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Article: Prospects for antigen-specific tolerance based therapies for the treatment of multiple sclerosis.

Turley, Danielle M / Miller, Stephen D

Results and problems in cell differentiation

2009 Volume 51, Page(s) 217–235

Abstract: A primary focus in autoimmunity is the breakdown of central and peripheral tolerance resulting in the survival and eventual activation of autoreactive T cells. As CD4(+) T cells are key contributors to the underlying pathogenic mechanisms responsible for ...

Abstract	A primary focus in autoimmunity is the breakdown of central and peripheral tolerance resulting in the survival and eventual activation of autoreactive T cells. As CD4(+) T cells are key contributors to the underlying pathogenic mechanisms responsible for onset and progression of most autoimmune diseases, they are a logical target for therapeutic strategies. One method for restoring self-tolerance is to exploit the endogenous regulatory mechanisms that govern CD4(+) T cell activation. In this review, we discuss tolerance strategies with the common goal of inducing antigen (Ag)-specific tolerance. Emphasis is given to the use of peptide-specific tolerance strategies, focusing on ethylene carbodiimide (ECDI)-peptide-coupled cells (Ag-SP) and nonmitogenic anti-CD3, which specifically target the T cell receptor (TCR) in the absence of costimulatory signals. These approaches induce a TCR signal of insufficient strength to cause CD4(+) T cell activation and instead lead to functional T cell anergy/deletion and activation of Ag-specific induced regulatory T cells (iTregs) while avoiding generalized long-term immunosuppression.
MeSH term(s)	Animals ; Antibodies, Monoclonal/therapeutic use ; Autoantigens ; Autoimmunity ; CD4-Positive T-Lymphocytes/immunology ; Carbodiimides ; Encephalomyelitis, Autoimmune, Experimental/immunology ; Encephalomyelitis, Autoimmune, Experimental/therapy ; Humans ; Immunity, Mucosal ; Immunosuppression/methods ; Immunosuppression/trends ; Mice ; Multiple Sclerosis/immunology ; Multiple Sclerosis/therapy ; Peptides/immunology ; Receptors, Antigen, T-Cell/immunology ; Self Tolerance ; T-Lymphocytes, Regulatory/immunology
Chemical Substances	Antibodies, Monoclonal ; Autoantigens ; Carbodiimides ; Peptides ; Receptors, Antigen, T-Cell
Language	English
Publishing date	2009-01-07
Publishing country	Germany
Document type	Journal Article ; Review
ISSN	0080-1844
ISSN	0080-1844
DOI	10.1007/400_2008_13
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Article: Peripheral tolerance induction using ethylenecarbodiimide-fixed APCs uses both direct and indirect mechanisms of antigen presentation for prevention of experimental autoimmune encephalomyelitis.

Turley, Danielle M / Miller, Stephen D

Journal of immunology (Baltimore, Md. : 1950)

2007 Volume 178, Issue 4, Page(s) 2212–2220

Abstract: MHC class II (MHC II)-restricted T cell responses are a common driving force of autoimmune disease. Accordingly, numerous therapeutic strategies target CD4(+) T cells with the hope of attenuating autoimmune responses and restoring self-tolerance. We have ...

