), and COVID-19 progression and mortality. METHODS A systematic literature search was conducted in PubMed, Web of Science, and Scopus for studies published between January 2020 and June 2022. RESULTS In 71 studies reporting the investigated parameters within 48 hours of admission, higher NLR (HR 1.21, 95% CI 1.16 to 1.27, p < 0.0001), relative neutrophilia (HR 1.62, 95% CI 1.46 to 1.80, p < 0.0001), relative lymphopenia (HR 1.62, 95% CI 1.27 to 2.08, p < 0.001), and relative thrombocytopenia (HR 1.74, 95% CI 1.36 to 2.22, p < 0.001), but not PLR (p = 0.11), were significantly associated with disease progression and mortality. Between-study heterogeneity was large-to-extreme. The magnitude and direction of the effect size were not modified in sensitivity analysis. CONCLUSIONS NLR and neutrophil, lymphocyte, and platelet count significantly discriminate COVID-19 patients with different progression and survival outcomes. (PROSPERO registration number: CRD42021267875).
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Affiliation(s)
- Angelo Zinellu
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Arduino A Mangoni
- Discipline of Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Adelaide, Australia.,Department of Clinical Pharmacology, Flinders Medical Centre, Southern Adelaide Local Health Network, Adelaide, Australia
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24
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Chitadze G, Kabelitz D. Immune surveillance in glioblastoma: role of the NKG2D system and novel cell-based therapeutic approaches. Scand J Immunol 2022; 96:e13201. [PMID: 35778892 DOI: 10.1111/sji.13201] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 06/28/2022] [Accepted: 06/30/2022] [Indexed: 11/27/2022]
Abstract
Glioblastoma, formerly known as Glioblastoma multiforme (GBM) is the most frequent and most aggressive brain tumor in adults. The brain is an immunopriviledged organ and the blood brain barrier shields the brain from immune surveillance. In this review we discuss the composition of the immunosuppressive tumor micromilieu and potential immune escape mechanisms in GBM. In this respect, we focus on the role of the NKG2D receptor/ligand system. NKG2D ligands are frequently expressed on GBM tumor cells and can activate NKG2D-expressing killer cells including NK cells and Ī³Ī“ T cells. Soluble NKG2D ligands, however, contribute to tumor escape from immunological attack. We also discuss the current immunotherapeutic strategies to improve the survival of GBM patients. Such approaches include the modulation of the NKG2D receptor/ligand system, the application of checkpoint inhibitors, the adoptive transfer of ex vivo expanded and/or modified immune cells, or the application of antibodies and antibody constructs to target cytotoxic effector cells in vivo. In view of the multitude of pursued strategies, there is hope for improved overall survival of GBM patients in the future.
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Affiliation(s)
- Guranda Chitadze
- Unit for Hematological Diagnostics, Department of Internal Medicine II
| | - Dieter Kabelitz
- Institute of Immunology, University Hospital Schleswig-Holstein (UKSH) Campus Kiel, Kiel, Germany
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25
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Prolonged SARS-CoV-2 infection associated with long-term corticosteroid use in a patient with impaired B-cell immunity. J Infect Chemother 2022; 28:971-974. [PMID: 35184976 PMCID: PMC8828425 DOI: 10.1016/j.jiac.2022.02.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/13/2022] [Accepted: 02/07/2022] [Indexed: 01/12/2023]
Abstract
Corticosteroids are widely used to treat severe COVID-19, but in immunocompromised individuals, who are susceptible to persistent infection, long term corticosteroid use may delay viral clearance. We present a case of prolonged SARS-CoV-2 infection in a man with significantly impaired B-cell immunity due to non-Hodgkin lymphoma which had been treated with rituximab. SARS-CoV-2 shedding persisted, despite treatment with remdesivir. Viral sequencing confirmed the persistence of the same viral strain, ruling out the possibility of reinfection. Although SARS-CoV-2 IgG, IgA and IgM remained negative throughout the treatment period, after reduction of the corticosteroid dose, PCR became negative. Long-term corticosteroid treatment, especially in immunocompromised individuals, may result in suppression of cell-mediated immunity and prolonged SARS-CoV-2 infection.
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26
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Prolonged shedding of infectious viruses with haplotype switches of SARS-CoV-2 in an immunocompromised patient. J Infect Chemother 2022; 28:1001-1004. [PMID: 35430092 PMCID: PMC8986523 DOI: 10.1016/j.jiac.2022.04.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 03/20/2022] [Accepted: 04/03/2022] [Indexed: 12/14/2022]
Abstract
A concern has been raised that the persistent COVID-19 infection in an immunocompromised host can be the source of the SARS-CoV-2 variants. This is the case of a 61-year-old man in complete remission of a follicular lymphoma after six cycles of rituximab and bendamustine with additional two cycles of rituximab completed eight months prior to the episode of COVID-19 pneumonia. The patient's respiratory failure was long-lasting, and required mechanical ventilation until day 75. Acquired immunity tested negative throughout the observational period. The viral RNA was detectable until day 100 while the infectious virus was isolated until day 79. Seven haplotypes were identified and the non-synonymous mutations accumulated in the spike gene which included E484Q and S494P. In the management of COVID-19 cases with suppressed immune statuses, initial evaluation of existing immunity and monitoring for infectiousness throughout the clinical course including the convalescent stage may be necessary.
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27
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ErbaÅ Ä°M, Hajikhanova A, Besci Ć, Acinikli KY, Demir K, Bƶber E, Abacı A. Initial neutrophil/lymphocyte and lymphocyte/monocyte ratios can predict future insulin need in newly diagnosed type 1 diabetes mellitus. J Pediatr Endocrinol Metab 2022; 35:593-602. [PMID: 35304840 DOI: 10.1515/jpem-2021-0564] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Accepted: 02/19/2022] [Indexed: 01/03/2023]
Abstract
OBJECTIVES The exact mechanism of partial clinical remission in type 1 diabetes mellitus (T1DM) has not been elucidated yet. The severity of the inflammation at the time of diagnosis may affect the occurrence or duration of this phase. We aimed to investigate the relationship between hematological inflammatory parameters at the time of diagnosis in T1DM and (i) daily insulin requirement during the follow-up and (ii) the presence of partial clinical remission period, which was determined according to insulin dose-adjusted HbA1c levels. METHODS A single-center retrospective study was conducted, including children who were diagnosed with T1DM, were positive for at least one autoantibody, and were followed up for one year in our clinic between 2010 and 2020. RESULTS Sixty-eight patients (55.9% female, 64.7% prepubertal) were included in the study, whose mean age was 8.4 Ā± 4.2 years. A total of 38 patients (55.9%) had partial clinical remission. None of the initial hematological indices were associated with the occurrence of partial remission. Initial neutrophil/lymphocyte ratio (NLR) and derived-NLR (d-NLR) levels were significantly lower (p=0.011 and 0.033, respectively) and lymphocyte/monocyte ratio (LMR) levels were significantly higher (p=0.005) in patients who showed an insulin requirement of <0.5 IU/kg/day at the 3rd month after diagnosis. CONCLUSIONS Initial hematological parameters were not found as a predictor of partial clinical remission period in T1DM in children. However, a lower NLR and d-NLR, or a higher LMR at the time of diagnosis can be used as an indicator of a low daily insulin need at the 3rd month of T1DM.
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Affiliation(s)
- Ä°brahim Mert ErbaÅ
- Division of Pediatric Endocrinology, Faculty of Medicine, Dokuz EylĆ¼l University, Ä°zmir, Turkey
| | - AygĆ¼n Hajikhanova
- Department of Pediatrics, Faculty of Medicine, Dokuz EylĆ¼l University, Ä°zmir, Turkey
| | - Ćzge Besci
- Division of Pediatric Endocrinology, Faculty of Medicine, Dokuz EylĆ¼l University, Ä°zmir, Turkey
| | - KĆ¼bra YĆ¼ksek Acinikli
- Division of Pediatric Endocrinology, Faculty of Medicine, Dokuz EylĆ¼l University, Ä°zmir, Turkey
| | - Korcan Demir
- Division of Pediatric Endocrinology, Faculty of Medicine, Dokuz EylĆ¼l University, Ä°zmir, Turkey
| | - Ece Bƶber
- Division of Pediatric Endocrinology, Faculty of Medicine, Dokuz EylĆ¼l University, Ä°zmir, Turkey
| | - Ayhan Abacı
- Division of Pediatric Endocrinology, Faculty of Medicine, Dokuz EylĆ¼l University, Ä°zmir, Turkey
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28
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Skirecki T, Adamik B, Frostell C, PasÅawska U, ZieliÅski S, Glatzel-PluciÅska N, Olbromski M, DziÄgiel P, Gozdzik W. Compartment-Specific Differences in the Activation of Monocyte Subpopulations Are Not Affected by Nitric Oxide and Glucocorticoid Treatment in a Model of Resuscitated Porcine Endotoxemic Shock. J Clin Med 2022; 11:2641. [PMID: 35566768 PMCID: PMC9100570 DOI: 10.3390/jcm11092641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/03/2022] [Accepted: 05/06/2022] [Indexed: 11/16/2022] Open
Abstract
Inhaled nitric oxide (iNO) remains one of the treatment modalities in shock, and in addition to its vasoactive properties, iNO exerts immunomodulatory effects. We used a porcine model of endotoxemia with shock resuscitation (control) and additional treatment with iNO and a steroid (treatment group). After 20 h, bone marrow (BM), peripheral blood (PB), and bronchoalveolar lavage fluid (BALF) were collected to analyze the immunophenotype and mitochondrial membrane potential (ĪĻ) in three subsets of monocytes. In both groups, SLA-DR expression decreased twofold on the circulating CD14+CD163+ and CD14āCD163+ monocytes, while it did not change on the CD14+CD163+. ĪĻ increased only in the CD14āCD163+ subpopulation (0.8 vs. 2.0, p < 0.001). The analysis of compartment-specific alterations showed that nearly 100% of BALF CD14+CD163+ and CD14āCD163+ monocytes expressed SLA-DR, and it was higher compared to PB (32% and 20%, p < 0.0001) and BM (93% and 67%, p < 0.001, respectively) counterparts. BALF CD14+CD163+ had a threefold higher ĪĻ than PB and BM monocytes, while the ĪĻ of the other subsets was highest in PB monocytes. We confirmed the compartmentalization of the monocyte response during endotoxemic shock, which highlights the importance of studying tissue-resident cells in addition to their circulating counterparts. The iNO/steroid treatment did not further impair monocyte fitness.
