Acute respiratory distress syndrome (ARDS) is defined as a syndrome of acute onset, with bilateral opacities on chest imaging and respiratory failure not caused by cardiac failure, leading to mild, ...moderate, or severe oxygenation impairment. The syndrome is most commonly a manifestation of sepsis-induced organ dysfunction, characterized by disruption of endothelial barrier integrity and diffuse lung damage. Imbalance between coagulation and inflammation is a predominant characteristic of ARDS, leading to extreme inflammatory response and diffuse fibrin deposition in vascular capillary bed and alveoli. Activated platelets, neutrophils, endothelial cells, neutrophil extracellular traps, microparticles, and coagulation proteases, participate in the complex process of immunothrombosis, which is a key event in ARDS pathophysiology. The present review is focused on the elucidation of immunothrombosis in ARDS and the potential therapeutic implications.
Invasive fungal infections are a growing problem in critically ill patients and are associated with increased morbidity and mortality. Most of them are due to Candida species, especially Candida ...albicans. Invasive candidiasis includes candidaemia, disseminated candidiasis with deep organ involvement and chronic disseminated candidiasis. During the last decades rare pathogenic fungi, such as Aspergillus species, Zygomycetes, Fusarium species and Scedosporium have also emerged. Timely diagnosis and proper treatment are of paramount importance for a favorable outcome. Besides blood cultures, several laboratory tests have been developed in the hope of facilitating an earlier detection of infection. The antifungal armamentarium has also been expanded allowing a treatment choice tailored to individual patients' needs. The physician can choose among the old class of polyenes, the older and newer azoles and the echinocandins. Factors related to patient's clinical situation and present co-morbidities, local epidemiology data and purpose of treatment (prophylactic, pre-emptive, empiric or definitive) should be taken into account for the appropriate choice of antifungal agent.
Abstract
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.
Abstract Purpose Cytomegalovirus (CMV) reactivation, a significant cause of morbidity and mortality in immunosuppression, may affect “immunocompetent” seropositive critically ill patients. The aim of ...this prospective, observational study was to define the incidence, risk factors, and the association with morbidity and mortality of CMV reactivation in a general population of critically ill immunocompetent patients. We also studied the relationship between reactivation and patients' inflammatory response, as expressed by cytokine levels and stress up-regulation by salivary cortisol. Methods This study included mechanically ventilated CMV-seropositive patients. A quantitative real-time polymerase chain reaction (PCR) was performed for CMV plasma DNAemia determination, upon intensive care unit (ICU) admission and weekly thereafter until day 28. Cytomegalovirus reactivation was defined as CMV plasma DNAemia greater than or equal to 500 copies/mL. Upon ICU admission, interferon γ , interleukin (IL) 10, IL-17A, IL-2, IL-6, and tumor necrosis factor α were quantified in plasma, and morning saliva was obtained to measure cortisol. Disease severity was assessed by Acute Physiology and Chronic Health Evaluation II score, whereas the degree of organ dysfunction was quantified by Sequential Organ Failure Assessment score. Mortality, duration of mechanical ventilation, and ICU length of stay were recorded. Results During the study period, 80 (51 men) patients with a median age of 63 years fulfilled the inclusion criteria. Reactivation of CMV occurred in 11 patients (13.75%). Median day of reactivation was day 7 post ICU admission. Total number of red blood cell units transfused (odds ratio OR, 1.50; confidence interval CI, 1.06-2.13; P = .02) and C-reactive protein levels upon ICU admission (OR, 1.01; CI, 1.00-1.02; P = .02) were independently associated with CMV reactivation. High IL-10 was marginally related to reactivation ( P = .06). Sequential Organ Failure Assessment scores were higher in the group with CMV reactivation compared with patients without reactivation during the entire 28-day observation period ( P < .006). Salivary cortisol, mortality, length of ICU stay, and duration of mechanical ventilation were similar in the 2 groups. Conclusions Cytomegalovirus reactivation occurred in 13.75% of critically ill, immunocompetent patients. The degree of inflammation and the total number of transfused red blood cells units constituted risk factors. Cytomegalovirus reactivation was associated with more severe of organ dysfunction, but not with a worse clinical outcome.
Summary Objective To compare the safety and efficacy of ampicillin/sulbactam (Amp/Sulb) and colistin (COL) in the treatment of multidrug resistant Acinetobacter baumannii ventilator-associated ...pneumonia (VAP). Methods A prospective cohort study in adult critically ill patients with VAP. Patients were randomly assigned to receive Amp/Sulb (9 g every 8 h) or COL (3 MIU every 8 h) intravenously. Dosage was adjusted according to creatinine clearance. Results A total of 28 patients were enrolled (15 COL, 13 Amp/Sulb). Resolution of symptoms and signs occurred in 60% (9/15) of the COL group and 61.5% (9/13) of the Amp/Sulb group, improvement in 13.3% (2/15) vs. 15.3% (1/13) and failure in 26.6% (4/15) vs. 23% (3/13), respectively. The difference was not statistically significant. Bacteriologic success was achieved in 66.6% (10/15) vs. 61.5% (8/13) in the COL and Amp/Sulb groups, respectively ( p < 0.2). Mortality rates (14 days and 28 days) were 15.3% and 30% for the Amp/Sulb and 20% and 33% for the COL group, respectively. Adverse events were 39.6% (including 33% nephrotoxicity) for the COL group and 30.7% (15.3% nephrotoxicity) for the Amp/Sulb group ( p = NS). Conclusion Colistin and high-dose ampicillin/sulbactam were comparably safe and effective treatments for critically ill patients with MDR A. baumannii VAP.
