The complement cascade in lung injury and disease.

BACKGROUND: The complement system is an important arm of immune defense bringing innate and adaptive immunity. Although originally regarded as a major complementary defense mechanism against pathogens, continuously emerging evidence has uncovered a central role of this complex system in several diseases including lung pathologies. MAIN BODY: Complement factors such as anaphylatoxins C3a and C5a, their receptors C3aR, C5aR and C5aR2 as well as complement inhibitory proteins CD55, CD46 and CD59 have been implicated in pathologies such as the acute respiratory distress syndrome, pneumonia, chronic obstructive pulmonary disease, asthma, interstitial lung diseases, and lung cancer. However, the exact mechanisms by which complement factors induce these diseases remain unclear. Several complement-targeting monoclonal antibodies are reported to treat lung diseases. CONCLUSIONS: The complement system contributes to the progression of the acute and chronic lung diseases. Better understanding of the underlying mechanisms will provide groundwork to develop new strategy to target complement factors for treatment of lung diseases.

Adrenal function in relation to cytokines and outcome in non-critically ill patients with COVID-19.

PURPOSE: We aimed to identify whether hypothalamic-pituitary-adrenal (HPA) axis dysfunction is related to deterioration in a percentage of patients who progress to severe COVID-19. METHODS: In this cohort observational study, we evaluated HPA axis activation by measuring cortisol, adrenocorticotropic hormone (ACTH), dehydroepiandrosterone sulfate (DHEA-S) levels, whole blood expression levels of the key glucocorticoid receptor, GCR-α, and the glucocorticoid-induced leucine zipper (GILZ), and cytokines, as markers of the inflammatory phase, in 149 patients with respiratory infection admitted in the ward, without known adrenal disease and/or confounding medications (glucocorticoids). One hundred and four (104) patients were SARS-CoV-2 positive (C +) and controls consisted of 45 SARS-CoV-2-negative patients (NC). RESULTS: No differences in cortisol levels were observed between the C + and the NC patients. Cortisol levels correlated with ACTH (r = 0.284, p = 0.001) and IL-6 (r = 0.289, p = 0.04). In C + patients, cortisol levels mainly correlated with IL-6 levels (r = 0.28; p = 0.017). GCR-α expression was significantly higher in C + patients compared to NC. Patients with higher cortisol levels were more likely to progress to respiratory function deterioration or die. Both GCR-α and GILZ expression were significantly higher in C + non-survivors. CONCLUSION: Our findings indicate that cortisol serves as an indicator of disease severity. GILZ expression appears to be a more effective marker of mortality prediction in moderate COVID-19 cases. However, routine measurement of GILZ levels is currently unavailable. Elevated levels of cortisol may be indicative of patients with moderate COVID-19 who are at a higher risk of deterioration. This information can aid in identifying individuals who require early medical attention.

Accuracy of T2 magnetic resonance assays as point-of-care methods in the intensive care unit.

BACKGROUND: Novel molecular diagnostic methods are being evaluated in order to expedite pathogen identification in patients with bacteraemia. AIMS: To evaluate the feasibility and diagnostic accuracy of the T2 magnetic resonance (T2MR) assays - T2 Bacteria (T2B) and T2 Resistance (T2R) - as point-of-care tests in the intensive care unit compared with blood-culture-based tests. METHODS: Prospective cross-sectional study of consecutive patients with suspected bacteraemia. Diagnostic accuracy was evaluated using blood culture as the reference method. FINDINGS: In total, 208 cases were included in the study. The mean time from sampling to report was lower for the T2MR assays compared with blood-culture-based methods (P<0.001). The rate of invalid reports was 6.73% for the T2B assay and 9.9% for the T2R assay. For the T2B assay, overall positive percentage agreement (PPA) was 84.6% [95% confidence interval (CI) 71.9-93.1%], negative percentage agreement (NPA) was 64.3% (95% CI 55.4-72.6%), positive predictive value (PPV) was 48.9% (95% CI 42.5-55.3%) and negative predictive value (NPV) was 91.2% (95% CI 84.4-95.2%). Cohen's kappa coefficient was 0.402. For the T2R assay, overall PPA was 80% (95% CI 51.9-95.7%), NPA was 69.2% (95% CI 54.9-81.3%), PPV was 42.9% (95% CI 31.7-54.8%) and NPV was 92.3% (95% CI 81.1-97.1%). Cohen's kappa coefficient was 0.376. CONCLUSION: T2MR assays have high NPV for rapid exclusion of bacteraemia, and could potentially assist with antimicrobial stewardship when applied as point-of-care diagnostic tests in the intensive care unit.

