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Background Procalcitonin (PCT)-guided antibiotic duration for critically ill adults with sepsis may be clinically effective and safe. However, cost-effectiveness analyses using clinical trial data for this precision medicine approach in critical care are lacking. This economic evaluation investigates the cost-effectiveness of a daily PCT-guided protocol to guide the duration of antibiotic treatment in adult patients with sepsis. Methods Two analyses were conducted, the first estimating the cost per quality-adjusted life year (QALY) of the ADAPT-Sepsis study, which recruited 2760 patients randomized to a daily PCT-guided protocol, a daily C-reactive protein-guided protocol and standard care. The second analysis used meta-analyzed results from ADAPT-Sepsis and other PCT-guided treatment studies and employed a lifetime horizon. Key outcomes were the incremental costs and QALYs gained from using the daily PCT-guided protocol approach compared with standard care. Other outcome measures included changes in days of antibiotics, days of hospital stay, days of intensive care unit stay, the percentage of deaths and the number of PCT tests performed. Results Cost-effectiveness results were driven by the assumed impact of PCT testing on mortality although the confidence/credible intervals for ADAPT-Sepsis and the meta-analyzed data both included no effect. Within ADAPT-Sepsis, the use of PCT tests cost €427 more per patient and was associated with a small QALY loss (0.001), which suggests the daily PCT-guided protocol is dominated. Using meta-analyzed data, the daily PCT-guided protocol was assumed to cost €330 more per patient but was associated with 0.139 more QALYs, resulting in a cost per QALY gained of €2384. If only antibiotic use and PCT tests were assumed to differ then PCT testing is estimated to cost no more than €110 per patient with QALYs equal in both arms regardless of whether ADAPT-Sepsis or meta-analyzed data were used. Conclusions This economic analysis has shown that a PCT-guided protocol to guide the duration of antibiotic treatment could be cost-effective. Where only differences in antibiotic use and PCT testing are assumed, the increased costs per patient are modest which may be seen as worthwhile to safely improve antibiotic stewardship for critically ill adult patients with sepsis. Graphical abstract

The clinical utility of procalcitonin in the diagnosis and management of pneumonia remains controversial. We assessed the clinical utility of procalcitonin in 2 prospective studies: first, a multicenter diagnostic study in patients presenting to the emergency department with acute dyspnea to directly compare the diagnostic accuracy of procalcitonin with that of interleukin 6 and C-reactive protein (CRP) in the diagnosis of pneumonia; second, a randomized management study of procalcitonin guidance in patients with acute heart failure and suspected pneumonia. Diagnostic accuracy for pneumonia as centrally adjudicated by 2 independent experts was quantified with the area under the ROC curve (AUC). Among 690 patients in the diagnostic study, 178 (25.8%) had an adjudicated final diagnosis of pneumonia. Procalcitonin, interleukin 6, and CRP were significantly higher in patients with pneumonia than in those without. When compared to procalcitonin (AUC = 0.75; 95% CI, 0.71-0.78), interleukin 6 (AUC = 0.80; 95% CI, 0.77-0.83) and CRP (AUC = 0.82; 95% CI, 0.79-0.85) had significantly higher diagnostic accuracy ( = 0.010 and < 0.001, respectively). The management study was stopped early owing to the unexpectedly low AUC of procalcitonin in the diagnostic study. Among 45 randomized patients, the number of days on antibiotic therapy and the length of hospital stay were similar (both = 0.39) in patients randomized to the procalcitonin-guided group (n = 25) and usual-care group (n = 20). In patients presenting with dyspnea, diagnostic accuracy of procalcitonin for pneumonia is only moderate and lower than that of interleukin 6 and CRP. The clinical utility of procalcitonin was lower than expected. Pneumonia has diverse and often unspecific symptoms. As the role of biomarkers in the diagnosis of pneumonia remains controversial, it is often difficult to distinguish pneumonia from other illnesses causing shortness of breath. The current study prospectively enrolled unselected patients presenting with acute dyspnea and directly compared the diagnostic accuracy of procalcitonin, interleukin 6, and CRP for the diagnosis of pneumonia. In this setting, diagnostic accuracy of procalcitonin for pneumonia was lower as compared to interleukin 6 and CRP. The clinical utility of procalcitonin was lower than expected. NCT01831115.

