Μια διπλή τυφλή, τυχαιοποιημένη, ελεγχόμενη με εικονικό φάρμακο κλινική μελέτη για την αποτελεσματικότητα της ενδοφλέβιας κλαριθρομυκίνης ως επικουρικής θεραπείας σε ασθενείς με σήψη και αναπνευστική και πολυοργανική ανεπάρκεια: Μελέτη INCLASS

Εισαγωγή: Η κλαριθρομυκίνη μπορεί να δράσει ως ανοσο-ρυθμιστική αγωγή στη σήψη και το σύνδρομο οξείας αναπνευστικής δυσχέρειας. Ωστόσο, δεν έχει αποδειχθεί ξεκάθαρη κλινική ωφέλεια από τη δράση της σε αυτή την ένδειξη. Στόχος της παρούσας μελέτης ήταν να αξιολογηθεί εάν η κλαριθρομυκίνη βελτιώνει τη θνητότητα μετά από 28 ημέρες, στους ασθενείς με σήψη, αναπνευστική και πολυ-οργανική ανεπάρκεια. Μέθοδοι: Σε αυτή την πολυκεντρική, τυχαιοποημένη, ελεγχόμενη κλινική μελέτη, εντάχθηκαν ασθενείς με σήψη, μερική πίεση οξυγόνου προς μείγμα αναπνεόμενου αέρα μικρότερο από 200, και βαθμολογία SOFA μεγαλύτερη του 3 για ανεπάρκειες οργάνων, εκτός του αναπνευστικού. Η ένταξη πραγματοποιήθηκε μεταξύ Δεκεμβρίου 2017 και Σεπτεμβρίου 2019 και οι ασθενείς τυχαιοποιήθηκαν να λάβουν 1gr κλαριθρομυκίνης ή εικονικό φάρμακο άπαξ ημερησίως για 4 συνεχόμενες ημέρες. Το πρωτογενές καταληκτικό σημείο ήταν η διαφορά στη θνητότητα μετά από 28 ημέρες. Δευτερογενή καταληκτικά σημεία ήταν η θνητότητα μετά από 90 ημέρες, η κλινική ανταπόκριση στη σήψη (οριζόμενη ως μείωση της αρχικής βαθμολογίας SOFA κατά ≥25% την 7η ημέρα), η εμφάνιση νέου σηπτικού επεισοδίου στους ασθενείς που είχαν κλινική ανταπόκριση της σήψης, οι διαφορές στους κυτταρικούς πληθυσμούς και τη γονιδιακή έκφραση μεταξύ των ομάδων θεραπείας. Αποτελέσματα: Σύνολο 55 ασθενών εντάχθηκαν σε κάθε ομάδα θεραπείας. Έως την ημέρα 28, 27 (49,1%) ασθενείς στην ομάδα κλαριθρομυκίνης και 25 (45,5%) στην ομάδα του εικονικού φαρμάκου είχαν πεθάνει [απόλυτη διαφορά 3,6%, 95% διάστημα εμπιστοσύνης (ΔΕ) -15,7 έως 22,7; P =0,703, προσαρμοσμένο πηλίκο συμπληρωματικών πιθανοτήτων (odds ratio- OR) 1,03 (95% ΔΕ 0,35-3,06; P =0,959)]. Δεν υπήρχε στατιστικά σημαντική διαφορά στη θνητότητα μετά από 90 ημέρες ή την κλινική ανταπόκριση στη σήψη. Η επίπτωση της υποτροπής της σήψης ήταν χαμηλότερη στην ομάδα της κλαριθρομυκίνης [OR 0,21 (95% ΔΕ 0,06-0,68); P = 0.012]. Αυτό συνδυάστηκε με αύξηση σην έκφραση του HLA-DR επί των μονοκυττάρων, αύξηση του πληθυσμού των μη-κλασσικών μονοκυττάρων και υπερέκφραση των γονιδίων που εμπλέκονται στην ομοιοστασία του μεταβολισμού της χοληστερόλης. Η επίπτωση των σοβαρών και μη σοβαρών ανεπιθύμητων συμβάντων ήταν παρόμοια, στις δύο ομάδες θεραπείας. Συμπεράσματα: Η κλαριθρομυκίνη δεν είχε επίδραση στη θνητότητα των ασθενών με σήψη, αναπνευστική και πολυ-οργανική ανεπάρκεια. Ωστόσο, συνδυάστηκε με μικρότερο κίνδυνο σηπτικής υποτροπής, πιθανά μέσω ενός μηχανισμού ανοσιακής ανάκαμψης.Background: Clarithromycin may act as immune‐regulating treatment in sepsis and acute respiratory dysfunction syndrome. However, clinical evidence remains inconclusive. We aimed to evaluate whether clarithromycin improves 28‐day mortality among patients with sepsis, respiratory and multiple organ dysfunction syndrome. Methods: We conducted a multicenter, randomized, clinical trial in patients with sepsis. Participants with ratio of partial oxygen pressure to fraction of inspired oxygen less than 200 and more than 3 SOFA points from systems other than the respiratory function were enrolled between December 2017 and September 2019. Patients were randomized to receive 1 gr of clarithromycin or placebo intravenously once daily for 4 consecutive days. The primary endpoint was 28‐day all‐cause mortality. Secondary outcomes were 90‐day mortality; sepsis response (defined as at least 25% decrease in SOFA score by day 7); sepsis recurrence; and differences in peripheral blood cell populations and leuko‐ cyte transcriptomics. Results: Fifty‐five patients were allocated to each arm. By day 28, 27 (49.1%) patients in the clarithromycin and 25 (45.5%) in the placebo group died (risk difference 3.6% [95% confidence interval (CI) − 15.7 to 22.7]; P = 0.703, adjusted OR 1.03 [95%CI 0.35–3.06]; P = 0.959). There were no statistical differences in 90‐day mortality and sepsis response. Clarithromycin was associated with lower incidence of sepsis recurrence (OR 0.21 [95%CI 0.06–0.68]; P = 0.012); significant increase in monocyte HLA‐DR expression; expansion of non‐classical monocytes; and upregulation of genes involved in cholesterol homeostasis. Serious and non‐serious adverse events were equally distributed. Conclusion: Clarithromycin did not reduce mortality among patients with sepsis with respiratory and multiple organ dysfunction. Clarithromycin was associated with lower sepsis recurrence, possibly through a mechanism of immune restoration