Abstract	MHC class II (MHC II)-restricted T cell responses are a common driving force of autoimmune disease. Accordingly, numerous therapeutic strategies target CD4(+) T cells with the hope of attenuating autoimmune responses and restoring self-tolerance. We have previously reported that i.v. treatment with Ag-pulsed, ethylenecarbodiimide (ECDI)-fixed splenocytes (Ag-SPs) is an efficient protocol to induce Ag-specific tolerance for prevention and treatment of experimental autoimmune encephalomyelitis (EAE). Ag-SPs coupled with peptide can directly present peptide:MHC II complexes to target CD4(+) T cells in the absence of costimulation to induce anergy. However, Ag-SPs coupled with whole protein also efficiently attenuates Ag-specific T cell responses suggesting the potential contribution of alternative indirect mechanisms/interactions between the Ag-SPs and target CD4(+) T cells. Thus, we investigated whether MHC II compatibility was essential to the underlying mechanisms by which Ag-SP induces tolerance during autoimmune disease. Using MHC-deficient, allogeneic, and/or syngeneic donor Ag-SPs, we show that MHC compatibility between the Ag-SP donor and the host is not required for tolerance induction. Interestingly, we found that ECDI treatment induces apoptosis of the donor cell population which promotes uptake and reprocessing of donor cell peptides by host APCs resulting in the apparent MHC II-independent induction of tolerance. However, syngeneic donor cells are more efficient at inducing tolerance, suggesting that Ag-SPs induce functional Ag-SP tolerance via both direct and indirect (cross-tolerance) mechanisms leading to prevention and effective treatment of autoimmune disease.
MeSH term(s)	Animals ; Antigen Presentation/drug effects ; Antigen Presentation/immunology ; Antigen-Presenting Cells/immunology ; Antigen-Presenting Cells/transplantation ; Apoptosis/immunology ; Autoantigens/immunology ; Autoantigens/pharmacology ; CD4-Positive T-Lymphocytes/immunology ; Carbodiimides/chemistry ; Cell Communication/drug effects ; Cell Communication/immunology ; Cells, Cultured ; Encephalomyelitis, Autoimmune, Experimental/immunology ; Encephalomyelitis, Autoimmune, Experimental/prevention & control ; Fixatives/chemistry ; Histocompatibility Antigens Class II/immunology ; Immune Tolerance/drug effects ; Mice ; Mice, Inbred BALB C ; Transplantation, Homologous ; Transplantation, Isogeneic
Chemical Substances	Autoantigens ; Carbodiimides ; Fixatives ; Histocompatibility Antigens Class II
Language	English
Publishing date	2007-03-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.178.4.2212
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Article ; Online: Cancer multidisciplinary team meetings in practice: Results from a multi-institutional quantitative survey and implications for policy change.

Rankin, Nicole M / Lai, Michelle / Miller, Danielle / Beale, Philip / Spigelman, Allan / Prest, Gabrielle / Turley, Kim / Simes, John

Asia-Pacific journal of clinical oncology

2017

Abstract: Aim: Multidisciplinary care is advocated as best practice in cancer care. Relatively little is documented about multidisciplinary team (MDT) meeting functioning, decision making and the use of evidence to support decision making in Australia. This ... ...

Abstract	Aim: Multidisciplinary care is advocated as best practice in cancer care. Relatively little is documented about multidisciplinary team (MDT) meeting functioning, decision making and the use of evidence to support decision making in Australia. This descriptive study aimed to examine team functioning, the role of team meetings and evidence use in MDTs whose institutions are members of Sydney Catalyst Translational Cancer Research Centre. Methods: We designed a structured 40-item survey instrument about topics that included meeting purpose, organization, resources and documentation; caseload estimates; use of evidence and quality assurance; patient involvement and supportive care needs; and open-ended items about the MDTs strengths and weaknesses. Participants were invited to participate via email and the survey was administered online. Data were analyzed using descriptive and comparative statistics. Results: Thirty-seven MDTs from seven hospitals participated (100% response) and represented common (70%) and rare tumor groups (30%). MDT meeting purpose was reported as treatment (100%) or diagnostic decision making (88%), or for education purposes (70%). Most MDTs based treatment decisions on group consensus (92%), adherence to clinical practice guidelines (57%) or other evidence-based medicine sources (33%). The majority of MDTs discussed only a proportion of new patients at each meeting emphasizing the importance of educational aspects for other cases. Barriers exist in the availability of data to enable audit and reflection on evidence-based practice. MDT strengths included collaboration and quality discussion about patients. Conclusions: MDT meetings focus on treatment decision making, with group consensus playing a significant role in translating research evidence from guidelines into clinical decision making. With a varying proportion of patients discussed in each MDT meeting, a wider audit of multidisciplinary care would enable more accurate assessments of whether treatment recommendations are in accordance with best-practice evidence.
Language	English
Publishing date	2017-09-26
Publishing country	Australia
Document type	Journal Article
ZDB-ID	2187409-8
ISSN	1743-7563 ; 1743-7555
ISSN (online)	1743-7563
ISSN	1743-7555
DOI	10.1111/ajco.12765
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Article ; Online: Regulatory perspective on minimal residual disease flow cytometry testing in multiple myeloma.

Gormley, Nicole J / Turley, Danielle M / Dickey, Jennifer S / Farrell, Ann T / Reaman, Gregory H / Stafford, Elizabeth / Carrington, Lea / Marti, Gerald E

Cytometry. Part B, Clinical cytometry

2016 Volume 90, Issue 1, Page(s) 73–80

Abstract: The FDA has co-sponsored three workshops to address minimal residual disease (MRD) detection in acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), and acute myeloid leukemia (AML) as well as an FDA-NCI roundtable symposium on MRD ... ...

