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Background The early recognition and management of sepsis improves outcomes. Biomarkers may help in identifying earlier sub-clinical signs of sepsis. We explored the potential of serial measurements of C-reactive protein (CRP), procalcitonin (PCT) and pancreatic stone protein (PSP) for the early recognition of sepsis in patients hospitalized in the intensive care unit (ICU). Methods This was a multicentric international prospective observational clinical study conducted in 14 ICUs in France, Switzerland, Italy, and the United Kingdom. Adult ICU patients at risk of nosocomial sepsis were included. A biomarker-blinded adjudication committee identified sepsis events and the days on which they began. The association of clinical sepsis diagnoses with the trajectories of PSP, CRP, and PCT in the 3 days preceding these diagnoses of sepsis were tested for markers of early sepsis detection. The performance of the biomarkers in sepsis diagnosis was assessed by receiver operating characteristic (ROC) analysis. Results Of the 243 patients included, 53 developed nosocomial sepsis after a median of 6 days (interquartile range, 3–8 days). Clinical sepsis diagnosis was associated with an increase in biomarkers value over the 3 days preceding this diagnosis [PSP ( p  = 0.003), PCT ( p  = 0.025) and CRP ( p  = 0.009)]. PSP started to increase 5 days before the clinical diagnosis of sepsis, PCT 3 and CRP 2 days, respectively. The area under the ROC curve at the time of clinical sepsis was similar for all markers (PSP, 0.75; CRP, 0.77; PCT, 0.75). Conclusions While the diagnostic accuracy of PSP, CRP and PCT for sepsis were similar in this cohort, serial PSP measurement demonstrated an increase of this marker the days preceding the onset of signs necessary to clinical diagnose sepsis. This observation justifies further evaluation of the potential clinical benefit of serial PSP measurement in the management of critically ill patients developing nosocomial sepsis. Trial registration The study has been registered at ClinicalTrials.gov (no. NCT03474809), on March 16, 2018. https://www.clinicaltrials.gov/ct2/show/NCT03474809?term=NCT03474809&draw=2&rank=1 .

Background Except in a few retrospective studies mainly including patients under chemotherapy, information regarding the impact of immunosuppressive therapy on the prognosis of patients admitted to the intensive care unit (ICU) for septic shock is scarce. Accordingly, the PACIFIC study aimed to asses if immunosuppressive therapy is associated with an increased mortality in patients admitted to the ICU for septic shock. Methods This was a retrospective epidemiological multicentre study. Eight high enroller centres in septic shock randomised controlled trials (RCTs) participated in the study. Patients in the “exposed” group were selected from the screen failure logs of seven recent RCTs and excluded because of immunosuppressive treatment. The “non-exposed” patients were those included in the placebo arm of the same RCTs. A multivariate logistic regression model was used to estimate the risk of death. Results Among the 433 patients enrolled, 103 were included in the “exposed” group and 330 in the “non-exposed” group. Reason for immunosuppressive therapy included organ transplantation (n = 45 [44%]) or systemic disease (n = 58 [56%]). ICU mortality rate was 24% in the “exposed” group and 25% in the “non-exposed” group ( p  = 0.9). Neither in univariate nor in multivariate analysis immunosuppressive therapy was associated with a higher ICU mortality (OR: 0.95; [95% CI 0.56–1.58]: p  =  0.86 and 1.13 [95% CI 0.61–2.05]: p  =  0.69, respectively) or 3-month mortality (OR: 1.13; [95% CI 0.69–1.82]: p  =  0.62 and OR: 1.36 [95% CI 0.78–2.37]: p  =  0.28, respectively). Conclusions In this study, long-term immunosuppressive therapy excluding chemotherapy was not associated with significantly higher or lower ICU and 3-month mortality in patients admitted to the ICU for septic shock.

Background Urinary tract infection (UTI) is frequently diagnosed in the Emergency Department (ED). Staphylococcus aureus (SA) is an uncommon isolate in urine cultures (0.5–6% of positive urine cultures), except in patients with risk factors for urinary tract colonization. In the absence of risk factors, community-acquired SA bacteriuria may be related to deep-seated SA infection including infective endocarditis. We hypothesized that SA bacteriuria could be a warning microbiological marker of unsuspected infective endocarditis in the ED. Methods This is a retrospective chart review of consecutive adult patients between December 2005 and February 2018. All patients admitted in the ED with both SA bacteriuria (10 4  CFU/ml SA isolated from a single urine sample) and SA bacteremia, without risk factors for UT colonization (i.e., < 1 month UT surgery, UT catheterization) were analyzed. Diagnosis of infective endocarditis was based on the Duke criteria. Results During the study period, 27 patients (18 men; median age: 61 [IQR: 52–73] years) were diagnosed with community-acquired SA bacteriuria and had subsequently documented bacteremia and SA infective endocarditis. Only 5 patients (18%) had symptoms related to UT infection. Median delay between ED admission and SA bacteriuria identification was significantly shorter than that between ED admission and the diagnosis of infective endocarditis (1.4 ± 0.8 vs. 4.3 ± 4.2 days: p  = 0.01). Mitral and aortic valves were most frequently involved by infective endocarditis (93%). Mortality on day 60 reached 56%. Conclusions This study suggests that community-acquired SA bacteriuria should warn the emergency physician about a potentially associated left-sided infective endocarditis in ED patients without risk factors for UT colonization.

