J Cohen

Ealing, Hammersmith & West London College, Londinium, England, United Kingdom

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Publications (91)587.21 Total impact

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    ABSTRACT: Global epidemiological data regarding outcomes for patients in intensive care units (ICUs) are scarce, but are important in understanding the worldwide burden of critical illness. We, therefore, did an international audit of ICU patients worldwide and assessed variations between hospitals and countries in terms of ICU mortality. 730 participating centres in 84 countries prospectively collected data on all adult (>16 years) patients admitted to their ICU between May 8 and May 18, 2012, except those admitted for fewer than 24 h for routine postoperative monitoring. Participation was voluntary. Data were collected daily for a maximum of 28 days in the ICU and patients were followed up for outcome data until death or hospital discharge. In-hospital death was analysed using multilevel logistic regression with three levels: patient, hospital, and country. 10 069 patients were included from ICUs in Europe (5445 patients; 54·1%), Asia (1928; 19·2%), the Americas (1723; 17·1%), Oceania (439; 4·4%), the Middle East (393; 3·9%), and Africa (141; 1·4%). Overall, 2973 patients (29·5%) had sepsis on admission or during the ICU stay. ICU mortality rates were 16·2% (95% CI 15·5-16·9) across the whole population and 25·8% (24·2-27·4) in patients with sepsis. Hospital mortality rates were 22·4% (21·6-23·2) in the whole population and 35·3% (33·5-37·1) in patients with sepsis. Using a multilevel analysis, the unconditional model suggested significant between-country variations (var=0·19, p=0·002) and between-hospital variations (var=0·43, p<0·0001) in the individual risk of in-hospital death. There was a stepwise increase in the adjusted risk of in-hospital death according to decrease in global national income. This large database highlights that sepsis remains a major health problem worldwide, associated with high mortality rates in all countries. Our findings also show a significant association between the risk of death and the global national income and suggest that ICU organisation has an important effect on risk of death. None.
    04/2014; DOI:10.1016/S2213-2600(14)70061-X
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    ABSTRACT: Background Infections are a leading cause of death in patients with advanced cirrhosis, but there are relatively few data on the epidemiology of infection in intensive care unit (ICU) patients with cirrhosis. AimsWe used data from the Extended Prevalence of Infection in Intensive Care (EPIC) II one-day point-prevalence study to better define the characteristics of infection in these patients. Methods We compared characteristics, including occurrence and types of infections in non-cirrhotic and cirrhotic patients who had not undergone liver transplantation. ResultsThe EPIC II database includes 13,796 adult patients from 1,265 ICUs: 410 of the patients had cirrhosis. The prevalence of infection was higher in cirrhotic than in non-cirrhotic patients (59 vs. 51%, p<0.01). The lungs were the most common site of infection in all patients, but abdominal infections were more common in cirrhotic than in non-cirrhotic patients (30 vs. 19%, p<0.01). Infected cirrhotic patients more often had Gram-positive (56 vs. 47%, p<0.05) isolates than did infected non-cirrhotic patients. Methicillin-resistant Staphylococcus aureus (MRSA) was more frequent in cirrhotic patients. The hospital mortality rate of cirrhotic patients was 42%, compared to 24% in the non-cirrhotic population (p<0.001). Severe sepsis and septic shock were associated with higher in-hospital mortality rates in cirrhotic than in non-cirrhotic patients (41% and 71% vs. 30% and 49%, respectively, p<0.05). Conclusions Infection is more common in cirrhotic than in non-cirrhotic ICU patients and more commonly due to Gram-positive organisms, including MRSA. Infection in patients with cirrhosis was associated with higher mortality rates than in non-cirrhotic patients.This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 03/2014; DOI:10.1111/liv.12520 · 4.41 Impact Factor
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    ABSTRACT: Introduction and Objectives Streptococcus pneumoniae is the commonest cause of pneumonia and associated with marked inflammatory responses that underpin its immunopathogenesis. Surprisingly little is known about the molecular determinants of host-pathogen interactions that mediate these responses. We have studied the role of the pneumococcal capsule and surface lipoproteins in innate immune responses by macrophages that comprise the first line of cellular immune defence within the lung.