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Affiliation(s)
- Tomasz Skirecki
- Laboratory of Flow Cytometry, Centre of Postgraduate Medical Education Marymoncka 99/103, 01-813 Warsaw, Poland
| | - Barbara Adamik
- Clinical Department of the Anaesthesiology and Intensive Therapy, Wroclaw Medical University, 50-367 Wroclaw, Poland; (B.A.); (S.Z.); (W.G.)
| | - Claes Frostell
- Department of Anaesthesia and Intensive Care, Karolinska Institutet, Danderyd Hospital, 182 57 Stockholm, Sweden;
| | - Urszula PasÅawska
- Institute of Veterinary Medicine, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland;
- Department of Internal Medicine and Clinic for Horses, Dogs and Cats, Wroclaw University of Environmental and Life Sciences, 50-375 Wroclaw, Poland
| | - StanisÅaw ZieliÅski
- Clinical Department of the Anaesthesiology and Intensive Therapy, Wroclaw Medical University, 50-367 Wroclaw, Poland; (B.A.); (S.Z.); (W.G.)
| | - Natalia Glatzel-PluciÅska
- Department of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-367 Wroclaw, Poland; (N.G.-P.); (M.O.); (P.D.)
| | - Mateusz Olbromski
- Department of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-367 Wroclaw, Poland; (N.G.-P.); (M.O.); (P.D.)
| | - Piotr DziÄgiel
- Department of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-367 Wroclaw, Poland; (N.G.-P.); (M.O.); (P.D.)
- Department of Physiotherapy, University School of Physical Education, 51-612 Wroclaw, Poland
| | - Waldemar Gozdzik
- Clinical Department of the Anaesthesiology and Intensive Therapy, Wroclaw Medical University, 50-367 Wroclaw, Poland; (B.A.); (S.Z.); (W.G.)
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29
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Lidou-Renault V, Baudouin E, Courtois-Amiot P, Bianco C, Esnault H, Rouet A, Baque M, Tomeo C, Rainone A, Thietart S, Veber R, Ayache C, Pepin M, Lafuente-Lafuente C, Duron E, Cailleaux PE, Haguenauer D, LemariƩ N, Paillaud E, Raynaud-Simon A, Thomas C, Boddaert J, Zerah L, Vallet H. Corticosteroid therapy in COVID-19 associated with in-hospital mortality in geriatric patients: a propensity matched cohort study. J Gerontol A Biol Sci Med Sci 2022; 77:1352-1360. [PMID: 35395678 PMCID: PMC9129112 DOI: 10.1093/gerona/glac084] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Indexed: 12/15/2022] Open
Abstract
Background Few data are available on the prognosis of older patients who received corticosteroids for COVID-19. We aimed to compare the in-hospital mortality of geriatric patients hospitalized for COVID-19 who received corticosteroids or not. Methods We conducted a multicentric retrospective cohort study in 15 acute COVID-19 geriatric wards in the Paris area from March to April 2020 and November 2020 to May 2021. We included all consecutive patients aged 70 years and older who were hospitalized with confirmed COVID-19 in these wards. Propensity score and multivariate analyses were used. Results Of the 1 579 patients included (535 received corticosteroids), the median age was 86 (interquartile range 81ā91) years, 56% of patients were female, the median Charlson Comorbidity Index (CCI) was 2.6 (interquartile range 1ā4), and 64% of patients were frail (Clinical Frailty Score 5ā9). The propensity score analysis paired 984 patients (492 with and without corticosteroids). The in-hospital mortality was 32.3% in the matched cohort. On multivariate analysis, the probability of in-hospital mortality was increased with corticosteroid use (odds ratio [OR] = 2.61 [95% confidence interval (CI) 1.63ā4.20]). Other factors associated with in-hospital mortality were age (OR = 1.04 [1.01ā1.07], CCI (OR = 1.18 [1.07ā1.29], activities of daily living (OR = 0.85 [0.75ā0.95], oxygen saturation < 90% on room air (OR = 2.15 [1.45ā3.17], C-reactive protein level (OR = 2.06 [1.69ā2.51], and lowest lymphocyte count (OR = 0.49 [0.38ā0.63]). Among the 535 patients who received corticosteroids, 68.3% had at least one corticosteroid side effect, including delirium (32.9%), secondary infections (32.7%), and decompensated diabetes (14.4%). Conclusions In this multicentric matched-cohort study of geriatric patients hospitalized for COVID-19, the use of corticosteroids was significantly associated with in-hospital mortality.
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Affiliation(s)
| | | | - Pauline Courtois-Amiot
- Assistance Publique-HƓpitaux de Paris (APHP), UniversitƩ de Paris, HƓpital Bichat, Department of Geriatric Medicine, Paris, France
| | - Celine Bianco
- Assistance Publique-HƓpitaux de Paris (APHP), Sorbonne UniversitƩ, HƓpital Saint Antoine, Department of Geriatric Medicine, Paris, France
| | - HĆ©lĆØne Esnault
- Assistance Publique-HƓpitaux de Paris (APHP), UniversitƩ de Paris, HƓpital Bichat, Department of Geriatric Medicine, Paris, France
| | - Audrey Rouet
- Assistance Publique-HƓpitaux de Paris (APHP), Sorbonne UniversitƩ, HƓpital Tenon, Department of Geriatric Medicine, Paris, France
| | - Margaux Baque
- Assistance Publique-HƓpitaux de Paris (APHP), Sorbonne UniversitƩ, HƓpital Saint Antoine, Department of Geriatric Medicine, Paris, France
- Sorbonne UniversitĆ©, INSERM UMR1135, Centre dāimmunologie et des Maladies Infectieuses, Paris, France
| | - Charlotte Tomeo
- Assistance Publique-HƓpitaux de Paris (APHP), Sorbonne UniversitƩ, HƓpital Rothschild, Department of Geriatric Medicine, Paris, France
| | - Antonio Rainone
- Assistance Publique-HƓpitaux de Paris (APHP), Sorbonne UniversitƩ, HƓpital Charles Foix, Department of Geriatric Medicine, Ivry Sur Seine, France
| | - Sara Thietart
- Assistance Publique-HĆ“pitaux de Paris (APHP), Sorbonne UniversitĆ©, HĆ“pital PitiĆ© SalpĆŖtriĆØre, Department of Geriatric Medicine, Paris, France
| | - Romain Veber
- Assistance Publique-HƓpitaux de Paris (APHP), Sorbonne UniversitƩ, HƓpital Rothschild, Department of Geriatric Medicine, Paris, France
| | - Clementine Ayache
- Assistance Publique-HƓpitaux de Paris (APHP), Sorbonne UniversitƩ, HƓpital Rothschild, Department of Geriatric Medicine, Paris, France
| | - Marion Pepin
- Assistance Publique-HƓpitaux de Paris (APHP), HƓpital Ambroise ParƩ, Department of Geriatric Medicine, Boulogne, Billancourt, France
- UniversitƩ de Versailles Saint-Quentin en Yvelines, UniversitƩ Paris-Saclay, INSERM, CESP, Clinical Epidemiology, Villejuif, France
| | - Carmelo Lafuente-Lafuente
- Assistance Publique-HƓpitaux de Paris (APHP), Sorbonne UniversitƩ, HƓpital Charles Foix, Department of Geriatric Medicine, Ivry Sur Seine, France
| | - Emmanuelle Duron
- Assistance Publique-HĆ“pitaux de Paris (APHP), University hospital of Paris-Saclay, Department of Geriatric Medicine, Paul Brousse Hospital, Villejuif, France
- UniversitĆ© Paris-Saclay, INSERM 1178, CESP, Ćquipe MOODS, Le Kremlin-BicĆŖtre, France
| | - Pierre-Emmanuel Cailleaux
- Assistance Publique-HĆ“pitaux de Paris (APHP), HĆ“pital Louis Mourier, Department of Geriatric Medicine, Colombes, France
| | - Didier Haguenauer
- Assistance Publique-HĆ“pitaux de Paris (APHP), HĆ“pital Louis Mourier, Department of Geriatric Medicine, Colombes, France
| | - NadĆØge LemariĆ©
- Assistance Publique-HƓpitaux de Paris (APHP), Sorbonne UniversitƩ, HƓpital Tenon, Department of Geriatric Medicine, Paris, France
| | - Elena Paillaud
- Assistance Publique-HƓpitaux de Paris (APHP), UniversitƩ de Paris, Paris Cancer Institute CARPEM, Department of Geriatric Medicine, HƓpital EuropƩen Georges Pompidou, Paris, France
| | - Agathe Raynaud-Simon
- Assistance Publique-HƓpitaux de Paris (APHP), UniversitƩ de Paris, HƓpital Bichat, Department of Geriatric Medicine, Paris, France
| | - Caroline Thomas
- Assistance Publique-HƓpitaux de Paris (APHP), Sorbonne UniversitƩ, HƓpital Saint Antoine, Department of Geriatric Medicine, Paris, France
| | - Jacques Boddaert
- Sorbonne UniversitĆ©, INSERM UMR1135, Centre dāimmunologie et des Maladies Infectieuses, Paris, France
- Assistance Publique-HĆ“pitaux de Paris (APHP), Sorbonne UniversitĆ©, HĆ“pital PitiĆ© SalpĆŖtriĆØre, Department of Geriatric Medicine, Paris, France
| | - LorĆØne Zerah
- Assistance Publique-HĆ“pitaux de Paris (APHP), Sorbonne UniversitĆ©, HĆ“pital PitiĆ© SalpĆŖtriĆØre, Department of Geriatric Medicine, Paris, France
- Sorbonne UniversitĆ©, INSERM, Institut Pierre Louis dāĆpidĆ©miologie et de SantĆ© Publique, IPLESP, Paris, France
| | - HĆ©lĆØne Vallet
- Address correspondence to: HĆ©lĆØne Vallet, MD, PhD, Assistance Publique-HĆ“pitaux de Paris (APHP), Sorbonne UniversitĆ©, HĆ“pital Saint Antoine, Department of Geriatric Medicine, 184 rue du Faubourg Saint Antoine, Paris 75012, France. E-mail:
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30
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Rovina N, Koukaki E, Romanou V, Ampelioti S, Loverdos K, Chantziara V, Koutsoukou A, Dimopoulos G. Fungal Infections in Critically Ill COVID-19 Patients: Inevitabile Malum. J Clin Med 2022; 11:2017. [PMID: 35407625 PMCID: PMC8999371 DOI: 10.3390/jcm11072017] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 03/28/2022] [Accepted: 03/31/2022] [Indexed: 02/04/2023] Open
Abstract
Patients with severe COVID-19 belong to a population at high risk of invasive fungal infections (IFIs), with a reported incidence of IFIs in critically ill COVID-19 patients ranging between 5% and 26.7%. Common factors in these patients, such as multiple organ failure, immunomodulating/immunocompromising treatments, the longer time on mechanical ventilation, renal replacement therapy or extracorporeal membrane oxygenation, make them vulnerable candidates for fungal infections. In addition to that, SARS-CoV2 itself is associated with significant dysfunction in the patient's immune system involving both innate and acquired immunity, with reduction in both CD4+ T and CD8+ T lymphocyte counts and cytokine storm. The emerging question is whether SARS-CoV-2 inherently predisposes critically ill patients to fungal infections or the immunosuppressive therapy constitutes the igniting factor for invasive mycoses. To approach the dilemma, one must consider the unique pathogenicity of SARS-CoV-2 with the deranged immune response it provokes, review the well-known effects of immunosuppressants and finally refer to current literature to probe possible causal relationships, synergistic effects or independent risk factors. In this review, we aimed to identify the prevalence, risk factors and mortality associated with IFIs in mechanically ventilated patients with COVID-19.
