Publications by authors named "Antonia Koutsoukou"

55 Publications

Disease severity-specific neutrophil signatures in blood transcriptomes stratify COVID-19 patients.

Genome Med 2021 01 13;13(1). Epub 2021 Jan 13.

Systems Medicine, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.

Background: The SARS-CoV-2 pandemic is currently leading to increasing numbers of COVID-19 patients all over the world. Clinical presentations range from asymptomatic, mild respiratory tract infection, to severe cases with acute respiratory distress syndrome, respiratory failure, and death. Reports on a dysregulated immune system in the severe cases call for a better characterization and understanding of the changes in the immune system.

Methods: In order to dissect COVID-19-driven immune host responses, we performed RNA-seq of whole blood cell transcriptomes and granulocyte preparations from mild and severe COVID-19 patients and analyzed the data using a combination of conventional and data-driven co-expression analysis. Additionally, publicly available data was used to show the distinction from COVID-19 to other diseases. Reverse drug target prediction was used to identify known or novel drug candidates based on finding from data-driven findings.

Results: Here, we profiled whole blood transcriptomes of 39 COVID-19 patients and 10 control donors enabling a data-driven stratification based on molecular phenotype. Neutrophil activation-associated signatures were prominently enriched in severe patient groups, which was corroborated in whole blood transcriptomes from an independent second cohort of 30 as well as in granulocyte samples from a third cohort of 16 COVID-19 patients (44 samples). Comparison of COVID-19 blood transcriptomes with those of a collection of over 3100 samples derived from 12 different viral infections, inflammatory diseases, and independent control samples revealed highly specific transcriptome signatures for COVID-19. Further, stratified transcriptomes predicted patient subgroup-specific drug candidates targeting the dysregulated systemic immune response of the host.

Conclusions: Our study provides novel insights in the distinct molecular subgroups or phenotypes that are not simply explained by clinical parameters. We show that whole blood transcriptomes are extremely informative for COVID-19 since they capture granulocytes which are major drivers of disease severity.
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http://dx.doi.org/10.1186/s13073-020-00823-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805430PMC
January 2021

Study of inflammatory biomarkers in COPD and asthma exacerbations.

Adv Respir Med 2020 ;88(6):558-566

1st Department of Critical Care Medicine & Pulmonary Services, National and Kapodistrian University of Athens, Medical School, Evangelismos Hospital, Athens, Greece, Athens.

Introduction: Exacerbations are critical events in the course of asthma and chronic obstructive pulmonary disease (COPD). These events are potentially life-threatening, and the studies have shown that they have tremendous implications on long-term disease control and the overall prognosis of the patients. The aim of this study was to examine adipokines, cytokines and C-reactive protein (CRP) as potential biomarkers in asthma and COPD.

Material And Methods: Prospective cohort study of COPD and asthma patients treated for acute exacerbations. Thirty-nine COPD patients and 15 asthmatic patients were included in the study. Leptin, adiponectin, resistin, interleukin (Il)-6, 8, 18, tumor necrosis factor-a (TNF-a), and CRP were measured at three time points: on admission, at resolution and at the stable phase. Pre- and post-bronchodilation spirometry was additionally performed at resolution and at the stable phase.

Results: In COPD patients, leptin, leptin/adiponectin (L/A) ratio and resistin were elevated on admission compared to the stable phase. In asthmatic patients, leptin levels were raised on admission compared to the stable phase, and adiponectin was elevated at resolution compared to admission. In both diseases, CRP was significantly increased on admission compared to both resolution and stable disease. Finally, TNF-a could distinguish between asthma and COPD stable phase.

Conclusions: Leptin and CRP levels may be useful biomarkers in monitoring COPD and asthma response to treatment during an exacerbation episode. Hypoadiponectinemia was detected in asthma and COPD during all stages of the diseases. TNF-a could distinguish between asthma and COPD stable phase.
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http://dx.doi.org/10.5603/ARM.a2020.0188DOI Listing
January 2020

Untuned antiviral immunity in COVID-19 revealed by temporal type I/III interferon patterns and flu comparison.

Nat Immunol 2021 01 4;22(1):32-40. Epub 2020 Dec 4.

Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.

A central paradigm of immunity is that interferon (IFN)-mediated antiviral responses precede pro-inflammatory ones, optimizing host protection and minimizing collateral damage. Here, we report that for coronavirus disease 2019 (COVID-19) this paradigm does not apply. By investigating temporal IFN and inflammatory cytokine patterns in 32 moderate-to-severe patients with COVID-19 hospitalized for pneumonia and longitudinally followed for the development of respiratory failure and death, we reveal that IFN-λ and type I IFN production were both diminished and delayed, induced only in a fraction of patients as they became critically ill. On the contrary, pro-inflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-6 and IL-8 were produced before IFNs in all patients and persisted for a prolonged time. This condition was reflected in blood transcriptomes wherein prominent IFN signatures were only seen in critically ill patients who also exhibited augmented inflammation. By comparison, in 16 patients with influenza (flu) hospitalized for pneumonia with similar clinicopathological characteristics to those of COVID-19 and 24 nonhospitalized patients with flu with milder symptoms, IFN-λ and type I IFN were robustly induced earlier, at higher levels and independently of disease severity, whereas pro-inflammatory cytokines were only acutely produced. Notably, higher IFN-λ concentrations in patients with COVID-19 correlated with lower viral load in bronchial aspirates and faster viral clearance and a higher IFN-λ to type I IFN ratio correlated with improved outcome for critically ill patients. Moreover, altered cytokine patterns in patients with COVID-19 correlated with longer hospitalization and higher incidence of critical disease and mortality compared to flu. These data point to an untuned antiviral response in COVID-19, contributing to persistent viral presence, hyperinflammation and respiratory failure.
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http://dx.doi.org/10.1038/s41590-020-00840-xDOI Listing
January 2021

A Comparative Study Between Two Support Surfaces for Pressure Ulcer Prevention and Healing in ICU Patients.

