Soluble fms-like tyrosine kinase 1, placental growth factor and procalcitonin as biomarkers of gram-negative sepsis: Analysis through a derivation and a validation cohort.

ABSTRACT: Further improvement of the diagnostic and prognostic performance of biomarkers for the critically ill is needed. Procalcitonin (PCT), placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 raise interest for sepsis diagnosis and prognosis.Serum samples from 2 cohorts of 172 patients (derivation cohort) and of 164 patients (validation cohort) comprising only patients with microbiologically confirmed gram-negative infections were analyzed. PlGF, s-Flt-1 and procalcitonin (PCT) were measured in serum within 24 hours from sepsis onset and repeated on days 3 and 7.PCT and s-Flt-1 baseline levels were higher in sepsis and septic shock compared to non-sepsis; this was not the case for PlGF. s-Flt-1 at concentrations greater than 60 pg/ml diagnosed sepsis with sensitivity 72.3% and specificity 54.9% whereas at concentrations greater than 70 pg/ml predicted unfavorable outcome with specificity 73.0% and sensitivity 63.7%. At least 80% decrease of PCT and/or PCT less than 0.5 ng/ml on day 7 was protective from sepsis-associated death.Both s-Flt-1 and PCT should be measured in the critically ill since they provide additive information for sepsis diagnosis and prognosis.ClinicalTrials.gov numbers NCT01223690 and NCT00297674.

Integration of heparin-binding protein and interleukin-6 in the early prediction of respiratory failure and mortality in pneumonia by SARS-CoV-2 (COVID-19).

Recent publications on the probable role of heparin-binding protein (HBP) as a biomarker in sepsis prompted us to investigate its diagnostic and prognostic performance in severe COVID-19. HBP and IL-6 were measured by immunoassays at admission and on day 7 in 178 patients with pneumonia by SARS-CoV-2. Patients were classified into non-sepsis and sepsis as per the Sepsis-3 definitions and were followed up for the development of severe respiratory failure (SRF) and for outcome. Results were confirmed by multivariate analyses. HBP was significantly higher in patients classified as having sepsis and was negatively associated with the oxygenation ratio and positively associated with creatinine and lactate. Logistic regression analysis evidenced admission HBP more than 18 ng/ml and IL-6 more than 30 pg/ml as independent risk factors for the development of SRP. Their integration prognosticated SRF with respective sensitivity, specificity, positive predictive value, and negative predictive 59.1%, 96.3%, 83.9%, and 87.8%. Cox regression analysis evidenced admission HBP more than 35 ng/ml and IL-6 more than 30 pg/ml as independent risk factors for 28-day mortality. Their integration prognosticated 28-day mortality with respective sensitivity, specificity, positive predictive value, and negative predictive value 69.2%, 92.7%, 42.9%, and 97.5%. HBP remained unchanged over-time course. A prediction score of the disposition of patients with COVID-19 is proposed taking into consideration admission levels of IL-6 and HBP. Using different cut-offs, the score may predict the likelihood for SRF and for 28-day outcome.

Procalcitonin to Reduce Long-Term Infection-associated Adverse Events in Sepsis. A Randomized Trial.