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Affiliation(s)
- Nikoletta Rovina
- 1st Department of Respiratory Medicine, Medical School, National and Kapodistrian University of Athens and āSotiriaā Chest Disease Hospital, 152 Mesogeion Ave, 11527 Athens, Greece; (E.K.); (V.R.); (S.A.); (K.L.); (V.C.); (A.K.); (G.D.)
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31
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Goyal NA, Coulis G, Duarte J, Farahat PK, Mannaa AH, Cauchii J, Irani T, Araujo N, Wang L, Wencel M, Li V, Zhang L, Greenberg SA, Mozaffar T, Villalta SA. Immunophenotyping of Inclusion Body Myositis Blood T and NK Cells. Neurology 2022; 98:e1374-e1383. [PMID: 35131904 PMCID: PMC8967422 DOI: 10.1212/wnl.0000000000200013] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 01/03/2022] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND AND OBJECTIVES To evaluate the therapeutic potential of targeting highly differentiated T cells in patients with inclusion body myositis (IBM) by establishing high-resolution mapping of killer cell lectin-like receptor subfamily G member 1 (KLRG1+) within the T and natural killer (NK) cell compartments. METHODS Blood was collected from 51 patients with IBM and 19 healthy age-matched donors. Peripheral blood mononuclear cells were interrogated by flow cytometry using a 12-marker antibody panel. The panel allowed the delineation of naive T cells (Tn), central memory T cells (Tcm), 4 stages of effector memory differentiation T cells (Tem 1-4), and effector memory re-expressing CD45RA T cells (TemRA), as well as total and subpopulations of NK cells based on the differential expression of CD16 and C56. RESULTS We found that a population of KLRG1+ Tem and TemRA were expanded in both the CD4+ and CD8+ T-cell subpopulations in patients with IBM. KLRG1 expression in CD8+ T cells increased with T-cell differentiation with the lowest levels of expression in Tn and highest in highly differentiated TemRA and CD56+CD8+ T cells. The frequency of KLRG1+ total NK cells and subpopulations did not differ between patients with IBM and healthy donors. IBM disease duration correlated with increased CD8+ T-cell differentiation. DISCUSSION Our findings reveal that the selective expansion of blood KLRG1+ T cells in patients with IBM is confined to the TemRA and Tem cellular compartments.
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Affiliation(s)
- Namita A Goyal
- Department of Neurology (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M., S.A.V.), MDA ALS and Neuromuscular Center (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M.), Department of Pathology and Laboratory Medicine (T.M.), Department of Physiology and Biophysics (G.C., J.D., P.K.F., A.H.M., S.A.V.), Institute for Immunology (G.C., J.D., P.K.F., A.H.M., T.M., S.A.V.), and Biostatistics, Epidemiology, and Research Design (BERD) Unit, Institute for Clinical Translational Sciences (L.Z.), University of California, Irvine; Department of Neurology (J.C.), University of New Mexico, Albuquerque; Department of Neurology (L.W.), University of Washington Medical Center, Seattle; Department of Neurology, Division of Neuromuscular Disease (S.A.G.), Brigham and Women's Hospital and Harvard Medical School; and Computational Health Informatics Program (S.A.G.), Boston Children's Hospital and Harvard Medical School, MA
| | - GĆ©rald Coulis
- Department of Neurology (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M., S.A.V.), MDA ALS and Neuromuscular Center (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M.), Department of Pathology and Laboratory Medicine (T.M.), Department of Physiology and Biophysics (G.C., J.D., P.K.F., A.H.M., S.A.V.), Institute for Immunology (G.C., J.D., P.K.F., A.H.M., T.M., S.A.V.), and Biostatistics, Epidemiology, and Research Design (BERD) Unit, Institute for Clinical Translational Sciences (L.Z.), University of California, Irvine; Department of Neurology (J.C.), University of New Mexico, Albuquerque; Department of Neurology (L.W.), University of Washington Medical Center, Seattle; Department of Neurology, Division of Neuromuscular Disease (S.A.G.), Brigham and Women's Hospital and Harvard Medical School; and Computational Health Informatics Program (S.A.G.), Boston Children's Hospital and Harvard Medical School, MA
| | - Jorge Duarte
- Department of Neurology (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M., S.A.V.), MDA ALS and Neuromuscular Center (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M.), Department of Pathology and Laboratory Medicine (T.M.), Department of Physiology and Biophysics (G.C., J.D., P.K.F., A.H.M., S.A.V.), Institute for Immunology (G.C., J.D., P.K.F., A.H.M., T.M., S.A.V.), and Biostatistics, Epidemiology, and Research Design (BERD) Unit, Institute for Clinical Translational Sciences (L.Z.), University of California, Irvine; Department of Neurology (J.C.), University of New Mexico, Albuquerque; Department of Neurology (L.W.), University of Washington Medical Center, Seattle; Department of Neurology, Division of Neuromuscular Disease (S.A.G.), Brigham and Women's Hospital and Harvard Medical School; and Computational Health Informatics Program (S.A.G.), Boston Children's Hospital and Harvard Medical School, MA
| | - Philip K Farahat
- Department of Neurology (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M., S.A.V.), MDA ALS and Neuromuscular Center (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M.), Department of Pathology and Laboratory Medicine (T.M.), Department of Physiology and Biophysics (G.C., J.D., P.K.F., A.H.M., S.A.V.), Institute for Immunology (G.C., J.D., P.K.F., A.H.M., T.M., S.A.V.), and Biostatistics, Epidemiology, and Research Design (BERD) Unit, Institute for Clinical Translational Sciences (L.Z.), University of California, Irvine; Department of Neurology (J.C.), University of New Mexico, Albuquerque; Department of Neurology (L.W.), University of Washington Medical Center, Seattle; Department of Neurology, Division of Neuromuscular Disease (S.A.G.), Brigham and Women's Hospital and Harvard Medical School; and Computational Health Informatics Program (S.A.G.), Boston Children's Hospital and Harvard Medical School, MA
| | - Ali H Mannaa
- Department of Neurology (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M., S.A.V.), MDA ALS and Neuromuscular Center (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M.), Department of Pathology and Laboratory Medicine (T.M.), Department of Physiology and Biophysics (G.C., J.D., P.K.F., A.H.M., S.A.V.), Institute for Immunology (G.C., J.D., P.K.F., A.H.M., T.M., S.A.V.), and Biostatistics, Epidemiology, and Research Design (BERD) Unit, Institute for Clinical Translational Sciences (L.Z.), University of California, Irvine; Department of Neurology (J.C.), University of New Mexico, Albuquerque; Department of Neurology (L.W.), University of Washington Medical Center, Seattle; Department of Neurology, Division of Neuromuscular Disease (S.A.G.), Brigham and Women's Hospital and Harvard Medical School; and Computational Health Informatics Program (S.A.G.), Boston Children's Hospital and Harvard Medical School, MA
| | - Jonathan Cauchii
- Department of Neurology (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M., S.A.V.), MDA ALS and Neuromuscular Center (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M.), Department of Pathology and Laboratory Medicine (T.M.), Department of Physiology and Biophysics (G.C., J.D., P.K.F., A.H.M., S.A.V.), Institute for Immunology (G.C., J.D., P.K.F., A.H.M., T.M., S.A.V.), and Biostatistics, Epidemiology, and Research Design (BERD) Unit, Institute for Clinical Translational Sciences (L.Z.), University of California, Irvine; Department of Neurology (J.C.), University of New Mexico, Albuquerque; Department of Neurology (L.W.), University of Washington Medical Center, Seattle; Department of Neurology, Division of Neuromuscular Disease (S.A.G.), Brigham and Women's Hospital and Harvard Medical School; and Computational Health Informatics Program (S.A.G.), Boston Children's Hospital and Harvard Medical School, MA
| | - Tyler Irani
- Department of Neurology (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M., S.A.V.), MDA ALS and Neuromuscular Center (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M.), Department of Pathology and Laboratory Medicine (T.M.), Department of Physiology and Biophysics (G.C., J.D., P.K.F., A.H.M., S.A.V.), Institute for Immunology (G.C., J.D., P.K.F., A.H.M., T.M., S.A.V.), and Biostatistics, Epidemiology, and Research Design (BERD) Unit, Institute for Clinical Translational Sciences (L.Z.), University of California, Irvine; Department of Neurology (J.C.), University of New Mexico, Albuquerque; Department of Neurology (L.W.), University of Washington Medical Center, Seattle; Department of Neurology, Division of Neuromuscular Disease (S.A.G.), Brigham and Women's Hospital and Harvard Medical School; and Computational Health Informatics Program (S.A.G.), Boston Children's Hospital and Harvard Medical School, MA
| | - Nadia Araujo
- Department of Neurology (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M., S.A.V.), MDA ALS and Neuromuscular Center (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M.), Department of Pathology and Laboratory Medicine (T.M.), Department of Physiology and Biophysics (G.C., J.D., P.K.F., A.H.M., S.A.V.), Institute for Immunology (G.C., J.D., P.K.F., A.H.M., T.M., S.A.V.), and Biostatistics, Epidemiology, and Research Design (BERD) Unit, Institute for Clinical Translational Sciences (L.Z.), University of California, Irvine; Department of Neurology (J.C.), University of New Mexico, Albuquerque; Department of Neurology (L.W.), University of Washington Medical Center, Seattle; Department of Neurology, Division of Neuromuscular Disease (S.A.G.), Brigham and Women's Hospital and Harvard Medical School; and Computational Health Informatics Program (S.A.G.), Boston Children's Hospital and Harvard Medical School, MA
| | - Leo Wang
- Department of Neurology (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M., S.A.V.), MDA ALS and Neuromuscular Center (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M.), Department of Pathology and Laboratory Medicine (T.M.), Department of Physiology and Biophysics (G.C., J.D., P.K.F., A.H.M., S.A.V.), Institute for Immunology (G.C., J.D., P.K.F., A.H.M., T.M., S.A.V.), and Biostatistics, Epidemiology, and Research Design (BERD) Unit, Institute for Clinical Translational Sciences (L.Z.), University of California, Irvine; Department of Neurology (J.C.), University of New Mexico, Albuquerque; Department of Neurology (L.W.), University of Washington Medical Center, Seattle; Department of Neurology, Division of Neuromuscular Disease (S.A.G.), Brigham and Women's Hospital and Harvard Medical School; and Computational Health Informatics Program (S.A.G.), Boston Children's Hospital and Harvard Medical School, MA