    Thorax 11/2010; 65(Suppl 4):A37-A37. DOI:10.1136/thx.2010.150938.29 · 8.56 Impact Factor
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    ABSTRACT: The non-specific acute phase response in mice is associated with increased resistance to bacterial infection, which is critically mediated by granulocyte colony stimulating factor (G-CSF), but the behaviour of G-CSF in the human acute phase response is not known. Cardiothoracic surgery is a powerful acute phase stimulus and we show here that this procedure caused increased production of G-CSF, in addition to increases in the circulating concentrations of the proinflammatory cytokine interleukin (IL)-6 and the acute phase plasma proteins C-reactive protein (CRP) and serum amyloid A protein (SAA). Values of G-CSF correlated positively with IL-6 concentrations and circulating neutrophil counts, but not with CRP values. These results confirm that G-CSF is a physiological component of the acute phase response in humans that shares some of the same regulatory controls as IL-6, but its downstream effects are on neutrophils, not hepatic acute phase protein synthesis. Our observations are compatible with a protective role against bacterial infection for G-CSF in the human acute phase response, and support investigation of the prophylactic use of G-CSF in at-risk patients.
    Clinical & Experimental Immunology 05/2005; 140(1):97-100. DOI:10.1111/j.1365-2249.2005.02732.x · 3.28 Impact Factor
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    ABSTRACT: In this paper we review evidence in favor of a protective role for antibodies directed at the lipopolysaccharide (LPS) core region of Gram-negative bacilli. It will be shown that, given the right animal model, polyclonal antisera raised against O-antigen lacking, rough mutant strains, can be shown to protect animals against lethal sepsis due to a variety a bacterial species. Evidence for a protective role obtained from clinical studies will also be discussed. It will be stressed how difficult it is to prove that the antibodies directed against the LPS-core, and not other proteins present in the polyclonal anti-rough strain antisera, were responsible for the observed protective effects. The solution to some of these problems is the production of monoclonal antibodies (Mabs). We will discuss the findings that purified anti-core Mabs may give false-positive outcomes of protection studies, due to the induction of tolerance by small amounts of contaminating endotoxin, present in the antibody preparation. The need to administer the Mab therapeutically instead of prophylactically to the test animals, will be stressed. It will be shown how we succeeded in determining the epitope-specificities of several anti-core antibodies. It will be shown also that use of Elisa alone for characterization of anti-core Mabs may lead to false conclusions concerning epitope specificities. We will prove that synthetic KDO-(=ketodeoxycctanate) and lipid A-containing antigens are indispensable tools for thorough characterization of Mabs. Using this methodology we were able to discriminate between specific antigen-antibody interactions, and the ability of some Mabs to bind “non-specifically” to hydrophobic surfaces. The relationship between epitope specificity and protective effects of anti-core Mabs will be described. Finally, we will demonstrate that a KDO-specific Mabs is capable of protecting mice against lethal sepsis; in other words, it will be shown conclusively that Mabs to defined epitopes in LPS core region are cross-protective.
    Acta Biotechnologica 02/2004; 10(1):13 - 22. DOI:10.1002/abio.370100106
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    ABSTRACT: A case of an 18 year old woman is reported who presented with a pyrexia of unknown origin having returned from a trip to India. She initially had constitutional symptoms only, which rapidly progressed to a multisystem disorder. The difficulty in making the diagnosis of polyarteritis nodosa, especially with the possible differential diagnosis of infection after her recent travel, is discussed. The discussion reviews the condition of polyarteritis nodosa and analyses the diagnostic difficulties in this case.