Background In the Emergency Department (ED), early and accurate recognition of infection is crucial to prompt antibiotic therapy but the initial presentation of patients is variable and poorly characterized. Lymphopenia is commonly associated with bacteraemia and poor outcome in intensive care unit patients. The objective of this retrospective study was to assess the prevalence of community-acquired infection in a cohort of unselected patients admitted to the ED with undifferentiated symptoms and severe lymphopenia. Methods This is a retrospective single-center study conducted over a 1 year-period before the COVID-19 pandemic. Consecutive adult patients admitted to the ED with severe lymphopenia (lymphocyte count < 0.5 G/L) were studied. Patients with hematological or oncological diseases, HIV infection, hepato-cellular deficiency, immunosuppression, or patients over 85 years old were excluded. Diagnoses of infection were validated by an independent adjudication committee. The association between various parameters and infection was assessed using a multivariate logistic regression analysis. Results Of 953 patients admitted to the ED with severe lymphopenia, 245 were studied (148 men; mean age: 63 ± 19 years). Infection was confirmed in 159 patients (65%) (bacterial: 60%, viral: 30%, other: 10%). Only 61 patients (25%) were referred to the ED for a suspected infection. In the univariate analysis, SIRS criteria (OR: 5.39; 95%CI: 3.04–9.70; p  < 0.001) and temperature ≥ 38.3 °C (OR: 10.95; 95%CI: 5.39–22.26; p  < 0.001) were strongly associate with infection. In the multivariate analysis, only SIRS criteria (OR: 2.4; 95%CI: 1.48–3.9; p  < 0.01) and fever (OR: 3.35; 95%CI: 1.26–8.93; p  = 0.016) were independently associated with infection. Conclusions The prevalence of underlying infection is high in patients admitted to the ED with lymphopenia, irrespective of the reason for admission. Whether lymphopenia could constitute a valuable marker of underlying infection in this clinical setting remains to be confirmed prospectively in larger cohorts. Trial registration: No registration required as this is a retrospective study.

During COVID-19, immature granulocyte (IG) concentration is heterogeneous with higher concentrations than those found in bacterial sepsis. We investigated the relationship between IG levels at ICU admission and on days 7 (± 2) and 15 (± 2) and associated pulmonary bacterial infections in intensive care unit (ICU) patients hospitalized for an acute respiratory distress syndrome (ARDS) related to SARS-CoV-2. Patients with associated pulmonary bacterial infection had a peak of IGs. IG thresholds of 18% or 2 G/L allowed discriminating patients with ventilator associated pneumonia with 100% sensitivity and specificity. Our study supports that IGs could help identifying pulmonary bacterial infections in this population.

IntroductionSome intensive care unit (ICU) patients develop an extremely deep and sustained immunosuppression that increases the risk of secondary infections and can ultimately compromise survival. Thanks to an easily accessible and simplified immune monitoring to identify immunological failure, a personalised immune restoration approach is now feasible. Among the different therapeutic strategies in this field, interferon gamma (IFN-γ) is probably the most interesting drug to reduce the burden of secondary infections in the ICU.Methods and analysisThis is a two parallel group multicentre blinded add-on randomised trial comparing immunorestoration by subcutaneous injection of IFN-γ to standard of care in targeted ICU patients. The study will be performed in 23 ICUs in France. Patients hospitalised in the ICU for a week, with multiple organ failure defined by a sequential organ failure assessment score ≥6 during this first week, will be enrolled. If within 96 hours after inclusion, these patients express immunosuppressed features defined by a low absolute lymphocyte count (<1000/×109/L) and low expression of human leucocyte antigen-DR (HLA-DR) on monocytes (<8000 antibodies bound per cell [Ab/c]) they will be randomised (1:1) to receive either five subcutaneous injections of IFN-γ or placebo in addition to standard of care. The primary outcome will be the incidence of secondary infection episodes at day 90 validated by an independent adjudication committee based on the current definitions (Centers for Disease Control and Prevention surveillance definitions). Secondary outcomes will be all-cause ICU mortality at day 90, length of stay in the ICU and in the hospital at day 90, antibiotic and antifungal consumption at day 90, percentage of biological immune restoration (defined as a monocytic HLA-DR >13 500 antibodies bound per cell and an absolute lymphocyte count >1200 ×109/L) at day 10, healthcare costs at day 90 and rate of serious adverse reactions and suspected unexpected serious adverse reaction at day 90. We plan to randomise 326 patients.Ethics and disseminationThe study will be implemented in accordance with European regulations and was independently reviewed and approved by the French Ethics Committee Comité de Protection des Personnes Ile de France III (EUCT number: 2024-516780-93-00). The results will be reported in international peer-reviewed journals and presented at international and national conferences.Trial registration numberNCT06774235.