| | - Marie Wencel
- Department of Neurology (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M., S.A.V.), MDA ALS and Neuromuscular Center (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M.), Department of Pathology and Laboratory Medicine (T.M.), Department of Physiology and Biophysics (G.C., J.D., P.K.F., A.H.M., S.A.V.), Institute for Immunology (G.C., J.D., P.K.F., A.H.M., T.M., S.A.V.), and Biostatistics, Epidemiology, and Research Design (BERD) Unit, Institute for Clinical Translational Sciences (L.Z.), University of California, Irvine; Department of Neurology (J.C.), University of New Mexico, Albuquerque; Department of Neurology (L.W.), University of Washington Medical Center, Seattle; Department of Neurology, Division of Neuromuscular Disease (S.A.G.), Brigham and Women's Hospital and Harvard Medical School; and Computational Health Informatics Program (S.A.G.), Boston Children's Hospital and Harvard Medical School, MA
| | - Vivian Li
- Department of Neurology (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M., S.A.V.), MDA ALS and Neuromuscular Center (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M.), Department of Pathology and Laboratory Medicine (T.M.), Department of Physiology and Biophysics (G.C., J.D., P.K.F., A.H.M., S.A.V.), Institute for Immunology (G.C., J.D., P.K.F., A.H.M., T.M., S.A.V.), and Biostatistics, Epidemiology, and Research Design (BERD) Unit, Institute for Clinical Translational Sciences (L.Z.), University of California, Irvine; Department of Neurology (J.C.), University of New Mexico, Albuquerque; Department of Neurology (L.W.), University of Washington Medical Center, Seattle; Department of Neurology, Division of Neuromuscular Disease (S.A.G.), Brigham and Women's Hospital and Harvard Medical School; and Computational Health Informatics Program (S.A.G.), Boston Children's Hospital and Harvard Medical School, MA
| | - Lishi Zhang
- Department of Neurology (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M., S.A.V.), MDA ALS and Neuromuscular Center (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M.), Department of Pathology and Laboratory Medicine (T.M.), Department of Physiology and Biophysics (G.C., J.D., P.K.F., A.H.M., S.A.V.), Institute for Immunology (G.C., J.D., P.K.F., A.H.M., T.M., S.A.V.), and Biostatistics, Epidemiology, and Research Design (BERD) Unit, Institute for Clinical Translational Sciences (L.Z.), University of California, Irvine; Department of Neurology (J.C.), University of New Mexico, Albuquerque; Department of Neurology (L.W.), University of Washington Medical Center, Seattle; Department of Neurology, Division of Neuromuscular Disease (S.A.G.), Brigham and Women's Hospital and Harvard Medical School; and Computational Health Informatics Program (S.A.G.), Boston Children's Hospital and Harvard Medical School, MA
| | - Steven A Greenberg
- Department of Neurology (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M., S.A.V.), MDA ALS and Neuromuscular Center (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M.), Department of Pathology and Laboratory Medicine (T.M.), Department of Physiology and Biophysics (G.C., J.D., P.K.F., A.H.M., S.A.V.), Institute for Immunology (G.C., J.D., P.K.F., A.H.M., T.M., S.A.V.), and Biostatistics, Epidemiology, and Research Design (BERD) Unit, Institute for Clinical Translational Sciences (L.Z.), University of California, Irvine; Department of Neurology (J.C.), University of New Mexico, Albuquerque; Department of Neurology (L.W.), University of Washington Medical Center, Seattle; Department of Neurology, Division of Neuromuscular Disease (S.A.G.), Brigham and Women's Hospital and Harvard Medical School; and Computational Health Informatics Program (S.A.G.), Boston Children's Hospital and Harvard Medical School, MA
| | - Tahseen Mozaffar
- Department of Neurology (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M., S.A.V.), MDA ALS and Neuromuscular Center (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M.), Department of Pathology and Laboratory Medicine (T.M.), Department of Physiology and Biophysics (G.C., J.D., P.K.F., A.H.M., S.A.V.), Institute for Immunology (G.C., J.D., P.K.F., A.H.M., T.M., S.A.V.), and Biostatistics, Epidemiology, and Research Design (BERD) Unit, Institute for Clinical Translational Sciences (L.Z.), University of California, Irvine; Department of Neurology (J.C.), University of New Mexico, Albuquerque; Department of Neurology (L.W.), University of Washington Medical Center, Seattle; Department of Neurology, Division of Neuromuscular Disease (S.A.G.), Brigham and Women's Hospital and Harvard Medical School; and Computational Health Informatics Program (S.A.G.), Boston Children's Hospital and Harvard Medical School, MA
| | - S Armando Villalta
- Department of Neurology (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M., S.A.V.), MDA ALS and Neuromuscular Center (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M.), Department of Pathology and Laboratory Medicine (T.M.), Department of Physiology and Biophysics (G.C., J.D., P.K.F., A.H.M., S.A.V.), Institute for Immunology (G.C., J.D., P.K.F., A.H.M., T.M., S.A.V.), and Biostatistics, Epidemiology, and Research Design (BERD) Unit, Institute for Clinical Translational Sciences (L.Z.), University of California, Irvine; Department of Neurology (J.C.), University of New Mexico, Albuquerque; Department of Neurology (L.W.), University of Washington Medical Center, Seattle; Department of Neurology, Division of Neuromuscular Disease (S.A.G.), Brigham and Women's Hospital and Harvard Medical School; and Computational Health Informatics Program (S.A.G.), Boston Children's Hospital and Harvard Medical School, MA.
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32
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Zhang M, Bai X, Zhang H, You Y, Lv H, Li Y, Tan B, Li J, Xu H, Zheng W, Yang H, Qian J. The role of cytomegalovirus colitis on short- and long-term outcomes for patients with ulcerative colitis. Scand J Gastroenterol 2022; 57:282-289. [PMID: 34894997 DOI: 10.1080/00365521.2021.2006298] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIM Cytomegalovirus (CMV) colitis brings great obstacles for treatment of ulcerative colitis (UC). We aimed to assess the impact of CMV colitis on prognostic outcomes and associated risk factors for UC patients. METHODS A consecutive 77 inpatients diagnosed as UC were collected retrospectively from January 2012 to December 2015. About 33 patients were defined with CMV colitis by histological tests of colon mucosa. Clinical characteristics and outcomes were compared between patients with CMV colitis or those without. The primary outcomes were UC-related colectomy or the first time of disease relapse after discharge. RESULTS 33 CMV colitis patients had higher frequency of recent steroid treatment (81.8% vs. 31.8%, pā<ā.001), older age of onset (45.3āĀ±ā13.0 vs. 44.5āĀ±ā15.7 years, pā=ā.028) and more severe colitis (pā<ā.001) characterized by lower hemoglobin (99.0āĀ±ā23.2 vs. 114.6āĀ±ā22.6āg/L, pā=ā.004), albumin (29.7āĀ±ā4.6 vs. 35.4āĀ±ā6.5āg/L, pā<ā.001), immunoglobulin G [8.8 (5.9-10.6) vs. 12.3 (9.3-16.2) g/L, pā=ā.003] and higher C reactive protein [48.5 (21.6-73.8) vs. 9.1 (3.6-35.0) mg/L, pā<ā.001]. The occurrence of UC-related colectomy in patients with CMV colitis was more frequent (48.5% vs 20.5%, p<.01) and CMV colitis was proved to be one of risk factors of colectomy with a hazard ratio of 3.15 (95%CI 1.387-7.171, pā=ā.006), mainly in a short term period. UC-related complications almost occurred within 1 year since CMV colitis diagnosis. And UC patients with CMV colitis always experienced early relapse. CONCLUSIONS CMV colitis increases the colectomy risk mainly in a short term due to severe inflammatory response, early-onset complications or medication treatment failure. There is also potential correlation between CMV colitis and early relapse. Short-term therapy for UC patients with CMV colitis should be more concerned on controlling systemic inflammation and reducing complications whereas long-term maintenance therapy may not require more aggressive intervention.
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Affiliation(s)
- Mengmeng Zhang
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaoyin Bai
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Huimin Zhang
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yan You
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hong Lv
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yue Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bei Tan
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ji Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hui Xu
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Weiyang Zheng
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hong Yang
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jiaming Qian
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Kalfeist L, Galland L, Ledys F, Ghiringhelli F, Limagne E, Ladoire S. Impact of Glucocorticoid Use in Oncology in the Immunotherapy Era. Cells 2022; 11:770. [PMID: 35269392 PMCID: PMC8909189 DOI: 10.3390/cells11050770] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/18/2022] [Accepted: 02/18/2022] [Indexed: 12/11/2022] Open
Abstract
Thanks to their anti-inflammatory, anti-oedema, and anti-allergy properties, glucocorticoids are among the most widely prescribed drugs in patients with cancer. The indications for glucocorticoid use are very wide and varied in the context of cancer and include the symptomatic management of cancer-related symptoms (compression, pain, oedema, altered general state) but also prevention or treatment of common side effects of anti-cancer therapies (nausea, allergies, etc.) or immune-related adverse events (irAE). In this review, we first give an overview of the different clinical situations where glucocorticoids are used in oncology. Next, we describe the current state of knowledge regarding the effects of these molecules on immune response, in particular anti-tumour response, and we summarize available data evaluating how these effects may interfere with the efficacy of immunotherapy using immune checkpoint inhibitors.
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Affiliation(s)
- Laura Kalfeist
- Platform of Transfer in Cancer Biology, Georges-Francois Leclerc Center, 21000 Dijon, France; (L.K.); (L.G.); (F.L.); (F.G.); (E.L.)
- UMR INSERM 1231 āLipides Nutrition Cancerā, 21000 Dijon, France
| | - LoĆÆck Galland
- Platform of Transfer in Cancer Biology, Georges-Francois Leclerc Center, 21000 Dijon, France; (L.K.); (L.G.); (F.L.); (F.G.); (E.L.)
- UMR INSERM 1231 āLipides Nutrition Cancerā, 21000 Dijon, France
- Department of Medical Oncology, Georges-FranƧois Leclerc Center, 21000 Dijon, France
| | - Fanny Ledys
- Platform of Transfer in Cancer Biology, Georges-Francois Leclerc Center, 21000 Dijon, France; (L.K.); (L.G.); (F.L.); (F.G.); (E.L.)
