Effect of intravenous clarithromycin in patients with sepsis, respiratory and multiple organ dysfunction syndrome: a randomized clinical trial.

BACKGROUND: Clarithromycin may act as immune-regulating treatment in sepsis and acute respiratory dysfunction syndrome. However, clinical evidence remains inconclusive. We aimed to evaluate whether clarithromycin improves 28-day mortality among patients with sepsis, respiratory and multiple organ dysfunction syndrome. METHODS: We conducted a multicenter, randomized, clinical trial in patients with sepsis. Participants with ratio of partial oxygen pressure to fraction of inspired oxygen less than 200 and more than 3 SOFA points from systems other than the respiratory function were enrolled between December 2017 and September 2019. Patients were randomized to receive 1 gr of clarithromycin or placebo intravenously once daily for 4 consecutive days. The primary endpoint was 28-day all-cause mortality. Secondary outcomes were 90-day mortality; sepsis response (defined as at least 25% decrease in SOFA score by day 7); sepsis recurrence; and differences in peripheral blood cell populations and leukocyte transcriptomics. RESULTS: Fifty-five patients were allocated to each arm. By day 28, 27 (49.1%) patients in the clarithromycin and 25 (45.5%) in the placebo group died (risk difference 3.6% [95% confidence interval (CI) - 15.7 to 22.7]; P = 0.703, adjusted OR 1.03 [95%CI 0.35-3.06]; P = 0.959). There were no statistical differences in 90-day mortality and sepsis response. Clarithromycin was associated with lower incidence of sepsis recurrence (OR 0.21 [95%CI 0.06-0.68]; P = 0.012); significant increase in monocyte HLA-DR expression; expansion of non-classical monocytes; and upregulation of genes involved in cholesterol homeostasis. Serious and non-serious adverse events were equally distributed. CONCLUSIONS: Clarithromycin did not reduce mortality among patients with sepsis with respiratory and multiple organ dysfunction. Clarithromycin was associated with lower sepsis recurrence, possibly through a mechanism of immune restoration. Clinical trial registration clinicaltrials.gov identifier NCT03345992 registered 17 November 2017; EudraCT 2017-001056-55.

Community-acquired Klebsiella spp Meningitis/Invasive Infection in Filipino-descent Patients Living in Greece: A Case Series.

Klebsiella spp community-acquired meningitis caused by hypervirulent strains is well described as part of a distinct syndrome consisting of liver abscess and multiple septic metastatic lesions (Klebsiella pneumoniae invasive syndrome) occurring usually in diabetic, alcoholic, elderly or cancer patients, in Taiwan and other South-East Asian countries. In Western countries, these infections are very rare in natives and usually occur in patients of Asian origin. We report three cases of Filipino-origin patients, residents of Greece, with community-acquired invasive Klebsiella meningitis, who were treated in our ICU over a 10-year period. LEARNING POINTS: Community-acquired Klebsiella spp meningitis has a very bad prognosis.A physician must suspect an invasive Klebsiella infection in patients of Asian origin, even though they are residents of Western countries and have not visited their homeland recently.

Non-interventional monitoring of expiratory flow limitation during experimental mechanical ventilation.

BACKGROUND: Expiratory flow limitation (EFL) is common among patients in the intensive care unit under mechanical ventilation (MV) and may have significant clinical consequences. In the present study, we examine the possibility of non-interventional detection of EFL during experimental MV. METHODS: Eight artificially ventilated New Zealand rabbits were included in the experiments. EFL was induced during MV by application of negative expiratory pressure (-5, -8 and -10 hPa) and detected by the negative expiratory pressure technique. Airway pressure (P aw) and gas flow (V') were digitally recorded and processed off-line for the evaluation of respiratory mechanics. The method is based on the computation and monitoring of instantaneous respiratory resistance R rs(t). The resistive pressure (P aw,res(t)) is calculated by subtracting from P aw its elastic component and the end-expiratory pressure, as assessed by linear regression. Then, R rs(t) is computed as the instant ratio P aw,res(t)/V'(t). RESULTS: Two completely different patterns of expiratory R rs(t) separate the cases with EFL from those without EFL. Small and random fluctuations are noticed when EFL is absent, whereas the onset of EFL is accompanied by an abrupt and continuous rise in R rs(t), towards the end of expiration. Thus, EFL is not only detected but may also be quantified from the volume still to be expired at the time EFL occurs. CONCLUSION: The proposed technique is a simple, accurate and non-interventional tool for EFL monitoring during MV.