Abstract	The FDA has co-sponsored three workshops to address minimal residual disease (MRD) detection in acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), and acute myeloid leukemia (AML) as well as an FDA-NCI roundtable symposium on MRD detection and its use as a response biomarker in Multiple Myeloma (MM). As clinical outcomes in MM continue to improve with the introduction of new therapeutics, consideration of biomarkers and their development as validated surrogate endpoints that can be used in the place of traditional clinical trial endpoints of progression-free survival (PFS) will be fundamental to expeditious drug development. This article will describe the FDA drug approval process, the regulatory framework through which a biomarker can be used as a surrogate endpoint for drug approval, and how MRD detection in MM fits within this context. In parallel, this article will also describe the FDA current device clearance process with emphasis on the analytical development as it might apply to an in vitro diagnostic assay for the detection of MRD in MM. It is anticipated that this Special Issue may possibly represent how MRD might serve as a drug development tool in hematological malignancies.
MeSH term(s)	Antigens, CD/analysis ; Antigens, CD/genetics ; Antigens, CD/immunology ; Antineoplastic Agents/therapeutic use ; Biomarkers, Pharmacological/analysis ; Device Approval/legislation & jurisprudence ; Drug Approval/legislation & jurisprudence ; Flow Cytometry/standards ; Gene Expression ; Humans ; Immunophenotyping ; Multiple Myeloma/diagnosis ; Multiple Myeloma/drug therapy ; Multiple Myeloma/immunology ; Multiple Myeloma/mortality ; Neoplasm, Residual/diagnosis ; Neoplasm, Residual/drug therapy ; Neoplasm, Residual/immunology ; Neoplasm, Residual/mortality ; Plasma Cells/drug effects ; Plasma Cells/immunology ; Plasma Cells/pathology ; Prognosis ; Remission Induction ; Survival Analysis ; United States ; United States Food and Drug Administration
Chemical Substances	Antigens, CD ; Antineoplastic Agents ; Biomarkers, Pharmacological
Language	English
Publishing date	2016-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2099657-3
ISSN	1552-4957 ; 1552-4949 ; 0196-4763
ISSN (online)	1552-4957
ISSN	1552-4949 ; 0196-4763
DOI	10.1002/cyto.b.21268
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Article: Therapeutic blockade of T-cell antigen receptor signal transduction and costimulation in autoimmune disease.

Podojil, Joseph R / Turley, Danielle M / Miller, Stephen D

Advances in experimental medicine and biology

2008 Volume 640, Page(s) 234–251

Abstract: CD4+ T-cell-mediated autoimmune diseases are initiated and maintained by the presentation of self-antigen by antigen-presenting cells (APCs) to self-reactive CD4+ T-cells. According to the two-signal hypothesis, activation of a naive antigen-specific CD4+ ...

Abstract	CD4+ T-cell-mediated autoimmune diseases are initiated and maintained by the presentation of self-antigen by antigen-presenting cells (APCs) to self-reactive CD4+ T-cells. According to the two-signal hypothesis, activation of a naive antigen-specific CD4+ T-cell requires stimulation of both the T-cell antigen receptor (signal 1) and costimulatory molecules such as CD28 (signal 2). To date, the majority of therapies for autoimmune diseases approved by the Food and Drug Administration primarily focus on the global inhibition of immune inflammatory activity. The goal of ongoing research in this field is to develop antigen-specific treatments which block the deleterious effects of self-reactive immune cell function while maintaining the ability of the immune system to clear nonself antigens. To this end, the signaling pathways involved in the induction of CD4+ T-cell anergy, as apposed to activation, are a topic of intense interest. This chapter discusses components of the CD4+ T-cell activation pathway that may serve as therapeutic targets for the treatment of autoimmune disease.
MeSH term(s)	Animals ; Autoimmune Diseases/immunology ; Autoimmune Diseases/therapy ; Humans ; Immune Tolerance/immunology ; Immunological Synapses/immunology ; Lymphocyte Activation/immunology ; Receptors, Antigen, T-Cell/immunology ; Signal Transduction/immunology
Chemical Substances	Receptors, Antigen, T-Cell
Language	English
Publishing date	2008-12-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-0-387-09789-3_18
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Article ; Online: Antigen-specific tolerance strategies for the prevention and treatment of autoimmune disease.