- UMR INSERM 1231 āLipides Nutrition Cancerā, 21000 Dijon, France
| | - FranƧois Ghiringhelli
- Platform of Transfer in Cancer Biology, Georges-Francois Leclerc Center, 21000 Dijon, France; (L.K.); (L.G.); (F.L.); (F.G.); (E.L.)
- UMR INSERM 1231 āLipides Nutrition Cancerā, 21000 Dijon, France
- Department of Medical Oncology, Georges-FranƧois Leclerc Center, 21000 Dijon, France
- School of Medicine, University of Burgundy Franche-ComtƩ, 21000 Dijon, France
| | - Emeric Limagne
- Platform of Transfer in Cancer Biology, Georges-Francois Leclerc Center, 21000 Dijon, France; (L.K.); (L.G.); (F.L.); (F.G.); (E.L.)
- UMR INSERM 1231 āLipides Nutrition Cancerā, 21000 Dijon, France
| | - Sylvain Ladoire
- Platform of Transfer in Cancer Biology, Georges-Francois Leclerc Center, 21000 Dijon, France; (L.K.); (L.G.); (F.L.); (F.G.); (E.L.)
- UMR INSERM 1231 āLipides Nutrition Cancerā, 21000 Dijon, France
- Department of Medical Oncology, Georges-FranƧois Leclerc Center, 21000 Dijon, France
- School of Medicine, University of Burgundy Franche-ComtƩ, 21000 Dijon, France
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34
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Immunotherapeutic Approaches for Glioblastoma Treatment. Biomedicines 2022; 10:biomedicines10020427. [PMID: 35203636 PMCID: PMC8962267 DOI: 10.3390/biomedicines10020427] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 02/05/2022] [Accepted: 02/08/2022] [Indexed: 11/17/2022] Open
Abstract
Glioblastoma remains a challenging disease to treat, despite well-established standard-of-care treatments, with a median survival consistently of less than 2 years. In this review, we delineate the unique disease-specific challenges for immunotherapies, both brain-related and non-brain-related, which will need to be adequately overcome for the development of effective treatments. We also review current immunotherapy treatments, with a focus on clinical applications, and propose future directions for the field of GBM immunotherapy.
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35
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Wessels I, Rolles B, Slusarenko AJ, Rink L. Zinc deficiency as a possible risk factor for increased susceptibility and severe progression of Corona Virus Disease 19. Br J Nutr 2022; 127:214-232. [PMID: 33641685 PMCID: PMC8047403 DOI: 10.1017/s0007114521000738] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 01/07/2021] [Accepted: 02/21/2021] [Indexed: 01/08/2023]
Abstract
The importance of Zn for human health becomes obvious during Zn deficiency. Even mild insufficiencies of Zn cause alterations in haematopoiesis and immune functions, resulting in a proinflammatory phenotype and a disturbed redox metabolism. Although immune system malfunction has the most obvious effect, the functions of several tissue cell types are disturbed if Zn supply is limiting. Adhesion molecules and tight junction proteins decrease, while cell death increases, generating barrier dysfunction and possibly organ failure. Taken together, Zn deficiency both weakens the resistance of the human body towards pathogens and at the same time increases the danger of an overactive immune response that may cause tissue damage. The case numbers of Corona Virus Disease 19 (COVID-19) are still increasing, which is causing enormous problems for health systems and economies. There is an urgent need to reduce both the number of severe cases and the resulting deaths. While therapeutic options are still under investigation, and first vaccines have been approved, cost-effective ways to reduce the likelihood of or even prevent infection, and the transition from mild symptoms to more serious detrimental disease, are highly desirable. Nutritional supplementation might be an effective option to achieve these aims. In this review, we discuss known Zn deficiency effects in the context of an infection with Severe Acute Respiratory Syndrome-Coronavirus-2 and its currently known pathogenic mechanisms and elaborate on how severe pre-existing Zn deficiency may pre-dispose patients to a severe progression of COVID-19. First published clinical data on the association of Zn homoeostasis with COVID-19 and registered studies in progress are listed.
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Affiliation(s)
- Inga Wessels
- Institute of Immunology, Faculty of Medicine, RWTH Aachen University Hospital, Pauwelsstr. 30, 52074Aachen, Germany
| | - Benjamin Rolles
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University Hospital, Pauwelsstrasse 30, 52074Aachen, Germany
| | - Alan J. Slusarenko
- Department of Plant Physiology, RWTH Aachen University, Worringer Weg 1, 52074Aachen, Germany
| | - Lothar Rink
- Institute of Immunology, Faculty of Medicine, RWTH Aachen University Hospital, Pauwelsstr. 30, 52074Aachen, Germany
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36
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Yedinak C, Ross IL. Significant risk of COVID-19 and related-hospitalization among patients with adrenal insufficiency: A large multinational survey. Front Endocrinol (Lausanne) 2022; 13:1042119. [PMID: 36440212 PMCID: PMC9684629 DOI: 10.3389/fendo.2022.1042119] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 10/19/2022] [Indexed: 11/11/2022] Open
Abstract
OBJECTIVE To determine self-reported incidence and potential risk factors for COVID-19 in patients with adrenal insufficiency (AI). METHODS A 27-item AI survey was developed for AI and COVID-19 status, vetted by specialists and patients, and distributed via social media, websites, and advocacy groups. Participation was voluntary and anonymous. Data were collected from September 20th, 2020 until December 31st, 2020. RESULTS Respondents (n=1291) with self-reported glucocorticoid treatment for AI, completed the survey, with 456 who reported having symptoms and were screened for COVID-19 during 2020; 40 tested positive (+ve), representing an 8.8% incidence. Of the COVID-19+ve, 31 were female (78%), with mean age of 39.9 years. COVID-19 among AI patients occurred most commonly in those aged 40-59 years (n=17; 42.5%); mean time since AI diagnosis was 13.5 years (range 0.2-42.0 years). Pulmonary disease, congenital adrenal hyperplasia, and higher maintenance doses of glucocorticoids were significantly associated with +ve COVID-19 (p=0.04, p=0.01, and p=0.001, respectively. In respondents the cumulative incidence of COVID-19+ve during 2020 was 3.1%; greater than the 1.03% worldwide-incidence reported by WHO, by December 31st, 2020. There was a 3-fold (95% CI 2.16-3.98) greater relative risk (RR) of COVID-19 infection and a 23.8- fold (95% CI 20.7-31.2) RR of hospitalization in patients with AI, compared with the global population. CONCLUSION A markedly raised RR of COVID-19 and hospitalization in respondents reporting chronic AI was detected. We found that a diagnosis of congenital adrenal hyperplasia, age>40 years, male gender, pulmonary disease, and higher maintenance doses of glucocorticoids were associated with greatest risk.
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Affiliation(s)
- Christine Yedinak
- Department of Neurosurgical Services, Oregon Health and Science University, Portland, OR, United States
- *Correspondence: Christine Yedinak,
| | - Ian Louis Ross
- Department of Medicine, University of Cape Town, Cape Town, South Africa
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37
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Della-Torre E, Lanzillotta M, Ramirez GA, Dagna L, Tresoldi M. Serum IgG4 elevation in hyper-inflamed COVID-19 patients. Author's reply. Eur J Intern Med 2022; 95:98-99. [PMID: 34711472 PMCID: PMC8531494 DOI: 10.1016/j.ejim.2021.10.025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 10/20/2021] [Indexed: 01/28/2023]
Affiliation(s)
- Emanuel Della-Torre
- IRCCS San Raffaele Scientific Institute, UniversitĆ Vita-Salute San Raffaele, via Olgettina 60, Milan 20132, Italy; Unit of Immunology, Rheumatology, Allergy and Rare Diseases, Milan, Italy.
| | - Marco Lanzillotta
- IRCCS San Raffaele Scientific Institute, UniversitĆ Vita-Salute San Raffaele, via Olgettina 60, Milan 20132, Italy; Unit of Immunology, Rheumatology, Allergy and Rare Diseases, Milan, Italy
| | - Giuseppe Alvise Ramirez
- IRCCS San Raffaele Scientific Institute, UniversitĆ Vita-Salute San Raffaele, via Olgettina 60, Milan 20132, Italy; Unit of Immunology, Rheumatology, Allergy and Rare Diseases, Milan, Italy
| | - Lorenzo Dagna
- Unit of Immunology, Rheumatology, Allergy and Rare Diseases, Milan, Italy
| | - Moreno Tresoldi
- General Medicine and Advanced Care Unit. All at IRCCS San Raffaele Scientific Institute, Milan, Italy
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38
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Jahan P, Tahseen R, Parvez M, Kumar GS. A correlational study on neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in bronchial asthma. ADVANCES IN HUMAN BIOLOGY 2022. [DOI: 10.4103/aihb.aihb_44_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
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39
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Zhang Y, Chen H, Mo H, Hu X, Gao R, Zhao Y, Liu B, Niu L, Sun X, Yu X, Wang Y, Chang Q, Gong T, Guan X, Hu T, Qian T, Xu B, Ma F, Zhang Z, Liu Z. Single-cell analyses reveal key immune cell subsets associated with response to PD-L1 blockade in triple-negative breast cancer. Cancer Cell 2021; 39:1578-1593.e8. [PMID: 34653365 DOI: 10.1016/j.ccell.2021.09.010] [Citation(s) in RCA: 403] [Impact Index Per Article: 100.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 06/28/2021] [Accepted: 09/17/2021] [Indexed: 12/11/2022]
Abstract
In triple-negative breast cancer (TNBC), the benefit of combining chemotherapy with checkpoint inhibitors is still not very clear. We utilize single-cell RNA- and ATAC-sequencing to examine the immune cell dynamics in 22 patients with advanced TNBC treated with paclitaxel or its combination with the anti-PD-L1 atezolizumab. We demonstrate that high levels of baseline CXCL13+ T cells are linked to the proinflammatory features of macrophages and can predict effective responses to the combination therapy. In responsive patients, lymphoid tissue inducer (LTi) cells, follicular B (Bfoc) cells, CXCL13+ T cells, and conventional type 1 dendritic cells (cDC1) concertedly increase following the combination therapy, but instead decrease after paclitaxel monotherapy. Our data highlight the importance of CXCL13+ T cells in effective responses to anti-PD-L1 therapies and suggest that their reduction by paclitaxel regimen may compromise the clinical outcomes of accompanying atezolizumab for TNBC treatment.