    Postgraduate Medical Journal 12/2002; 78(925):685-6. DOI:10.1136/pmj.78.925.685 · 1.55 Impact Factor
  • W P Hanage, J Cohen
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    ABSTRACT: The viridans streptococci (VS) are associated with the development of a rapidly fulminant shock syndrome in neutropenic patients. A panel of 52 VS strains isolated from the blood of neutropenic patients was used to demonstrate the ability of culture supernatants and cell walls of VS to induce release of the proinflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-8 from whole blood in a dose- and strain-dependent fashion. Intercellular adhesion molecule-1 was shown to be markedly up-regulated on endothelial cells after incubation with plasma from blood exposed to cell walls or culture supernatants. This up-regulation was blocked by IL-1 receptor antagonist but not neutralizing antibody against TNF-alpha. These data may help explain the pathogenesis of the viridans streptococcal shock syndrome in neutropenic patients.
    The Journal of Infectious Diseases 03/2002; 185(3):357-67. DOI:10.1086/338375 · 5.78 Impact Factor
  • J Cohen
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    ABSTRACT: Sepsis is the systemic response to infection, and is caused by gram positive and gram negative bacteria in approximately equal numbers. In recent years it has become increasingly clear that there are significant differences between sepsis caused by gram positive and gram negative infections, both in the microbial components that initiate the injury, and the host responses that follow it. These differences will assume greater importance in developing targeted therapeutic interventions to severe sepsis.
    Journal of chemotherapy (Florence, Italy) 12/2001; 13 Spec No 1(1):153-8. DOI:10.1179/joc.2001.13.Supplement-2.153 · 1.07 Impact Factor
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    ABSTRACT: Bacterial superantigens are believed to cause septic shock, although, because of the lack of superantigen-sensitive infection models, proof that superantigenicity underlies shock pathogenesis is lacking. This work demonstrates a clear superantigen effect in septic shock resulting from bacterial infection. Transgenic expression of human leukocyte antigen (HLA)-DQ, but not HLA-DR, specifically augments lymphocyte responses to streptococcal pyrogenic exotoxin A (SPEA). HLA-DQ transgenic mice had increased mortality after administration of SPEA or infection with Streptococcus pyogenes. Immune activation during infection was HLA-DQ transgene-dependent and was manifested by Vbeta-specific T cell repertoire changes and widespread lymphoblastic tissue infiltration. Unlike earlier models, which used toxin-induced shock, these T cell superantigen responses and lymphoblastoid changes were observed during invasive streptococcal sepsis. Lymphoid activation was undetectable in HLA-DQ mice infected with an isogenic SPEA(-) strain, which proves that a single superantigen can play a role in sepsis pathogenesis.
    The Journal of Infectious Diseases 08/2001; 184(2):166-73. DOI:10.1086/322018 · 5.78 Impact Factor
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    ABSTRACT: The difficulty in identifying new treatment modalities that significantly reduce the mortality and morbidity rates associated with sepsis has highlighted the need to reevaluate the approach to clinical trial design. The United Kingdom Medical Research Council convened an International Working Party to address these issues. The subject areas that were to be the focus of discussion were identified by the co-chairs, and group leaders were nominated. Preconference reading material was circulated to group members. Small-group discussion fed into an iterative process of feedback from plenary sessions, followed by the formulation of recommendations. Finally, each working group prepared a summary of its recommendations and these are reported herein. There were five key recommendations. First, investigators should no longer rely solely on the American College of Chest Physicians/Society of Critical Care Medicine definitions of sepsis or sepsis syndrome as the basis of trial entry. Entry criteria should be based on three principles: a) All patients should have infection; b) there should be evidence of a pathologic process that represents a biologically plausible target for the proposed intervention, for example, an abnormal circulating level of a biological marker pertinent to the study drug; and c) patients should fall into an appropriate category of severity (usually severe sepsis). Second, investigators should use a scoring system for organ dysfunctions that has been validated and that can be incorporated into all sepsis studies; agreement on the use of a single system would simplify comparisons between studies. Third, the primary outcome measure generally should be mortality rates, but under appropriate circumstances major morbidities could be considered as primary end points. Regardless of choice of the duration to primary end point, patients should be followed for > or =90 days. Fourth, sample size needs to be based on a realistic assessment of achievable effect size based on knowledge of the at-risk population. Fifth, subgroups should be few in number and should be defined a priori on the basis of variables present before randomization. Important changes in several aspects of trial design may improve the quality of clinical studies in sepsis and maximize the chance of identifying effective therapeutic agents.