Past history of stage I/II solid tumor malignancy impacts considerably on sepsis mortality: a propensity score matching analysis from the hellenic sepsis study group.

BACKGROUND: Whether past history of solid stage I/II inactive cancer has an impact on 28-day mortality of sepsis remains unclear. We aimed to determine the impact of history of stage I or II solid tumor malignancy in complete remission the last 3 years on sepsis outcome. METHODS: Using the database of the Hellenic Sepsis Study Group from 1553 patients with sepsis admitted in the ICU, 83 patients with sepsis by Sepsis-3 definition with past-history of stage I/II inactive solid malignancy the last 3 years were depicted. A comparator group of 83 patients fully matched for age, severity, type of infection and comorbidities was selected by propensity score matching. RESULTS: Mortality after 28 days was 37.3% in the comparator group and 54.2% in the solid tumor stage I/II group (odds ratio for death 1.98; p: 0.030). Following step-wise forward Cox regression analysis, septic shock (hazard ratio 1.80), acute renal injury (hazard ratio 2.06), history of coronary heart disease (hazard ratio 0.36) and history of stage I/II solid tumor malignancy (hazard ratio 1.79) were the only independent variables associated with 28-day mortality. Serum levels of procalcitonin and of soluble urokinase plasminogen activator receptor were similar between the two groups of comparisons. CONCLUSIONS: Past history of stage I/II solid malignancy is an independent risk factor for unfavorable outcome from sepsis the first 28 days.

Soluble urokinase plasminogen activator receptor informs on the progression course after multiple injuries.

PURPOSE: The purpose of this study is to study the use of soluble urokinase plasminogen activator receptor (suPAR) for the prognosis of multiple organ dysfunction (MOF) after multiple traumas. METHODS: Serum suPAR was measured within the first 24 h after multiple injuries in 85 patients. Measurements were repeated after 4 d or at sepsis onset. RESULTS: Odds ratio for trauma-associated MOF was 4.09 (p: 0.026) with admission suPAR greater than 8 ng/ml. More than 40% increases of suPAR were associated with odds ratio 9.33 (p: 0.047) for severe sepsis. CONCLUSIONS: suPAR is a useful surrogate biomarker for development of MOF and severe sepsis after multiple traumas.

Defective cytokine production early after multiple traumas: Modulation in severe sepsis.

The exact time frame of multiple trauma-induced immunosuppression and the immune mechanisms mediating transition to severe sepsis are largely unknown. Peripheral blood mononuclear cells were isolated from 69 patients with multiple injuries within the first 24h from injury and from 36 healthy volunteers and stimulated for cytokine production. Circulating endotoxins were measured by the kinetic LAL assay. Measurements were repeated the first 24h of sepsis onset. Patients had defective responses for tumour necrosis factor-alpha (TNFα), interleukin (IL)-10, IL-17 and interferon-gamma (IFNγ) using a broad-panel of bacterial stimuli. Production of IFNγ was pronounced for patients with trauma-related multiple organ failure (MOF). Thirty-six patients developed severe sepsis. At that time, production of TNFα was increased compared to baseline. The increase was greater among non-survivors than among survivors. Enhanced TNFα production on sepsis onset was a main finding of patients without endotoxemia. Immunosuppression of both innate and adaptive cytokine responses appears as early as the first 24h from injury. Transition into severe sepsis due to bacterial superinfection is accompanied by enhanced production of TNFα and this is linked with unfavorable outcome.

Early changes of the kinetics of monocyte trem-1 reflect final outcome in human sepsis.