Cureus 2020 Jun 23;12(6):e8785. Epub 2020 Jun 23.

Internal Medicine, National and Kapodistrian University of Athens Medical School, Athens, GRC.

Objective The aim of this research was to compare the effectiveness of two mattresses used in intensive care unit (ICU) high-risk patients in terms of pressure ulcers (PUs) prevention and healing. Materials and Methods The studied sample consisted of 70 consecutive patients aged 18 to 65 years hospitalized in two ICUs of a general hospital in Athens, Greece. Virtuoso Mattress System (LINET, Slaný, Czech Republic) was used in 35 patients, and standard memory foam mattress was used in the rest of participants. Patients were firstly assessed on enrollment and then every 72 hours in order to record the appearance or not of PUs, location of PUs, and stage of PUs, with the maximum follow-up not exceeding the 21 days. A number of clinical and biochemical factors, medical treatment, and vital signs were also recorded at each time point. Results Of the 70 patients, 40 (57.1%) were men, and the mean ± standard deviation age of the sample was 46.1 ± 14.5 years. The most common area of PUs was the buttocks (34.3%) followed by the shoulders (22.3%), with no statistically significant difference detected between the two groups. Moreover, the proportion of patients having PUs at stage 2 or higher was 23.8% on the third day after admission and 61.1% on the sixth day, with no difference detected between the two groups. Cox proportional hazard model revealed that the Virtuoso mattress was associated with almost 56% lower risk of developing PUs compared with standard foam mattress (HR [95% CI]: 0.44 [0.20-0.93]). The percentage of patients healed using the Virtuoso mattress was significantly lower compared with the standard foam mattress at all time points, with the results reaching statistical significance only on the 12th day after admission (7.7% vs. 66.7%; p < 0.05). Conclusions The Virtuoso mattress seems to be more effective compared with standard foam mattresses in the prevention of PUs, whereas the standard foam mattresses are more effective in PU healing process.
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http://dx.doi.org/10.7759/cureus.8785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381843PMC
June 2020

Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure.

Cell Host Microbe 2020 06 21;27(6):992-1000.e3. Epub 2020 Apr 21.

1(st) Department of Pulmonary Medicine and Intensive Care Unit, National and Kapodistrian University of Athens, Medical School, 115 27 Athens, Greece.

Proper management of COVID-19 mandates better understanding of disease pathogenesis. The sudden clinical deterioration 7-8 days after initial symptom onset suggests that severe respiratory failure (SRF) in COVID-19 is driven by a unique pattern of immune dysfunction. We studied immune responses of 54 COVID-19 patients, 28 of whom had SRF. All patients with SRF displayed either macrophage activation syndrome (MAS) or very low human leukocyte antigen D related (HLA-DR) expression accompanied by profound depletion of CD4 lymphocytes, CD19 lymphocytes, and natural killer (NK) cells. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production by circulating monocytes was sustained, a pattern distinct from bacterial sepsis or influenza. SARS-CoV-2 patient plasma inhibited HLA-DR expression, and this was partially restored by the IL-6 blocker Tocilizumab; off-label Tocilizumab treatment of patients was accompanied by increase in circulating lymphocytes. Thus, the unique pattern of immune dysregulation in severe COVID-19 is characterized by IL-6-mediated low HLA-DR expression and lymphopenia, associated with sustained cytokine production and hyper-inflammation.
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http://dx.doi.org/10.1016/j.chom.2020.04.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7172841PMC
June 2020

The development of various forms of lung injury with increasing tidal volume in normal rats.

Respir Physiol Neurobiol 2020 03 3;274:103369. Epub 2020 Jan 3.

Department of Physiopathology and Transplantations, Università di Milano, Milan, Italy.

Sixty-three, open-chest normal rats were subjected to mechanical ventilation (MV) with tidal volumes (V) ranging from 7.5-39.5ml kg and PEEP 2.3 cmHO. Arterial blood gasses and pressure, and lung mechanics were measured during baseline ventilation (V = 7.5ml kg) before and after test ventilation, when cytokine, von Willebrand factor (vWF), and albumin concentration in serum and broncho-alveolar lavage fluid (BALF), wet-to-dry weight ratio (W/D), and histologic injury scores were assessed. Elevation of W/D and serum vWF and cytokine concentration occurred with V > 25ml kg. With V > 30ml kg cytokine and albumin concentration increased also in BALF, arterial oxygen tension decreased, lung mechanics and histology deteriorated, while W/D and vWF and cytokine concentration increased further. Hence, the initial manifestation of injurious MV consists of damage of extra-alveolar vessels leading to interstitial edema, as shown by elevated vWF and cytokine levels in serum but not in BALF. Failure of the endothelial-epithelial barrier occurs at higher stress-strain levels, with alveolar edema, small airway injury, and mechanical alterations.
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http://dx.doi.org/10.1016/j.resp.2020.103369DOI Listing
March 2020

Daily sedation interruption and mechanical ventilation weaning: a literature review.