    Critical Care Medicine 04/2001; 29(4):880-6. DOI:10.1097/00003246-200104000-00039 · 6.15 Impact Factor
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    ABSTRACT: Serum amyloid P component (SAP) binds to Streptococcus pyogenes, and we show here that it also binds to Neisseria meningitidis, including a lipopolysaccharide (LPS)-negative mutant, and to rough variants of Escherichia coli. Surprisingly, this binding had a powerful antiopsonic effect both in vitro and in vivo, reducing phagocytosis and killing of bacteria. Furthermore, SAP knockout mice survived lethal infection with S. pyogenes and rough E. coli J5, organisms to which SAP binds. The susceptibility of SAP(-/-) mice was fully restored by injection of isolated human SAP. However, SAP(-/-) mice were more susceptible than wild-type animals to lethal infection with E. coli O111:B4, a smooth strain to which SAP does not bind, suggesting that SAP also has some host defense function. Although SAP binds to LPS in vitro, SAP(-/-) mice were only marginally more susceptible to lethal LPS challenge, and injection of large amounts of human SAP into wild-type mice did not affect sensitivity to LPS, indicating that SAP is not a significant modulator of LPS toxicity in vivo. In contrast, the binding of SAP to pathogenic bacteria enabled them to evade neutrophil phagocytosis and display enhanced virulence. Abrogation of this molecular camouflage is thus potentially a novel therapeutic approach, and we show here that administration to wild-type mice of (R)-1-[6-(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine -2- carboxylic acid, a drug that inhibits SAP binding, significantly prolonged survival during lethal infection with E. coli J5.
    Proceedings of the National Academy of Sciences 01/2001; 97(26):14584-9. DOI:10.1073/pnas.97.26.14584 · 9.81 Impact Factor
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    ABSTRACT: To investigate the role of mitogenic factor (MF) in streptococcal pathogenesis, the structural gene (mf) encoding this protein was disrupted in a clinical isolate of Streptococcus pyogenes H293, to yield the isogenic mutant H363. Growth in enriched broth and on blood agar was unaffected by disruption of mf. Cell-free broth supernatants from H293 and H363 demonstrated identical promitogenic activities when co-incubated with human peripheral blood mononuclear cells, even when diluted 100000-fold, showing that MF is not a major streptococcal mitogen compared with other secreted superantigens. Disruption of mf resulted in complete loss of DNase B production and detectable DNase activity in H363 compared with the parent strain, confirming that the single gene mf, which is present in all group A streptococcal M serotypes studied, encodes DNase B. Despite loss of DNase activity, the virulence of S. pyogenes in a mouse model of necrotizing fasciitis and myositis was unaffected.
    Microbiology 12/2000; 146 ( Pt 11):2785-92. · 2.84 Impact Factor
  • Critical Care Medicine 10/2000; 28(9 Suppl):S81-2. · 6.15 Impact Factor
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    J Cohen
    Clinical Microbiology and Infection 09/2000; 6(8):449-52. DOI:10.1046/j.1469-0691.2000.00123.x · 5.20 Impact Factor
  • S Sriskandan, J Cohen
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    ABSTRACT: A retrospective analysis of 7 patients with streptococcal toxic shock revealed isolated prolongation of the activated partial thromboplastin time, which returned to normal during recovery. Levels of factor XII were reduced in 2 patients who had single factor assays performed, consistent with activation of the kallikrein-kinin system. We speculate that bradykinin release following activation of the kallikrein-kinin system in streptococcal toxic shock may underlie the features of pain, capillary leaking, and severe hypotension characteristic of this syndrome.