More than half of patients under mechanical ventilation in the intensive care unit (ICU) are field-intubated, which is a known risk factor for ventilator associated pneumonia (VAP). We assessed whether field endobronchial intubation (EBI) is associated with the development of subsequent VAP during the ICU stay. This retrospective, nested case-control study was conducted in a cohort of field-intubated patients admitted to an ICU of a teaching hospital during a three-year period. Cases were defined as field-intubated patients with EBI and controls corresponded to field-intubated patients with proper position of the tracheal tube on admission chest X-ray. Primary endpoint was the development of early VAP. Secondary endpoints included the development of early ventilator associated tracheo-bronchitis, late VAP, duration of mechanical ventilation, length of stay and mortality in the ICU. A total of 145 patients were studied (mean age: 54 ± 19 years; men: 74%). Reasons for field intubation were predominantly multiple trauma (49%) and cardiorespiratory arrest (38%). EBI was identified in 33 patients (23%). Fifty-three patients (37%) developed early or late VAP. EBI after field intubation was associated with a nearly two-fold increase of early VAP, though not statistically significant (30% vs. 17%: p = 0.09). No statistically significant difference was found regarding secondary outcomes. The present study suggests that inadvertent prehospital EBI could be associated with a higher incidence of early-onset VAP. Larger studies are required to confirm this hypothesis. Whether strategies aimed at decreasing the incidence and duration of EBI could reduce the incidence of subsequent VAP remains to be determined.

Background Mediastinitis caused by hematogenous spread of an infection is rare. We report the first known case of community-acquired mediastinitis from hematogenous origin in an immunocompetent adult. This rare invasive infection was due to Panton-Valentine Leucocidin-producing (PVL+) methicillin-susceptible Staphylococcus aureus (MSSA). Case presentation A 22-year-old obese man without other medical history was hospitalized for febrile precordial chest pain. He reported a cutaneous back abscess 3 weeks before. CT-scan was consistent with mediastinitis and blood cultures grew for a PVL+ MSSA. Intravenous clindamycin (600 mg t.i.d) and cloxacillin (2 g q.i.d.), secondary changed for fosfomycin (4 g q.i.d.) because of a related toxidermia, was administered. Surgical drainage was performed and confirmed the presence of a mediastinal abscess associated with a fistula between the mediastinum and right pleural space. All local bacteriological samples also grew for PVL+ MSSA. In addition to clindamycin, intravenous fosfomycin was switched to trimethoprim-sulfamethoxazole after 4 weeks for a total of 10 weeks of antibiotics. Conclusions We present the first community-acquired mediastinitis of hematogenous origin with PVL+ MSSA. Clinical evolution was favorable after surgical drainage and 10 weeks of antibiotics. The specific virulence of MSSA PVL+ strains played presumably a key role in this rare invasive clinical presentation.

Lymphopenia and failure of lymphocytes to mount an early IFN-γ response correlate with increased mortality in COVID-19. Given the essential role of CD4 helper and CD8 cytotoxic cells in eliminating viral pathogens, this profound loss in lymphocytes may impair patients' ability to eliminate the virus. IL-7 is a pleiotropic cytokine that is obligatory for lymphocyte survival and optimal function. We conducted a prospective, double-blind, randomized, placebo-controlled trial of CYT107, recombinant human IL-7, in 109 critically ill, patients with lymphopenia who have COVID-19. The primary endpoint was to assess CYT107's effect on lymphocyte recovery with secondary clinical endpoints including safety, ICU and hospital length-of-stay, incidence of secondary infections, and mortality. CYT107 was well tolerated without precipitating a cytokine storm or worsening pulmonary function. Absolute lymphocyte counts increased in both groups without a significant difference between CYT107 and placebo. Patients with COVID-19 receiving CYT107 but not concomitant antiviral medications, known inducers of lymphopenia, had a final lymphocyte count that was 43% greater than placebo (P = 0.067). There were significantly fewer treatment-emergent adverse events in CYT107 versus placebo-treated patients (P < 0.001), consistent with a beneficial drug effect. Importantly, CYT107-treated patients had 44% fewer hospital-acquired infections versus placebo-treated patients (P = 0.014). Given that hospital-acquired infections are responsible for a large percentage of COVID-19 deaths, this effect of CYT107 to decrease nosocomial infections could substantially reduce late morbidity and mortality in this highly lethal disease. The strong safety profile of CYT107 and its excellent tolerability provide support for trials of CYT107 in other potential pandemic respiratory viral infections. NCT04379076, NCT04426201, NCT04442178, NCT04407689, NCT04927169. Funding for the trial was provided by RevImmune and the Cancer Research Institute.