Anaesthesiol Intensive Ther 2019 ;51(5):380-389

1st Department of Respiratory Medicine, "Sotiria" Hospital, National and Kapodistrian University of Athens, Greece.

Daily sedation interruption (DSI) is a method used since the beginning of the millennium to streamline sedation in critically ill patients under mechanical ventilation and improve clinical outcomes. The purpose was to assess whether there is a correlation between DSI and weaning from mechanical ventilation. We designed a literature review via searching PubMed, UpToDate and Google Scholar for relevant key terms from inception until March 2019. Literature retrieved included nine randomized controlled trials. When compared to usual practice, it is superior in terms of duration of mechanical ventilation, stay in the intensive care unit, hospitalization, adverse effect occurrence and total cost of therapy. Comparison with other sedation protocols produces conflicting results. DSI, and protocolized sedation in general, are safe methods to perform to facilitate earlier weaning and improved clinical outcomes. Future research should focus on minimizing bias by conducting double-blinded studies and studying different patient subgroups.
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http://dx.doi.org/10.5114/ait.2019.90921DOI Listing
September 2020

Lung Microbiome in Asthma: Current Perspectives.

J Clin Med 2019 Nov 14;8(11). Epub 2019 Nov 14.

ICU, 1st Department of Pulmonary Medicine, "Sotiria" Hospital; Athens School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece.

A growing body of evidence implicates the human microbiome as a potentially influential player actively engaged in shaping the pathogenetic processes underlying the endotypes and phenotypes of chronic respiratory diseases, particularly of the airways. In this article, we specifically review current evidence on the characteristics of lung microbiome, and specifically the bacteriome, the modes of interaction between lung microbiota and host immune system, the role of the "lung-gut axis", and the functional effects thereof on asthma pathogenesis. We also attempt to explore the possibilities of therapeutic manipulation of the microbiome, aiming at the establishment of asthma prevention strategies and the optimization of asthma treatment.
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http://dx.doi.org/10.3390/jcm8111967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912699PMC
November 2019

Buffering Capacity in Sepsis: A Prospective Cohort Study in Critically Ill Patients.

J Clin Med 2019 Oct 23;8(11). Epub 2019 Oct 23.

Intensive Care Unit, First Department of Respiratory Medicine, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece.

Background: The concept of buffering generally refers to the ability of a system/organism to withstand attempted changes. For acid-base balance in particular, it is the body's ability to limit pH aberrations when factors that potentially affect it change. Buffering is vital for maintaining homeostasis of an organism. The present study was undertaken in order to investigate the probable buffering capacity changes in septic patients.

Materials And Methods: This prospective cohort study included 113 ICU patients (96 septic and 17 critically-ill non-septic/controls). The buffering capacity indices were assessed upon ICU admission and reassessed only in septic patients, either at improvement or upon severe deterioration. Applying Stewart's approach, the buffering capacity was assessed with indices calculated from the observed central venous-arterial gradients: a) ΔPCO/Δ[H] or ΔpH, b) ΔSID/Δ[H] or ΔpH.

Results: In a generalized estimating equation linear regression model, septic patients displayed significant differences in ΔPCO/ΔpH [beta coefficient = -47.63, 95% CI (-80.09) - (-15.17), = 0.004], compared to non-septic patients on admission. Lower absolute value of ΔPCO/ΔpH (%) on admission was associated with a significant reduction in ICU mortality (HR 0.98, 95% CI: 0.97-0.99, = 0.02). At septic-group reassessment (remission or deterioration), one-unit increase of ΔPCO/Δ[H] reduced the ICU death hazard by 44% (HR 0.56, 95% CI: 0.33-0.96, = 0.03).

Conclusions: In the particular cohort of patients studied, a difference in the buffering capacity was recorded between septic and non-septic patients on admission. Moreover, buffering capacity was an independent predictor of fatal ICU outcome at both assessments, ICU-admission and sepsis remission or deterioration.
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http://dx.doi.org/10.3390/jcm8111759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912238PMC
October 2019

The lung microbiome dynamics between stability and exacerbation in chronic obstructive pulmonary disease (COPD): Current perspectives.

Respir Med 2019 10 21;157:1-6. Epub 2019 Aug 21.

1th Department of Respiratory Medicine, Medical School, National and Kapodistrian University of Athens and "Sotiria" Chest Disease Hospital, 11527, Athens, Greece. Electronic address:

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disorder with a course that is not uniform for all COPD patients. Although smoking is considered as the major cause of the disease, persistent or recurrent infections seem to play a particular role in the disease establishment and progression. COPD is characterized by dysregulated immunity that has been associated with the bacterial colonization and infections. The establishment of culture-independent techniques has shed new light on the relationships between bacterial ecology and health status and expanded our knowledge on the lung microbiome. Interactions between the host and lung microbiome result in inflammation and activation of resident cells. The lung microbiome contains populations of symbionts and pathobionts in balance which lose their equilibrium and disturb the balance of T-helper and regulatory T-cells (Treg) upon infection, or lung disease. In COPD factors such as disease severity, exacerbations, degree of inflammation, and type of treatment used (e.g inhaled or systemic steroids and antibiotics) affect the composition of lung microbiota. Recent data indicate that the presence of specific bacterial taxa in the airways has the potential to influence the host immune response and possibly to interfere with disease phenotype. Although, there is a growing body of evidence for the role of microbiome in COPD several unanswered questions still exist for its clinical relevance.
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http://dx.doi.org/10.1016/j.rmed.2019.08.012DOI Listing
October 2019

Acute Severe Asthma in Adolescent and Adult Patients: Current Perspectives on Assessment and Management.