    Clinical Infectious Diseases 07/2000; 30(6):961-2. DOI:10.1086/313827 · 9.42 Impact Factor
  • J Cohen
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    ABSTRACT: A considerable body of evidence has accumulated that implicates endotoxin in the pathogenesis of the sepsis syndrome. This has raised interest in the possibility of measuring endotoxin as a surrogate marker of Gram negative infection, particularly since conventional microbiological tests have an inevitable delay. The Limulus amoebocyte lysate (LAL) assay has been used most widely to measure endotoxin in clinical samples. However, there are several important limitations that need to be borne in mind. These include the dangers of contamination, lack of precision and accuracy, and both false positive and false negative results. Endotoxaemia is present in the blood of about 30% of patients with bacteraemia, but endotoxaemia does not predict either Gram negative bacteraemia or Gram negative infection, nor does it predict survival from sepsis. There is some correlation with severity of sepsis, but the level of precision is poor. At the present time, there is no place for routine endotoxin testing in clinical practice. In particular, the positive predictive value of the test is insufficiently high to be of clinical use. It may be that the LAL assay, or one of the newer developments, may be more useful in excluding Gram negative infection, but that remains to be shown.
    Intensive Care Medicine 02/2000; 26 Suppl 1:S51-6. DOI:10.1007/s001340051119 · 5.54 Impact Factor
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    ABSTRACT: The effect of growth phase on expression of virulence-associated factors was studied by Northern hybridization in an M1T1 clinical isolate of Streptococcus pyogenes. Expression of M protein, C5a peptidase, and capsule was maximal in the exponential phase of growth, while streptococcal pyrogenic exotoxins A and B and mitogenic factor were maximally expressed in later phases of growth.
    Infection and Immunity 11/1999; 67(10):5495-9. · 4.16 Impact Factor
  • S Sriskandan, J Cohen
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    ABSTRACT: This article has reviewed the mechanisms by which gram-positive bacteria lead to septic shock, with regard to bacterial structure and toxicology and the host responses elicited both in animal models and in the clinical setting. Gram-positive organisms are better suited to invade host tissues and elicit, in general, a brisker phagocytic response than gram-negative organisms. The lack of endotoxin in the outer cell wall is compensated for by the presence of exposed peptidoglycan and a range of other toxic secreted products. It appears that cell wall components of gram-positive bacteria may signal via the same receptor as gram-negative endotoxin, although the type of signal and coreceptor may differ. Both animal and clinical data suggest that, unlike endotoxin-mediated shock, gram-positive infection produces a modest TNF response only and does not respond well to anti-TNF therapies. This leads one to conclude that the mechanisms leading to shock in gram-positive infection may be multifactorial and perhaps more difficult to treat. A thorough review of gram-positive mechanisms of sepsis is hampered by a lack of basic research in this field. Understanding of gram-negative bacterial structure and the regulation of virulence genes is at an advanced stage, yet the molecular tools to analyse virulence factors in the gram-positive genome have only recently become available. There is a paucity of good animal models of gram-positive infection and a lack of microbiologic data from some of the major trials in sepsis that might have given greater insight into the mechanisms leading to shock in various infections.
    Infectious Disease Clinics of North America 07/1999; 13(2):397-412. · 2.31 Impact Factor
  • Journal of Infection 07/1999; 39(1):A8. DOI:10.1016/S0163-4453(99)90136-6 · 4.02 Impact Factor
  • Shock 01/1999; 12(Supplement):21-22. DOI:10.1097/00024382-199911001-00066 · 2.73 Impact Factor

Publication Stats

3k Citations
587.21 Total Impact Points

Institutions

  • 1985–2004
    • Ealing, Hammersmith & West London College
      Londinium, England, United Kingdom
  • 2000–2001
    • Imperial College London
      • • Department of Infectious Disease Epidemiology
      • • Division of Infectious Diseases
      London, ENG, United Kingdom
  • 1996
    • Hôpital Paris Saint Joseph
      Lutetia Parisorum, Île-de-France, France
  • 1993
    • Royal United Hospital Bath NHS Trust
      Bath, England, United Kingdom