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Special Issue "Clinical, Epidemiologic and Translational Studies of Sepsis and Septic Shock"

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Hematology".

Deadline for manuscript submissions: 5 June 2019

Special Issue Editors

Guest Editor
Prof. Adam Linder

Department of Infectious Diseases, University of Lund and Skåne University Hospital, Getingevägen, Lund, SE-221 85, Sweden
Website | E-Mail
Interests: sepsis; pathophysiology; epidemiology; long-term outcome
Guest Editor
Prof. Konrad Reinhart

Department of Anaesthesiology and Intensive Care Medicine, Centre for Sepsis Care and Control, Jena University Hospital, Jena, Germany
Website | E-Mail
Interests: sepsis; epidemiology; public awareness

Special Issue Information

Dear Colleagues,

Sepsis is a very complex and dynamic syndrome defined as a dysregulated host response to an infection but manifests as a complex infectious and immunological disorder. At present, over 20 million people are estimated to suffer from sepsis worldwide every year, where 6 million die in hospitals and another 5 million die within a year. There is a lack of early diagnostic tools and also novel non-antibiotic therapies. Also, in recent years it has become increasingly evident that sepsis survivors suffer serious negative long-term consequences. Sepsis results in massive activation of the host immune defense system both from innate and adaptive immune system. However, the sepsis can vary widely over the course of the infection and the molecular response in sepsis may be highly specific to individuals or group of individuals as a result of several factors such as i) different infecting pathogens, ii) different sites of infection, iii) host phenotypes such as gender, age, comorbidities, genetic predisposition, and iv) stage or time point of the pro- or anti-inflammatory cascades. Further understanding of the epidemiology and pathophysiology of sepsis is essential for development of diagnostic tools and novel treatment options.

Please join us in presenting this Special Issue that reveals novel evidence of sepsis epidemiology, pathophysiology, diagnostic tools, treatments and long-term consequences.

Prof. Adam Linder
Prof. Konrad Reinhart
Guest Editors

Manuscript Submission Information

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Keywords

  • Sepsis
  • Septic shock
  • Organ failure
  • Immune system

Published Papers (9 papers)