J Clin Med 2019 Aug 22;8(9). Epub 2019 Aug 22.

ICU, 1st Department of Pulmonary Medicine, "Sotiria" Hospital, Athens School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece.

Asthma is a chronic airway inflammatory disease that is associated with variable expiratory flow, variable respiratory symptoms, and exacerbations which sometimes require hospitalization or may be fatal. It is not only patients with severe and poorly controlled asthma that are at risk for an acute severe exacerbation, but this has also been observed in patients with otherwise mild or moderate asthma. This review discusses current aspects on the pathogenesis and pathophysiology of acute severe asthma exacerbations and provides the current perspectives on the management of acute severe asthma attacks in the emergency department and the intensive care unit.
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http://dx.doi.org/10.3390/jcm8091283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6780340PMC
August 2019

Acid-Base Disturbances in Patients with Asthma: A Literature Review and Comments on Their Pathophysiology.

J Clin Med 2019 Apr 25;8(4). Epub 2019 Apr 25.

Intensive Care Unit, 1st Department of Respiratory Medicine, National and Kapodistrian University of Athens, Sotiria Hospital, 115 27 Athens, Greece.

Asthma is a common illness throughout the world that affects the respiratory system function, i.e., a system whose operational adequacy determines the respiratory gases exchange. It is therefore expected that acute severe asthma will be associated with respiratory acid-base disorders. In addition, the resulting hypoxemia along with the circulatory compromise due to heart-lung interactions can reduce tissue oxygenation, with a particular impact on respiratory muscles that have increased energy needs due to the increased workload. Thus, anaerobic metabolism may ensue, leading to lactic acidosis. Additionally, chronic hypocapnia in asthma can cause a compensatory drop in plasma bicarbonate concentration, resulting in non-anion gap acidosis. Indeed, studies have shown that in acute severe asthma, metabolic acid-base disorders may occur, i.e., high anion gap or non-anion gap metabolic acidosis. This review briefly presents studies that have investigated acid-base disorders in asthma, with comments on their underlying pathophysiology.
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http://dx.doi.org/10.3390/jcm8040563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518237PMC
April 2019

Characteristics, risk factors and outcomes of Clostridium difficile infections in Greek Intensive Care Units.

Intensive Crit Care Nurs 2019 Aug 9;53:73-78. Epub 2019 Apr 9.

Department of Critical Care Medicine, "ATTIKON" University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece. Electronic address:

Background: Clostridium difficile is one of the major causes of diarrhoea among critically ill patients and its prevalence increases exponentially in relation to the use of antibiotics and medical devices. We sought to investigate the incidence of C. difficile infection in Greek units, and identify potential risk factors related to C. difficile infection.

Methods: A prospective multicenter cohort analysis of critically ill patients (3 ICUs from 1/1/2014 to 31/12/2014).

Results: Among 970(100%) patients, 95(9.79%) with diarrhoea, were included. Their demographic, comorbidity and clinical characteristics were recorded on admission to the unit. The known predisposing factors for the infection were recorded and the diagnostic tests to confirm C. difficile were conducted, based on the current guidelines. The incidence of C. difficile infection was 1.3% (n = 13). All-cause mortality in patients with diarrhoea, C. difficile infection and attributable mortality in patients with C. difficile infection was 28%, 38.5% and 30.8% respectively. Sequential Organ Failure Assessment (SOFA) scores on admission were significantly lower and prior C. difficile infection was more common in patients with current C. difficile infection. Regarding other potential risk factors, no difference was found between groups. No factor was independently associated with C. difficile infection.

Conclusions: C. difficile infection is low in Greek intensive care units, but remains a serious problem among the critically-ill. Mortality was similar to reports from other countries. No factor was independently associated with C. difficile infection.
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http://dx.doi.org/10.1016/j.iccn.2019.03.008DOI Listing
August 2019

Expiratory flow-limitation in mechanically ventilated patients: A risk for ventilator-induced lung injury?

World J Crit Care Med 2019 Jan 23;8(1):1-8. Epub 2019 Jan 23.

Dipartimento di Fisiopatologia e dei Trapianti, Università degli Studi di Milano, Milan 20133, Italy.

Expiratory flow limitation (EFL), that is the inability of expiratory flow to increase in spite of an increase of the driving pressure, is a common and unrecognized occurrence during mechanical ventilation in a variety of intensive care unit conditions. Recent evidence suggests that the presence of EFL is associated with an increase in mortality, at least in acute respiratory distress syndrome (ARDS) patients, and in pulmonary complications in patients undergoing surgery. EFL is a major cause of intrinsic positive end-expiratory pressure (PEEPi), which in ARDS patients is heterogeneously distributed, with a consequent increase of ventilation/perfusion mismatch and reduction of arterial oxygenation. Airway collapse is frequently concomitant to the presence of EFL. When airways close and reopen during tidal ventilation, abnormally high stresses are generated that can damage the bronchiolar epithelium and uncouple small airways from the alveolar septa, possibly generating the small airways abnormalities detected at autopsy in ARDS. Finally, the high stresses and airway distortion generated downstream the choke points may contribute to parenchymal injury, but this possibility is still unproven. PEEP application can abolish EFL, decrease PEEPi heterogeneity, and limit recruitment/derecruitment. Whether increasing PEEP up to EFL disappearance is a useful criterion for PEEP titration can only be determined by future studies.
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http://dx.doi.org/10.5492/wjccm.v8.i1.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347666PMC
January 2019

Expiratory Flow Limitation and Airway Closure in Patients with Acute Respiratory Distress Syndrome.