Neuromuscular blockade administration is associated with altered energy expenditure in critically ill intubated patients with COVID-19.

BACKGROUND & AIMS: ESPEN guidelines advocate that energy needs of critically ill patients with COVID 19 should be assessed using indirect calorimetry, if safely available. This study described energy needs of intubated patients with COVID-19 and explores whether neuromuscular blockade administration (NMBAs) is associated with altered energy expenditure. METHODS: Resting energy expenditure (REE) and respiratory exchange rate (RER) evaluated among critically ill intubated COVID-19 patients until 28th day of intensive care unit stay (ICU-S) by indirect calorimetry. Paralysed patients were defined as those with drug induced paralysis using cicatracurium, for at least 3 days during their ICU-S. RESULTS: 34 adult COVID 19 patients (59.8% male, 35.2% obese) requiring mechanical ventilation were assessed prospectively. REE measurements suggest a gradual increase of energy needs post 3rd day of ICU-S in both patients without obesity (non ob) ((from 17.8 kcal/kgr up to 29.3 kcal/kgr actual body weight (AcBW) during 28th day of ICU-S, p = 0.011)) and patients with obesity (ob) ((from 18.1 kcal/kgr up to 30.1 kcal/kgr adjusted body weight (AjBW) during 28th day of ICU-S, p = 0.021)). NMBAs use was accompanied by a significant drop in REE, especially during first 7 days of hospitalization, both in non ob (22.9 vs 17.9 kcal/kgr AcBW, p = 0.014) and ob patients (22.5 vs 19.5 kcal/kgr ABW, p = 0.027). CONCLUSION: We identified the energy needs of COVID-19 intubated patients and highlighted a significant increase beyond the 1st week in the ICU. Administration of NMBAs should be considered, as it may impact resting energy expenditure.

Demographic and clinical features of critically ill patients with COVID-19 in Greece: The burden of diabetes and obesity.

AIMS: The aim of the study was to investigate the association between type-2 diabetes mellitus, other underlying diseases and obesity with the outcomes of critically ill Covid-19 patients in Greece. METHODS: In this retrospective observational multi-centre study, data and outcomes of 90 RNA 2109-nCoV confirmed critically ill patients from 8 hospitals throughout Greece, were analysed. All reported information stand through April 13th 2020. RESULTS: The median age of the patients was 65.5 (IQR 56-73), majority were male (80%) and obesity was present in 34.4% of patients most prevalent to younger than 55 years. Hypertension was the prevailing comorbidity (50%), followed by cardiovascular diseases (21.1%) and type-2 diabetes (18.9%). At admission, common symptoms duration had a median of 8 (IQR 5-11) days. A 13.3% of the patients were discharged, 53.4% were still in the ICUs and 28.9% deceased who were hospitalised for fewer days than the survivors [6 (IQR 3-9) vs. 9 (IQR 7-14.5) respectively]. Aging was not a risk factor but diabetes deteriorates the outcomes. Obesity poses a suggestive burden as it was more notable in deceased versus survivors. CONCLUSIONS: Type 2 diabetes and obesity may have contributed to disease severity and mortality in COVID-19 critically ill patients in Greece.

Ghrelin alterations during experimental and human sepsis.