Background Severe complicated intra-abdominal sepsis (SCIAS) has an increasing incidence with mortality rates over 80% in some settings. Mortality typically results from disruption of the gastrointestinal tract, progressive and self-perpetuating bio-mediator generation, systemic inflammation, and multiple organ failure. Principles of treatment include early antibiotic administration and operative source control. A further therapeutic option may be open abdomen (OA) management with active negative peritoneal pressure therapy (ANPPT) to remove inflammatory ascites and ameliorate the systemic damage from SCIAS. Although there is now a biologic rationale for such an intervention as well as non-standardized and erratic clinical utilization, this remains a novel therapy with potential side effects and clinical equipoise. Methods The Closed Or Open after Laparotomy (COOL) study will constitute a prospective randomized controlled trial that will randomly allocate eligible surgical patients intra-operatively to either formal closure of the fascia or use of the OA with application of an ANPTT dressing. Patients will be eligible if they have free uncontained intra-peritoneal contamination and physiologic derangements exemplified by septic shock OR a Predisposition-Infection-Response-Organ Dysfunction Score ≥ 3 or a World-Society-of-Emergency-Surgery-Sepsis-Severity-Score ≥ 8. The primary outcome will be 90-day survival. Secondary outcomes will be logistical, physiologic, safety, bio-mediators, microbiological, quality of life, and health-care costs. Secondary outcomes will include days free of ICU, ventilation, renal replacement therapy, and hospital at 30 days from the index laparotomy. Physiologic secondary outcomes will include changes in intensive care unit illness severity scores after laparotomy. Bio-mediator outcomes for participating centers will involve measurement of interleukin (IL)-6 and IL-10, procalcitonin, activated protein C (APC), high-mobility group box protein-1, complement factors, and mitochondrial DNA. Economic outcomes will comprise standard costing for utilization of health-care resources. Discussion Although facial closure after SCIAS is considered the current standard of care, many reports are suggesting that OA management may improve outcomes in these patients. This trial will be powered to demonstrate a mortality difference in this highly lethal and morbid condition to ensure critically ill patients are receiving the best care possible and not being harmed by inappropriate therapies based on opinion only. Trial registration ClinicalTrials.gov , NCT03163095 .

Background A reduction in duration of antibiotic therapy is crucial in minimizing the development of antimicrobial resistance, drug-related side effects and health care costs. The minimal effective duration of antimicrobial therapy for febrile urinary tract infections (fUTI) remains a topic of uncertainty, especially in male patients, those of older age or with comorbidities. Biomarkers have the potential to objectively identify the optimal moment for cessation of therapy. Methods A secondary analysis of a randomized placebo-controlled trial among 35 primary care centers and 7 emergency departments of regional hospitals in the Netherlands. Women and men aged ≥18 years with a diagnosis of fUTI were randomly assigned to receive antibiotic treatment for 7 or 14 days. Patients indicated to receive antimicrobial treatment for more than 14 days were excluded from randomization. The biomarkers procalcitonin (PCT), mid-regional proadrenomedullin (MR-proADM), and C-reactive protein (CRP) were compared in their ability to predict clinical cure or failure through the 10–18 day post-treatment visit. Results Biomarker concentrations were measured in 249 patients, with a clinical cure rate of 94% in the 165 randomized and 88% in the 84 non-randomized patients. PCT, MR-proADM and CRP concentrations did not differ between patients with clinical cure and treatment failure, and did not predict treatment outcome, irrespective of 7 or 14 day treatment duration (ROC AUC 0.521; 0.515; 0.512, respectively). PCT concentrations at presentation were positively correlated with bacteraemia (τ = 0.33, p  < 0.001) and presence of shaking chills (τ = 0.25, p  < 0.001), and MR-proADM levels with length of hospital stay (τ = 0.40, p  < 0.001), bacteraemia (τ = 0.33, p  < 0.001), initial intravenous treatment (τ = 0.22, p  < 0.001) and time to defervescence (τ = 0.21, p  < 0.001). CRP did not display any correlation to relevant clinical parameters. Conclusions Although the biomarkers PCT and MR-proADM were correlated to clinical parameters indicating disease severity, they did not predict treatment outcome in patients with community acquired febrile urinary tract infection who were treated for either 7 or 14 days. CRP had no added value in the management of patients with fUTI. Trial registration The study was registered at ClinicalTrials.gov [ NCT00809913 ; December 16, 2008] and trialregister.nl [ NTR1583 ; December 19, 2008].

