Expert perspectives on ECCO2R for acute hypoxemic respiratory failure: consensus of a 2022 European roundtable meeting.

BACKGROUND: By controlling hypercapnia, respiratory acidosis, and associated consequences, extracorporeal CO2 removal (ECCO2R) has the potential to facilitate ultra-protective lung ventilation (UPLV) strategies and to decrease injury from mechanical ventilation. We convened a meeting of European intensivists and nephrologists and used a modified Delphi process to provide updated insights into the role of ECCO2R in acute respiratory distress syndrome (ARDS) and to identify recommendations for a future randomized controlled trial. RESULTS: The group agreed that lung protective ventilation and UPLV should have distinct definitions, with UPLV primarily defined by a tidal volume (VT) of 4-6 mL/kg predicted body weight with a driving pressure (ΔP) ≤ 14-15 cmH2O. Fourteen (93%) participants agreed that ECCO2R would be needed in the majority of patients to implement UPLV. Furthermore, 10 participants (majority, 63%) would select patients with PaO2:FiO2 > 100 mmHg (> 13.3 kPa) and 14 (consensus, 88%) would select patients with a ventilatory ratio of > 2.5-3. A minimum CO2 removal rate of 80 mL/min delivered by continuous renal support machines was suggested (11/14 participants, 79%) for this objective, using a short, double-lumen catheter inserted into the right internal jugular vein as the preferred vascular access. Of the participants, 14/15 (93%, consensus) stated that a new randomized trial of ECCO2R is needed in patients with ARDS. A ΔP of ≥ 14-15 cmH2O was suggested by 12/14 participants (86%) as the primary inclusion criterion. CONCLUSIONS: ECCO2R may facilitate UPLV with lower volume and pressures provided by the ventilator, while controlling respiratory acidosis. Since recent European Society of Intensive Care Medicine guidelines on ARDS recommended against the use of ECCO2R for the treatment of ARDS outside of randomized controlled trials, new trials of ECCO2R are urgently needed, with a ΔP of ≥ 14-15 cmH2O suggested as the primary inclusion criterion.

Restoration of Pulmonary Compliance after Laparoscopic Gynecologic Surgery Using a Recruitment Maneuver.

BACKGROUND/OBJECTIVES: This study aimed to investigate the hypothesis that an alveolar recruitment maneuver can restore lung compliance to initial values after laparoscopic gynecological surgery. METHODS: A total of 31 patients who underwent laparoscopic gynecological surgery were enrolled. Protective mechanical ventilation was applied, and the radial artery was catheterized in all patients. An alveolar recruitment maneuver (incremental and decremental positive end-expiratory pressure) was applied ten minutes after the release of pneumoperitoneum. The respiratory mechanics and blood gas results were recorded at eight different time points: after induction of anesthesia (T1), in the lithotomy position (T2), in the Trendelenburg position (T3), 10 and 90 min after insufflation of carbon dioxide (T4 and T5), in the supine position (T6), after desufflation (T7), and 10 min after an alveolar recruitment maneuver at the end of surgery (T8). RESULTS: Pneumoperitoneum and the Trendelenburg position caused a decline of 15 units in compliance (T7 vs. T1; p < 0.05) compared to baseline. After the alveolar recruitment maneuver, compliance increased by 17.5% compared with the mean value of compliance at time T1 (T8 vs. T1; p < 0.05). The recruitment maneuver had favorable results in patients with low initial compliance (41.5 mL/cmH2O, IQR: 9.75 mL/cmH2O), high Body Mass Index 30.32 kg/m2 (IQR: 1.05 kg/m2), and high initial plateau airway pressure (16.5 cmH2O, IQR: 0.75 cmH2O). CONCLUSIONS: Lung compliance does not return to initial values after performing laparoscopic gynecological procedures. However, after the release of pneumoperitoneum, an alveolar recruitment maneuver is beneficial as it improves compliance and gas exchange.

Prevalence and Characteristics of Self-Reported Adult Asthma in Cyprus: A Population-Based Observational Study.