BACKGROUND: Ghrelin is a hormone mainly produced by cells of the gastric mucosa, which has been shown to possess anti-inflammatory and immunomodulatory properties. The objective of the study was to investigate ghrelin levels during sepsis, as well as in an experimental sepsis model. METHODS: All consecutive admissions to the ICU of a tertiary hospital in Athens, Greece were screened for eligibility during the study. Thirty four non-septic patients upon ICU admission who subsequently developed sepsis were enrolled. Clinical data and scores were recorded, and blood samples were obtained at baseline (upon ICU admission), and at sepsis development. Total and active ghrelin, leptin, and cytokines were measured. Moreover, lipopolysaccharide (LPS) was administered to mice in order to induce endotoxemia and at specified time points, blood and tissue samples were collected. RESULTS: In patients, serum total and active ghrelin concentrations were significantly elevated in sepsis compared to baseline (553.8 ±â€¯213.4 vs 193.5 ±â€¯123.2, p < 0.001; 254.3 ±â€¯70.6 vs 56.49 ±â€¯16.3, p < 0.001). Active ghrelin levels at the sepsis stage were inversely correlated with SOFA score and length of stay in the ICU (p = 0.023 and p = 0.027 respectively). In the mouse endotoxemia model ghrelin levels were elevated following LPS treatment, and the same trend was observed for leptin, TNFα and IL-6. Ghrelin administration managed to reduce IL-6 levels in mouse serum and in BALF. Pulmonary expression of ghrelin and its receptor GHSR1a was found decreased in LPS-treated mice. CONCLUSIONS: In a well-defined cohort of ICU patients, we have demonstrated that active and total ghrelin increase in sepsis. The same is true for the experimental sepsis model used in the study. The inverse correlation of active ghrelin levels with SOFA score and length of ICU stay among septic patients is indicative of a potential protective role of active ghrelin during the septic process.

Association of leukocyte DNA methylation changes with dietary folate and alcohol intake in the EPIC study.

BACKGROUND: There is increasing evidence that folate, an important component of one-carbon metabolism, modulates the epigenome. Alcohol, which can disrupt folate absorption, is also known to affect the epigenome. We investigated the association of dietary folate and alcohol intake on leukocyte DNA methylation levels in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Leukocyte genome-wide DNA methylation profiles on approximately 450,000 CpG sites were acquired with Illumina HumanMethylation 450K BeadChip measured among 450 women control participants of a case-control study on breast cancer nested within the EPIC cohort. After data preprocessing using surrogate variable analysis to reduce systematic variation, associations of DNA methylation with dietary folate and alcohol intake, assessed with dietary questionnaires, were investigated using CpG site-specific linear models. Specific regions of the methylome were explored using differentially methylated region (DMR) analysis and fused lasso (FL) regressions. The DMR analysis combined results from the feature-specific analysis for a specific chromosome and using distances between features as weights whereas FL regression combined two penalties to encourage sparsity of single features and the difference between two consecutive features. RESULTS: After correction for multiple testing, intake of dietary folate was not associated with methylation level at any DNA methylation site, while weak associations were observed between alcohol intake and methylation level at CpG sites cg03199996 and cg07382687, with qval = 0.029 and qval = 0.048, respectively. Interestingly, the DMR analysis revealed a total of 24 and 90 regions associated with dietary folate and alcohol, respectively. For alcohol intake, 6 of the 15 most significant DMRs were identified through FL. CONCLUSIONS: Alcohol intake was associated with methylation levels at two CpG sites. Evidence from DMR and FL analyses indicated that dietary folate and alcohol intake may be associated with genomic regions with tumor suppressor activity such as the GSDMD and HOXA5 genes. These results were in line with the hypothesis that epigenetic mechanisms play a role in the association between folate and alcohol, although further studies are warranted to clarify the importance of these mechanisms in cancer.

Validation of the new Sepsis-3 definitions: proposal for improvement in early risk identification.

