COVID-19: θεραπευτική προσέγγιση με τη χρήση κλαριθρομυκίνης

Η ανθρωπότητα από τον Δεκέμβριο του 2019 βιώνει μία νέα πανδημία από τον ιό SARS-CoV-2. Έως και τις 18 Μαΐου του 2021, έχουν καταγραφεί 163.212.543 περιστατικά και 3.383.979 ασθενείς απεβίωσαν. Η ανάλυση των κλινικών χαρακτηριστικών αυτών των ασθενών έδειξε ότι η φυσική πορεία της νόσου, γνωστή με το ακρωνύμιο Covid-19, είναι πολλές φορές απρόβλεπτη. Οι περισσότεροι ασθενείς που αναπτύσσουν πνευμονία δεν εμφανίζουν ανησυχητικά συμπτώματα, παρά το γεγονός ότι η ακτινογραφία τους ή η αξονική τομογραφία μπορεί να απεικονίζει διάχυτα διηθήματα. Ξαφνικά, ένα συγκεκριμένο ποσοστό αυτών των ασθενών επιδεινώνονται κλινικά και εμφανίζουν σοβαρή αναπνευστική ανεπάρκεια. Αυτό συνήθως συμβαίνει μεταξύ της 5ης και της 10ης ημέρας της νόσου και εμφανίζεται χωρίς να προηγηθούν προειδοποιητικά συμπτώματα. Τα δημοσιευμένα δεδομένα προτείνουν ότι αυτό οφείλεται στην οξεία προ-φλεγμονώδη αντίδραση του ξενιστή. Έχοντας αυτό υπόψιν, είναι λογικό να υποθέσουμε ότι η πρόωρη θεραπεία με ένα φάρμακο που μπορεί να τροποποιήσει αποτελεσματικά την απάντηση του ξενιστή και να προλάβει την ξαφνική υπερ-φλεγμονώδη αντίδραση πιθανώς να αποτρέψει την εκδήλωση σοβαρής αναπνευστικής ανεπάρκειας. Βασιζόμενοι στην αντιφλεγμονώδη και ανοσοτροποιητική δράση της κλαριθρομυκίνης, είναι πιθανό ότι η θεραπεία ασθενών με COVID-19 με από του στόματος κλαροθρομυκίνη θα μειώσει τις πιθανότητες εκδήλωσης σοβαρής αναπνευστικής ανεπάρκειας. Με σκοπό να μελετήσουμε την αποτελεσματικότητα της από του στόματος κλαριθρομυκίνης στην μέτριας βαρύτητας COVID-19 λοίμωξη, πραγματοποιήσαμε μια ανοικτού τύπου, μη τυχαιοποιημένη μελέτη σε 90 ασθενείς με μέτριας βαρύτητας COVID-19 λοίμωξη μεταξύ Μαΐου και Οκτωβρίου του 2020. Το πρωτογενές καταληκτικό σημείο ορίστηκε στο τέλος της θεραπείας ως απουσία ανάγκης επανεισαγωγής στο Νοσοκομείο και εξέλιξης σε λοίμωξη κατώτερου αναπνευστικού για τους ασθενείς με λοίμωξη ανώτερου αναπνευστικού. Για τους ασθενείς με λοίμωξη κατώτερου αναπνευστικού ορίστηκε ως τουλάχιστον 50% μείωση της βαθμολογίας συμπτωμάτων του αναπνευστικού χωρίς εμφάνιση σοβαρής αναπνευστικής ανεπάρκειας. Παράλληλα, αξιολογήθηκαν το ιικό φορτίο, οι βιοδείκτες, η λειτουργεία των μονοκυττάρων και η ασφάλεια. Το πρωτογενές καταληκτικό σημείο επιτεύχθηκε στο 86.7% των ασθενών που έλαβαν κλαριθρομυκίνη (95% CIs 78.1-92.2%), στο 91.7% των ασθενών που έλαβαν κλαριθρομυκίνη εντός 5 ημερών από την έναρξη των συμπτωμάτων και 81.4% των ασθενών που έλαβαν αργότερα (odds ratio μετά από πολυπαραγοντική ανάλυση 6.62, p: 0.030). Η χρήση κλαριθρομυκίνης συσχετίστηκε με μείωση της CRP, του TNF-a, της ιντερλευκίνης (IL)-6 και του ιικού φορτίου, καθώς και από αύξηση της Th1 και Τh2 απόκρισης των μονοκυττάρων. Δεν προέκυψαν προβληματισμοί ως αναφορά τα δεδομένα