BACKGROUND: TREM-1 (triggering receptor expressed on myeloid cells), a receptor expressed on neutrophils and monocytes, is upregulated in sepsis and seems to tune the inflammatory response. We explored the expression of TREM-1 at the gene level and on cell membranes of monocytes and association with clinical outcome. METHODS: Peripheral venous blood was sampled from 75 septic patients (39 patients with sepsis, 25 with severe sepsis and 11 with septic shock) on sepsis days 1, 3 and 7. TREM-1 on monocytes was measured by flow cytometry; gene expression of TREM-1 in circulating mononuclear cells was assessed by real-time PCR. sTREM-1 was measured in serum by an enzyme immunoassay. RESULTS: Although surface TREM-1, sTREM-1 and TREM-1 gene expression did not differ between sepsis, severe sepsis and septic shock on day 1, survivors had greater expression of surface TREM-1 on days 3 and 7 compared to non-survivors. sTREM-1 on non-survivors decreased on day 3 compared to baseline. Patients with increase of monocyte gene expression of TREM-1 from day 1 to day 3 had prolonged survival compared to patients with decrease of gene expression of TREM-1 from day 1 to day 3 (p: 0.031). CONCLUSIONS: Early decrease of gene expression of TREM-1 in monocytes is associated with poor outcome. A reciprocal decrease of the pro-inflammatory surface receptor TREM-1 linked with sepsis-induced immunosuppression may be part of the explanation.

Early administration of hydrocortisone replacement after the advent of septic shock: impact on survival and immune response*.

OBJECTIVES: To investigate the impact of early initiation of hydrocortisone therapy on the clinical course of septic shock and on cytokine release. DESIGN: Prospective study in patients with septic shock treated with low doses of hydrocortisone. SETTING: ICUs and general wards. PATIENTS: Over a 2-year period, 170 patients with septic shock treated with low doses of hydrocortisone were enrolled. Blood was sampled from 34 patients for isolation of peripheral blood mononuclear cells and cytokine stimulation before and 24 hours after the start of hydrocortisone. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: After quartile analysis, patients were divided into those with early initiation of hydrocortisone (< 9 hr after vasopressors, n = 46) and those with late initiation of hydrocortisone (> 9 hr after vasopressors, n = 124). After adjusting for disease severity and type of infection, a protective effect of early hydrocortisone administration against unfavorable outcome was found (hazard ratio, 0.20; p = 0.012). Time of discontinuation of vasopressors was earlier among patients with initiation of hydrocortisone within 9 hours. Production of tumor necrosis factor-α was lower among patients who had had hydrocortisone early. CONCLUSIONS: In patients receiving hydrocortisone for septic shock, early initiation of treatment was associated with improved survival. This treatment was also associated with attenuated stimulation of tumor necrosis factor-α.

Early alterations of the innate and adaptive immune statuses in sepsis according to the type of underlying infection.

INTRODUCTION: Although major changes of the immune system have been described in sepsis, it has never been studied whether these may differ in relation to the type of underlying infection or not. This was studied for the first time. METHODS: The statuses of the innate and adaptive immune systems were prospectively compared in 505 patients. Whole blood was sampled within less than 24 hours of advent of sepsis; white blood cells were stained with monoclonal antibodies and analyzed though a flow cytometer. RESULTS: Expression of HLA-DR was significantly decreased among patients with severe sepsis/shock due to acute pyelonephritis and intraabdominal infections compared with sepsis. The rate of apoptosis of natural killer (NK) cells differed significantly among patients with severe sepsis/shock due to ventilator-associated pneumonia (VAP) and hospital-acquired pneumonia (HAP) compared with sepsis. The rate of apoptosis of NKT cells differed significantly among patients with severe sepsis/shock due to acute pyelonephritis, primary bacteremia and VAP/HAP compared with sepsis. Regarding adaptive immunity, absolute counts of CD4-lymphocytes were significantly decreased among patients with severe sepsis/shock due to community-acquired pneumonia (CAP) and intraabdominal infections compared with sepsis. Absolute counts of B-lymphocytes were significantly decreased among patients with severe sepsis/shock due to CAP compared with sepsis. CONCLUSIONS: Major differences of the early statuses of the innate and adaptive immune systems exist between sepsis and severe sepsis/shock in relation to the underlying type of infection. These results may have a major impact on therapeutics.

Salmonella enteritidis meningitis in a first time diagnosed AIDS patient: case report.

UNLABELLED: We describe a patient with salmonella enteritidis meningitis and unknown HIV infection. SETTING: A 14-bed adult intensive care unit in a tertiary hospital.The patient was brought to the emergency department with fever, nuchal rigidity and confusion. A first cerebrospinal fluid examination was non diagnostic. After a short period of improvement the patient developed septic shock. A second cerebrospinal fluid specimen was purulent. Both specimens yielded salmonella enteritidis and a blood culture as well. An Eliza reaction was performed and showed positive for HIV. The CD4(+) cells count was 16/mm3. The patient died with refractory shock eight days after admission in the intensive care unit.