Am J Respir Crit Care Med 2019 01;199(1):127-128

1 National and Kapodistrian University of Athens Athens, Greece.

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http://dx.doi.org/10.1164/rccm.201807-1253LEDOI Listing
January 2019

Variation of endothelium-related hemostatic factors during sepsis.

Microcirculation 2018 11 10;25(8):e12500. Epub 2018 Oct 10.

Intensive Care Unit, 1st Department of Respiratory Medicine, Sotiria Hospital, National and Kapodistrian University of Athens, Athens, Greece.

Objective: The thrombomodulin/protein C and VWF/ADAMTS-13 pathways are disturbed in sepsis and have been implicated in the coagulation disorders that characterize the septic syndrome. We aimed to assess the variation of these endothelial parameters during sepsis and their putative association with outcome, in critically ill, septic patients.

Methods: We monitored 34 septic patients, 23 of whom improved (group A) while 11 deteriorated (group B). We assessed ADAMTS-13 levels, VWF activity, soluble thrombomodulin, and protein C activity upon admission to the ICU (time point 0) and at the time of a change in the clinical condition (remission or deterioration, time point 1).

Results: In group A, thrombomodulin and VWF increased at time point 1 compared to time point 0 (P = 0.011, P = 0.028, respectively). In group B, protein C and ADAMTS-13 significantly decreased (P = 0.023, P = 0.026, respectively), while VWF, VWF/ADAMTS-13 ratio, and the thrombomodulin/protein C ratio increased (P = 0.02, P = 0.002, P = 0.01, respectively). Protein C (> or ≤17%) and ADAMTS-13 percentage difference (> or ≤22%) were independently associated with sepsis outcome among the endothelial variables tested.

Conclusions: An ongoing endothelial/hemostatic disorder was established during sepsis, observed even at clinical improvement. Among the variables tested, protein C and ADAMTS-13 change were associated with outcome.
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http://dx.doi.org/10.1111/micc.12500DOI Listing
November 2018

Hyperchloraemia in sepsis.

Ann Intensive Care 2018 Mar 27;8(1):43. Epub 2018 Mar 27.

Intensive Care Unit, 1st Department of Respiratory Medicine, "Sotiria" Hospital, National and Kapodistrian University of Athens, 152 Mesogion Av., 115 27, Athens, Greece.

Chloride represents-quantitatively-the most prevalent, negatively charged, strong plasma electrolyte. Control of chloride concentration is a probable major mechanism for regulating the body's acid-base balance and for maintaining homeostasis of the entire internal environment. The difference between the concentrations of chloride and sodium constitutes the major contributor to the strong ion difference (SID); SID is the key pH regulator in the body, according to the physicochemical approach. Hyperchloraemia resulting from either underlying diseases or medical interventions is common in intensive care units. Recent studies have demonstrated the importance of hyperchloraemia in metabolic acidosis and in other pathophysiological disorders present in sepsis. The aim of this narrative review is to present the current knowledge about the effects of hyperchloraemia, in relation to the underlying pathophysiology, in septic patients.
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http://dx.doi.org/10.1186/s13613-018-0388-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5869346PMC
March 2018

Should age be a criterion for intensive care unit admission in cancer patients?-Still an issue of uncertainty.

J Thorac Dis 2017 Oct;9(10):3506-3508

ICU, 1 Department of Respiratory Medicine, National and Kapodistrian University of Athens Medical School, "Sotiria" Hospital, Athens, Greece.

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http://dx.doi.org/10.21037/jtd.2017.08.161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5723769PMC
October 2017

Admission of critically ill patients with cancer to the ICU: many uncertainties remain.

ESMO Open 2017 12;2(4):e000105. Epub 2017 Oct 12.

ICU, 1st Department of Respiratory Medicine, National and Kapodistrian University of Athens Medical School, 'Sotiria' Hospital, Athens, Greece.

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http://dx.doi.org/10.1136/esmoopen-2016-000105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652547PMC
October 2017

Effect of pulmonary rehabilitation on tidal expiratory flow limitation at rest and during exercise in COPD patients.

Respir Physiol Neurobiol 2017 04 18;238:47-54. Epub 2017 Jan 18.

Pulmonary Rehabilitation Unit, 1st Department of Respiratory Medicine, National & Kapodistrian University of Athens Medical School, "Sotiria" Hospital for Chest Diseases, Athens, Greece. Electronic address:

We hypothesized that severe COPD patients who present with the disadvantageous phenomenon of Expiratory Flow Limitation (EFL) may benefit as COPD patients without EFL do after implementation of a Pulmonary Rehabilitation (PR) program. Forty-two stable COPD patients were studied at rest and during exercise. EFL and dynamic hyperinflation (DH) were documented using the negative expiratory pressure (NEP) technique and inspiratory capacity (IC) maneuvers, respectively. Patient centered outcomes were evaluated by the Saint-George's Respiratory Questionnaire (SGRQ) and the mMRC dyspnea scale. Before PR, 16 patients presented with EFL at rest and/or during exercise. After PR, EFL was abolished in 15 out of those 16 EFL patients who exhibited a significant increase in IC values. These were mainly accomplished through a modification of the breathing pattern. In the 26 NFL patients no increase was noted in their IC or a modification of their breathing pattern. However, both NFL and EFL COPD patients improved exercise capacity and patients centered outcomes undergoing the same PR program.
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http://dx.doi.org/10.1016/j.resp.2017.01.008DOI Listing
April 2017

Clostridium subterminale septicemia in an immunocompetent patient.