ασφαλείας. Συμπερασματικά, η πρώιμη χορήγηση κλαριθρομυκίνης συμβάλλει σημαντικά στην κλινική βελτίωση της μέτριας βαρύτητας COVID-19 λοίμωξης.Humanity is experiencing since December 2019 a new pandemic by the novel SARS Coronavirus-19 (SARS-CoV-2). As of May 18 2021, 163.212.543 documented case were reported worldwide and 3.383.979 patients died. The analysis of the clinical characteristics of these patients showed that the natural course of this disease, known with the acronym Covid-19, is several times unpredictable. Most patients who develop pneumonia do not have worrying symptoms although their chest X-ray or chest computed tomography may be positive for diffuse infiltrates. Suddenly a certain proportion of these patients deteriorate into severe respiratory failure; this usually takes place between the 5th and the 10th day of illness and arrives without any preceding symptom. Published evidence suggests that this is due to the sudden arrival of an acute pro-inflammatory reaction of the host. With this in mind, it is reasonable to make the assumption than the early treatment with an agent that can efficiently modulate the host response and prevent sudden hyper-inflammatory reaction may prevent the development of severe respiratory failure. Based on the anti-inflammatory and immunomodulatory properties of clarithromycin, it seems likely that treatment of patients with Covid-19 with oral clarithromycin will substantially decrease the chances for development of severe respiratory failure. To study the efficacy of oral clarithromycin in moderate COVID-19, we conducted an open-label non-randomized trial in 90 patients with COVID-19 of moderate severity between May and October 2020. The primary endpoint was defined at the end-of-treatment (EOT) as no need for hospital readmission and no progression into lower respiratory tract infection (LRTI) for patients with upper respiratory tract infection; and as at least 50% decrease of the respiratory symptoms score the without progression into severe respiratory failure (SRF) for patients with LRTI. Viral load, biomarkers, the function of mononuclear cells, and safety were assessed. The primary endpoint was attained in 86.7% of patients treated with clarithromycin (95% CIs 78.1-92.2%); this was 91.7% and 81.4% among patients starting clarithromycin the first 5 days from symptoms onset or later (odds ratio after multivariate analysis 6.62; p: 0.030). Clarithromycin use was associated with decreases in circulating Creactive protein, tumour necrosis factor-alpha and interleukin (IL)-6; by increase of Th1 to Τh2 mononuclear responses; and by suppression of SARS-CoV-2 viral load. No safety concerns were reported. In conclusion, early clarithromycin treatment provides most of clinical improvement in moderate COVID-19