OBJECTIVES: Sepsis-3 definitions generated controversies regarding their general applicability. The Sepsis-3 Task Force outlined the need for validation with emphasis on the quick Sequential Organ Failure Assessment (qSOFA) score. This was done in a prospective cohort from a different healthcare setting. METHODS: Patients with infections and at least two signs of systemic inflammatory response syndrome (SIRS) were analysed. Sepsis was defined as total SOFA ≥2 outside the intensive care unit (ICU) or as an increase of ICU admission SOFA ≥2. The primary endpoints were the sensitivity of qSOFA outside the ICU and sepsis definition both outside and within the ICU to predict mortality. RESULTS: In all, 3346 infections outside the ICU and 1058 infections in the ICU were analysed. Outside the ICU, respective mortality with ≥2 SIRS and qSOFA ≥2 was 25.3% and 41.2% (p <0.0001); the sensitivities of qSOFA and of sepsis definition to predict death were 60.8% and 87.2%, respectively. This was 95.9% for sepsis definition in the ICU. The sensitivity of qSOFA and of ≥3 SIRS criteria for organ dysfunction outside the ICU was 48.7% and 72.5%, respectively (p <0.0001). Misclassification outside the ICU with the 1991 and Sepsis-3 definitions into stages of lower severity was 21.4% and 3.7%, respectively (p <0.0001) and 14.9% and 3.7%, respectively, in the ICU (p <0.0001). Adding arterial pH ≤7.30 to qSOFA increased sensitivity for prediction of death to 67.5% (p 0.004). CONCLUSIONS: Our analysis positively validated the use of SOFA score to predict unfavourable outcome and to limit misclassification into lower severity. However, qSOFA score had inadequate sensitivity for early risk assessment.

Exhaled nitric oxide and carbon monoxide in mechanically ventilated brain-injured patients.

The inflammatory influence and biological markers of prolonged mechanical-ventilation in uninjured human lungs remains controversial. We investigated exhaled nitric oxide (NO) and carbon monoxide (CO) in mechanically-ventilated, brain-injured patients in the absence of lung injury or sepsis at two different levels of positive end-expiratory pressure (PEEP). Exhaled NO and CO were assessed in 27 patients, without lung injury or sepsis, who were ventilated with 8 ml kg(-1) tidal volumes under zero end-expiratory pressure (ZEEP group, n = 12) or 8 cm H2O PEEP (PEEP group, n = 15). Exhaled NO and CO was analysed on days 1, 3 and 5 of mechanical ventilation and correlated with previously reported markers of inflammation and gas exchange. Exhaled NO was higher on day 3 and 5 in both patient groups compared to day 1: (PEEP group: 5.8 (4.4-9.7) versus 11.7 (6.9-13.9) versus 10.7 (5.6-16.6) ppb (p < 0.05); ZEEP group: 5.3 (3.8-8.8) versus 9.8 (5.3-12.4) versus 9.6 (6.2-13.5) ppb NO peak levels for days 1, 3 and 5, respectively, p < 0.05). Exhaled CO remained stable on day 3 but significantly decreased by day 5 in the ZEEP group only (6.3 (4.3-9.0) versus 8.1 (5.8-12.1) ppm CO peak levels for day 5 versus 1, p < 0.05). The change scores for peak exhaled CO over day 1 and 5 showed significant correlations with arterial blood pH and plasma TNF levels (r s = 0.49, p = 0.02 and r s = -0.51 p = 0.02, respectively). Exhaled NO correlated with blood pH in the ZEEP group and with plasma levels of IL-6 in the PEEP group. We observed differential changes in exhaled NO and CO in mechanically-ventilated patients even in the absence of manifest lung injury or sepsis. These may suggest subtle pulmonary inflammation and support application of real time breath analysis for molecular monitoring in critically ill patients.

Elevated soluble endothelial protein C receptor levels at ICU admission are associated with sepsis development.

BACKGROUND: The endothelial protein C receptor (EPCR) is a protein that regulates the protein C anticoagulant and anti-inflammatory pathways. A soluble form of EPCR (sEPCR) circulates in plasma and inhibits activated protein C (APC) activities. The clinical impact of sEPCR and its involvement in the septic process is under investigation. In this study, we assessed the role of sEPCR levels as an early indicator of sepsis development. METHODS: Plasma sEPCR levels were measured in 59 critically-ill non-septic patients at the time of admission to the intensive care unit (ICU). Multiple logistic regression analysis was performed to identify potential risk factors for sepsis development and Cox-Regression models were fitted for variables to examine their relationship with time to sepsis development. RESULTS: Thirty patients subsequently developed sepsis and 29 did not. At ICU admission, sequential organ failure assessment (SOFA) scores were significantly higher in the subsequent sepsis group as compared to the non sepsis group (mean ± SD: 6.4±2.7 and 5±2.3, respectively, P=0.037). sEPCR levels were also higher in the patients who subsequently developed sepsis compared to the patients who did not (median and interquartile range: 173.4 [104.5-223.5] ng/mL vs. 98.3 [69.8-147.7] ng/mL, respectively; P=0.004). Cox regression analysis identified sEPCR as the only parameter related to sepsis development with time (relative risk: 1.078, 95% confidence interval: 1.016-1.144, by 10 units; P=0.013). CONCLUSION: Upon ICU admission, sEPCR levels in initially non-septic critically-ill patients appear elevated in the subjects who will subsequently become septic.