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Research

Open AccessArticle
Prevalence and Outcome of Secondary Hemophagocytic Lymphohistiocytosis Among SIRS Patients: Results from a Prospective Cohort Study
J. Clin. Med. 2019, 8(4), 541; https://doi.org/10.3390/jcm8040541
Received: 7 March 2019 / Revised: 12 April 2019 / Accepted: 16 April 2019 / Published: 19 April 2019
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Abstract
Secondary hemophagocytic lymphohistiocytosis (sHLH) is a life-threatening condition clinically presenting as SIRS (Systemic Inflammatory Response Syndrome). However, there is no comprehensive data concerning diagnostic algorithms, prevalence, outcome and biomarker performance in SIRS patients. We conducted a prospective observational cohort study on 451 consecutive [...] Read more.
Secondary hemophagocytic lymphohistiocytosis (sHLH) is a life-threatening condition clinically presenting as SIRS (Systemic Inflammatory Response Syndrome). However, there is no comprehensive data concerning diagnostic algorithms, prevalence, outcome and biomarker performance in SIRS patients. We conducted a prospective observational cohort study on 451 consecutive patients fulfilling ≥2 SIRS criteria. The Hscore and the HLH-2004 criteria were used to determine the presence of sHLH, and the correlation of the screening-biomarkers ferritin, sCD25, and sCD163 with both scores was assessed. Out of 451 standard-care SIRS patients, five patients had high Hscores (≥169), suggesting incipient or HLH-like disease, and these patients were in urgent need for intensified therapy. However, none of these patients fulfilled five HLH-2004 criteria required for formal diagnosis. From the studied biomarkers, ferritin correlated strongest to both the HLH-2004 criteria and the Hscore (rs = 0.72, 0.41, respectively), and was the best predictor of 30-day survival (HR:1.012 per 100 μg/L, 95% CI: 1.004–1.021), when adjusted for patient’s age, sex, bacteremia and malignant underlying-disease. Also, the HLH-2004 (HR per point increase: 1.435, 95% CI: 1.1012–2.086) and the Hscore (HR per point increase:1.011, 95% CI: 1.002–1.020) were independent predictors of 30-day-survival. The Hscore detected patients in hyperinflammatory states requiring urgent therapy escalation. Degrees of hyperinflammation, as assessed by ferritin and both HLH scores, are associated with worse outcomes. Full article
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Open AccessArticle
Vitamin C, Hydrocortisone, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Analysis of Real-World Application
J. Clin. Med. 2019, 8(4), 478; https://doi.org/10.3390/jcm8040478
Received: 12 March 2019 / Revised: 2 April 2019 / Accepted: 4 April 2019 / Published: 9 April 2019
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Abstract
A recent study suggested mortality benefits using vitamin C, hydrocortisone, and thiamine combination therapy (triple therapy) in addition to standard care in patients with severe sepsis and septic shock. In order to further evaluate the effects of triple therapy in real-world clinical practice, [...] Read more.
A recent study suggested mortality benefits using vitamin C, hydrocortisone, and thiamine combination therapy (triple therapy) in addition to standard care in patients with severe sepsis and septic shock. In order to further evaluate the effects of triple therapy in real-world clinical practice, we conducted a retrospective observational cohort study at an academic tertiary care hospital. A total of 94 patients (47 in triple therapy group and 47 in standard care group) were included in the analysis. Baseline characteristics in both groups were well-matched. No significant difference in the primary outcome, hospital mortality, was seen between triple therapy and standard care groups (40.4% vs. 40.4%; p = 1.000). In addition, there were no significant differences in secondary outcomes, including intensive care unit (ICU) mortality, requirement for renal replacement therapy for acute kidney injury, ICU length of stay, hospital length of stay, and time to vasopressor independence. When compared to standard care, triple therapy did not improve hospital or ICU mortality in patients with septic shock. A randomized controlled trial evaluating the effects of triple therapy is necessary prior to implementing vitamin C, hydrocortisone, and thiamine combination therapy as a standard of care in patients with septic shock. Full article
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Open AccessArticle
Application of the Sepsis-3 Consensus Criteria in a Geriatric Acute Care Unit: A Prospective Study
J. Clin. Med. 2019, 8(3), 359; https://doi.org/10.3390/jcm8030359
Received: 24 January 2019 / Revised: 8 March 2019 / Accepted: 9 March 2019 / Published: 13 March 2019
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Abstract