Miller, Stephen D / Turley, Danielle M / Podojil, Joseph R

Nature reviews. Immunology

2007 Volume 7, Issue 9, Page(s) 665–677

Abstract: The development of safe and effective antigen-specific therapies is needed to treat patients with autoimmune diseases. These therapies must allow for the specific tolerization of self-reactive immune cells without altering host immunity to infectious ... ...

Abstract	The development of safe and effective antigen-specific therapies is needed to treat patients with autoimmune diseases. These therapies must allow for the specific tolerization of self-reactive immune cells without altering host immunity to infectious insults. Experimental models and clinical trials for the treatment of autoimmune disease have identified putative mechanisms by which antigen-specific therapies induce tolerance. Although advances have been made in the development of efficient antigen-specific therapies, translating these therapies from bench to bedside has remained difficult. Here, we discuss the recent advances in our understanding of antigen-specific therapies for the treatment of autoimmune diseases.
MeSH term(s)	Animals ; Autoantigens/immunology ; Autoimmune Diseases/drug therapy ; Autoimmune Diseases/prevention & control ; Autoimmune Diseases/therapy ; Clinical Trials as Topic ; Disease Models, Animal ; Humans ; Immune Tolerance ; Immunotherapy/methods ; Mice ; Peptides/immunology ; Peptides/therapeutic use
Chemical Substances	Autoantigens ; Peptides
Language	English
Publishing date	2007-09
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2062776-2
ISSN	1474-1741 ; 1474-1733
ISSN (online)	1474-1741
ISSN	1474-1733
DOI	10.1038/nri2153
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Article: Targeting the TCR: T-cell receptor and peptide-specific tolerance-based strategies for restoring self-tolerance in CNS autoimmune disease.

Kohm, Adam P / Turley, Danielle M / Miller, Stephen D

International reviews of immunology

2005 Volume 24, Issue 5-6, Page(s) 361–392

Abstract: A principal theme in autoimmunity is the breakdown of central tolerance resulting in the persistence and eventual activation of autoreactive T cells. Because CD4(+) T cells are key contributors to the underlying pathogenic mechanisms responsible for the ... ...

Abstract	A principal theme in autoimmunity is the breakdown of central tolerance resulting in the persistence and eventual activation of autoreactive T cells. Because CD4(+) T cells are key contributors to the underlying pathogenic mechanisms responsible for the onset and progression of most autoimmune diseases, they are a logical target for therapeutic interventions. One technique for restoring self-tolerance is to exploit the endogenous regulatory mechanisms that govern CD4(+) T-cell activation. In this review, we discuss promising techniques with the common goal of inducing antigen (Ag)-specific tolerance. Emphasis is given to the use of non-mitogenic anti-CD3 and peptide-specific tolerance strategies that specifically target the T-cell receptor (TCR) in the absence of costimulatory signals. These approaches produce a TCR signal of insufficient strength to cause CD4(+) T-cell activation and instead induce functional T-cell anergy or deletion while avoiding generalized long-term immunosuppression.
MeSH term(s)	Animals ; Antibodies, Monoclonal/immunology ; Antibodies, Monoclonal/therapeutic use ; Autoimmune Diseases of the Nervous System/immunology ; Autoimmune Diseases of the Nervous System/therapy ; CD3 Complex/immunology ; Clinical Trials as Topic ; Cytokines/immunology ; Humans ; Immunosuppression/methods ; Immunotherapy/methods ; Models, Immunological ; Multiple Sclerosis/immunology ; Multiple Sclerosis/therapy ; Peptides/immunology ; Peptides/therapeutic use ; Receptors, Antigen, T-Cell/immunology ; Receptors, Interleukin-2/immunology ; Self Tolerance/immunology ; T-Lymphocyte Subsets/immunology ; T-Lymphocytes, Regulatory/immunology
Chemical Substances	Antibodies, Monoclonal ; CD3 Complex ; Cytokines ; Peptides ; Receptors, Antigen, T-Cell ; Receptors, Interleukin-2
Language	English
Publishing date	2005-09
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	632825-8
ISSN	1545-5858 ; 0883-0185
ISSN (online)	1545-5858
ISSN	0883-0185
DOI	10.1080/08830180500371207
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Article ; Online: Sepsis Prevalence and Outcome on the General Wards and Emergency Departments in Wales: Results of a Multi-Centre, Observational, Point Prevalence Study.