Infections in severe alcoholic hepatitis

Abstract Severe alcoholic hepatitis (sAH), defined by a modified discriminant function ≥32, is the most severe form of alcohol-induced liver disease and is associated with a 1-month mortality rate of around 30%. Corticosteroid treatment remains the only therapeutic option that improves shortterm survival. Infectious complications, occurring in approximately 50% of patients, are the main causes of death, even in patients who benefit from corticosteroids. Liver failure, recent alcohol consumption and immunosuppressive drugs contribute to this infectious risk. Although infection is a well-described feature of cirrhosis, little is known about the characteristics of infections in sAH. Infection is mainly of bacterial origin and frequently affects the respiratory tract. Pathogens classically observed in cirrhosis, such as gram-negative bacilli, are frequently involved, but opportunistic pathogens, such as fungi (Aspergillus fumigatus, Pneumocystis jirovecii) or viruses (Cytomegalovirus, Herpes simplex) may appear, mainly related to corticosteroid treatment. A high level of suspicion with systematic screening and prompt, adequate treatment are warranted to improve outcomes in these patients. Prophylactic strategies in this high-risk population should be assessed in well-designed trials

Infections in severe alcoholic hepatitis.

Severe alcoholic hepatitis (sAH), defined by a modified discriminant function ≥32, is the most severe form of alcohol-induced liver disease and is associated with a 1-month mortality rate of around 30%. Corticosteroid treatment remains the only therapeutic option that improves short-term survival. Infectious complications, occurring in approximately 50% of patients, are the main causes of death, even in patients who benefit from corticosteroids. Liver failure, recent alcohol consumption and immunosuppressive drugs contribute to this infectious risk. Although infection is a well-described feature of cirrhosis, little is known about the characteristics of infections in sAH. Infection is mainly of bacterial origin and frequently affects the respiratory tract. Pathogens classically observed in cirrhosis, such as gram-negative bacilli, are frequently involved, but opportunistic pathogens, such as fungi (Aspergillus fumigatus, Pneumocystis jirovecii) or viruses (Cytomegalovirus, Herpes simplex) may appear, mainly related to corticosteroid treatment. A high level of suspicion with systematic screening and prompt, adequate treatment are warranted to improve outcomes in these patients. Prophylactic strategies in this high-risk population should be assessed in well-designed trials.SCOPUS: re.jinfo:eu-repo/semantics/publishe