The prognostic value of quick Sepsis-related Organ Failure Assessment (qSOFA) score in geriatric patients is uncertain. We aimed to compare qSOFA vs. Systemic Inflammatory Response Syndrome (SIRS) criteria for mortality prediction in older multimorbid subjects, admitted for suspected sepsis in a geriatric ward. [...] Read more.
The prognostic value of quick Sepsis-related Organ Failure Assessment (qSOFA) score in geriatric patients is uncertain. We aimed to compare qSOFA vs. Systemic Inflammatory Response Syndrome (SIRS) criteria for mortality prediction in older multimorbid subjects, admitted for suspected sepsis in a geriatric ward. We prospectively enrolled 272 patients (aged 83.7 ± 7.4). At admission, qSOFA and SIRS scores were calculated. Mortality was assessed during hospital stay and three months after discharge. The predictive capacity of qSOFA and SIRS was assessed by calculating the Area Under the Receiver Operating Characteristic Curve (AUROC), through pairwise AUROC comparison, and multivariable logistic regression analysis. Both qSOFA and SIRS exhibited a poor prognostic performance (AUROCs 0.676, 95% CI 0.609–0.738, and 0.626, 95% CI 0.558–0.691 for in-hospital mortality; 0.684, 95% CI 0.614–0.748, and 0.596, 95% CI 0.558–0.691 for pooled three-month mortality, respectively). The predictive capacity of qSOFA showed no difference to that of SIRS for in-hospital mortality (difference between AUROCs 0.05, 95% CI −0.05 to 0.14, p = 0.31), but was superior for pooled three-month mortality (difference between AUROCs 0.09, 95% CI 0.01–0.17, p = 0.029). Multivariable logistic regression analysis, accounting for possible confounders, including frailty, showed that both scores were not associated with in-hospital mortality, although qSOFA, unlike SIRS, was associated with pooled three-month mortality. In conclusion, neither qSOFA nor SIRS at admission were strong predictors of mortality in a geriatric acute-care setting. Traditional geriatric measures of frailty may be more useful for predicting adverse outcomes in this setting. Full article
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Open AccessArticle
Prognostic Relevance of Altered Lymphocyte Subpopulations in Critical Illness and Sepsis
J. Clin. Med. 2019, 8(3), 353; https://doi.org/10.3390/jcm8030353
Received: 8 February 2019 / Revised: 6 March 2019 / Accepted: 9 March 2019 / Published: 12 March 2019
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Abstract
Lymphopenia and functional defects in lymphocytes may impact the prognosis in patients with critical illness or sepsis. Therefore, we prospectively analyzed peripheral blood leukocytes from 63 healthy volunteers, 50 non-critically ill standard care (SC) patients with infections, and 105 intensive care unit (ICU) [...] Read more.
Lymphopenia and functional defects in lymphocytes may impact the prognosis in patients with critical illness or sepsis. Therefore, we prospectively analyzed peripheral blood leukocytes from 63 healthy volunteers, 50 non-critically ill standard care (SC) patients with infections, and 105 intensive care unit (ICU) patients (52 with sepsis, 53 without sepsis) using flow cytometry. Compared to healthy volunteers, SC and ICU patients showed significant leukocytosis, especially in sepsis, while lymphocyte numbers were significantly decreased. All major lymphocyte populations (B, T, and natural killer (NK) cells) decreased in ICU patients. However, we observed a relative reduction of T cells, alongside decreased CD8+ T cells, in critically ill patients, independent of sepsis. High absolute T cell counts (>0.36/nL) at ICU admission were associated with a significantly reduced mortality, independent of patient’s age. Moreover, patients that survived ICU treatment showed dynamic changes within 48 h towards restoration of lymphopenia and T cell depletion, while non-surviving patients failed to restore lymphocyte counts. In conclusion, the flow-cytometric analysis of peripheral blood revealed striking changes in circulating lymphocyte subsets in critically ill patients, independent of sepsis. Lymphopenia and T cell depletion at ICU admission were associated with increased mortality, supporting their relevance as predictive biomarkers and potential therapeutic targets in intensive care medicine. Full article
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Open AccessArticle
TNFAIP3, TNIP1, and MyD88 Polymorphisms Predict Septic-Shock-Related Death in Patients Who Underwent Major Surgery
J. Clin. Med. 2019, 8(3), 283; https://doi.org/10.3390/jcm8030283
Received: 28 January 2019 / Revised: 15 February 2019 / Accepted: 18 February 2019 / Published: 26 February 2019
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Abstract