IDCases 2016 30;5:43-5. Epub 2016 Jun 30.

ICU First Department of Respiratory Medicine, Medical School, University of Athens, Sotiria Hospital, Athens, Greece.

Clostridium subterminale is a Clostridium species that has been rarely isolated in the blood of immunocompromised patients. We report a case of C. subterminale septicemia in an immunocompetent patient who presented with acute mediastinitis following spontaneous esophageal rupture.
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http://dx.doi.org/10.1016/j.idcr.2016.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4954936PMC
August 2016

Respiratory mechanics in brain injury: A review.

World J Crit Care Med 2016 Feb 4;5(1):65-73. Epub 2016 Feb 4.

Antonia Koutsoukou, Maria Daganou, Magdalini Kyriakopoulou, Nikoletta Rovina, ICU, First Department of Respiratory Medicine, University of Athens Medical School, Sotiria Hospital, 11527 Athens, Greece.

Several clinical and experimental studies have shown that lung injury occurs shortly after brain damage. The responsible mechanisms involve neurogenic pulmonary edema, inflammation, the harmful action of neurotransmitters, or autonomic system dysfunction. Mechanical ventilation, an essential component of life support in brain-damaged patients (BD), may be an additional traumatic factor to the already injured or susceptible to injury lungs of these patients thus worsening lung injury, in case that non lung protective ventilator settings are applied. Measurement of respiratory mechanics in BD patients, as well as assessment of their evolution during mechanical ventilation, may lead to preclinical lung injury detection early enough, allowing thus the selection of the appropriate ventilator settings to avoid ventilator-induced lung injury. The aim of this review is to explore the mechanical properties of the respiratory system in BD patients along with the underlying mechanisms, and to translate the evidence of animal and clinical studies into therapeutic implications regarding the mechanical ventilation of these critically ill patients.
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http://dx.doi.org/10.5492/wjccm.v5.i1.65DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4733457PMC
February 2016

Therapeutic exercise in improving acute lung injury: a long distance to be covered.

Ann Transl Med 2015 Oct;3(18):273

Intensive Care Unit, 1st Department of Respiratory Medicine, National & Kapodistrian University of Athens Medical School, "Sotiria" Hospital for Chest Diseases, Athens, Greece.

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http://dx.doi.org/10.3978/j.issn.2305-5839.2015.09.13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630552PMC
October 2015

Colistin Population Pharmacokinetics after Application of a Loading Dose of 9 MU Colistin Methanesulfonate in Critically Ill Patients.

Antimicrob Agents Chemother 2015 Dec 14;59(12):7240-8. Epub 2015 Sep 14.

6th Department of Internal Medicine, Hygeia General Hospital, Athens, Greece.

Colistin has been revived, in the era of extensively drug-resistant (XDR) Gram-negative infections, as the last-resort treatment in critically ill patients. Recent studies focusing on the optimal dosing strategy of colistin have demonstrated the necessity of a loading dose at treatment initiation (D. Plachouras, M. Karvanen, L. E. Friberg, E. Papadomichelakis, A. Antoniadou, I. Tsangaris, I. Karaiskos, G. Poulakou, F. Kontopidou, A. Armaganidis, O. Cars, and H. Giamarellou, Antimicrob Agents Chemother 53:3430-3436, 2009, http://dx.doi.org/10.1128/AAC.01361-08; A. F. Mohamed, I. Karaiskos, D. Plachouras, M. Karvanen, K. Pontikis, B. Jansson, E. Papadomichelakis, A. Antoniadou, H. Giamarellou, A. Armaganidis, O. Cars, and L. E. Friberg, Antimicrob Agents Chemother 56:4241- 4249, 2012, http://dx.doi.org/10.1128/AAC.06426-11; S. M. Garonzik, J. Li, V. Thamlikitkul, D. L. Paterson, S. Shoham, J. Jacob, F. P. Silveira, A. Forrest, and R. L. Nation, Antimicrob Agents Chemother 55:3284-3294, 2011, http://dx.doi.org/10.1128/AAC.01733-10). In 19 critically ill patients with suspected or microbiologically documented infections caused by XDR Gram-negative strains, a loading dose of 9 MU colistin methanesulfonate (CMS) (∼ 270 mg colistin base activity) was administered with a maintenance dose of 4.5 MU every 12 h, commenced after 24 h. Patients on renal replacement were excluded. CMS infusion was given over 30 min or 1 h. Repeated blood sampling was performed after the loading dose and after the 5th or 6th dose. Colistin concentrations and measured CMS, determined after hydrolization to colistin and including the partially sulfomethylated derivatives, were determined with a liquid chromatography-tandem mass spectrometry assay. Population pharmacokinetic analysis was conducted in NONMEM with the new data combined with data from previous studies. Measured colistimethate concentrations were described by 4 compartments for distribution and removal of sulfomethyl groups, while colistin disposition followed a 1-compartment model. The average observed maximum colistin A plus B concentration was 2.65 mg/liter after the loading dose (maximum time was 8 h). A significantly higher availability of the measured A and B forms of colistimethate and colistin explained the higher-than-expected concentrations in the present study compared to those in previous studies. Creatinine clearance was a time-varying covariate of colistimethate clearance. The incidence of acute renal injury was 20%.
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http://dx.doi.org/10.1128/AAC.00554-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4649253PMC
December 2015

Implication of Interleukin (IL)-18 in the pathogenesis of chronic obstructive pulmonary disease (COPD).