PloS one

2016 Volume 11, Issue 12, Page(s) e0167230

Abstract: Data on sepsis prevalence on the general wards is lacking on the UK and in the developed world. We conducted a multicentre, prospective, observational study of the prevalence of patients with sepsis or severe sepsis on the general wards and Emergency ... ...

Abstract	Data on sepsis prevalence on the general wards is lacking on the UK and in the developed world. We conducted a multicentre, prospective, observational study of the prevalence of patients with sepsis or severe sepsis on the general wards and Emergency Departments (ED) in Wales. During the 24-hour study period all patients with NEWS≥3 were screened for presence of 2 or more SIRS criteria. To be eligible for inclusion, patients had to have a high clinical suspicion of an infection, together with a systemic inflammatory response (sepsis) and evidence of acute organ dysfunction and/or shock (severe sepsis). There were 5317 in-patients in the 24-hour study period. Data were returned on 1198 digital data collection forms on patients with NEWS≥3 of which 87 were removed, leaving 1111 for analysis. 146 patients had sepsis and 144 patients had severe sepsis. Combined prevalence of sepsis and severe sepsis was 5.5% amongst all in-patients. Patients with sepsis had significantly higher NEWS scores (3 IQR 3-4 for non-sepsis and 4 IQR 3-6 for sepsis patients, respectively). Common organ dysfunctions in severe sepsis were hypoxia (47%), hypoperfusion (40%) and acute kidney injury (25%). Mortality at 90 days was 31% with a median (IQR) hospital free stay of 78 (36-85) days. Screening for sepsis, referral to Critical Care and completion of Sepsis 6 bundle was low: 26%, 16% and 12% in the sepsis group. Multivariable logistic regression analysis identified higher National Early Warning Score, diabetes, COPD, heart failure, malignancy and current or previous smoking habits as independent variables suggesting the diagnosis of sepsis. We observed that sepsis is more prevalent in the general ward and ED than previously suggested before and that screening and effective treatment for sepsis and severe sepsis is far from being operationalized in this environment, leading to high 90 days mortality.
MeSH term(s)	Aged ; Aged, 80 and over ; Comorbidity ; Cross Infection/epidemiology ; Cross Infection/mortality ; Emergency Service, Hospital/statistics & numerical data ; Female ; Humans ; Logistic Models ; Male ; Middle Aged ; Patient Outcome Assessment ; Patients' Rooms/statistics & numerical data ; Prevalence ; Risk Factors ; Sepsis/diagnosis ; Sepsis/epidemiology ; Sepsis/mortality ; Wales/epidemiology
Language	English
Publishing date	2016
Publishing country	United States
Document type	Journal Article ; Multicenter Study ; Observational Study
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0167230
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Article ; Online: Tolerance induced by apoptotic antigen-coupled leukocytes is induced by PD-L1+ and IL-10-producing splenic macrophages and maintained by T regulatory cells.

Getts, Daniel R / Turley, Danielle M / Smith, Cassandra E / Harp, Christopher T / McCarthy, Derrick / Feeney, Emma M / Getts, Meghann Teague / Martin, Aaron J / Luo, Xunrong / Terry, Rachael L / King, Nicholas J C / Miller, Stephen D

Journal of immunology (Baltimore, Md. : 1950)

2011 Volume 187, Issue 5, Page(s) 2405–2417

Abstract: Ag-specific tolerance is a highly desired therapy for immune-mediated diseases. Intravenous infusion of protein/peptide Ags linked to syngeneic splenic leukocytes with ethylene carbodiimide (Ag-coupled splenocytes [Ag-SP]) has been demonstrated to be a ... ...