Infections in severe forms of alcohol-related liver disease - Need a closer look - Authors’ reply

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The early change of SOFA score as a prognostic marker of 28-day sepsis mortality: Analysis through a derivation and a validation cohort

Background: Since the Sepsis-3 criteria, change in Sequential Organ Failure Assessment (SOFA) score has become a key component of sepsis identification. Thus, it could be argued that reversal of this change (ΔSOFA) may reflect sepsis response and could be used as measure of efficacy in interventional trials. We aimed to assess the predictive performance of ΔSOFA for 28-day mortality. Methods: Data from two previously published randomized controlled trials were studied: the first reporting on patients with severe Gram-negative infections as a derivation cohort and the second reporting on patients with ventilator-associated pneumonia as a validation cohort. Only patients with sepsis according to the Sepsis-3 definition were included in this analysis. SOFA scores were calculated on days 1, 2, 3, 5, 7, 14, and 28. Results: We included 448 patients within the derivation cohort and 199 within the validation cohort. Mean SOFA scores on day 1 were 6.06 ± 4.07 and 7.84 ± 3.39, and 28 day mortality 22.8% and 29.6%, respectively. In the derivation cohort, the earliest time point where ΔSOFA score predicted mortality was day 7 (AUROC (95% CI) 0.84 (0.80-0.89); p < 0.001). The best tradeoff for prediction was found with 25% changes (78% sensitivity, 80% specificity); less than 25% decrease of admission SOFA was associated with increased mortality (odds ratio for death 14.87). This finding was confirmed in the validation cohort. Conclusions: ΔSOFA on day 7 is a useful early prognostic marker of 28-day mortality and could serve as an endpoint in future sepsis trials alongside mortality.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Acute myocardial infarction following thalidomide treatment for AIDS-related ulcers.

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Comparisons of infectious complications in severe alcoholic hepatitis and decompensated alcoholic cirrhosis

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High levels of monocytic myeloid-derived suppressor cells are associated with favorable outcome in patients with pneumonia and sepsis with multi-organ failure

Background: Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells with immunosuppressive functions sub-classified into monocytic and polymorphonuclear MDSCs (M-MDSCs and PMN-MDSCs). Clinical studies reported increased levels of MDSCs that were associated with poor outcome in sepsis patients. Since sepsis patients exhibit signs of inflammation and immunosuppression, MDSCs may provide benefit by dampening deleterious inflammation in some patients. To test this hypothesis, we measured MDSCs in critically ill sepsis patients with pneumonia and multi-organ dysfunctions and a high likelihood of death. Methods: This was a prospective multicenter observational cohort study performed in eight ICUs in Athens and Thessaloniki, Greece, enrolling critically ill patients with pneumonia and sepsis with multi-organ dysfunctions. A flow cytometry approach using blood collected at study inclusion in tubes containing lyophilized antibodies combined to unsupervised clustering was developed to quantify M-MDSCs and PMN-MDSCs. Results: Forty-eight patients were included, of whom 34 died within 90 days. At study inclusion, M-MDSCs and PMN-MDSCs were increased in sepsis patients when compared to healthy subjects (3.07% vs 0.96% and 22% vs 2.1% of leukocytes, respectively; p &lt; 10(-4)). Increased PMN-MDSCs were associated with secondary infections (p = 0.024) and new sepsis episodes (p = 0.036). M-MDSCs were more abundant in survivors than in patients who died within 28 days (p = 0.028). Stratification of patients according to M-MDSC levels revealed that high levels of M-MDSC were associated with reduced 90-day mortality (high vs low M-MDSCs: 47% vs 84% mortality, p = 0.003, hazard ratio [HR] = 3.2, 95% CI 1.4-7.2). Combining high M-MDSC levels with low Acute Physiology and Chronic Health Evaluation (APACHE) II score improved patient stratification (M-MDSCshigh/APACHE IIlow vs M-MDSCslow/APACHE IIlow: 20% vs 80% 90-day mortality, p = 0.0096, HR = 7.2, 95% CI 1.6-32). In multivariate analyses high M-MDSCs remained correlated with improved survival in patients with low APACHE II score (p = 0.05, HR = 5.26, 95% CI 1.0-27.8). Conclusion: This is the first study to associate high levels of M-MDSCs with improved survival in sepsis patients

