scholarly journals Revising Host Phenotypes of Sepsis Using Microbiology

2021 ◽  
Vol 8 ◽  
Author(s):  
Huiying Zhao ◽  
Jason N. Kennedy ◽  
Shu Wang ◽  
Emily B. Brant ◽  
Gordon R. Bernard ◽  
...  
Keyword(s):  
Severe Sepsis ◽  
Latent Class ◽  
Secondary Analysis ◽  
Activated Protein C ◽  
Plasminogen Activator Inhibitor ◽  
Rank Test ◽  
Clinical Variables ◽  
Host Pathogen ◽  
Individual Variables ◽  
Abdominal Infections

Background: There is wide heterogeneity in sepsis in causative pathogens, host response, organ dysfunction, and outcomes. Clinical and biologic phenotypes of sepsis are proposed, but the role of pathogen data on sepsis classification is unknown.Methods: We conducted a secondary analysis of the Recombinant Human Activated Protein C (rhAPC) Worldwide Evaluation in Severe Sepsis (PROWESS) Study. We used latent class analysis (LCA) to identify sepsis phenotypes using, (i) only clinical variables (“host model”) and, (ii) combining clinical with microbiology variables (e.g., site of infection, culture-derived pathogen type, and anti-microbial resistance characteristics, “host-pathogen model”). We describe clinical characteristics, serum biomarkers, and outcomes of host and host-pathogen models. We tested the treatment effects of rhAPC by phenotype using Kaplan-Meier curves.Results: Among 1,690 subjects with severe sepsis, latent class modeling derived a 4-class host model and a 4-class host-pathogen model. In the host model, alpha type (N = 327, 19%) was younger and had less shock; beta type (N=518, 31%) was older with more comorbidities; gamma type (N = 532, 32%) had more pulmonary dysfunction; delta type (N = 313, 19%) had more liver, renal and hematologic dysfunction and shock. After the addition of microbiologic variables, 772 (46%) patients changed phenotype membership, and the median probability of phenotype membership increased from 0.95 to 0.97 (P < 0.01). When microbiology data were added, the contribution of individual variables to phenotypes showed greater change for beta and gamma types. In beta type, the proportion of abdominal infections (from 20 to 40%) increased, while gamma type patients had an increased rate of lung infections (from 50 to 78%) with worsening pulmonary function. Markers of coagulation such as d-dimer and plasminogen activator inhibitor (PAI)-1 were greater in the beta type and lower in the gamma type. The 28 day mortality was significantly different for individual phenotypes in host and host-pathogen models (both P < 0.01). The treatment effect of rhAPC obviously changed in gamma type when microbiology data were added (P-values of log rank test changed from 0.047 to 0.780).Conclusions: Sepsis host phenotype assignment was significantly modified when microbiology data were added to clinical variables, increasing cluster cohesiveness and homogeneity.

scholarly journals Pathogenetic and predictive value of biomarkers in patients with ALI and lower severity of illness: results from two clinical trials

2012 ◽  
Vol 303 (8) ◽  
pp. L634-L639 ◽  
Author(s):  
Ashish Agrawal ◽  
Hanjing Zhuo ◽  
Sandra Brady ◽  
Joseph Levitt ◽  
Jay Steingrub ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Clinical Outcomes ◽  
Predictive Value ◽  
Secondary Analysis ◽  
Activated Protein C ◽  
Oxygenation Index ◽  
Severity Of Illness ◽  
Plasminogen Activator Inhibitor ◽  
High Plasma ◽  
Plasminogen Activator Inhibitor 1