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Affiliation(s)
- Yuanyuan Zhang
- BIOPIC, Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, School of Life Sciences, International Cancer Institute, Peking University, Beijing 100871, China
| | - Hongyan Chen
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Hongnan Mo
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Xueda Hu
- BIOPIC, Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, School of Life Sciences, International Cancer Institute, Peking University, Beijing 100871, China
| | - Ranran Gao
- BIOPIC, Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, School of Life Sciences, International Cancer Institute, Peking University, Beijing 100871, China
| | - Yahui Zhao
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Baolin Liu
- BIOPIC, Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, School of Life Sciences, International Cancer Institute, Peking University, Beijing 100871, China
| | - Lijuan Niu
- Department of Ultrasound, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Xiaoying Sun
- Department of Medical Oncology, Cancer Hospital of HuanXing ChaoYang District, Beijing 100005, China
| | - Xiao Yu
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yong Wang
- Department of Ultrasound, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Qing Chang
- Department of Ultrasound, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Tongyang Gong
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Xiuwen Guan
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Ting Hu
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Tianyi Qian
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Binghe Xu
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
| | - Fei Ma
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
| | - Zemin Zhang
- BIOPIC, Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, School of Life Sciences, International Cancer Institute, Peking University, Beijing 100871, China; Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen 518132, China.
| | - Zhihua Liu
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
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40
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Saito S, Cao DY, Victor AR, Peng Z, Wu HY, Okwan-Duodu D. RASAL3 Is a Putative RasGAP Modulating Inflammatory Response by Neutrophils. Front Immunol 2021; 12:744300. [PMID: 34777356 PMCID: PMC8579101 DOI: 10.3389/fimmu.2021.744300] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 10/05/2021] [Indexed: 12/12/2022] Open
Abstract
As first responder cells in host defense, neutrophils must be carefully regulated to prevent collateral tissue injury. However, the intracellular events that titrate the neutrophilās response to inflammatory stimuli remain poorly understood. As a molecular switch, Ras activity is tightly regulated by Ras GTPase activating proteins (RasGAP) to maintain cellular active-inactive states. Here, we show that RASAL3, a RasGAP, is highly expressed in neutrophils and that its expression is upregulated by exogenous stimuli in neutrophils. RASAL3 deficiency triggers augmented neutrophil responses and enhanced immune activation in acute inflammatory conditions. Consequently, mice lacking RASAL3 (RASAL3-KO) demonstrate accelerated mortality in a septic shock model via induction of severe organ damage and hyperinflammatory response. The excessive neutrophilic hyperinflammation and increased mortality were recapitulated in a mouse model of sickle cell disease, which we found to have low neutrophil RASAL3 expression upon LPS activation. Thus, RASAL3 functions as a RasGAP that negatively regulates the cellular activity of neutrophils to modulate the inflammatory response. These results demonstrate that RASAL3 could serve as a therapeutic target to regulate excessive inflammation in sepsis and many inflammatory disease states.
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Affiliation(s)
- Suguru Saito
- Bio-fluid Biomarker Center, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.,Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States.,Division of Virology, Department of Immunology and Infection, School of Medicine, Jichi Medical University, Shimotsuke, Japan
| | - Duo-Yao Cao
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Aaron R Victor
- Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Zhenzi Peng
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States.,College of Animal Science and Technology, Northwest A&F University, Shaanxi, China
| | - Hui-Ya Wu
- College of Health Science, Trans World University, Douliu, Taiwan
| | - Derick Okwan-Duodu
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States.,Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, United States
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41
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Al Mushafi A, Ooi JD, Odobasic D. Crescentic Glomerulonephritis: Pathogenesis and Therapeutic Potential of Human Amniotic Stem Cells. Front Physiol 2021; 12:724186. [PMID: 34721059 PMCID: PMC8554237 DOI: 10.3389/fphys.2021.724186] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Accepted: 09/24/2021] [Indexed: 12/15/2022] Open
Abstract
Chronic kidney disease (CKD) leads to significant morbidity and mortality worldwide. Glomerulonephritis (GN) is the second leading cause of CKD resulting in end stage renal failure. The most severe and rapidly progressive type of GN is characterized by glomerular crescent formation. The current therapies for crescentic GN, which consist of broad immunosuppressive drugs, are partially effective, non-specific, toxic and cause many serious side effects including infections, cancer, and cardiovascular problems. Therefore, new and safer therapies are needed. Human amniotic epithelial cells (hAECs) are a type of stem cell which are isolated from the placenta after birth. They represent an attractive and novel therapeutic option for the treatment of various inflammatory conditions owing to their unique and selective immunosuppressive ability, as well as their excellent safety profile and clinical applicability. In this review, we will discuss the immunopathogenesis of crescentic GN, issues with currently available treatments and how hAECs offer potential to become a new and harmless treatment option for this condition.
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Affiliation(s)
- Ahmed Al Mushafi
- Department of Medicine, Monash Medical Centre, Centre for Inflammatory Diseases, Monash University, Clayton, VIC, Australia
| | - Joshua D Ooi
- Department of Medicine, Monash Medical Centre, Centre for Inflammatory Diseases, Monash University, Clayton, VIC, Australia
| | - Dragana Odobasic
- Department of Medicine, Monash Medical Centre, Centre for Inflammatory Diseases, Monash University, Clayton, VIC, Australia
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42
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Mirna M, Schmutzler L, Topf A, Hoppe UC, Lichtenauer M. Neutrophil-to-lymphocyte ratio and monocyte-to-lymphocyte ratio predict length of hospital stay in myocarditis. Sci Rep 2021; 11:18101. [PMID: 34518607 PMCID: PMC8438016 DOI: 10.1038/s41598-021-97678-6] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 08/20/2021] [Indexed: 02/08/2023] Open
Abstract
Neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR) are associated with the severity of various diseases. The aim of this study was to demonstrate the relationship of NLR and MLR with the severity of myocarditis. 202 consecutive patients with myocarditis were retrospectively enrolled in this study. Laboratory parameters and clinical data were extracted from hospital records and discharge letters. Median NLR was 2.48 (IQR 1.55-4.58) and median MLR was 0.42 (IQR 0.39-0.58). NLR and MLR correlated with HF, CRP and leukocyte count, MLR further correlated inversely with LV systolic function (rsā=ā-ā0.379, pā=ā0.030). Both ratios correlated better with length of hospital stay (NLR: rsā=ā0.435, pā=ā0.003; MLR: rsā=ā0.534, pā<ā0.0001) than CRP, leukocyte count, IL-6 or procalcitonin. AUCs for the prediction of prolonged hospital stay (NLRā=ā0.75, MLRā=ā0.80), and optimal cut-offs therefor were calculated. Patients who had in-hospital complications showed a higher NLR, however, this remained statistically insignificant. NLR and MLR correlated with the length of stay, as well as with several clinical and laboratory parameters in patients with myocarditis. Since white blood cell differentials are relatively easy and fast to perform, both ratios could facilitate further risk stratification in affected patients.
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Affiliation(s)
- Moritz Mirna
- Department of Internal Medicine II, Division of Cardiology, UniversitƤtsklinikum Der Paracelsus Medizinischen UniversitƤt, MĆ¼llner HauptstraĆe 48, 5020, Salzburg, Austria.
| | - Lukas Schmutzler
- Department of Internal Medicine II, Division of Cardiology, UniversitƤtsklinikum Der Paracelsus Medizinischen UniversitƤt, MĆ¼llner HauptstraĆe 48, 5020, Salzburg, Austria
| | - Albert Topf
- Department of Internal Medicine II, Division of Cardiology, UniversitƤtsklinikum Der Paracelsus Medizinischen UniversitƤt, MĆ¼llner HauptstraĆe 48, 5020, Salzburg, Austria
| | - Uta C Hoppe
- Department of Internal Medicine II, Division of Cardiology, UniversitƤtsklinikum Der Paracelsus Medizinischen UniversitƤt, MĆ¼llner HauptstraĆe 48, 5020, Salzburg, Austria
| | - Michael Lichtenauer
- Department of Internal Medicine II, Division of Cardiology, UniversitƤtsklinikum Der Paracelsus Medizinischen UniversitƤt, MĆ¼llner HauptstraĆe 48, 5020, Salzburg, Austria
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43
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Kelly WJ, Giles AJ, Gilbert M. T lymphocyte-targeted immune checkpoint modulation in glioma. J Immunother Cancer 2021; 8:jitc-2019-000379. [PMID: 32051289 PMCID: PMC7057419 DOI: 10.1136/jitc-2019-000379] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/05/2020] [Indexed: 02/07/2023] Open
Abstract
Immunomodulatory therapies targeting inhibitory checkpoint molecules have revolutionized the treatment of solid tumor malignancies. Concerns about whether systemic administration of an immune checkpoint inhibitor could impact primary brain tumors were answered with the observation of definitive responses in pediatric patients harboring hypermutated gliomas. Although initial clinical results in patients with glioblastoma (GBM) were disappointing, recently published results have demonstrated a potential survival benefit in patients with recurrent GBM treated with neoadjuvant programmed cell death protein 1 blockade. While these findings necessitate verification in subsequent studies, they support the possibility of achieving clinical meaningful immune responses in malignant primary brain tumors including GBM, a disease in dire need of additional therapeutic options. There are several challenges involved in treating glioma with immune checkpoint modulators including the immunosuppressive nature of GBM itself with high inhibitory checkpoint expression, the immunoselective blood brain barrier impairing the ability for peripheral lymphocytes to traffic to the tumor microenvironment and the high prevalence of corticosteroid use which suppress lymphocyte activation. However, by simultaneously targeting multiple costimulatory and inhibitory pathways, it may be possible to achieve an effective antitumoral immune response. To this end, there are now several novel agents targeting more recently uncovered āsecond generationā checkpoint molecules. Given the multiplicity of drugs being considered for combination regimens, an increased understanding of the mechanisms of action and resistance combined with more robust preclinical and early clinical testing will be needed to be able to adequately test these agents. This review summarizes our current understanding of T lymphocyte-modulating checkpoint molecules as it pertains to glioma with the hope for a renewed focus on the most promising therapeutic strategies.
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Affiliation(s)
| | - Amber Jin Giles
- Neuro-Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA
| | - Mark Gilbert
- Neuro-Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA
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44
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CortĆ©s-Vieyra R, GutiĆ©rrez-Castellanos S, Ćlvarez-Aguilar C, Baizabal-Aguirre VM, NuƱez-Anita RE, Rocha-LĆ³pez AG, GĆ³mez-GarcĆa A. Behavior of Eosinophil Counts in Recovered and Deceased COVID-19 Patients over the Course of the Disease. Viruses 2021; 13:v13091675. [PMID: 34578258 PMCID: PMC8473128 DOI: 10.3390/v13091675] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 07/22/2021] [Accepted: 08/18/2021] [Indexed: 01/08/2023] Open
Abstract
Knowledge about the immune responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, particularly regarding the function of eosinophils, has been steadily emerging recently. There exists controversy regarding the implications of eosinophils in the coronavirus disease 2019 (COVID-19)ās pathology. We report a retrospective cohort study including the comparison of leukocyte counts in COVID-19 patients, considering the outcomes of recovery (n = 59) and death (n = 60). Among the different types of leukocytes, the eosinophil counts were those that showed the greatest difference between recovered and deceased patients. Eosinopenia (eosinophil count < 0.01 Ć 109/L) was more frequently observed in deceased than recovered patients (p = 0.0012). The eosinophil counts more rapidly increased and showed a greater proportion over the course of the disease in the recovered than deceased patients. Furthermore, the estimated survival rate was greater in patients without eosinopenia than in patients with eosinopenia (p = 0.0070) during hospitalization. Importantly, recovered but not deceased patients showed high negative correlations of the eosinophils with the neutrophil-to-lymphocyte ratio (NLR) and neutrophil counts at Day 9 of the onset of clinical symptoms (p ā¤ 0.0220). Our analysis suggests that eosinopenia may be associated with unfavorable disease outcomes and that the eosinophils have a beneficial function in COVID-19 patients, probably contributing by controlling the exacerbated inflammation induced by neutrophils.