Abstract	Ag-specific tolerance is a highly desired therapy for immune-mediated diseases. Intravenous infusion of protein/peptide Ags linked to syngeneic splenic leukocytes with ethylene carbodiimide (Ag-coupled splenocytes [Ag-SP]) has been demonstrated to be a highly efficient method for inducing peripheral, Ag-specific T cell tolerance for treatment of autoimmune disease. However, little is understood about the mechanisms underlying this therapy. In this study, we show that apoptotic Ag-SP accumulate in the splenic marginal zone, where their uptake by F4/80(+) macrophages induces production of IL-10, which upregulates the expression of the immunomodulatory costimulatory molecule PD-L1 that is essential for Ag-SP tolerance induction. Ag-SP infusion also induces T regulatory cells that are dispensable for tolerance induction but required for long-term tolerance maintenance. Collectively, these results indicate that Ag-SP tolerance recapitulates how tolerance is normally maintained in the hematopoietic compartment and highlight the interplay between the innate and adaptive immune systems in the induction of Ag-SP tolerance. To our knowledge, we show for the first time that tolerance results from the synergistic effects of two distinct mechanisms, PD-L1-dependent T cell-intrinsic unresponsiveness and the activation of T regulatory cells. These findings are particularly relevant as this tolerance protocol is currently being tested in a Phase I/IIa clinical trial in new-onset relapsing-remitting multiple sclerosis.
MeSH term(s)	Animals ; Antigens/immunology ; Apoptosis/immunology ; B7-1 Antigen/biosynthesis ; B7-1 Antigen/immunology ; B7-H1 Antigen ; Cell Separation ; Encephalomyelitis, Autoimmune, Experimental/immunology ; Enzyme-Linked Immunosorbent Assay ; Female ; Flow Cytometry ; Immune Tolerance/immunology ; Immunohistochemistry ; Interleukin-10/biosynthesis ; Interleukin-10/immunology ; Lymphocyte Activation/immunology ; Lymphocytes/immunology ; Macrophage Activation/immunology ; Macrophages/immunology ; Macrophages/metabolism ; Membrane Glycoproteins/biosynthesis ; Membrane Glycoproteins/immunology ; Mice ; Mice, Inbred C57BL ; Myelin Proteolipid Protein/immunology ; Peptide Fragments/immunology ; Peptides/immunology ; Spleen/cytology ; Spleen/immunology ; T-Lymphocytes, Regulatory/immunology
Chemical Substances	Antigens ; B7-1 Antigen ; B7-H1 Antigen ; Cd274 protein, mouse ; Membrane Glycoproteins ; Myelin Proteolipid Protein ; Peptide Fragments ; Peptides ; myelin proteolipid protein (139-151) ; Interleukin-10 (130068-27-8)
Language	English
Publishing date	2011-08-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.1004175
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Article ; Online: Sepsis Prevalence and Outcome on the General Wards and Emergency Departments in Wales

PLoS ONE, Vol 11, Iss 12, p e

Results of a Multi-Centre, Observational, Point Prevalence Study.

2016 Volume 0167230

Abstract	Data on sepsis prevalence on the general wards is lacking on the UK and in the developed world. We conducted a multicentre, prospective, observational study of the prevalence of patients with sepsis or severe sepsis on the general wards and Emergency Departments (ED) in Wales. During the 24-hour study period all patients with NEWS≥3 were screened for presence of 2 or more SIRS criteria. To be eligible for inclusion, patients had to have a high clinical suspicion of an infection, together with a systemic inflammatory response (sepsis) and evidence of acute organ dysfunction and/or shock (severe sepsis). There were 5317 in-patients in the 24-hour study period. Data were returned on 1198 digital data collection forms on patients with NEWS≥3 of which 87 were removed, leaving 1111 for analysis. 146 patients had sepsis and 144 patients had severe sepsis. Combined prevalence of sepsis and severe sepsis was 5.5% amongst all in-patients. Patients with sepsis had significantly higher NEWS scores (3 IQR 3-4 for non-sepsis and 4 IQR 3-6 for sepsis patients, respectively). Common organ dysfunctions in severe sepsis were hypoxia (47%), hypoperfusion (40%) and acute kidney injury (25%). Mortality at 90 days was 31% with a median (IQR) hospital free stay of 78 (36-85) days. Screening for sepsis, referral to Critical Care and completion of Sepsis 6 bundle was low: 26%, 16% and 12% in the sepsis group. Multivariable logistic regression analysis identified higher National Early Warning Score, diabetes, COPD, heart failure, malignancy and current or previous smoking habits as independent variables suggesting the diagnosis of sepsis. We observed that sepsis is more prevalent in the general ward and ED than previously suggested before and that screening and effective treatment for sepsis and severe sepsis is far from being operationalized in this environment, leading to high 90 days mortality.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2016-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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