Rationale: Although early antimicrobial discontinuation guided by procalcitonin (PCT) has shown decreased antibiotic consumption in lower respiratory tract infections, the outcomes in long-term sepsis sequelae remain unclear.Objectives: To investigate if PCT guidance may reduce the incidence of long-term infection-associated adverse events in sepsis.Methods: In this multicenter trial, 266 patients with sepsis (by Sepsis-3 definitions) with lower respiratory tract infections, acute pyelonephritis, or primary bloodstream infection were randomized (1:1) to receive either PCT-guided discontinuation of antimicrobials or standard of care. The discontinuation criterion was ≥80% reduction in PCT levels or any PCT ≤0.5 µg/L at Day 5 or later. The primary outcome was the rate of infection-associated adverse events at Day 180, a composite of the incidence of any new infection by Clostridioides difficile or multidrug-resistant organisms, or any death attributed to baseline C. difficile or multidrug-resistant organism infection. Secondary outcomes included 28-day mortality, length of antibiotic therapy, and cost of hospitalization.Measurements and Main Results: The rate of infection-associated adverse events was 7.2% (95% confidence interval [CI], 3.8-13.1%; 9/125) versus 15.3% (95% CI, 10.1-22.4%; 20/131) (hazard ratio, 0.45; 95% CI, 0.20-0.98; P = 0.045); 28-day mortality 15.2% (95% CI, 10-22.5%; 19/125) versus 28.2% (95% CI, 21.2-36.5%; 37/131) (hazard ratio, 0.51; 95% CI, 0.29-0.89; P = 0.02); and median length of antibiotic therapy 5 (range, 5-7) versus 10 (range, 7-15) days (P < 0.001) in the PCT and standard-of-care arms, respectively. The cost of hospitalization was also reduced in the PCT arm.Conclusions: In sepsis, PCT guidance was effective in reducing infection-associated adverse events, 28-day mortality, and cost of hospitalization.Clinical trial registered with www.clinicaltrials.gov (NCT03333304).

Serum Hydrogen Sulfide and Outcome Association in Pneumonia by the SARS-CoV-2 Coronavirus.

BACKGROUND: The pneumonia of COVID-19 illness has often a subtle initial presentation making mandatory the use of biomarkers for evaluation of severity and prediction of final patient disposition. We evaluated the use of hydrogen sulfide (H2S) for the outcome of COVID-19 pneumonia. PATIENTS AND METHODS: We studied 74 patients with COVID-19. Clinical data were collected, and survival predictors were calculated. Blood was collected within 24 h after admission (day 1) and on day 7. H2S was measured in sera by monobromobimane derivation followed by high-performance liquid chromatography and correlated to other markers like procalcitonin and C-reactive protein (CRP). Tumor necrosis factor alpha and interleukin (IL)-6 were also measured in serum. RESULTS: Survivors had significantly higher H2S levels on days 1 and 7 after admission. A cut-off point of 150.44 µM could discriminate survivors from non-survivors with 80% sensitivity, 73.4% specificity, and negative predictive value 95.9%. Mortality after 28 days was 32% with admission levels lower than or equal to 150.44 µM and 4.1% with levels above 150.44 µM (P: 0.0008). Mortality was significantly greater among patients with a decrease of H2S levels from day 1 to day 7 greater than or equal to 36% (p: 0.0005). Serum H2S on day 1 was negatively correlated with IL-6 and CRP and positively correlated with the absolute lymphocyte count in peripheral blood. CONCLUSION: It is concluded that H2S is a potential marker for severity and final outcome of pneumonia by the SARS-CoV-2 coronavirus. Its correlation with IL-6 suggests anti-inflammatory properties.

Microbiology of acute bacterial skin and skin-structure infections in Greece: A proposed clinical prediction score for the causative pathogen.

Although clinical definitions of acute bacterial skin and skin-structure infection (ABSSSI) are now well established, guidance of the prediction of likely pathogens based on evidence is missing. This was a large survey of the microbiology of ABSSSIs in Greece. During the period November 2014 to December 2016, all admissions for ABSSSI in 16 departments of internal medicine or surgery in Greece were screened to determine the likely bacterial aetiology. Samples were cultured on conventional media. Expression of the SA442, mecA/mecC and SCCmec-orfX junction genes was assessed. Following univariate and forward logistic regression analysis, clinical characteristics were used to develop scores to predict the likely pathogen with a target of 90% specificity. In total, 1027 patients were screened and 633 had positive microbiology. Monomicrobial infection by Gram-positive cocci occurred in 52.1% and by Gram-negative bacteria in 20.5%, and mixed infection by Gram-positive cocci and Gram-negative bacteria in 27.3%. The most common isolated pathogens were Staphylococcus aureus and coagulase-negative staphylococci. Resistance to methicillin was 57.3% (53.5-61.1%). Three predictive scores were developed: one for infection by methicillin-resistant S. aureus, incorporating recent hospitalisation, atrial fibrillation, residency in long-term care facility (LTCF) and stroke; one for mixed Gram-positive and Gram-negative infections, incorporating localisation of ABSSSI in lumbar area, fluoroquinolone intake in last 6 days, residency in LTCF and stroke; and another for Gram-negative infection, incorporating skin ulcer presentation, peptic ulcer and solid tumour malignancy. In conclusion, methicillin-resistant staphylococci are the main pathogens of ABSSSIs. The scores developed may help to predict the likely pathogen.