Purpose: To estimate the prevalence of asthma in adults, by gender and age, in urban and rural areas of Cyprus. Patients and Methods: This was a population-based, random-digit dialing, telephone nation-wide survey to recruit patients with asthma. Among 8996 random landline-telephone contacted from the five major urban and rural regions of Cyprus, 1914 were finally met the age criterion of ≥18 years old and 572 completed valid screening for prevalence estimation. The participants filled a short screening questionnaire in order for asthma cases to be recognized. Then, asthma cases filled the main ECRHS II questionnaire and were evaluated by a pulmonary physician. All underwent spirometry. Data on demographic characteristics, educational level, profession, smoking status, Body Mass Index (BMI), Total IgE and Eosinophil Cationic Protein levels were measured. Results: The overall prevalence of bronchial asthma in adults in Cyprus was 5.57% (61.1% men and 38.9% women). Among the participants with self-reported bronchial asthma 36.1% were current smokers, while 12.3% were obese (BMI >30). A total value of IgE >115 IU and Eosinophil Cationic Protein (ECP) >20 IU was found in 40% of the participants with established bronchial asthma. Wheezing and chest tightness were the most frequently reported symptoms in asthma patients (36.1% and 34.5%, respectively), while 36.5% experienced at least one exacerbation during the last year. Interestingly, most of the patients were under-treated (14.2% were on maintenance asthma treatment, and 18% used solely reliever medication). Conclusion: This was the first study estimating asthma prevalence in Cyprus. Asthma affects almost 6% of the adult population, with higher prevalence in urban areas and in men compared to women. Interestingly, one-third of the patients were uncontrolled and under-treated. This study revealed that in Cyprus there is space for improvement in the management of asthma.

C-Reactive Protein as a Predictor of Survival and Length of Hospital Stay in Community-Acquired Pneumonia.

Introduction: Community-acquired pneumonia (CAP) presents high mortality rates and high healthcare costs worldwide. C-reactive protein (CRP) has been widely used as a biomarker for the management of CAP. We evaluated the performance of CRP threshold values and ΔCRP as predictors of CAP survival and length of hospital stay. Methods: A total of 173 adult patients with CAP were followed for up to 30 days. We measured serum CRP levels on days 1, 4, and 7 (D1, D4, and D7) of hospitalization, and their variations between different days were calculated (ΔCRP). A multivariate logistic regression model was created with CAP 30-day survival and length of hospital stay as dependent variables, and absolute CRP values and ΔCRP, age, sex, smoking habit (pack-years), pO2/FiO2 ratio on D1, WBC on D1, and CURB-65 score as independent variables. Results: A total of six patients with CAP died (30-day mortality 3.47%). No difference was found in CRP levels and ΔCRP between survivors and non-survivors. Using a cut-off level of 9 mg/dL, the AUC (95% CI) for the prediction of survival of CRP on D4 and D7 were 0.765 (0.538−0.992) and 0.784 (0.580−0.989), respectively. A correlation between CRP values on any day and length of hospital stay was found, with it being stronger for CRPD4 and CRPD7 (p < 0.0001 and p = 0.0024, respectively). A reduction of CRP > 50% from D1 to D4 was associated with 4.11 fewer days of hospitalization (p = 0.0308). Conclusions: CRP levels on D4 and D7, but not ΔCRP, could fairly predict CAP survival. A reduction of CRP > 50% by the fourth day of hospitalization could predict a shorter hospital stay.

Adherence and quality of life assessment in patients with asthma treatment with budesonide/formoterol via the Elpenhaler device: the COMPLETE study.