Cytokine 2015 Aug 25;74(2):313-7. Epub 2015 Apr 25.

1st Department of Respiratory Medicine, Medical School, National and Kapodistrian University of Athens and "Sotiria" Chest Disease Hospital, 11527 Athens, Greece. Electronic address:

Interleukin (IL)-18 is a pro-inflammatory cytokine that was firstly described as an interferon (IFN)-γ-inducing factor. Similar to IL-1β, IL-18 is synthesized as an inactive precursor requiring processing by caspase-1 into an active cytokine. The platform for activating caspase-1 is known as the inflammasome, a multiple protein complex. Macrophages and dendritic cells are the primary sources for the release of active IL-18, whereas the inactive precursor remains in the intracellular compartment of mesenchymal cells. Finally, the IL-18 precursor is released from dying cells and processed extracellularly. IL-18 has crucial host defense and antitumor activities, and gene therapy to increase IL-18 levels in tissues protects experimental animals from infection and tumor growth and metastasis. Moreover, multiple studies in experimental animal models have shown that IL-18 over-expression results to emphysematous lesions in mice. The published data prompt to the hypothesis that IL-18 induces a broad spectrum of COPD-like inflammatory and remodeling responses in the murine lung and also induces a mixed type 1, type 2, and type 17 cytokine responses. The majority of studies identify IL-18 as a potential target for future COPD therapeutics to limit both the destructive and remodeling processes occurring in COPD lungs.
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http://dx.doi.org/10.1016/j.cyto.2015.04.008DOI Listing
August 2015

Low interleukin (IL)-18 levels in sputum supernatants of patients with severe refractory asthma.

Respir Med 2015 May 19;109(5):580-7. Epub 2015 Mar 19.

National and Kapodistrian University of Athens, 2nd Department of Pulmonary Medicine, "Atticon" Hospital, Athens Medical School, Greece.

Background: Severe refractory asthma (SRA) is characterized by persistent asthma symptoms, amplified airway inflammation despite treatment with high dose inhaled steroids and increased airway bacterial colonization. Interleukin (IL)-18 is a pleiotropic pro-inflammatory cytokine that modulates airway inflammation. Furthermore, as a product of the inflammasome, IL-18 is involved in host defence against viral and bacterial stimuli by modulating the immune response.

Objective: To determine IL-18 levels in sputum supernatants of patients with asthma and to investigate whether underlying severity affects its levels. Furthermore, possible associations with atopy and mediators and cells involved in the inflammatory process of the airways were examined.

Methods: Forty-five patients with mild intermittent asthma (21 smokers) and 18 patients with SRA in stable state were studied. All subjects underwent lung function tests, skin prick tests, and sputum induction for cell count identification. IL-18 and ECP levels were measured in sputum supernatants. Furthermore, sputum samples were examined for the commonest respiratory pathogens and viruses by real time polymerase chain reaction (RT-PCR).

Results: Patients with SRA had significantly lower IL-18 levels in sputum supernatants compared to mild asthmatics (p < 0.001). Twelve out of eighteen patients with SRA were colonized by viruses and/or bacterial pathogens. IL-18 levels correlated with the percentage of macrophages (r = 0.635, p = 0.026) and inversely correlated with the percentage of neutrophils in sputum (r = -0.715, p = 0.009). No correlations were found between IL-18, ECP and the percentage of eosinophils in the sputum of SRA.

Conclusions: In SRA IL-18 is possibly involved in chronic airway inflammation through an eosinophil independent pathway. The decreased levels of IL-18 in SRA support the hypothesis of deregulated inflammasome activation, justifying the susceptibility of these patients for bacterial colonization or infection.
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http://dx.doi.org/10.1016/j.rmed.2015.03.002DOI Listing
May 2015

Does serum lactate combined with soluble endothelial selectins at ICU admission predict sepsis development?

In Vivo 2015 Mar-Apr;29(2):305-8

First Department of Critical Care Medicine and Pulmonary Services, GP Livanos and M Simou Laboratories, Medical School of Athens University, Evangelismos Hospital, Athens, Greece First Department of Critical Care Medicine and Pulmonary Services, Medical School of Athens University, Evangelismos Hospital, Athens, Greece

Aim: We sought to determine for serum lactate its specificity and sensitivity in sepsis development prognosis in critically-ill, non-septic patients. Additionally, we evaluated whether sE-selectin or sP-selectin add prognostic value to lactate in sepsis.

Patients And Methods: Using a cohort previously studied in another context, in this retrospective investigation we plotted receiver operating characteristic (ROC) curves using sepsis development as the classification variable and serum lactate levels and their linear combinations with soluble sE-selectin and/or sP-selectin levels at intensive care unit (ICU) admission, as prognostic variables.