Plasma and bronchoalveolar lavage (BAL) biomarkers related to the pathogenesis of acute lung injury (ALI) have previously been associated with poorer clinical outcomes and increased disease severity among patients with ALI. Whether these biomarkers have predictive value in a less severely ill population that excludes septic patients with high APACHE II scores is currently unknown. We tested the association of plasma and BAL biomarkers with physiological markers of ALI severity or clinically relevant outcomes in a secondary analysis of a clinical trial of activated protein C for the treatment of ALI. Plasma plasminogen activator inhibitor-1 (PAI-1) and mini-BAL protein were both significantly associated with increased oxygenation index ( P = 0.02 and 0.01, respectively), whereas there was a trend toward an association between IL-6 and oxygenation index ( P = 0.057). High plasma IL-6, thrombomodulin, and mini-BAL protein were all significantly associated with fewer ventilator-free days (VFDs) ( P = 0.01, 0.01, and 0.05, respectively); no markers were associated with mortality, but we hypothesized that this was due to the small size of our cohort and the low death rate. To confirm these associations in a larger sample, we identified a restricted cohort of patients from the ARDS Network ALVEOLI study with similar baseline characteristics. We retested the associations of the significant biomarkers with markers of severity and clinical outcomes and studied IL-8 as an additional biomarker given its important predictive value in prior studies. In this restricted cohort, IL-6 was significantly associated with oxygenation index ( P = 0.02). Both IL-6 and IL-8 were associated with decreased VFDs and increased 28-day mortality. Future studies should be focused on examining larger numbers of patients with less severe ALI to further test the relative predictive value of plasma and mini-BAL biomarkers for clinically relevant outcomes, including VFDs and mortality, and for their prospective utility in risk stratification for future clinical trials.

APC Resistance and other Haemostatic Variables during Pregnancy and Puerperium

1999 ◽  
Vol 81 (04) ◽  
pp. 527-531 ◽  
Author(s):  
U. Kjellberg ◽  
N.-E. Andersson ◽  
S. Rosén ◽  
L. Tengborn ◽  
M. Hellgren
Keyword(s):  
Factor Viii ◽  
Plasminogen Activator ◽  
Protein C ◽  
Activated Protein C ◽  
Plasminogen Activator Inhibitor ◽  
Protein S ◽  
Reference Level ◽  
Soluble Fibrin ◽  
Prothrombin Fragment ◽  
D Dimer

SummaryForty-eight healthy pregnant women were studied prospectively and longitudinally. Blood sampling was performed at 10-15, 23-25, 32-34 and 38-40 weeks of gestation, within one week and at eight weeks postpartum. Classic and modified activated protein C ratio decreased as pregnancy progressed. In the third trimester 92% of the ratios measured with the classic test were above the lower reference level whereas all modified test ratios were normal. Slight activation of blood coagulation was shown with increased levels of prothrombin fragment 1+2, soluble fibrin and D-dimer. Fibrinogen, factor VIII and plasminogen activator inhibitor type 1 and type 2 increased. Protein S and tissue plasminogen activator activity decreased. Protein C remained unchanged. No correlation was found between the decrease in classic APC ratio and changes in factor VIII, fibrinogen, protein S, prothrombin fragment 1+2 or soluble fibrin, nor between the increase in soluble fibrin and changes in prothrombin fragment 1+2, fibrinogen and D-dimer.

071 Natalizumab extended interval dosing (EID) is associated with a significant reduction in progressive multifocal leukoencephalopathy (PML) risk compared with standard interval dosing (SID) in the touch® prescribing program

2018 ◽  
Vol 89 (6) ◽  
pp. A29.2-A29 ◽  
Author(s):  
Lana Zhovtis Ryerson ◽  
John Foley ◽  
Ih Chang ◽  
Ilya Kister ◽  
Gary Cutter ◽  
...  
Keyword(s):  
Cox Regression ◽  
Jc Virus ◽  
Secondary Analysis ◽  
Statistical Analysis Plan ◽  
Rank Test ◽  
Primary Analysis ◽  
Standard Interval ◽  
Kaplan Meier ◽  
Hazard Ratios ◽  
Dosing Intervals