BACKGROUND: Asthma is a chronic inflammatory disease of the airways that causes recurring episodes of wheezing, breathlessness, chest tightness and coughing. Inhaled drugs on a daily basis are the cornerstone of asthma treatment, therefore, patient adherence is very important. METHODS: We performed a multicenter, open, non-interventional, observational, prospective study of 716 adult patients diagnosed with asthma receiving FDC (Fixed-dose combination) budesonide/formoterol via the Elpenhaler device. We assessed the adherence to treatment at 3 and 6 months (based on the MMAS-8: 8-item Morisky Medication Adherence Scale), the quality of life and change in forced expiratory volume in 1 s (FEV1) from baseline to follow-up. RESULTS: Approximately 80% of the patients showed medium to high adherence throughout the study. The mean (SD) MMAS-8 score at 6 months was 6.85 (1.54) and we observed a statistically significant shift of patients from the low adherence group to the high adherence group at 6 months. Moreover, after 6 months of treatment with FDC budesonide/formoterol, we observed an increase in the patients' quality of life that as expressed by a change 2.01 (95%CI 1.93-2.10) units in Mini AQLQ (p < 0.0001) that was more pronounced in the high adherence group. The same trend was also observed in terms of spirometry (mean FEV1 2.58 L (0.85) at the end of the study, increased by 220 mL from baseline) with a higher improvement in the medium and high adherence groups. CONCLUSIONS: Treatment with FDC of budesonide/formoterol via the Elpenhaler device was associated with improvement in asthma-related quality of life and lung function over 6 months that were more prominent in patients with higher adherence. TRIAL REGISTRATION: 2017-HAL-EL-74 (ClinicalTrials.gov Identifier: NCT03300076).

Diabetes on sepsis outcomes in non-ICU patients: A cohort study and review of the literature.

AIMS: We sought to determine whether primary outcomes differ between non-ICU septic patients with and without type 2 diabetes (T2D). METHODS: This study utilized the Hellenic Sepsis Study Group Registry, collecting nationwide data for sepsis patients since 2006, and classified patients upon presence or absence of T2D. Patients were perfectly matched for a) Sepsis 3 definition criteria (including septic shock) b) gender, c) age, d) APACHE II score and e) Charlson's comorbidity index (CCI). Independent sample t-test and chi-square t-test was used to compare prognostic indices and primary outcomes. RESULTS: Of 4320 initially included non-ICU sepsis patients, 812 were finally analysed, following match on criteria. Baseline characteristics were age 76 [±10.3] years, 46% male, APACHE II 15.5 [±6], CCI 5.1 [±1.8], 24% infection, 63.8% sepsis and 12.2% septic shock. No significant difference was noted between two groups in qSOFA, SOFA, or suPAR1 levels (p = 0.7, 0.1 & 0.3) respectively. Primary sepsis syndrome resolved in 70.9% of cases (p = 0.9), while mortality was 24% in 28-days time. Cause of death was similar between patients with and without T2D (sepsis 17.8% vs 15.8%, heart event 3.7% vs 3.2%, CNS event 0.5% vs 0.5%, malignancy 0.7% vs 2% respectively, p = 0.6). CONCLUSIONS: DM does not appear to negatively affect outcomes in septic patients not requiring ICU.

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

A central paradigm of immunity is that interferon (IFN)-mediated antiviral responses precede pro-inflammatory ones, optimizing host protection and minimizing collateral damage1,2. 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.

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

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.

Study of inflammatory biomarkers in COPD and asthma exacerbations.

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.

Smoking cessation in pregnancy: An update for maternity care practitioners.

INTRODUCTION: This paper provides an up-to-date summary of the effects of smoking in pregnancy as well as challenges and best practices for supporting smoking cessation in maternity care settings. METHODS: We conducted a qualitative review of published peer reviewed and grey literature. RESULTS: There is strong evidence of the effects of maternal tobacco use and secondhand smoke exposure on adverse pregnancy outcomes. Tobacco use is the leading preventable cause of miscarriage, stillbirth and neonatal deaths, and evidence has shown that health effects extend into childhood. Women who smoke should be supported with quitting as early as possible in pregnancy and there are benefits of quitting before the 15th week of pregnancy. There are a variety of factors that are associated with tobacco use in pregnancy (socioeconomic status, nicotine addiction, unsupportive partner, stress, mental health illness etc.). Clinical-trial evidence has found counseling, when delivered in sufficient intensity, significantly increases cessation rates among pregnant women. There is evidence that the use of nicotine replacement therapy (NRT) may increase cessation rates, and, relative to continued smoking, the use of NRT is considered safer than continued smoking. The majority of women who smoke during pregnancy will require support throughout their pregnancy, delivered either by a trained maternity care provider or via referral to a specialized hospital or community quit-smoking service. The 5As (Ask, Advise, Assess, Assist, Arrange) approach is recommended for organizing screening and treatment in maternity care settings. Additionally, supporting smoking cessation in the postpartum period should also be a priority as relapse rates are high. CONCLUSIONS: There have been several recent updates to clinical practice regarding the treatment of tobacco use in pregnancy. It is important for the latest guidance to be put into practice, in all maternity care settings, in order to decrease rates of smoking in pregnancy and improve pregnancy outcomes.

