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

Effect of intravenous clarithromycin in patients with sepsis, respiratory and multiple organ dysfunction syndrome: a randomized clinical trial.

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. We conducted a multicenter, randomized, clinical trial in patients with sepsis. Participants with ratio of partial oxygen pressure to fraction of inspired oxygen less than 200 and more than 3 SOFA points from systems other than the respiratory function were enrolled between December 2017 and September 2019. Patients were randomized to receive 1 gr of clarithromycin or placebo intravenously once daily for 4 consecutive days. The primary endpoint was 28-day all-cause mortality. Secondary outcomes were 90-day mortality; sepsis response (defined as at least 25% decrease in SOFA score by day 7); sepsis recurrence; and differences in peripheral blood cell populations and leukocyte transcriptomics. 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. Clarithromycin did not reduce mortality among patients with sepsis with respiratory and multiple organ dysfunction. Clarithromycin was associated with lower sepsis recurrence, possibly through a mechanism of immune restoration. Clinical trial registration clinicaltrials.gov identifier NCT03345992 registered 17 November 2017; EudraCT 2017-001056-55

Efficacy of glutathione therapy in relieving dyspnea associated with COVID-19 pneumonia: A report of 2 cases

Purpose: Infection with COVID-19 potentially can result in severe outcomes and death from “cytokine storm syndrome”, resulting in novel coronavirus pneumonia (NCP) with severe dyspnea, acute respiratory distress syndrome (ARDS), fulminant myocarditis and multiorgan dysfunction with or without disseminated intravascular coagulation. No published treatment to date has been shown to adequately control the inflammation and respiratory symptoms associated with COVID-19, apart from oxygen therapy and assisted ventilation. We evaluated the effects of using high dose oral and/or IV glutathione in the treatment of 2 patients with dyspnea secondary to COVID-19 pneumonia. Methods: Two patients living in New York City (NYC) with a history of Lyme and tick-borne co-infections experienced a cough and dyspnea and demonstrated radiological findings consistent with novel coronavirus pneumonia (NCP). A trial of 2 g of PO or IV glutathione was used in both patients and improved their dyspnea within 1 h of use. Repeated use of both 2000 mg of PO and IV glutathione was effective in further relieving respiratory symptoms. Conclusion: Oral and IV glutathione, glutathione precursors (N-acetyl-cysteine) and alpha lipoic acid may represent a novel treatment approach for blocking NF-κB and addressing “cytokine storm syndrome” and respiratory distress in patients with COVID-19 pneumonia

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

Macrophage activation-like syndrome: A distinct entity leading to early death in sepsis

Hemophagocytic lymphohistocytosis (HLH) is characterized by fulminant cytokine storm leading to multiple organ dysfunction and high mortality. HLH is classified into familial (fHLH) and into secondary (sHLH). fHLH is rare and it is due to mutations of genes encoding for perforin or excretory granules of natural killer (NK) cells of CD8-lymphocytes. sHLH is also known as macrophage activation syndrome (MAS). Macrophage activation syndrome (MAS) in adults is poorly studied. Main features are fever, hepatosplenomegaly, hepatobiliary dysfunction (HBD), coagulopathy, cytopenia of two to three cell lineages, increased triglycerides and hemophagocytosis in the bone marrow. sHLH/MAS complicates hematologic malignancies, autoimmune disorders and infections mainly of viral origin. Pathogenesis is poorly understood and it is associated with increased activation of macrophages and NK cells. An autocrine loop of interleukin (IL)-1β over-secretion leads to cytokine storm of IL-6, IL-18, ferritin, and interferon-gamma; soluble CD163 is highly increased from macrophages. The true incidence of sHLH/MAS among patients with sepsis has only been studied in the cohort of the Hellenic Sepsis Study Group. Patients meeting the Sepsis-3 criteria and who had positive HSscore or co-presence of HBD and disseminated intravascular coagulation (DIC) were classified as patients with macrophage activation-like syndrome (MALS). The frequency of MALS ranged between 3 and 4% and it was an independent entity associated with early mortality after 10 days. Ferritin was proposed as a diagnostic and surrogate biomarker. Concentrations >4,420 ng/ml were associated with diagnosis of MALS with 97.1% specificity and 98% negative predictive value. Increased ferritin was also associated with increased IL-6, IL-18, IFNγ, and sCD163 and by decreased IL-10/TNFα ratio. A drop of ferritin by 15% the first 48 h was a surrogate finding of favorable outcome. There are 10 on-going trials in adults with sHLH; two for the development of biomarkers and eight for management. Only one of them is focusing in sepsis. The acronym of the trial is PROVIDE (ClinicalTrials.gov NCT03332225) and it is a double-blind randomized clinical trial aiming to deliver to patients with septic shock treatment targeting their precise immune state. Patients diagnosed with MALS are receiving randomized treatment with placebo or the IL-1β blocker anakinra. © 2007 - 2019 Frontiers Media S.A. All Rights Reserved

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

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

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