Abstract Purpose The purpose of the study is to evaluate the incidence, association with serum cytokine profile, and prognostic value of thrombocytopenia, in critically ill patients with severe ...sepsis/septic shock. Methods A cohort of 105 consecutive patients admitted in intensive care unit was included in our analysis. Serum levels of intercellular adhesion molecule, vascular cell adhesion molecule, interferon γ , interleukin 8, and soluble form of the urokinase-type plasminogen activator receptor (suPAR) were measured. Results Thrombocytopenia was observed in 53% of patients at the time of admission. Platelet counts showed a statistically significant negative correlation with serum levels of intercellular adhesion molecule, suPAR, and interleukin 8 ( P < .0001). In multivariate analysis, high Acute Physiological and Chronic Health Evaluation II score, high serum suPAR, and low platelet counts were associated with increased mortality, and receiver operating characteristic curve analysis was used to determine the best cutoff value for mortality prediction. Each variable with a value above or below the predefined cutoff levels were given 1 point. Patients were categorized in risk groups based on total point score. High-risk (2-3), intermediate-risk (1), and low-risk (0 points) groups consisted of 43%, 22%, and 35% and 28-day mortality was observed in 69%, 26%, and 3% of the patients in each group, respectively. Conclusion Thrombocytopenia is associated with poor prognosis and a distinct serum cytokine profile.
The isolation of a pan-echinocandin-resistant Candida parapsilosis strain (anidulafungin, caspofungin, micafungin and rezafungin EUCAST MICs > 8 mg/L) from urine of a patient following prolonged ...exposure to echinocandins (38 days of micafungin followed by 16 days of anidulafungin) is described. The isolate harbored the novel alteration F652S in the hotspot 1 region of fks1. Isogenic C. parapsilosis bloodstream isolates collected up to 1.5 months earlier from the same patient were susceptible to echinocandins (anidulafungin, caspofungin and micafungin EUCAST MICs 1−2, 1 and 1 mg/L, respectively) and contained wild-type FKS1 sequences. This is the first report of pan-echinocandin resistance in C. parapsilosis associated with an aminoacid change in hotspot 1 region of fks1.
Dysregulated hemostasis in cancer patients is associated with various clinical conditions, from thromboembolic complications to disseminated intravascular coagulation. Despite the well-established ...association between cancer and thromboembolic complications, the mechanisms involved are not completely elucidated. There are several predisposing factors in cancer for increased thrombus generation, such as immobilization and chemotherapy. The term cancer-associated thrombosis (CAT) has been introduced to describe the close bidirectional relationship between cancer and thromboembolic events. Conventional coagulation tests (PT/aPTT) are more accurate in detecting a hypocoagulable rather than a hypercoagulable state; thus, their contribution to CAT management is limited. Traditionally, D-dimer levels have been the most common laboratory study for the evaluation of thrombotic risk. However, D-dimer levels only display a snapshot of the coagulation cascade, and they cannot provide a dynamic evaluation of evolving clot formation. Non-conventional assays, such as viscoelastic methods and microparticle formation are promising tools for the identification of patients at risk for developing CAT. Recent guidelines from the American Society of Clinical Oncology counsel against the estimation of thrombotic risk through a single test and recommend the use of scoring systems that take into account several risk factors. The present review outlines the current insights into the pathophysiological mechanisms of CAT and provides a comprehensive review of the latest advances in the laboratory assessment of CAT and the recent guidelines for the management of patients at risk for developing thromboembolic complications.
Idiopathic pulmonary arterial hypertension (IPAH) initial evaluation and follow-up, a rare and incurable disease if left untreated, is based on a multiparametric approach (functional status of the ...patient, biomarkers, hemodynamic parameters and imaging evaluation of right heart impairment). Arterial stiffness (AS) and endothelial glycocalyx are indices of systemic circulation. We present the 3-years follow-up of a female IPAH patient. We propose aortic stiffness and endothelial glycocalyx indices as non-invasive markers of either improvement or deterioration of IPAH disease.
Hypercoagulability and thrombosis remain a challenge to diagnose and treat in severe COVID-19 infection. The ability of conventional global coagulation tests to accurately reflect in vivo hypo- or ...hypercoagulability is questioned. The currently available evidence suggests that markedly increased D-dimers can be used in identifying COVID-19 patients who may need intensive care unit (ICU) admission and close monitoring or not. Viscoelastic methods (VMs), like thromboelastography (TEG) and rotational thromboelastometry (ROTEM), estimate the dynamics of blood coagulation. The evaluation of coagulopathy by VMs in severe COVID-19 infection seems an increasingly attractive option. Available evidence supports that COVID-19 patients with acute respiratory failure suffer from severe hypercoagulability rather than consumptive coagulopathy often associated with fibrinolysis shutdown. However, the variability in definitions of both the procoagulant profile and the clinical outcome assessment, in parallel with the small sample sizes in most of these studies, do not allow the establishment of a clear association between the hypercoagulable state and thrombotic events. VMs can effectively provide insight into the pathophysiology of coagulopathy, detecting the presence of hypercoagulability in critically ill COVID-19 patients. However, it remains unknown whether the degree of coagulopathy can be used in order to predict the outcome, establish a diagnosis or guide anticoagulant therapy.
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