Background: In many immune-related diseases, inflammatory responses and several clinical outcomes are related to increased NF-κB activity. We aimed to evaluate whether SNPs related to the NF-κB signaling pathway are associated with higher susceptibility to infection, septic shock, and septic-shock-related death in European [...] Read more.
Background: In many immune-related diseases, inflammatory responses and several clinical outcomes are related to increased NF-κB activity. We aimed to evaluate whether SNPs related to the NF-κB signaling pathway are associated with higher susceptibility to infection, septic shock, and septic-shock-related death in European patients who underwent major surgery. Methods: We performed a case-control study on 184 patients with septic shock and 212 with systemic inflammatory response syndrome, and a longitudinal substudy on septic shock patients. Thirty-three SNPs within genes belonging to or regulating the NF-κB signaling pathway were genotyped by Agena Bioscience’s MassARRAY platform. Results: No significant results were found for susceptibility to infection and septic shock in the multivariate analysis after adjusting for multiple comparisons. Regarding septic-shock-related death, patients with TNFAIP3 rs6920220 AA, TNIP1 rs73272842 AA, TNIP1 rs3792783 GG, and TNIP1 rs7708392 CC genotypes had the highest risk of septic-shock-related death in the first 28 and 90 days. Also, the MyD88 rs7744 GG genotype was associated with a higher risk of death during the first 90 days. Haplotype analysis shows us that patients with the TNIP1 GAG haplotype (composed of rs73272842, rs3792783, and rs7708392) had a lower risk of death in the first 28 days and the TNIP1 AGC haplotype was associated with a higher risk of death in the first 90 days. Conclusions: The SNPs in the genes TNFAIP3, TNIP1, and MyD88 were linked to the risk of septic-shock-related death in patients who underwent major surgery. Full article
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Open AccessArticle
Troponin Testing for Assessing Sepsis-Induced Myocardial Dysfunction in Patients with Septic Shock
J. Clin. Med. 2019, 8(2), 239; https://doi.org/10.3390/jcm8020239
Received: 1 January 2019 / Revised: 31 January 2019 / Accepted: 11 February 2019 / Published: 12 February 2019
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Abstract
(1) Background: Myocardial dysfunction in patients with sepsis is not an uncommon phenomenon, yet reported results are conflicting and there is no objective definition. Measurement of troponin may reflect the state of the heart and may correlate with echocardiographically derived data. This study [...] Read more.
(1) Background: Myocardial dysfunction in patients with sepsis is not an uncommon phenomenon, yet reported results are conflicting and there is no objective definition. Measurement of troponin may reflect the state of the heart and may correlate with echocardiographically derived data. This study aimed to evaluate the role of admission and peak troponin-I testing for the identification of sepsis-induced myocardial dysfunction (SIMD) by transthoracic echocardiography (TTE). (2) Methods: This was a retrospective cohort study using a prospective registry of septic shock at an Emergency Department from January 2011 and April 2017. All 1,776 consecutive adult septic shock patients treated with protocol-driven resuscitation bundle therapy and tested troponin-I were enrolled. SIMD was defined as left ventricular (LV) systolic/diastolic dysfunction, right ventricular (RV) diastolic dysfunction, or global/regional wall motion abnormalities (WMA). (3) Results: Of 660 (38.4%) septic shock patients with an elevated hs-TnI (≥0.04 ng/mL) at admission, 397 patients underwent TTE and 258 cases (65%) showed SIMD (LV systolic dysfunction (n = 163, 63.2%), LV diastolic dysfunction (n = 104, 40.3%), RV dysfunction (n = 97, 37.6%), and WMA (n = 186, 72.1%)). In multivariate analysis, peak hs-TnI (odds ratio 1.03, 95% confidence interval 1.01–1.06, p = 0.008) and ST-T wave changes in the electrocardiogram (odds ratio 1.82, 95% confidence interval 1.04–2.39, p = 0.013) were associated with SIMD, in contrast to hs-TnI level at admission. The area under the curve of peak hs-TnI was 0.668. When the peak hs-TnI cutoff value was 0.634 ng/mL, the sensitivity and specificity for SIMD were 58.6% and 59.1%, respectively. 4) Conclusions: About two-thirds of patients with an elevated hs-TnI level have various cardiac dysfunctions in terms of TTE. Rather than the initial level, the peak hs-TnI and ST-T change may be considered as a risk factor of SIMD. Full article
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Open AccessArticle
Delayed Antibiotic Therapy and Organ Dysfunction in Critically Ill Septic Patients in the Emergency Department
J. Clin. Med. 2019, 8(2), 222; https://doi.org/10.3390/jcm8020222
Received: 11 January 2019 / Revised: 5 February 2019 / Accepted: 7 February 2019 / Published: 8 February 2019