Programmed Cell Death Protein 1 Axis Inhibition in Viral Infections: Clinical Data and Therapeutic Opportunities

A vital function of the immune system is the modulation of an evolving immune response. It is responsible for guarding against a wide variety of pathogens as well as the establishment of memory responses to some future hostile encounters. Simultaneously, it maintains self-tolerance and minimizes collateral tissue damage at sites of inflammation. In recent years, the regulation of T-cell responses to foreign or self-protein antigens and maintenance of balance between T-cell subsets have been linked to a distinct class of cell surface and extracellular components, the immune checkpoint molecules. The fact that both cancer and viral infections exploit similar, if not the same, immune checkpoint molecules to escape the host immune response highlights the need to study the impact of immune checkpoint blockade on viral infections. More importantly, the process through which immune checkpoint blockade completely changed the way we approach cancer could be the key to decipher the potential role of immunotherapy in the therapeutic algorithm of viral infections. This review focuses on the effect of programmed cell death protein 1/programmed death-ligand 1 blockade on the outcome of viral infections in cancer patients as well as the potential benefit from the incorporation of immune checkpoint inhibitors (ICIs) in treatment of viral infections

ICU-Associated Gram-Negative Bloodstream Infection: Risk Factors Affecting the Outcome Following the Emergence of Colistin-Resistant Isolates in a Regional Greek Hospital

Intensive care unit patients may present infections by difficult-to-treat-resistant Gram-negative microorganisms. Colistin resurfaced as a last resort antibiotic for the treatment of multi-drug-resistant Gram-negative bacteria. However, colistin might not improve survival, particularly after the emergence of colistin-resistant isolates. We aimed to (1) examine the first Gram-negative-associated-bloodstream infection (GN-BSI) effect on 28-day mortality and (2) distinguish mortality risk factors. From 1 January 2018 to 31 December 2019, we retrospectively studied all adult patients admitted for more than 48 h in the critical care department of a regional Greek hospital, with prevalent difficult-to-treat Gram-negative pathogens. We examined the patient records for the first GN-BSI. The local laboratory used broth microdilution to evaluate bacterial susceptibility to colistin. Seventy-eight patients fulfilled the entry criteria: adult and first GN-BSI. They developed GN-BSI on day 10 (6–18), while the overall mortality was 26.9%. Thirty-two and 46 individuals comprised the respective colistin-resistant and colistin-sensitive groups. The admission Acute Physiology Assessment and Chronic Health Evaluation II score was associated with acquiring colistin-resistant GN-BSI in the multivariable logistic regression analysis (οdds ratio (CI), 1.11 (1.03–1.21)). Regarding mortality, the index day sequential organ failure assessment score was solely associated with the outcome (hazard-ratio (CI), 1.23 (1.03–1.48), Cox proportional hazard analysis). GN-BSI was often caused by colistin-resistant bacteria. Concerning our data, sepsis severity was the independent predictor of mortality regardless of the colistin-resistance phenotype or empirical colistin treatment

ICU-Associated Gram-Negative Bloodstream Infection: Risk Factors Affecting the Outcome Following the Emergence of Colistin-Resistant Isolates in a Regional Greek Hospital

Intensive care unit patients may present infections by difficult-to-treat-resistant Gram-negative microorganisms. Colistin resurfaced as a last resort antibiotic for the treatment of multi-drug-resistant Gram-negative bacteria. However, colistin might not improve survival, particularly after the emergence of colistin-resistant isolates. We aimed to (1) examine the first Gram-negative-associated-bloodstream infection (GN-BSI) effect on 28-day mortality and (2) distinguish mortality risk factors. From 1 January 2018 to 31 December 2019, we retrospectively studied all adult patients admitted for more than 48 h in the critical care department of a regional Greek hospital, with prevalent difficult-to-treat Gram-negative pathogens. We examined the patient records for the first GN-BSI. The local laboratory used broth microdilution to evaluate bacterial susceptibility to colistin. Seventy-eight patients fulfilled the entry criteria: adult and first GN-BSI. They developed GN-BSI on day 10 (6–18), while the overall mortality was 26.9%. Thirty-two and 46 individuals comprised the respective colistin-resistant and colistin-sensitive groups. The admission Acute Physiology Assessment and Chronic Health Evaluation II score was associated with acquiring colistin-resistant GN-BSI in the multivariable logistic regression analysis (οdds ratio (CI), 1.11 (1.03–1.21)). Regarding mortality, the index day sequential organ failure assessment score was solely associated with the outcome (hazard-ratio (CI), 1.23 (1.03–1.48), Cox proportional hazard analysis). GN-BSI was often caused by colistin-resistant bacteria. Concerning our data, sepsis severity was the independent predictor of mortality regardless of the colistin-resistance phenotype or empirical colistin treatment

Early Start of Oral Clarithromycin Is Associated with Better Outcome in COVID-19 of Moderate Severity: The ACHIEVE Open-Label Single-Arm Trial