Background Early sepsis diagnosis has emerged as one of the main challenges in the emergency room. Measurement of sepsis biomarkers is largely used in current practice to improve the diagnosis accuracy. Monocyte distribution width (MDW) is a recent new sepsis biomarker, available as part of the complete blood count with differential. The objective was to evaluate the performance of MDW for the detection of sepsis in the emergency department (ED) and to compare to procalcitonin (PCT) and C-reactive protein (CRP). Methods Subjects whose initial evaluation included a complete blood count were enrolled consecutively in 2 EDs in France and Spain and categorized per Sepsis-2 and Sepsis-3 criteria. The performance of MDW for sepsis detection was compared to that of procalcitonin (PCT) and C-reactive protein (CRP). Results A total of 1,517 patients were analyzed: 837 men and 680 women, mean age 61 ± 19 years, 260 (17.1%) categorized as Sepsis-2 and 144 patients (9.5%) as Sepsis-3. The AUCs [95% confidence interval] for the diagnosis of Sepsis-2 were 0.81 [0.78–0.84] and 0.86 [0.84–0.88] for MDW and MDW combined with WBC, respectively. For Sepsis-3, MDW performance was 0.82 [0.79–0.85]. The performance of MDW combined with WBC for Sepsis-2 in a subgroup of patients with low sepsis pretest probability was 0.90 [0.84–0.95]. The AUC for sepsis detection using MDW combined with WBC was similar to CRP alone (0.85 [0.83–0.87]) and exceeded that of PCT. Combining the biomarkers did not improve the AUC. Compared to normal MDW, abnormal MDW increased the odds of Sepsis-2 by factor of 5.5 [4.2–7.1, 95% CI] and Sepsis-3 by 7.6 [5.1–11.3, 95% CI]. Conclusions MDW in combination with WBC has the diagnostic accuracy to detect sepsis, particularly when assessed in patients with lower pretest sepsis probability. We suggest the use of MDW as a systematic screening test, used together with qSOFA score to improve the accuracy of sepsis diagnosis in the emergency department. Trial Registration ClinicalTrials.gov (NCT03588325).

Background The clinical utility of serum procalcitonin levels in guiding antibiotic treatment decisions in patients with sepsis remains unclear. This patient-level meta-analysis based on 11 randomized trials investigates the impact of procalcitonin-guided antibiotic therapy on mortality in intensive care unit (ICU) patients with infection, both overall and stratified according to sepsis definition, severity, and type of infection. Methods For this meta-analysis focusing on procalcitonin-guided antibiotic management in critically ill patients with sepsis of any type, in February 2018 we updated the database of a previous individual patient data meta-analysis which was limited to patients with respiratory infections only. We used individual patient data from 11 trials that randomly assigned patients to receive antibiotics based on procalcitonin levels (the “procalcitonin-guided” group) or the current standard of care (the “controls”). The primary endpoint was mortality within 30 days. Secondary endpoints were duration of antibiotic treatment and length of stay. Results Mortality in the 2252 procalcitonin-guided patients was significantly lower compared with the 2230 control group patients (21.1% vs 23.7%; adjusted odds ratio 0.89, 95% confidence interval (CI) 0.8 to 0.99; p  = 0.03). These effects on mortality persisted in a subgroup of patients meeting the sepsis 3 definition and based on the severity of sepsis (assessed on the basis of the Sequential Organ Failure Assessment (SOFA) score, occurrence of septic shock or renal failure, and need for vasopressor or ventilatory support) and on the type of infection (respiratory, urinary tract, abdominal, skin, or central nervous system), with interaction for each analysis being > 0.05. Procalcitonin guidance also facilitated earlier discontinuation of antibiotics, with a reduction in treatment duration (9.3 vs 10.4 days; adjusted coefficient −1.19 days, 95% CI −1.73 to −0.66; p  <  0.001). Conclusion Procalcitonin-guided antibiotic treatment in ICU patients with infection and sepsis patients results in improved survival and lower antibiotic treatment duration.

