Management and outcomes of severe dengue patients presenting with sepsis in a tropical country.
ABSTRACT: BACKGROUND:Dengue is a common cause of infection in adults in tropical countries. Sepsis is a syndrome of systemic manifestations induced by infection of any organisms; including bacterial, fungal and viral agents. Here, we investigated the diagnosis, management and outcomes of dengue patients presenting with sepsis in a prospective study of community-acquired sepsis in Thailand. METHODS:From June to December 2015, 874 adult patients (age?18 years) with suspected or documented community-acquired infection, with ?3 diagnostic criteria for sepsis according to the Surviving Sepsis Campaign 2012, and within 24 hours of admission were evaluated. Serum was stored and later tested for dengue PCR assays. RESULTS:A total of 126 patients had dengue PCR assays positive (2 DENV-1, 12 DENV-2, 24 DENV-3 and 88 DENV-4), and 5 of them (4%) died. We found that attending physicians suspected dengue infection on admission in 84 patients (67%), and recorded dengue infection as the final diagnosis in 96 patients (76%). Four of five fatal cases were diagnosed and treated as septic shock not due to dengue. In multivariable analysis, there was a trend showing that age?60 years, hypoxemia and misdiagnosis of dengue by attending physicians were associated with 28-day mortality. CONCLUSIONS:A number of adult patients who died of dengue are misdiagnosed as severe sepsis and septic shock. Diagnosis of dengue based on clinical features alone is difficult. Rapid diagnostic tests for dengue may need to be routinely used in adult patients presenting with sepsis and septic shock in tropical countries. This approach could improve diagnosis and management of those patients.
Project description:OBJECTIVE:No studies have evaluated the diagnostic value of ischemia-modified albumin (IMA) for the early detection of sepsis/septic shock in patients presenting to the emergency department (ED). We aimed to assess the usefulness of IMA in diagnosing sepsis/septic shock in the ED. METHODS:This retrospective, observational study analyzed IMA, lactate, high sensitivity C-reactive protein, and procalcitonin levels measured within 1 hour of ED arrival. Patients with suspected infection meeting at least two systemic inflammatory response syndrome criteria were included and classified into the infection, sepsis, and septic shock groups using Sepsis-3 definitions. Areas under the receiver operating characteristic curves (AUCs) with 95% confidence intervals (CIs) and multivariate logistic regression were used to determine diagnostic performance. RESULTS:This study included 300 adult patients. The AUC (95% CI) of IMA levels (cut-off ?85.5 U/mL vs. ?87.5 U/mL) was higher for the diagnosis of sepsis than for that of septic shock (0.729 [0.667-0.791] vs. 0.681 [0.613-0.824]) and was higher than the AUC of procalcitonin levels (cut-off ?1.58 ng/mL, 0.678 [0.613-0.742]) for the diagnosis of sepsis. When IMA and lactate levels were combined, the AUCs were 0.815 (0.762-0.867) and 0.806 (0.754-0.858) for the diagnosis of sepsis and septic shock, respectively. IMA levels independently predicted sepsis (odds ratio, 1.05; 95% CI, 1.00-1.09; P=0.029) and septic shock (odds ratio, 1.07; 95% CI, 1.02-1.11; P=0.002). CONCLUSION:Our findings indicate that IMA levels are a useful biomarker for diagnosing sepsis/septic shock early, and their combination with lactate levels can enhance the predictive power for early diagnosis of sepsis/septic shock in the ED.
Project description:(1) Background: Septic shock survivors frequently readmit because of subsequent infection. This study aimed to determine the rate and risk factors for same pathogen sepsis readmissions following hospitalization for septic shock. (2) Methods: We performed this retrospective study using data from a prospective septic shock registry at a single urban tertiary center. All the patients were treated with a protocol-driven resuscitation bundle therapy between 2011 and 2016. We collected data from adult (older than 18 years) patients readmitted with sepsis within 90 days of discharge following hospitalization for septic shock. (3) Results: Among 2062 septic shock patients, 690 were readmitted within 90 days of discharge. After excluding scheduled and non-sepsis admissions, we analyzed the data from 274 (13.3%) patients readmitted for sepsis. Most of the readmissions following septic shock were new infections rather than relapses of the initial infection. The culture-negative rate was 51.4% (141/274), while the same pathogen was isolated in 25% of cases (69/274). Multivariate analysis revealed that previous gram-negative bacteremia (OR, 9.902; 95% CI, 2.843⁻34.489), urinary tract infection (OR, 4.331; 95% CI, 1.723⁻10.882) and same site infection (OR, 6.894; 95% CI, 2.390⁻19.886) were significantly associated with readmission for sepsis caused by the same pathogen. (4) Conclusions: The sepsis readmission rate following the previous hospitalization for septic shock was 13.3% and one-quarter of those patients had the same pathogen isolated. Previous gram-negative bacteremia, and/or same site infection are predisposing factors for recurrent same-pathogen sepsis.