Association of autophagy-related 16-like 1 (ATG16L1) gene polymorphism with sepsis severity in patients with sepsis and ventilator-associated pneumonia.

Autophagy is a highly conserved mechanism of eukaryotic cells implicated in cell homeostasis and elimination of intracellular pathogens. Functional polymorphisms in genes encoding for autophagy have been associated with susceptibility to inflammatory and infectious diseases, but data on severe infections are missing. The aim of the present study was to assess whether polymorphisms in genes encoding proteins involved in autophagy influence susceptibility to ventilator-associated pneumonia (VAP). Mechanically ventilated patients with VAP were studied. Genotyping for autophagy-related 16-like 1 (ATG16L1, rs2241880) functional polymorphism was performed using the TaqMan single-nucleotide assay. Monocytes were isolated from patients and stimulated with lipopolysaccharide (LPS). Tumor necrosis factor-α (TNF-α) was measured in the supernatants of monocytes using an enzyme-linked immunosorbent assay. Procalcitonin (PCT) was also measured in the serum of patients by an immuno-time-resolved amplified cryptate technology assay. A total of 155 patients with VAP were enrolled in the study. Carriage of the minor A allele of ATG16L1 was associated with septic shock with at least one organ failure (odds ratio (OR): 2.40, p: 0.036). TNF-α production was significantly greater among the carriers of the polymorphism presenting with at least one organ failure (p: 0.040). PCT was increased upon worsening to septic shock and organ failure only among carriers of the minor frequency A alleles. In a homogeneous cohort of septic patients with VAP, the carriage of autophagy polymorphisms predisposes to VAP severity and septic shock development. This may be related with predisposition to immunoparalysis.

Gelsolin expression is necessary for the development of modelled pulmonary inflammation and fibrosis.

BACKGROUND: Despite intense research efforts, the aetiology and pathogenesis of idiopathic pulmonary fibrosis remain poorly understood. Gelsolin, an actin-binding protein that modulates cytoskeletal dynamics, was recently highlighted as a likely disease modifier through comparative expression profiling and target prioritisation. METHODS: To decipher the possible role of gelsolin in pulmonary inflammation and fibrosis, immunocytochemistry on tissue microarrays of human patient samples was performed followed by computerised image analysis. The results were validated in the bleomycin-induced animal model of pulmonary inflammation and fibrosis using genetically-modified mice lacking gelsolin expression. Moreover, to gain mechanistic insights into the mode of gelsolin activity, a series of biochemical analyses was performed ex vivo in mouse embryonic fibroblasts. RESULTS: Increased gelsolin expression was detected in lung samples of patients with idiopathic interstitial pneumonia as well as in modelled pulmonary inflammation and fibrosis. Genetic ablation of gelsolin protected mice from the development of modelled pulmonary inflammation and fibrosis attributed to attenuated epithelial apoptosis. CONCLUSIONS: Gelsolin expression is necessary for the development of modelled pulmonary inflammation and fibrosis, while the caspase-3-mediated gelsolin fragmentation was shown to be an apoptotic effector mechanism in disease pathogenesis and a marker of lung injury.

Serum of patients with septic shock stimulates the expression of Trem-1 on U937 monocytes.