Although most patients with acute pancreatitis have the mild form of the disease, about 20–30% develops a severe form, often associated with single or multiple organ dysfunction requiring intensive care. Identifying the severe form early is one of the major challenges in managing severe acute pancreatitis. Infection of the pancreatic and peripancreatic necrosis occurs in about 20–40% of patients with severe acute pancreatitis, and is associated with worsening organ dysfunctions. While most patients with sterile necrosis can be managed nonoperatively, patients with infected necrosis usually require an intervention that can be percutaneous, endoscopic, or open surgical. These guidelines present evidence-based international consensus statements on the management of severe acute pancreatitis from collaboration of a panel of experts meeting during the World Congress of Emergency Surgery in June 27–30, 2018 in Bertinoro, Italy. The main topics of these guidelines fall under the following topics: Diagnosis, Antibiotic treatment, Management in the Intensive Care Unit, Surgical and operative management, and Open abdomen.

Pneumonia is the leading infectious cause of mortality worldwide and one of the most common lower respiratory tract infections that is contributing significantly to the burden of antibiotic consumption. Due to the complexity of its pathophysiology, it is widely accepted that clinical diagnosis and prognosis are inadequate for the accurate assessment of the severity of the disease. The most challenging task for a physician is the risk stratification of patients with community-acquired pneumonia. Herein, early diagnosis is essential in order to reduce hospitalization and mortality. Procalcitonin and C-reactive protein remain the most widely used biomarkers, while interleukin 6 has been of particular interest in the literature. However, none of them appear to be ideal, and the search for novel biomarkers that will most sufficiently predict the severity and treatment response in pneumonia has lately intensified. Although our insight has significantly increased over the last years, a translational approach with the application of genomics, metabolomics, microbiomics, and proteomics is required to better understand the disease. In this review, we discuss this rapidly evolving area and summarize the application of novel biomarkers that appear to be promising for the accurate diagnosis and risk stratification of pneumonia.

Background Major trauma is associated with high incidence of septic complications and multiple organ dysfunction (MOD), which markedly influence the outcome of injured patients. Early identification of patients at risk of developing posttraumatic complications is crucial to provide early treatment and improve outcomes. We sought to evaluate the prognostic value of serum procalcitonin (PCT) levels after trauma as related to severity of injury, sepsis, organ dysfunction, and mortality. Methods We searched PubMed, MEDLINE, EMBASE, the Cochrane Database, and references of included articles. Two investigators independently identified eligible studies and extracted data. We included original studies that assessed the prognostic value of serum PCT levels in predicting severity of injury, sepsis, organ dysfunction, and mortality among critically injured adult patients. Results Among 2015 citations, 19 studies (17 prospective; 2 retrospective) met inclusion criteria. Methodological quality of included studies was moderate. All studies showed a strong correlation between initial PCT levels and Injury Severity Score (ISS). Twelve out of 16 studies demonstrated significant elevation of initial PCT levels in patients who later developed sepsis after trauma. PCT level appeared a strong predictor of MOD in seven out of nine studies. While two studies did not show association between PCT levels and mortality, four studies demonstrated significant elevation of PCT levels in non-survivors versus survivors. One study reported that the PCT level of ≥ 5 ng/mL was associated with significantly increased mortality (OR 3.65; 95% CI 1.03–12.9; p  = 0.04). Conclusion PCT appears promising as a surrogate biomarker for trauma. Initial peak PCT level may be used as an early predictor of sepsis, MOD, and mortality in trauma population.

Systemic inflammatory response syndrome (SIRS) poses a serious threat that influences patient survival and life quality. Its early and accurate diagnosis is paramount in clinics, where procalcitonin (PCT) is recognized as a key serological biomarker. Herein, well-dispersed PtPdCo nanoalloy was efficiently anchored on hollow porous N-doped carbon fibers (termed PtPdCo HPCNFs) through a sequential process involving electrospinning, pyrolysis, etching, and co-reduction. The morphology, structure, and physicochemical properties of PtPdCo HPCNFs were characterized by a set of techniques. Subsequently, the synthesized PtPdCo HPCNF nanocomposite was applied to build a label-free electrochemical amperometric immunosensor for ultrasensitive detection of PCT. Its performance was evaluated by cyclic voltammetry (CV), differential pulse voltammetry (DPV), and electrochemical impedance spectroscopy (EIS). Notably, the biosensor demonstrated a wide dynamic linear range (0.0001–1000 ng mL −1 ) and a low detection limit (0.20 pg mL −1 ). Furthermore, the sensor achieved the bioassay of PCT in clinical samples, yielding acceptable results. This work offers a promising approach for synthesizing superior nanomaterials for bioanalytical applications, highlighting their potential in development of sensing devices, especially for early and sensitive diagnosis of SIRS through PCT detection. Graphical abstract