Project description:OBJECTIVES:Delayed initiation of appropriate antimicrobials is linked to higher sepsis mortality. We investigated interphysician variation in septic patients' door-to-antimicrobial time. DESIGN:Retrospective cohort study. SETTING:Emergency department of an academic medical center. SUBJECTS:Adult patients treated with antimicrobials in the emergency department between 2009 and 2015 for fluid-refractory severe sepsis or septic shock. Patients who were transferred, received antimicrobials prior to emergency department arrival, or were treated by an attending physician who cared for less than five study patients were excluded. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:We employed multivariable linear regression to evaluate the association between treating attending physician and door-to-antimicrobial time after adjustment for illness severity (Acute Physiology and Chronic Health Evaluation II score), patient age, prehospital or arrival hypotension, admission from a long-term care facility, mode of arrival, weekend or nighttime admission, source of infection, and trainee involvement in care. Among 421 eligible patients, 74% received antimicrobials within 3 hours of emergency department arrival. After covariate adjustment, attending physicians' (n = 40) median door-to-antimicrobial times varied significantly, ranging from 71 to 359 minutes (p = 0.002). The percentage of each physician's patients whose antimicrobials began within 3 hours of emergency department arrival ranged from 0% to 100%. Overall, 12% of variability in antimicrobial timing was explained by the attending physician compared with 4% attributable to illness severity as measured by the Acute Physiology and Chronic Health Evaluation II score (p < 0.001). Some but not all physicians started antimicrobials later for patients who were normotensive on presentation (p = 0.017) or who had a source of infection other than pneumonia (p = 0.006). The adjusted odds of in-hospital mortality increased by 20% for each 1 hour increase in door-to-antimicrobial time (p = 0.046). CONCLUSIONS:Among patients with severe sepsis or septic shock receiving antimicrobials in the emergency department, door-to-antimicrobial times varied five-fold among treating physicians. Given the association between antimicrobial delay and mortality, interventions to reduce physician variation in antimicrobial initiation are likely indicated.
Project description:Aggressive diagnosis and treatment of patients presenting to the emergency department (ED) with septic shock has been shown to reduce mortality. To enhance the ability to intervene in patients with lesser illness severity, a better understanding of the natural history of the early progression from simple infection to more severe illness is needed.The objectives were to 1) describe the clinical presentation of ED sepsis, including types of infection and causative microorganisms, and 2) determine the incidence, patient characteristics, and mortality associated with early progression to septic shock among ED patients with infection.This was a multicenter study of adult ED patients with sepsis but no evidence of shock. Multivariable logistic regression was used to identify patient factors for early progression to shock and its association with 30-day mortality.Of 472 patients not in shock at ED presentation (systolic blood pressure > 90 mm Hg and lactate < 4 mmol/L), 84 (17.8%) progressed to shock within 72 hours. Independent factors associated with early progression to shock included older age, female sex, hyperthermia, anemia, comorbid lung disease, and vascular access device infection. Early progression to shock (vs. no progression) was associated with higher 30-day mortality (13.1% vs. 3.1%, odds ratio [OR] = 4.72, 95% confidence interval [CI] = 2.01 to 11.1; p < or = 0.001). Among 379 patients with uncomplicated sepsis (i.e., no evidence of shock or any end-organ dysfunction), 86 (22.7%) progressed to severe sepsis or shock within 72 hours of hospital admission.A significant portion of ED patients with less severe sepsis progress to severe sepsis or shock within 72 hours. Additional diagnostic approaches are needed to risk stratify and more effectively treat ED patients with sepsis.