Results: Lactate levels combined with sE- and sP-selectin levels have the best prognostic accuracy showing a sensitivity and specificity of 76% and 84%, respectively, and an area under the curve (AUC) at 0.854 (95% confidence interval (CI)=0.775-0.932; p<0.001).

Conclusion: In our patient cohort, combining sE- and sP-selectin with serum lactate offers better prognostic value for sepsis development during ICU hospitalization.
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December 2015

Pleural fluid glucose: A predictor of unsuccessful pleurodesis in a preselected cohort of patients with malignant pleural effusion.

J BUON 2014 Oct-Dec;19(4):1018-23

4th Department of Respiratory Medicine, "Sotiria" General Hospital, Athens, Greece.

Purpose: To assess whether exclusion of patients with conditions that could lead to large fluctuations of serum glucose, would increase the accuracy of pleural fluid glucose in predicting pleurodesis outcome in patients with malignant pleural effusion subjected to bleomycin pleurodesis.

Methods: A retrospective analysis of 162 patients with recurrent, symptomatic malignant pleural disease was performed. Patients with diabetes mellitus or other causes of hyperglycemia were excluded, as pleural fluid glucose has been reported to be sensitive to serum glucose fluctuations. Assessment of pleurodesis outcome was based on radiologic appearance 30 days post-bleomycin pleurodesis.

Results: Successful pleurodesis was achieved in 64.8% of patients. Univariate analysis showed that pleural fluid glucose (p<0.001), pH (p<0.001), total proteins (p<0.001), albumin (p<0.001) and cholesterol (p<0.05) were significantly lower in patients with pleurodesis failure, while LDH was significantly higher (p<0.05). Pleural fluid glucose was the only independent predictor of pleurodesis outcome and with a cut-off point of 65 mg/dl had a high sensitivity (90.7%) with an acceptable specificity (76.8%) (p<0.001). The regression model exhibiting the highest predictive accuracy included pleural fluid glucose and albumin (sensitivity 89.3%, specificity 84.5%, p<0.001). Furthermore, a product of glucose and albumin less than 152 could predict pleurodesis failure with 88.9% sensitivity and 82.8% specificity (p<0.001).

Conclusions: Pleural glucose levels may reliably predict pleurodesis failure in patients without conditions that could lead to hyperglycemia, and its accuracy can increase if combined with pleural fluid albumin in an-easy-to calculate formula.
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June 2018

Virological and serological analysis of a recent Middle East respiratory syndrome coronavirus infection case on a triple combination antiviral regimen.

Int J Antimicrob Agents 2014 Dec 18;44(6):528-32. Epub 2014 Sep 18.

Department of Microbiology, University of Athens, Medical School, 75 Mikras Asias Street, 115 27 Athens, Greece. Electronic address:

Serological, molecular and phylogenetic analyses of a recently imported case of Middle East respiratory syndrome coronavirus (MERS-CoV) in Greece are reported. Although MERS-CoV remained detectable in the respiratory tract secretions of the patient until the fourth week of illness, viraemia was last detected 2 days after initiation of triple combination therapy with pegylated interferon, ribavirin and lopinavir/ritonavir, administered from Day 13 of illness. Phylogenetic analysis of the virus showed close similarity with other human MERS-CoVs from the recent Jeddah outbreak in Saudi Arabia. Immunoglobulin G (IgG) titres peaked 3 weeks after the onset of illness, whilst IgM levels remained constantly elevated during the follow-up period (second to fifth week of illness). Serological testing confirmed by virus neutralisation assay detected an additional case that was a close contact of the patient.
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http://dx.doi.org/10.1016/j.ijantimicag.2014.07.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7127532PMC
December 2014

Subjects hospitalized with the 2009 pandemic influenza A (H1N1) virus in a respiratory infection unit: clinical factors correlating with ICU admission.

Respir Care 2014 Oct 12;59(10):1560-8. Epub 2014 Aug 12.

First Department of Respiratory Medicine, Medical School, National and Kapodistrian University of Athens and "Sotiria" Chest Diseases Hospital, Athens, Greece.

Background: The 2009 pandemic influenza A (H1N1) virus was accompanied by high morbidity and mortality. The aim of this study was to describe the clinical characteristics of patients with documented 2009 influenza A (H1N1) virus admitted to a reference chest hospital, the disease outcome, and risk factors associated with ICU admission.

Methods: We assessed 109 subjects admitted to the respiratory infection unit of a hospital for chest disease with signs and symptoms of the 2009 influenza A (H1N1) virus between April 2009 and December 2010. Demographic data, comorbidities, clinical signs and symptoms, laboratory tests, radiographic findings, treatment, and final outcomes were all recorded. Factors associated with severe disease requiring ICU admission were determined.

Results: Ninety subjects (82.5%) had laboratory-confirmed 2009 influenza A (H1N1). Sixty-four percent of these subjects had pneumonia on admission, 26% had respiratory failure, and 11% required care in the ICU. Dyspnea and the presence of infiltrates on chest x-rays were the most common signs among the subjects with H1N1. All subjects were treated with antiviral therapy, and 75% received antibiotic treatment based on their clinical and laboratory findings. The predictive factors of ICU admission were severe hypoxemia and lymphocytosis.

Conclusions: The outcome of subjects with influenza A (H1N1) virus infection was influenced by the severity of the disease on admission, the subjects' underlying conditions, and complications during hospitalization.
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http://dx.doi.org/10.4187/respcare.03049DOI Listing
October 2014