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Affiliation(s)
- Ricarda CortƩs-Vieyra
- Centro de InvestigaciĆ³n BiomĆ©dica de MichoacĆ”n, DivisiĆ³n de InvestigaciĆ³n ClĆnica, Instituto Mexicano del Seguro Social (IMSS), Morelia 58341, MichoacĆ”n, Mexico;
- Correspondence: (R.C.-V.); (A.G.-G.); Tel.: +44-3-3222-600 (ext. 31015) (R.C.-V); +44-3-3222-600 (ext. 31004) (A.G.-G.)
| | - Sergio GutiƩrrez-Castellanos
- Centro de InvestigaciĆ³n BiomĆ©dica de MichoacĆ”n, DivisiĆ³n de InvestigaciĆ³n ClĆnica, Instituto Mexicano del Seguro Social (IMSS), Morelia 58341, MichoacĆ”n, Mexico;
- DivisiĆ³n de Estudios de Posgrado, Facultad de Ciencias MĆ©dicas y BiolĆ³gicas āDr. Ignacio ChĆ”vezā, Universidad Michoacana de San NicolĆ”s de Hidalgo (UMSNH), Morelia 58020, MichoacĆ”n, Mexico; (C.Ć.-A.); (A.G.R.-L.)
| | - Cleto Ćlvarez-Aguilar
- DivisiĆ³n de Estudios de Posgrado, Facultad de Ciencias MĆ©dicas y BiolĆ³gicas āDr. Ignacio ChĆ”vezā, Universidad Michoacana de San NicolĆ”s de Hidalgo (UMSNH), Morelia 58020, MichoacĆ”n, Mexico; (C.Ć.-A.); (A.G.R.-L.)
- CoordinaciĆ³n Auxiliar MĆ©dica de InvestigaciĆ³n en Salud, IMSS, Morelia 58000, MichoacĆ”n, Mexico
| | - VĆctor Manuel Baizabal-Aguirre
- Centro Multidisciplinario de Estudios en BiotecnologĆa, Facultad de Medicina Veterinaria y Zootecnia, UMSNH, Morelia 58890, MichoacĆ”n, Mexico; (V.M.B.-A.); (R.E.N.-A.)
| | - Rosa Elvira NuƱez-Anita
- Centro Multidisciplinario de Estudios en BiotecnologĆa, Facultad de Medicina Veterinaria y Zootecnia, UMSNH, Morelia 58890, MichoacĆ”n, Mexico; (V.M.B.-A.); (R.E.N.-A.)
| | - AngĆ©lica Georgina Rocha-LĆ³pez
- DivisiĆ³n de Estudios de Posgrado, Facultad de Ciencias MĆ©dicas y BiolĆ³gicas āDr. Ignacio ChĆ”vezā, Universidad Michoacana de San NicolĆ”s de Hidalgo (UMSNH), Morelia 58020, MichoacĆ”n, Mexico; (C.Ć.-A.); (A.G.R.-L.)
| | - Anel GĆ³mez-GarcĆa
- Centro de InvestigaciĆ³n BiomĆ©dica de MichoacĆ”n, DivisiĆ³n de InvestigaciĆ³n ClĆnica, Instituto Mexicano del Seguro Social (IMSS), Morelia 58341, MichoacĆ”n, Mexico;
- Correspondence: (R.C.-V.); (A.G.-G.); Tel.: +44-3-3222-600 (ext. 31015) (R.C.-V); +44-3-3222-600 (ext. 31004) (A.G.-G.)
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45
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McAleese J, Mooney L, Walls GM. Reducing the Risk of Death From Pneumocystis jirovecii Pneumonia After Radical Radiation Therapy to the Lung. Clin Oncol (R Coll Radiol) 2021; 33:780-787. [PMID: 34253423 DOI: 10.1016/j.clon.2021.06.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 05/31/2021] [Accepted: 06/17/2021] [Indexed: 12/25/2022]
Abstract
AIMS Lung cancer is the leading cause of cancer death. Radiotherapy given in the curative setting is associated with a 3% risk of death from Pneumocystis jirovecii pneumonia (PJP). Prolonged courses of high-dose steroids also increase the risk of PJP. International guidelines recommend the use of chemoprophylaxis with trimethoprim-sulfamethoxazole for patients at high risk. We assessed the effect of an intervention designed to reduce the impact of PJP. MATERIALS AND METHODS Prophylaxis guidelines were introduced in 2016. Case records of patients treated with radical radiotherapy were examined for the periods 2014 to 2015 (pre-intervention) and 2017 to 2018 (post-intervention). In total, 247 patients were treated pre-intervention and 334 post-intervention. RESULTS Freedom from PJP death at 1 year was 96% before intervention and 99% after (hazard ratio 0.3, 95% confidence interval 0.1-0.9, P = 0.029). Although the rate of use of chemoprophylaxis according to the guideline rose from 1% to 13% (P = 0.003), the use of high-dose steroids also fell from 35% to 16% (P < 0.00001). CONCLUSIONS Reducing radiotherapy-associated infections is an important component of radical treatment in lung cancer. Highlighting chemoprophylaxis guidelines reduced the death rate from PJP, with an associated more judicious use of steroids. Advocating prophylaxis in patients with lymphocyte count <0.6 Ć 109/l is the next intervention to be studied.
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Affiliation(s)
- J McAleese
- Cancer Centre Belfast City Hospital, Belfast, UK
| | - L Mooney
- Cancer Centre Belfast City Hospital, Belfast, UK
| | - G M Walls
- Cancer Centre Belfast City Hospital, Belfast, UK; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK.
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46
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Yamagami J, Ujiie H, Aoyama Y, Ishii N, Tateishi C, Ishiko A, Ichijima T, Hagihara S, Hashimoto K, Amagai M. A multicenter, open-label, uncontrolled, single-arm phase 2 study of tirabrutinib, an oral Bruton's tyrosine kinase inhibitor, in pemphigus. J Dermatol Sci 2021; 103:135-142. [PMID: 34376340 DOI: 10.1016/j.jdermsci.2021.07.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 07/02/2021] [Accepted: 07/04/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND The treatment of pemphigus is based on systemic corticosteroid use and adjuvant therapies, but some patients are resistant to conventional therapy. Tirabrutinib is a highly selective oral Bruton's tyrosine kinase inhibitor that may be clinically effective in treating pemphigus by suppressing B-cell signaling. OBJECTIVE We investigated the efficacy and safety of tirabrutinib in patients with refractory pemphigus. METHODS This was a multicenter, open-label, single-arm phase 2 study of Japanese patients with refractory pemphigus receiving appropriate treatment with an oral corticosteroid and adjuvant therapies. Patients received postprandial oral tirabrutinib 80 mg once daily for 52 weeks. After 16 weeks of tirabrutinib treatment, the corticosteroid dose was tapered to ā¤10 mg/day of prednisolone equivalent. RESULTS In total, 16 patients were evaluated (mean age, 52.5 years; 50 % male). The complete remission rate after 24 weeks of treatment (primary endpoint) was 18.8 % (3/16; 95 % confidence interval, 6.6 %-43.0 %). By Week 52, eight patients (50.0 %) achieved complete remission and 10 patients (62.5 %) achieved remission. Over 52 weeks of treatment, the mean prednisolone dose decreased from 17.03 to 7.65 mg/day. Incidences of adverse events (AEs) and adverse drug reactions were 87.5 % and 43.8 %, respectively. A relationship with tirabrutinib was ruled out for all serious AEs and Grade ā„3 AEs. CONCLUSION Treatment with tirabrutinib enabled remission and reduced oral corticosteroid exposure over time and did not result in any major safety concerns in patients with refractory pemphigus. Thus, oral tirabrutinib may be a new treatment option for patients with refractory pemphigus.
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Affiliation(s)
- Jun Yamagami
- Department of Dermatology, Keio University School of Medicine, Tokyo, Japan
| | - Hideyuki Ujiie
- Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Yumi Aoyama
- Department of Dermatology, Kawasaki Medical School, Okayama, Japan
| | - Norito Ishii
- Department of Dermatology, Kurume University School of Medicine, Kurume, Japan
| | - Chiharu Tateishi
- Department of Dermatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Akira Ishiko
- Department of Dermatology, School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Tomoki Ichijima
- Clinical Development Planning, Ono Pharmaceutical Co., Ltd., Osaka, Japan
| | - Shunsuke Hagihara
- Department of Statistical Analysis, Ono Pharmaceutical Co., Ltd., Osaka, Japan
| | - Koji Hashimoto
- Ehime University Graduate School of Medicine, Ehime, Japan
| | - Masayuki Amagai
- Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.
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47
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Kim JH, Choi SI, Lee YJ, Kim BK, Park HW, Cho SH, Chang YS, Kim SH. Pharmacological prevention of delayed hypersensitivity reactions caused by iodinated contrast media. World Allergy Organ J 2021; 14:100561. [PMID: 34257798 PMCID: PMC8256281 DOI: 10.1016/j.waojou.2021.100561] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 05/27/2021] [Accepted: 06/01/2021] [Indexed: 12/17/2022] Open
Abstract
Background Delayed hypersensitivity reactions (DHRs) to radiocontrast media (RCM) occur in approximately 0.5ā23.0% of patients and are thought to be caused by T cell-mediated mechanisms. However, an optimal pharmacological preventive strategy is not yet established in patients with histories of delayed reactions to RCM. Objective We aimed to evaluate the efficacy of pharmacological prevention in patients with histories of delayed reactions to non-ionic low-osmolar RCM when re-exposed to RCM. Methods A retrospective review of electronic medical records of 117 patients with previous histories of DHRs to RCM who visited an allergy clinic for the prevention of reactions after the re-exposure to RCM was conducted. The effects of pharmacological prevention were compared according to the symptom scores of previous reactions based on their intensities and durations with electronic medical records (EMRs). Results Of the 117 patients who experienced DHRs after RCM injection, we confirmed the outcomes of RCM re-exposure in 101 patients. For pharmacological prevention, 92 patients (91.1%) received steroids before RCM injection and among them, 50 patients (49.5%) received additional steroids after RCM injection. With this pharmacological prevention, patients of symptoms improved or no recurrence, recurrence of similar previous symptoms, and recurrence of worse symptoms were 98 (97.0%), 2 (2.0%), and 1 (1.0%), respectively. The proportions of no recurrence after pharmacological prevention were lower in patients with severe reactions and higher symptom scores. Conclusion Pharmacological prevention showed a beneficial effect in most patients with delayed hypersensitivity to RCM. Further investigations are needed to establish an effective protocol for the prevention of delayed reactions to RCM.