Project description:Sepsis is a syndrome with physiologic, pathologic, and biochemical abnormalities induced by infection. Sepsis can induce the dysregulation of systemic coagulation and fibrinolytic systems, resulting in disseminated intravascular coagulation (DIC), which is associated with a high mortality rate. Although there is no international consensus on available treatments for sepsis-induced DIC, DIC diagnosis and treatment are commonly performed in Japanese clinical settings. Therefore, clinical data related to sepsis-induced DIC diagnosis and treatment can be obtained from Japanese clinical settings. We performed a retrospective nationwide observational study (Japan Septic Disseminated Intravascular Coagulation [J-SEPTIC DIC] study) to collect data regarding characteristics of sepsis patients in Japan, with a focus on coagulofibrinolytic dysregulation and DIC treatment received by each patient. The J-SEPTIC DIC study collected information for a total of 3,195 patients with severe sepsis and septic shock and is the largest data set in Japan on DIC diagnosis and treatment in clinical settings.
Project description:OBJECTIVES:Our aim was to assess the release level of heparin-binding protein (HBP) in sepsis and septic shock under the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). DESIGN:Prospective cohort study. SETTING:A general teaching hospital in China. PARTICIPANTS:Adult infected patients with suspected sepsis and people who underwent physical examination were included. According to the health status and severity of illness, the research subjects were divided into healthy, local infection, sepsis non-shock and septic shock under Sepsis-3 definitions. MAIN OUTCOME MEASURES:Plasma levels of HBP, procalcitonin (PCT), C reactive protein (CRP) and complete blood count were detected in all subjects. Single-factor analysis of variance was used to compare the biomarker levels of multiple groups. A receiver operating characteristic (ROC) curve was used to assess the diagnostic capacity of each marker. RESULTS:HBP levels were significantly higher in patients with sepsis non-shock than in those with local infections (median 49.7ng/mL vs 11.8 ng/mL, p<0.01) at enrolment. Moreover, HBP levels in patients with septic shock were significantly higher than in patients with sepsis without shock (median 153.8ng/mL vs 49.7 ng/mL, p<0.01). The area under the ROC curve (AUC) of HBP (cut-off ≥28.1 ng/mL) was 0.893 for sepsis which was higher than those of PCT (0.856) for a cut-off ≥2.05 ng/mL and of CRP (0.699) for a cut-off ≥151.9 mg/L. Moreover, AUC of HBP (cut-off ≥103.5 ng/mL) was 0.760 for septic shock which was higher than the ROC curve of sequential [sepsis-related] organ failure assessment (SOFA) Score (0.656) for a cut-off ≥5.5. However, there was no significant difference between 28-d survivors (n=56) and 28-d non-survivors (n=37) with sepsis in terms of HBP value (p=0.182). CONCLUSIONS:A high level of HBP in plasma is associated with sepsis, which might be a useful diagnostic marker in patients with suspected sepsis.
Project description:BACKGROUND:Stratification of the severity of infection is currently based on the Sequential Organ Failure Assessment (SOFA) score, which is difficult to calculate outside the ICU. Biomarkers could help to stratify the severity of infection in surgical patients. METHODS:Levels of ten biomarkers indicating endothelial dysfunction, 22 indicating emergency granulopoiesis, and six denoting neutrophil degranulation were compared in three groups of patients in the first 12?h after diagnosis at three Spanish hospitals. RESULTS:There were 100 patients with infection, 95 with sepsis and 57 with septic shock. Seven biomarkers indicating endothelial dysfunction (mid-regional proadrenomedullin (MR-ProADM), syndecan 1, thrombomodulin, angiopoietin 2, endothelial cell-specific molecule 1, vascular cell adhesion molecule 1 and E-selectin) had stronger associations with sepsis than infection alone. MR-ProADM had the highest odds ratio (OR) in multivariable analysis (OR 11·53, 95 per cent c.i. 4·15 to 32·08; P?=?0·006) and the best area under the curve (AUC) for detecting sepsis (0·86, 95 per cent c.i. 0·80 to 0·91; P?<?0·001). In a comparison of sepsis with septic shock, two biomarkers of neutrophil degranulation, proteinase 3 (OR 8·09, 1·34 to 48·91; P?=?0·028) and lipocalin 2 (OR 6·62, 2·47 to 17·77; P?=?0·002), had the strongest association with septic shock, but lipocalin 2 exhibited the highest AUC (0·81, 0·73 to 0·90; P?<?0·001). CONCLUSION:MR-ProADM and lipocalin 2 could be alternatives to the SOFA score in the detection of sepsis and septic shock respectively in surgical patients with infection.