IntroductionNatalizumab, approved for 300 mg intravenous every-4-weeks dosing, is associated with PML risk. Prior studies have been inconclusive regarding EID’s impact on PML risk. The US REMS program (TOUCH) offers the largest data source that can inform on PML risk in patients on EID. This analysis aimed to determine whether natalizumab EID is associated with reduced PML risk compared with SID.MethodsInvestigators developed SID and EID definitions and finalised the statistical analysis plan while blinded to PML events. Average dosing intervals (ADIs) were ≥3 to<5 weeks for SID and >5 to≤12 weeks for EID. The primary analysis assessed ADI in the last 18 months of infusion history. The secondary analysis identified any prolonged period of EID at any time in the infusion history. The tertiary analysis assessed ADI over the full infusion history. Only anti-JC virus antibody positive (JCV Ab+) patients with dosing intervals≥3 to≤12 weeks were included. PML hazard ratios (HRs) were compared using adjusted Cox regression models and Kaplan-Meier estimates.ResultsAnalyses included 13,132 SID and 1988 EID patients (primary), 15,424 SID and 3331 EID patients (secondary), and 23,168 SID and 815 EID patients (tertiary). In primary analyses, ADI (days) was 30 for SID and 37 for EID; median exposure (months) was 44 for SID and 59 for EID. Most EID patients received >2 years SID prior to EID. The PML HR (95% CI) was 0.06 (0.01–0.22; p<0.001) for primary analysis and 0.12 (0.05–0.29; p<0.001) for secondary analysis (both in favour of EID); no EID PML cases were observed in tertiary analyses (Kaplan-Meier log-rank test p=0.02).ConclusionIn JCV Ab +patients, natalizumab EID is associated with a clinically and statistically significant reduction in PML risk as compared with SID. As TOUCH does not collect effectiveness data, further studies are needed.Study supportBiogen

ACTIVATED PROTEIN C IMPROVES SURVIVAL IN SEVERE SEPSIS PATIENTS WITH ELEVATED TROPONIN.

2007 ◽  
Vol 55 (1) ◽  
pp. S290
Author(s):  
J. John ◽  
A. Awab ◽  
D. Norman ◽  
G. T. Kinasewitz
Keyword(s):  
Severe Sepsis ◽  
Protein C ◽  
Activated Protein C ◽  
Elevated Troponin

Efficacy and Safety of Recombinant Human Activated Protein C for Severe Sepsis

2018 ◽  
pp. 61-67
Author(s):  
Anna M. Ward ◽  
Richard M. Pino
Keyword(s):  
Severe Sepsis ◽  
Study Design ◽  
Protein C ◽  
Clinical Case ◽  
Activated Protein C ◽  
Efficacy And Safety ◽  
Prowess Trial ◽  
Study Intervention ◽  
Prowess Study

This chapter provides a summary of the landmark study known as the PROWESS Study. Does treatment with DAA reduce the rate of death from any cause among patients with severe sepsis? Starting with that question, it describes the basics of the study, including funding, study location, who was studied, how many patients, study design, study intervention, follow-up, endpoints, results, and criticism and limitations. The chapter briefly reviews other relevant studies and information, discusses implications, and concludes with a relevant clinical case. The PROWESS trial demonstrated a mortality benefit for DAA among patients with severe sepsis. However, the subsequent ADDRESS, RESOLVE, and PROWESS-SHOCK trials did not demonstrate a benefit of the medication, thus calling the results of PROWESS into question.

scholarly journals Indices of Disease Activity in Psoriatic Arthritis

1987 ◽  
Vol 80 (9) ◽  
pp. 556-558 ◽  
Author(s):  
A O'N Daunt ◽  
N L Cox ◽  
J C Robertson ◽  
M I D Cawley
Keyword(s):  
Psoriatic Arthritis ◽  
Disease Activity ◽  
Rank Test ◽  
Poor Correlation ◽  
C Reactive Protein ◽  
Antirheumatic Therapy ◽  
Clinical Variables ◽  
Reactive Protein ◽  
Clinical Indices ◽  
Articular Index

Psoriatic arthritis (PA) may respond to disease-modifying antirheumatic therapy. The value of assessing disease activity with indices devised for rheumatoid arthritis (RA) was investigated in 72 patients with seronegative PA. Thirty patients had a peripheral polyarthritis including the distal inter-phalangeal joints (DIPJs) and 15 a symmetrical arthritis sparing DIPJs (RA-like). Significant correlations (Spearman rank test) were seen between the clinical variables (pain score, grip strength, Ritchie articular index and a summated index of disease activity) in these two groups. Ten patients with a markedly asymmetrical arthritis showed a poor correlation between clinical variables. Although the objective indices – erythrocyte sedimentation rate (ESR) and C-reactive protein – correlated together in the first two groups, the ESR correlated solely with clinical indices, and then only in RA-like patients. These results cast some doubt on the value of assessment methods based on RA when evaluating subgroups of PA other than RA-like disease.

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