Introduction The anti-inflammatory effect of macrolides prompted the study of oral clarithromycin in moderate COVID-19. Methods An open-label non-randomized trial in 90 patients with COVID-19 of moderate severity was conducted between May and October 2020. The primary endpoint was defined at the end of treatment (EOT) as no need for hospital re-admission and no progression into lower respiratory tract infection (LRTI) for patients with upper respiratory tract infection and as at least 50% decrease of the respiratory symptoms score without progression into severe respiratory failure (SRF) for patients with LRTI. Viral load, biomarkers, the function of mononuclear cells and safety were assessed. Results The primary endpoint was attained in 86.7% of patients treated with clarithromycin (95% CIs 78.1-92.2%); this was 91.7% and 81.4% among patients starting clarithromycin the first 5 days from symptoms onset or later (odds ratio after multivariate analysis 6.62; p 0.030). The responses were better for patients infected by non-B1.1 variants. Clarithromycin use was associated with decreases in circulating C-reactive protein, tumour necrosis factor-alpha and interleukin (IL)-6; by increase of production of interferon-gamma and decrease of production of interleukin-6 by mononuclear cells; and by suppression of SARS-CoV-2 viral load. No safety concerns were reported. Conclusions Early clarithromycin treatment provides most of the clinical improvement in moderate COVID-19

Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial

Early increase of soluble urokinase plasminogen activator receptor (suPAR) serum levels is indicative of increased risk of progression of coronavirus disease 2019 (COVID-19) to respiratory failure. The SAVE-MORE double-blind, randomized controlled trial evaluated the efficacy and safety of anakinra, an IL-1 alpha/beta inhibitor, in 594 patients with COVID-19 at risk of progressing to respiratory failure as identified by plasma suPAR >= 6 ng ml(-1), 85.9% (n = 510) of whom were receiving dexamethasone. At day 28, the adjusted proportional odds of having a worse clinical status (assessed by the 11-point World Health Organization Clinical Progression Scale (WHO-CPS)) with anakinra, as compared to placebo, was 0.36 (95% confidence interval 0.26-0.50). The median WHO-CPS decrease on day 28 from baseline in the placebo and anakinra groups was 3 and 4 points, respectively (odds ratio (OR) = 0.40, P < 0.0001); the respective median decrease of Sequential Organ Failure Assessment (SOFA) score on day 7 from baseline was 0 and 1 points (OR = 0.63, P = 0.004). Twenty-eight-day mortality decreased (hazard ratio = 0.45, P = 0.045), and hospital stay was shorter.The SAVE-MORE phase 3 study demonstrates the efficacy of anakinra, an IL-1 alpha/beta inhibitor, in patients with COVID-19 and high serum levels of soluble plasminogen activator receptor

Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial

Early increase of soluble urokinase plasminogen activator receptor (suPAR) serum levels is indicative of increased risk of progression of coronavirus disease 2019 (COVID-19) to respiratory failure. The SAVE-MORE double-blind, randomized controlled trial evaluated the efficacy and safety of anakinra, an IL-1 alpha/beta inhibitor, in 594 patients with COVID-19 at risk of progressing to respiratory failure as identified by plasma suPAR >= 6 ng ml(-1), 85.9% (n = 510) of whom were receiving dexamethasone. At day 28, the adjusted proportional odds of having a worse clinical status (assessed by the 11-point World Health Organization Clinical Progression Scale (WHO-CPS)) with anakinra, as compared to placebo, was 0.36 (95% confidence interval 0.26-0.50). The median WHO-CPS decrease on day 28 from baseline in the placebo and anakinra groups was 3 and 4 points, respectively (odds ratio (OR) = 0.40, P < 0.0001); the respective median decrease of Sequential Organ Failure Assessment (SOFA) score on day 7 from baseline was 0 and 1 points (OR = 0.63, P = 0.004). Twenty-eight-day mortality decreased (hazard ratio = 0.45, P = 0.045), and hospital stay was shorter. The SAVE-MORE phase 3 study demonstrates the efficacy of anakinra, an IL-1 alpha/beta inhibitor, in patients with COVID-19 and high serum levels of soluble plasminogen activator receptor

Effect of anakinra on mortality in patients with COVID-19: a systematic review and patient-level meta-analysis

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