Point-prevalence survey of healthcare facility-onset healthcare-associated Clostridium difficile infection in Greek hospitals outside the intensive care unit: The C. DEFINE study.

BACKGROUND: The correlation of Clostridium difficile infection (CDI) with in-hospital morbidity is important in hospital settings where broad-spectrum antimicrobial agents are routinely used, such as in Greece. The C. DEFINE study aimed to assess point-prevalence of CDI in Greece during two study periods in 2013. METHODS: There were two study periods consisting of a single day in March and another in October 2013. Stool samples from all patients hospitalized outside the ICU aged ≥18 years old with diarrhea on each day in 21 and 25 hospitals, respectively, were tested for CDI. Samples were tested for the presence of glutamate dehydrogenase antigen (GDH) and toxins A/B of C. difficile; samples positive for GDH and negative for toxins were further tested by culture and PCR for the presence of toxin genes. An analysis was performed to identify potential risk factors for CDI among patients with diarrhea. RESULTS: 5,536 and 6,523 patients were screened during the first and second study periods, respectively. The respective point-prevalence of CDI in all patients was 5.6 and 3.9 per 10,000 patient bed-days whereas the proportion of CDI among patients with diarrhea was 17% and 14.3%. Logistic regression analysis revealed that solid tumor malignancy [odds ratio (OR) 2.69, 95% confidence interval (CI): 1.18-6.15, p = 0.019] and antimicrobial administration (OR 3.61, 95% CI: 1.03-12.76, p = 0.045) were independent risk factors for CDI development. Charlson's Comorbidity Index (CCI) >6 was also found as a risk factor of marginal statistical significance (OR 2.24, 95% CI: 0.98-5.10). Median time to CDI from hospital admission was shorter with the presence of solid tumor malignancy (3 vs 5 days; p = 0.002) and of CCI >6 (4 vs 6 days, p = 0.009). CONCLUSIONS: The point-prevalence of CDI in Greek hospitals was consistent among cases of diarrhea over a 6-month period. Major risk factors were antimicrobial use, solid tumor malignancy and a CCI score >6.

Decreased cytokine production by mononuclear cells after severe gram-negative infections: early clinical signs and association with final outcome.

BACKGROUND: Failure of circulating monocytes for adequate cytokine production is a trait of sepsis-induced immunosuppression; however, its duration and association with final outcome are poorly understood. METHODS: We conducted a substudy of a large randomised clinical trial. Peripheral blood mononuclear cells (PBMCs) were isolated within the first 24 h from the onset of systemic inflammatory response syndrome in 95 patients with microbiologically confirmed or clinically suspected gram-negative infections. Isolation was repeated on days 3, 7 and 10. PBMCs were stimulated for cytokine production. The study endpoints were the differences between survivors and non-survivors, the persistence of immunosuppression, and determination of admission clinical signs that can lead to early identification of the likelihood of immunosuppression. RESULTS: PBMCs of survivors produced significantly greater concentrations of tumour necrosis factor-α (TNF-α), interleukin (IL)-6, IL-8, IL-10, interferon-γ and granulocyte-macrophage colony-stimulating factor after day 3. Using ROC analysis, we found that TNF-α production less than 250 pg/ml after lipopolysaccharide stimulation on day 3 could discriminate patients from healthy control subjects; this was associated with a 5.18 OR of having an unfavourable outcome (p = 0.046). This trait persisted as long as day 10. Logistic regression analysis showed that cardiovascular failure on admission was the only independent predictor of defective TNF-α production on day 3. CONCLUSIONS: Defective TNF-α production is a major trait of sepsis-induced immunosuppression. It is associated with significant risk for unfavourable outcome and persists until day 10. Cardiovascular failure on admission is predictive of defective TNF-α production during follow-up. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01223690 . Registered on 18 October 2010.