Project description:Infection with dengue viruses (DENVs) leads to a spectrum of disease outcomes. The pathophysiology of severe versus non-severe manifestations of DENV infection may be driven by host responses, which could be reflected in the transcriptional profiles of peripheral blood immune cells. We conducted genome-wide microarray analysis of whole blood RNA from 34 DENV-infected children in Nicaragua collected on days 3–6 of illness, with different disease manifestations. Gene expression analysis identified genes that are differentially regulated between clinical subgroups. The most striking transcriptional differences were observed between dengue patients with and without shock, especially in the expression of mitochondrial ribosomal proteins associated with protein biosynthesis. In the dengue hemorrhagic fever patients, one subset of differentially expressed genes encode neutrophil-derived anti-microbial peptides associated with innate immunity. We analyzed 44 HEEBO arrays on which were hybridized RNA amplified from whole blood collected into PAXgene tubes. 34 samples were collected from DENV-infected patients who presented between days 3-6 of illness. Six convalescent samples collected 14-19 days after onset of symptoms were from two dengue fever patients, one dengue hemorrhagic fever patient and three dengue shock syndrome patients. Additionally, samples from four normal healthy individuals were also analyzed.
Project description:Clinical symptoms of dengue virus (DENV) infection, the most prevalent arthropod-borne viral disease, range from classical mild dengue fever to severe, life-threatening dengue shock syndrome. However, most DENV infections cause few or no symptoms. Asymptomatic DENV-infected patients provide a unique opportunity to decipher the host immune responses leading to virus elimination without negative impact on an individual’s health. We used an integrated approach of transcriptional profiling and immunological analysis to compare a Cambodian population of strictly asymptomatic viremic individuals with clinical dengue patients. Whereas inflammatory pathways and innate immune response pathways were similar between asymptomatic individuals and clinical dengue patients, expression of proteins related to antigen presentation and subsequent T and B cell activation pathways were differentially regulated, independent of viral load and previous DENV infection history. Feedback mechanisms controlled the immune response in asymptomatic viremic individuals, as demonstrated by increased activation of T cell apoptosis-related pathways and FcγRIIB signaling associated with decreased anti-DENV specific antibody concentrations. Taken together, our data illustrate that symptom-free DENV infection in children is associated with determined by increased activation of the adaptive immune compartment and proper control mechanisms, leading to elimination of viral infection without excessive immune activation, with implications for novel vaccine development strategies Overall design: 33 Dengue patients samples analyzed, no replicates
Project description:Dengue virus (DENV) infection is prevalent across tropical regions and may cause severe disease. Early diagnosis may improve supportive care. We prospectively assessed the Standard Diagnostics (Korea) BIOLINE Dengue Duo DENV rapid diagnostic test (RDT) to NS1 antigen and anti-DENV IgM (NS1 and IgM) in children in Cambodia, with the aim of improving the diagnosis of DENV infection.We enrolled children admitted to hospital with non-localised febrile illnesses during the 5-month DENV transmission season. Clinical and laboratory variables, and DENV RDT results were recorded at admission. Children had blood culture and serological and molecular tests for common local pathogens, including reference laboratory DENV NS1 antigen and IgM assays. 337 children were admitted with non-localised febrile illness over 5 months. 71 (21%) had DENV infection (reference assay positive). Sensitivity was 58%, and specificity 85% for RDT NS1 and IgM combined. Conditional inference framework analysis showed the additional value of platelet and white cell counts for diagnosis of DENV infection. Variables associated with diagnosis of DENV infection were not associated with critical care admission (70 children, 21%) or mortality (19 children, 6%). Known causes of mortality were melioidosis (4), other sepsis (5), and malignancy (1). 22 (27%) children with a positive DENV RDT had a treatable other infection.The DENV RDT had low sensitivity for the diagnosis of DENV infection. The high co-prevalence of infections in our cohort indicates the need for a broad microbiological assessment of non-localised febrile illness in these children.