OBJECTIVES: To describe the concentrations of sTREM-1 in patients with sepsis and to explore the effects of their serum on the expression of TREM-1 on U937 monocytes. METHODS: Blood was sampled at regular time intervals in 56 patients with sepsis. Concentrations of tumour necrosis factor-alpha (TNFalpha), interleukin-1beta (IL-1alpha), IL-6, IL-8, IL-10 and IL-12p70 and sTREM-1 were measured. U937 monocytes were incubated in the presence of serum at sepsis onset. RESULTS: Median sTREM-1 concentration on day 1 for patients with septic shock was 915 pg/ml and 228.5 pg/ml for those without shock (p = 0.002). TNFalpha, IL-1alpha, IL-6, IL-8 and IL-10 did not differ between them. A positive correlation was found between changes of sTREM-1 and SOFA scores from day 1 to 7. Sera of patients with septic shock evoked a significant increase of the expression of TREM-1. The concentrations of TNFalpha and IL-8 in supernatants increased only after stimulating with sera of patients without shock, but not after stimulating with sera of patients with shock. CONCLUSIONS: Levels of sTREM-1 correlated with sepsis severity. sTREM-1 is considerably higher in patients with shock compared to patients without shock. The serum of shocked patients could stimulate the expression of TREM-1 on U937 monocytes.

Regulation of the expression of soluble guanylyl cyclase by reactive oxygen species.

BACKGROUND AND PURPOSE: Superoxide anions produced during vascular disease scavenge nitric oxide (NO), thereby reducing its biological activity. The aim of the present study was to investigate whether reactive oxygen species (ROS) have a direct effect on soluble guanylyl cyclase (sGC) subunit levels and function and to ascertain the mechanism(s) involved. EXPERIMENTAL APPROACH: Rat aortic smooth muscle cells (RASM) or freshly isolated vessels were exposed to reactive oxygen species (ROS)-generating agents and sGC subunit expression was determined at the mRNA and/or protein level. cGMP accumulation was also determined in RASM exposed to ROS. KEY RESULTS: Incubation of smooth muscle cells with H(2)O(2), xanthine/xanthine oxidase (X/XO) or menadione sodium bisulphite (MSB) significantly decreased protein levels of alpha1 and beta1 subunits of sGC and reduced SNP-induced cGMP formation. Similarly, sGC expression was reduced in freshly isolated vessels exposed to ROS-generating agents. The ROS-triggered inhibition of alpha1 and beta1 levels was not blocked by proteasome inhibitors, suggesting that decreased sGC protein was not due to protein degradation through this pathway. Real time RT-PCR analysis demonstrated a 68% reduction in steady state mRNA levels for the alpha1 subunit following exposure to H(2)O(2). In addition, alpha1 promoter-driven luciferase activity in RASM decreased by 60% after H(2)O(2) treatment. CONCLUSION AND IMPLICATIONS: We conclude that oxidative stress triggers a decrease in sGC expression and activity that results from reduced sGC steady state mRNA levels. Altered sGC expression is expected to contribute to the changes in vascular tone and remodeling observed in diseases associated with ROS overproduction.

Leptin alterations in the course of sepsis in humans.

Neuroendocrine response to sepsis may be divided into acute and prolonged phase. As leptin is implicated in the stress response, leptin's profile during both phases, and the possible relationships between leptin and the neuroendocrine response to sepsis were investigated. Thirty adult patients with sepsis in an intensive care unit were studied. Blood samples were collected at the acute and the prolonged phases. In acute sepsis, leptin levels were higher in patients than in controls (10.2 +/- 2.5 vs. 4.1 +/- 1.2 ng/ml, p =0.01) and correlated positively with insulin levels and insulin resistance. A decline in leptin levels was found during prolonged sepsis (from 10.2 +/- 2.5 to 6.2 +/- 1.7 ng/ml, p=0.001), which was not related to survival (p=0.913). At the onset of sepsis, leptin levels increased in correlation with insulin and insulin resistance, possibly indicating a cause-effect relationship. However, the decline in leptin levels during the prolonged phase of sepsis was not related either to survival or to metabolic and hormonal changes.

Acute mediastinitis: spectrum of computed tomography findings.