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

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

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

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.

Macrophage activation-like syndrome: an immunological entity associated with rapid progression to death in sepsis.

BACKGROUND: A subanalysis of a randomized clinical trial indicated sepsis survival benefit from interleukin (IL)-1 blockade in patients with features of the macrophage activation-like syndrome (MALS). This study aimed to investigate the frequency of MALS and to develop a biomarker of diagnosis and prognosis. METHODS: Patients with infections and systemic inflammatory response syndrome were assigned to one test cohort (n = 3417) and a validation cohort (n = 1704). MALS was diagnosed for patients scoring positive either for the hemophagocytic syndrome score and/or having both hepatobiliary dysfunction and disseminated intravascular coagulation. Logistic regression analysis was used to estimate the predictive value of MALS for 10-day mortality in both cohorts. Ferritin, sCD163, IL-6, IL-10, IL-18, interferon gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α) were measured in the blood the first 24 h; ferritin measurements were repeated in 747 patients on day 3. RESULTS: The frequency of MALS was 3.7% and 4.3% in the test and the validation cohort, respectively. In both cohorts, MALS was an independent risk factor for 10-day mortality. A ferritin level above 4420 ng/ml was accompanied by 66.7% and 66% mortality after 28 days, respectively. Ferritin levels above 4420 ng/ml were associated with an increase of IL-6, IL-18, INF-γ, and sCD163 and a decreased IL-10/TNF-α ratio, indicating predominance of pro-inflammatory phenomena. Any less than 15% decrease of ferritin on day 3 was associated with more than 90% sensitivity for unfavorable outcome after 10 days. This high mortality risk was also validated in an independent Swedish cohort (n = 109). CONCLUSIONS: MALS is an independent life-threatening entity in sepsis. Ferritin measurements can provide early diagnosis of MALS and may allow for specific treatment.

Prolonged occupational exposure leads to allergic airway sensitization and chronic airway and systemic inflammation in professional firefighters.

BACKGROUND AND OBJECTIVES: Little data exist on short- and long-term effects of occupational exposure on airway and systemic inflammation in professional firefighters. We aimed to characterize airway and systemic inflammation in training firefighters with a maximum occupational exposure of 1 year compared to the long-term exposure of professional firefighters. METHODS: A questionnaire for symptoms and exposure, pulmonary function, atopy, bronchial hyper-responsiveness, and markers of inflammation in induced sputum, serum, bronchoalveolar lavage (BAL) fluid and bronchial biopsies were assessed in a total of 92 firefighters (63 full-time professionals and 29 trainees). RESULTS: Professional firefighters showed allergic bronchial sensitization documented by the presence of atopy, and eosinophilia in induced sputum, BAL and bronchial biopsies. IL-8, ECP, VEGF, and TNF-α levels were statistically significantly higher in the sputum supernatants of professional firefighters compared to the trainees (p = 0.04, p = 0.02, p = 0.04, and p = 0.02, respectively). Serum IL-8 and TNF-α levels were also statistically significantly higher in the group of professional firefighters (p = 0.04, p = 0.03, respectively). Finally, there was a linear correlation between the duration of the occupation in Service and the degree of airway and systemic inflammation. CONCLUSIONS: These results indicate a "dose-response" effect of chronic exposure to a polluted environment on bronchial and systemic inflammation in professional firefighters.

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

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.