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Affiliation(s)
- Jung-Hyun Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.,Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, South Korea.,Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea.,Department of Internal Medicine, Korean Armed Forces Capital Hospital, Seongnam, South Korea
| | - Sang Il Choi
- Department of Radiology, Seoul National University Bundang Hospital, Seongnam-si, South Korea
| | - Yoon Jin Lee
- Department of Radiology, Seoul National University Bundang Hospital, Seongnam-si, South Korea
| | - Byung-Keun Kim
- Department of Internal Medicine, Korea University Medical Center Anam Hospital
| | - Heung-Woo Park
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.,Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, South Korea
| | - Sang-Heon Cho
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.,Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, South Korea
| | - Yoon-Seok Chang
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.,Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, South Korea.,Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Sae-Hoon Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.,Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, South Korea.,Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
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48
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Chen X, Hu Mt W, Yang M, Ling J, Zhang Y, Deng L, Li J, Lundkvist Ć
, Lindahl JF, Xiong Y. Risk factors for the delayed viral clearance in COVID-19 patients. J Clin Hypertens (Greenwich) 2021; 23:1483-1489. [PMID: 34171164 PMCID: PMC8420571 DOI: 10.1111/jch.14308] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 05/13/2021] [Accepted: 05/22/2021] [Indexed: 12/19/2022]
Abstract
Comorbidities are important for the disease outcome of COVIDā19, however, which underlying diseases that contribute the most to aggravate the conditions of COVIDā19 patients are still unclear. Viral clearance is the most important laboratory test for defining the recovery of COVIDā19 infections. To better understand which underlying diseases that are risk factors for delaying the viral clearance, we retrospectively analyzed 161 COVIDā19 clinical cases in the Zhongnan Hospital of Wuhan University, Wuhan, China between January 5 and March 13, 2020. The demographic, clinical and laboratory data, as well as patient treatment records were collected. Univariable and multivariable analysis were performed to explore the association between delayed viral clearance and other factors by using logistic regression. Survival analyses by KaplanāMeier and Cox regression modeling were employed to identify factors negatively influencing the viral clearance negatively. We found that hypertension and intravenous immunoglobulin adversely affected the time of viral RNA shedding. Hypertension was the most important risk factor to delay the SARSāCoVā2 virus clearance, however, the use of AngiotensināConverting Enzyme Inhibitors(ACEI)/Angiotensin Receptor Blockers(ARB) did not shorten the time for virus clearance in these hypertensive patientsā virus clearance. We conclude that patients having hypertension and intravenous immunoglobulin may delay the viral clearance in COVIDā19 patients.
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Affiliation(s)
- Xiaoping Chen
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Wenjia Hu Mt
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Miao Yang
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Jiaxin Ling
- Department of Medical Biochemistry and Microbiology, Zoonosis Science Center, University of Uppsala, Uppsala, Sweden
| | - Yongxi Zhang
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Liping Deng
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Jinlin Li
- Department of Medical Biochemistry and Microbiology, Zoonosis Science Center, University of Uppsala, Uppsala, Sweden.,Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Ć
ke Lundkvist
- Department of Medical Biochemistry and Microbiology, Zoonosis Science Center, University of Uppsala, Uppsala, Sweden
| | - Johanna F Lindahl
- Department of Medical Biochemistry and Microbiology, Zoonosis Science Center, University of Uppsala, Uppsala, Sweden.,Department of Biosciences, International Livestock Research Institute, Hanoi, Vietnam.,Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Yong Xiong
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
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49
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Rahman Qazi K, Jensen GB, van der Heiden M, Bjƶrkander S, Marchini G, Jenmalm MC, Abrahamsson T, Sverremark-Ekstrƶm E. Extreme prematurity and sepsis strongly influence frequencies and functional characteristics of circulating Ī³Ī“ T and natural killer cells. Clin Transl Immunology 2021; 10:e1294. [PMID: 34136218 PMCID: PMC8192243 DOI: 10.1002/cti2.1294] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 02/11/2021] [Accepted: 05/17/2021] [Indexed: 12/19/2022] Open
Abstract
Objectives Extremely low gestational age neonates with extremely low birthweight (ELGAN/ELBW) are highly susceptible to infection. This is linked to their relatively immature immune system which is not yet fully compatible with an extraāuterine environment. Here, we performed a longitudinal characterisation of unconventional T and natural killer (NK) cells in ELGAN/ELBW during their first months of life. Methods Peripheral blood mononuclear cells were collected from 97 ELGAN/ELBW at 14 and 28 days of life and at a time point corresponding to postmenstrual week 36 + 0. Ī³Ī“ Tācell, NKTācell, mucosaāassociated invariant Tācell and NK cell frequencies and characteristics were analysed by flow cytometry. As control, cells from 14ādayāold fullāterm (FT) infants were included. Results Extreme prematurity had significant bearing on Ī³Ī“ Tācell and NK cell frequencies and characteristics. ELGAN/ELBW had significantly higher proportions of Ī³Ī“ T cells that were skewed towards effector and effector memory phenotypes, characteristics that were maintained throughout the study period. Expression of the gut homing receptor CCR9 was also more common in Ī³Ī“ T cells from ELGAN/ELBW. Conversely, NK cell frequencies were markedly lower and skewed towards a cytotoxic phenotype in the ELGAN/ELBW group at 14 days of age. Cultureāproven sepsis with an onset during the first 14 days after birth further manifested these differences in the Ī³Ī“ Tā and NK cell populations at 14 days of age. Conclusion Prematurity strongly influences the levels of Ī³Ī“ T and NK cells, in particular in cases where sepsis debuts during the first 2 weeks of life.
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Affiliation(s)
- Khaleda Rahman Qazi
- Department of Molecular Biosciences The Wenner-Gren Institute Stockholm University Stockholm Sweden
| | - Georg B Jensen
- Department of Biomedical and Clinical Sciences Linkƶping University Linkƶping Sweden.,Department of Paediatrics Linkƶping University Linkƶping Sweden
| | - Marieke van der Heiden
- Department of Molecular Biosciences The Wenner-Gren Institute Stockholm University Stockholm Sweden
| | - Sophia Bjƶrkander
- Department of Molecular Biosciences The Wenner-Gren Institute Stockholm University Stockholm Sweden
| | - Giovanna Marchini
- Department of Women's and Children's Health Karolinska Institutet Stockholm Sweden
| | - Maria C Jenmalm
- Department of Biomedical and Clinical Sciences Linkƶping University Linkƶping Sweden
| | - Thomas Abrahamsson
- Department of Biomedical and Clinical Sciences Linkƶping University Linkƶping Sweden.,Department of Paediatrics Linkƶping University Linkƶping Sweden
| | - Eva Sverremark-Ekstrƶm
- Department of Molecular Biosciences The Wenner-Gren Institute Stockholm University Stockholm Sweden
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50
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Ali H, Harting R, de Vries R, Ali M, Wurdinger T, Best MG. Blood-Based Biomarkers for Glioma in the Context of Gliomagenesis: A Systematic Review. Front Oncol 2021; 11:665235. [PMID: 34150629 PMCID: PMC8211985 DOI: 10.3389/fonc.2021.665235] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 05/18/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Gliomas are the most common and aggressive tumors of the central nervous system. A robust and widely used blood-based biomarker for glioma has not yet been identified. In recent years, a plethora of new research on blood-based biomarkers for glial tumors has been published. In this review, we question which molecules, including proteins, nucleic acids, circulating cells, and metabolomics, are most promising blood-based biomarkers for glioma diagnosis, prognosis, monitoring and other purposes, and align them to the seminal processes of cancer. METHODS The Pubmed and Embase databases were systematically searched. Biomarkers were categorized in the identified biomolecules and biosources. Biomarker characteristics were assessed using the area under the curve (AUC), accuracy, sensitivity and/or specificity values and the degree of statistical significance among the assessed clinical groups was reported. RESULTS 7,919 references were identified: 3,596 in PubMed and 4,323 in Embase. Following screening of titles, abstracts and availability of full-text, 262 articles were included in the final systematic review. Panels of multiple biomarkers together consistently reached AUCs >0.8 and accuracies >80% for various purposes but especially for diagnostics. The accuracy of single biomarkers, consisting of only one measurement, was far more variable, but single microRNAs and proteins are generally more promising as compared to other biomarker types. CONCLUSION Panels of microRNAs and proteins are most promising biomarkers, while single biomarkers such as GFAP, IL-10 and individual miRNAs also hold promise. It is possible that panels are more accurate once these are involved in different, complementary cancer-related molecular pathways, because not all pathways may be dysregulated in cancer patients. As biomarkers seem to be increasingly dysregulated in patients with short survival, higher tumor grades and more pathological tumor types, it can be hypothesized that more pathways are dysregulated as the degree of malignancy of the glial tumor increases. Despite, none of the biomarkers found in the literature search seem to be currently ready for clinical implementation, and most of the studies report only preliminary application of the identified biomarkers. Hence, large-scale validation of currently identified and potential novel biomarkers to show clinical utility is warranted.
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Affiliation(s)
- Hamza Ali
- Department of Neurosurgery, Brain Tumor Center Amsterdam, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center and Academic Medical Center, Amsterdam, Netherlands
| | - RomƩe Harting
- Department of Neurosurgery, Brain Tumor Center Amsterdam, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center and Academic Medical Center, Amsterdam, Netherlands
| | - Ralph de Vries
- Medical Library, Vrije Universiteit, Amsterdam, Netherlands
| | - Meedie Ali
- Department of Neurosurgery, Brain Tumor Center Amsterdam, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center and Academic Medical Center, Amsterdam, Netherlands
| | - Thomas Wurdinger
- Department of Neurosurgery, Brain Tumor Center Amsterdam, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center and Academic Medical Center, Amsterdam, Netherlands
| | - Myron G. Best
- Department of Neurosurgery, Brain Tumor Center Amsterdam, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center and Academic Medical Center, Amsterdam, Netherlands
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