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Abstract
Background: We investigated the effect of antibiotic timing on outcomes based on changes in surrogate markers of organ failure, including platelet, serum bilirubin, serum creatinine levels, and the PaO2/FiO2 (P/F) ratio. Methods: This was a single-center, retrospective observational study of [...] Read more.
Background: We investigated the effect of antibiotic timing on outcomes based on changes in surrogate markers of organ failure, including platelet, serum bilirubin, serum creatinine levels, and the PaO2/FiO2 (P/F) ratio. Methods: This was a single-center, retrospective observational study of critically ill septic patients who presented to the emergency department (ED). The study period extended from August 2008 to September 2016. The primary outcomes included changes in platelet, serum bilirubin, serum creatinine levels, and the P/F ratio (δ-platelet, δ-serum bilirubin, δ-serum creatinine, and δ-P/F ratio were calculated as values measured on Day 3; values measured at ED enrollment). A multivariable linear regression model was developed to assess variables related to outcomes (δ-platelet, δ-serum bilirubin, δ-serum creatinine, and δ-P/F ratio). Results: We analyzed 1784 patients who met the inclusion criteria. The overall 28-day mortality was 14% (n = 256/1784). On multivariable linear regression analysis, the hourly delay in antibiotic therapy was significantly associated with a decrease in δ-platelet count (coefficient, −1.741; standard error, 0.740; p = 0.019), and an increase in δ-serum bilirubin (coefficient, 0.054; standard error, 0.021; p = 0.009). In contrast, it was not associated with δ-creatinine (coefficient, 0.008; standard error, 0.010; p = 0.434) or the δ-P/F ratio (coefficient, −0.797; standard error, 1.858; p = 0.668). Conclusion: The hourly delay of antibiotic therapy was associated with decreased platelet count and increased serum bilirubin concentration in critically ill septic patients during the first three days of ED admission. Full article
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Open AccessArticle
Risk Factors for Same Pathogen Sepsis Readmission Following Hospitalization for Septic Shock
J. Clin. Med. 2019, 8(2), 181; https://doi.org/10.3390/jcm8020181
Received: 15 December 2018 / Revised: 30 January 2019 / Accepted: 1 February 2019 / Published: 3 February 2019
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Abstract
(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 [...] Read more.
(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. Full article
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Open AccessArticle
Early Vitamin C and Thiamine Administration to Patients with Septic Shock in Emergency Departments: Propensity Score-Based Analysis of a Before-and-After Cohort Study
J. Clin. Med. 2019, 8(1), 102; https://doi.org/10.3390/jcm8010102
Received: 16 December 2018 / Revised: 10 January 2019 / Accepted: 11 January 2019 / Published: 16 January 2019
Cited by 1 | PDF Full-text (479 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Background: Intravenous vitamin C and thiamine administration may be a potential adjuvant therapy for septic shock. We aimed to investigate the impact of early vitamin C and thiamine administration in septic shock patients. Methods: This retrospective before-and-after cohort study used data extracted from [...] Read more.
Background: Intravenous vitamin C and thiamine administration may be a potential adjuvant therapy for septic shock. We aimed to investigate the impact of early vitamin C and thiamine administration in septic shock patients. Methods: This retrospective before-and-after cohort study used data extracted from the Korean Shock Society’s prospective septic shock registry. We compared 28-day and in-hospital mortality rates between patients treated with intravenous vitamin C (3 g/12 h or 1.5 g/6 h) and thiamine (200 mg/12 h) <6 h after shock recognition from July through December 2017 (n = 229) and control patients from October 2015 through June 2017 (n = 915) using propensity score matching. Results: The 28-day (18.3% vs. 17.5%; p = 0.76) and in-hospital (16.6% vs. 18.3%; p = 0.55) mortality rates did not differ between treatment and control groups, nor did 28-day (18.5% vs. 17.5%; p = 0.84) and in-hospital (16.7% vs. 18.4%; p = 0.54) mortality rates after matching. In the subgroup analysis, treatment was associated with lower in-hospital mortality rates in patients with albumin <3.0 mg/dL or a Sequential Organ Failure Assessment (SOFA) score >10. Conclusion: Early vitamin C and thiamine administration in patients with septic shock did not improve survival; however, administration could benefit conditions that are more severe, such as hypoalbuminemia or severe organ failure. Full article
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