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

Interleukin (IL)-18 is a pro-inflammatory cytokine that was firstly described as an interferon (IFN)-γ-inducing factor. Similar to IL-1ß, 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.

Critically ill cancer patient in intensive care unit: issues that arise.

Advances in the management of malignancies and organ failures have led to substantial increases in survival as well as in the number of cancer patients requiring intensive care unit (ICU) admission. Although effectiveness of ICU in this group remains controversial, the heterogeneity of its population in terms of the nature and curability of their disease and the severity of critical illness and underlying conditions may explain the plethora of issues arising when considering cancer patients for ICU admission, especially from the view of limited resources and ICU beds. The most frequent reasons leading a cancer patient to ICU are postoperative, respiratory failure, infection, and sepsis. Although reasons of admission, nature and number of organ failures, type of malignancy, and therapies that have preceded ICU admission may affect outcome, reliable scoring systems or survival predictors are missing. Literature suggests that organ dysfunction should be managed at its onset, whereas aggressive ICU management should be reappraised after a few days of full support. A multidisciplinary treating team of physicians should aid in changing the goals from restorative to palliative care when there appears to be no possible benefit from any treatment. End-of life-decisions and code status should be made by consensus, based on patients' autonomy and dignity. Further interventional multicenter studies are required to assess post-ICU burden, long-term medical outcomes, and quality of life in this cohort of patients.

Inflammation and immune response in COPD: where do we stand?

Increasing evidence indicates that chronic inflammatory and immune responses play key roles in the development and progression of COPD. Recent data provide evidence for a role in the NLRP3 inflammasome in the airway inflammation observed in COPD. Cigarette smoke activates innate immune cells by triggering pattern recognition receptors (PRRs) to release "danger signal". These signals act as ligands to Toll-like receptors (TLRs), triggering the production of cytokines and inducing innate inflammation. In smokers who develop COPD there appears to be a specific pattern of inflammation in the airways and parenchyma as a result of both innate and adaptive immune responses, with the predominance of CD8+ and CD4+ cells, and in the more severe disease, with the presence of lymphoid follicles containing B lymphocytes and T cells. Furthermore, viral and bacterial infections interfere with the chronic inflammation seen in stable COPD and exacerbations via pathogen-associated molecular patterns (PAMPs). Finally, autoimmunity is another novel aspect that may play a critical role in the pathogenesis of COPD. This review is un update of the currently discussed roles of inflammatory and immune responses in the pathogenesis of COPD.

Interleukin-18 is up-regulated in infectious pleural effusions.

The aim of this study was to investigate the pleural and systemic expression of interleukin-18 (IL-18) in patients with pleural effusions (PEs), and the effects of the cytokine in mouse pleural space. One hundred and sixty patients, 23 with pleural effusions (PEs) due to heart failure, 60 malignant, 25 parapneumonic/empyemas, 15 tuberculous and 37 with exudates of miscellaneous etiologies were included in the study. Pleural fluid (PF) and serum IL-18 content was determined using ELISA. IL-18 was injected intrapleurally in mice and pleural inflammation was assessed using pleural lavage. The highest PF IL-18 levels were observed in parapneumonic PEs and the lowest PF IL-18 levels in patients with exudates of miscellaneous aetiologies and transudates. PF IL-18 levels were significantly higher in patients with empyemas compared to those with uncomplicated (p=0.009) or complicated (p=0.028) parapneumonic effusions, while serum levels did not differ significantly among the three groups. Pleural IL-18 content was higher than that of blood only in patients with empyemas. In patients with pleural exudates of all etiologies and in those with parapneumonic PEs/empyema, PF IL-18 levels were correlated with markers of acute pleural inflammation such as the percentage of PF neutrophils, PF LDH and PF/serum LDH ratio, low PF glucose and PF/serum glucose ratio and low PF pH. In mice, intrapleural IL-18 caused neutrophil-predominant pleural inflammation. In conclusion, IL-18 is linked to the intensity of neutrophilic pleural inflammation in patients with PEs, it is up-regulated in the pleural space of patients with empyema and it stimulates the accumulation of neutrophils in mouse pleura.