The objective of this study was to describe CT findings and to determine the diagnostic value of CT in diagnosis of acute mediastinitis. CT findings were retrospectively studied in 40 patients with suspected acute mediastinitis, including 28 postoperative patients, five with acute descending necrotizing mediastinitis (ADNM), and seven with suspected post-traumatic perforation of the esophagus. Findings included increased attenuation of mediastinal fat (100%), localized mediastinal fluid collections (55%), free gas bubbles in the mediastinum (57.5%), mediastinal lymph nodes (35%), pericardial effusions (27.5%), pleural effusions (85%), lung infiltrates (35%), sternal dehiscence (40%), and pleuromediastinal fistula (2.5%). The sensitivity and specificity of CT in postoperative patients in the first 17 days was 100% and 33% respectively, and after day 17, 100% and 90%. In patients with ADNM sensitivity was 100% while in patients with suspected esophageal perforation sensitivity and specificity were 100%. CT is a highly sensitive technique for the detection of mediastinitis of various causes. For the postoperative patients there is clear time dependence for CT interpretation and accuracy. In patients with suspected ADNM, and traumatic esophageal perforation CT is highly specific early after clinical presentation.

Mediastinal mass with Dysphagia in an elderly patient.

We report the use of endoscopic techniques for successful diagnosis in a case of atypical esophageal tuberculosis. Tuberculosis of the esophagus is an unusual presentation of this disease, having been estimated to occur in 0.15% of the people who die of tuberculosis. A few cases of possible primary tuberculous esophagitis have been described. This report describes a patient with dysphagia who appeared to have esophageal tuberculosis without HIV and in the absence of other signs of tuberculosis. The patient responded promptly to treatment with tuberculostatics.

Activation of the fibrinolytic system and utilization of the coagulation inhibitors in sepsis: comparison with severe sepsis and septic shock.

OBJECTIVES: To determine whether the fibrinolytic system is activated and coagulation inhibitors are utilized in sepsis, to compare the findings detected in sepsis with those found in severe sepsis and septic shock, and to compare the role played by different infectious pathogens on fibrinolysis and coagulation inhibitors. DESIGN AND SETTING: Prospective study comparing patients with sepsis, severe sepsis, and septic shock and healthy volunteers in the general intensive care unit of a tertiary university hospital. PATIENTS: Eighty-two consecutive septic patients (47 with sepsis, 18 with severe sepsis, and 17 with septic shock), and 14 healthy volunteers (controls). MEASUREMENTS AND RESULTS: After blood sampling we measured activation markers of fibrinolysis [plasmin/alpha(2)-antiplasmin complexes (PAP), complexes of tissue plasminogen activator/plasminogen activator inhibitor (tPA/PAI), fibrin(ogen) degradation products (FDPs), D-dimmers fibrin degradation products (D-d)], the utilization marker of antithrombin III (ATIII) thrombin/antithrombin complexes (TAT), several factors of fibrinolysis [plasminogen, tissue plasminogen activator (tPA), plasminogen activator inhibitor 1 (PAI-1), alpha(2)-antiplasmin], and the natural coagulation inhibitors [ATIII, protein C (PrC), protein S (PrS)]. In sepsis, PAP, FDPs, D-d, and TAT were increased to 439.8+/-32.35 microg/l, 57% positive, 49% positive, and 3.46+/-0.27 microg/l, respectively, compared with control subjects (205.57+/-28.58 microg/l, 0% positive, 7% positive, and 1.61+/-0.1 microg/l, respectively). These markers further increased in severe sepsis and septic shock. With the exception of a decrease in ATIII and an increase in tPA and PAI-1, coagulation inhibitors and factors of fibrinolysis were not changed in sepsis. In severe sepsis and mainly in septic shock, coagulation inhibitors (ATIII, PrC) and plasminogen were markedly decreased, whereas tPA and PAI-1 were further increased. All changes were independent of the causative infectious pathogen. CONCLUSIONS: Fibrinolysis is strongly activated and ATIII is utilized in sepsis. These findings are further enhanced in severe sepsis and septic shock. In sepsis only ATIII is decreased. In contrast, in severe sepsis and mainly in septic shock plasminogen and the main coagulation inhibitors (i.e., ATIII, PrC) are depleted, indicating exhaustion of fibrinolysis and coagulation inhibitors. Finally, Gram-positive, Gram-negative and other micro-organisms produce identical impairment.