Clinical Course and Risk Factors for Infection in Severe Forms of Alcohol-Associated Liver Disease

Background and Aims: Infection is a major driver of mortality in patients with advanced alcohol-associated liver disease (ALD). The epidemiology and clinical course of patients infected with life-threatening forms of ALD, including severe alcohol-associated hepatitis (sAH) and decompensated alcohol-associated cirrhosis (DAC), and specific risk factors for infection remain mostly unknown. Approach and Results: In this observational study, we assessed all infectious episodes occurring within a 90-day period from diagnosis in all consecutive patients with biopsy-proven sAH (modified Maddrey’s discriminant function ≥ 32, Model for End-Stage Liver Disease [MELD] ≥ 18) and DAC (MELD ≥ 18) without alcohol-associated hepatitis in our tertiary hospital between 2003 and 2016. A total of 207 patients were included: 139 with sAH and 68 with DAC. One hundred seventeen (84%) patients with sAH and 41 (60%) patients with DAC experienced at least one infection episode at 90 days (P < 0.001). In multivariable analysis, factors associated with the development of infection were the presence of sAH and baseline MELD score. Bacterial infections represented the most common infection in the two groups, and only the MELD score was independently associated with the occurrence of bacterial infection. In both groups, pneumonia was the most prevalent bacterial infection, and gram-negative bacilli were the main pathogens. Invasive fungal infections (IFI) occurred in 20 (14.5%) patients with sAH and 3 (4.5%) with patients with DAC (P < 0.05). Multivariable regression showed that younger age, higher MELD, and corticosteroid therapy were independently associated with IFI. The 90-day cumulative incidence of death in patients infected with sAH and patients infected with DAC was 46% and 41.5%, respectively (P = 0.43). Conclusions: Patients with sAH are more susceptible to develop infection than those with DAC. In life-threatening forms of ALD, patients who were infected share a similar mortality rate. Corticosteroid treatment, not sAH, seems to be the main risk factor triggering IFI.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Coronavirus Disease 2019 as Cause of Viral Sepsis: A Systematic Review and Meta-Analysis*

Objective: Coronavirus disease 2019 is a heterogeneous disease most frequently causing respiratory tract infection, which can induce respiratory failure and multiple organ dysfunction syndrome in its severe forms. The prevalence of coronavirus disease 2019-related sepsis is still unclear; we aimed to describe this in a systematic review. Data Sources: MEDLINE (PubMed), Cochrane, and Google Scholar databases were searched based on a prespecified protocol (International Prospective Register for Systematic Reviews: CRD42020202018). Study Selection: Studies reporting on patients with confirmed coronavirus disease 2019 diagnosed with sepsis according to sepsis-3 or according to the presence of infection-related organ dysfunctions necessitating organ support/replacement were included in the analysis. The primary end point was prevalence of coronavirus disease 2019-related sepsis among adults hospitalized in the ICU and the general ward. Among secondary end points were the need for ICU admission among patients initially hospitalized in the general ward and the prevalence of new onset of organ dysfunction in the ICU. Outcomes were expressed as proportions with respective 95% CI. Data Extraction: Two reviewers independently screened and reviewed existing literature and assessed study quality with the Newcastle-Ottawa Scale and the Methodological index for nonrandomized studies. Data Synthesis: Of 3,825 articles, 151 were analyzed, only five of which directly reported sepsis prevalence. Noting the high heterogeneity observed, coronavirus disease 2019-related sepsis prevalence was 77.9% (95% CI, 75.9-79.8; I-2 = 91%; 57 studies) in the ICU, and 33.3% (95% CI, 30.3-36.4; I-2 = 99%; 86 studies) in the general ward. ICU admission was required for 17.7% (95% CI, 12.9-23.6; I-2 = 100%) of ward patients. Acute respiratory distress syndrome was the most common organ dysfunction in the ICU (87.5%; 95% CI, 83.3-90.7; I-2 = 98%). CONCLUSIONS: The majority of coronavirus disease 2019 patients hospitalized in the ICU meet Sepsis-3 criteria and present infection-associated organ dysfunction. The medical and scientific community should be aware and systematically report viral sepsis for prognostic and treatment implications