Tο υδρόθειο στην πρόγνωση της νόσου COVID-19

Το υδρόθειο (H2S) απαντάται σε μορφή αερίου και προέρχεται από τη βιοσύνθεση της L-κυστεϊνης, η οποία εξαρτάται από την ενεργότητα τριών ενζύμων: τη γ-λυάση της κυσταθειονίνης (CSE), τη β-συνθετάση της κυσταθειονίνης (CBS) και τη 3-μερκαπτοπυροσταφυλική θειϊκή τρανσφεράση (3-MST). Το μονοπάτι άρχεται από την ομοκυστεϊνη και ακολουθούνται περισσότερες της μίας ενζυμικές οδοί προς την παραγωγή του υδροθείου. Το υδρόθειο κατέχει πολλαπλούς ρόλους στην παθοφυσιολογία μεταξύ των οποίων τη νευροδιαβίβαση, τη διαμεσολάβηση προφλεγμονωδών διεργασιών, την κυτταροπροστασία έναντι του οξειδωτικού στρες και την προαγωγή της αγγειογένεσης. Μεταβολίζεται ως ανόργανο υπόστρωμα ενώ όσον αφορά τη σηματοδότηση, αλληλεπιδρά με πολλαπλά είδη μοριακών στόχων. Κατέχει σημαντικό ρόλο στη φλεγμονή. Μέσω πολλαπλών μελετών φαίνεται οτι το μόριο του υδροθείου διαθέτει τόσο προφλεγμονώδεις όσο και αντιφλεγμονώδεις δράσεις. Ομοίως κατέχει αξιοσημείωτο ρόλο και στις λοιμώξεις αναπνευστικού. Ειδικότερα στη νόσο COVID-19 ,φαίνεται να κατέχει προγνωστικό ρόλο ως προς την έκβαση των ασθενών αυτών. Συγκεκριμένα μετά από μελέτη στην οποία συμμετείχαν 74 ασθενείς φάνηκε οτι η υψηλότερη τιμή υδροθείου ορού (μεγαλύτερη των 150.44 μΜ ) κατά την προσέλευση ,αλλά και η χαμηλότερη μεταβολή αυτού (λιγότερο από 36%) μεταξύ της 1ης και 7ης ημέρας κατέχει σημαντικό ρόλο στην καλύτερη έκβαση των ασθενών αυτών κατά την 28η ημέρα. Επιπλέον, αναλύσεις παραγματοποιήθηκαν μεταξύ του υδροθείου στον ορό των ασθενών και βιοχημικών δεικτών όπως ο παράγοντας νέκρωσης όγκου-α, η ιντερλευκίνη-6, η προκαλσιτονίνη και η c-αντιδρώσα πρωτεϊνη. Σημειώνεται η θετική συσχέτιση μεταξύ της απόλυτης τιμής των λεμφοκυττάρων και του υδροθείου καθώς και η αρνητική συσχέτιση της τιμής ιντερλευκίνης-6 και υδροθείου. Τα αποτελέσματα αυτών συνηγορούν υπέρ της προγνωστικής αξίας του υδροθείου ως ανεξάρτητος προγνωστικός δείκτης για την έκβαση της νόσου COVID-19, υπό την προοπτική διεξαγωγής μεγαλύτερων κοορτών.Hydrogen sulfide (H2S) is found in the form of a gas and is derived from the biosynthesis of L-cysteine, which is depended on the activity of three enzymes: cystathionine γ-lyase (CSE), cystathionine β-synthetase (CBS) and 3 -mercaptopyrostaphyl sulfate transferase (3-MST). The pathway begins with homocysteine and more than one enzymatic pathways are followed for the production of hydrogen sulfide. Hydrogen sulfide has multiple roles in pathophysiology including neurotransmission, mediation of proinflammatory processes, cell protection against oxidative stress and promotion of angiogenesis. It is metabolized as an inorganic substrate while in terms of signaling, it interacts with multiple types of molecular targets. It plays an important role in inflammation. Multiple studies show that the hydrogen sulfide molecule has both pro-inflammatory and anti-inflammatory effects. It also plays a significant role in respiratory infections. In COVID-19 in particular, it appears as a prognostic indicator for the outcome of these patients. Specifically, the results from a study involving 74 patients, have shown that the highest value of serum hydrogen sulfide (greater than 150.44 μM) at patient’s admission, and at the same time the lowest fold change (less than 36%) between days 1 and 7 play an important role fot the outcome of these patients on day 28. In addition, assays were performed between patients' serum hydrogen sulfide and biochemical markers such as tumor necrosis factor-α, interleukin-6, procalcitonin and c-reactive protein. There is a positive correlation between the absolute lymphocyte count and hydrogen sulfide as well as a negative correlation between interleukin-6 and hydrogen sulfide. These results support the prognostic value of hydrogen sulfide as an independent prognostic indicator for the outcome of COVID-19 disease, with a view to conducting larger cohorts

Pan-Echinocandin Resistant C. parapsilosis Harboring an F652S Fks1 Alteration in a Patient with Prolonged Echinocandin Therapy

The isolation of a pan-echinocandin-resistant Candida parapsilosis strain (anidulafungin, caspofungin, micafungin and rezafungin EUCAST MICs > 8 mg/L) from urine of a patient following prolonged exposure to echinocandins (38 days of micafungin followed by 16 days of anidulafungin) is described. The isolate harbored the novel alteration F652S in the hotspot 1 region of fks1. Isogenic C. parapsilosis bloodstream isolates collected up to 1.5 months earlier from the same patient were susceptible to echinocandins (anidulafungin, caspofungin and micafungin EUCAST MICs 1–2, 1 and 1 mg/L, respectively) and contained wild-type FKS1 sequences. This is the first report of pan-echinocandin resistance in C. parapsilosis associated with an aminoacid change in hotspot 1 region of fks1

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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