Thyroid hormone alterations in critically and non-critically ill patients with SARS-CoV-2 infection

Objective: Following the evolution of COVID-19 pandemic, reports pointed on a high prevalence of thyroiditis-related thyrotoxicosis. Interpretation of thyroid tests during illness, however, is hampered by changes occurring in the context of non-thyroidal illness syndrome (NTIS). In order to elucidate these findings, w e studied thyroid function in carefully selected cohorts of COVID-19 positive and negative patients. Design: Cohort observational study. Methods: We measured TSH, FT4, T3 within 24 h of admission in 196 patients without thyroid disease and/or confounding medications. In this study, 102 patients were SARS-CoV-2 positive; 41 admitted in the ICU, 46 in the ward and 15 outpatients. Controls consisted of 94 SARS-CoV-2 negative patients; 39 in the ICU and 55 in the ward. We designated the thyroid hormone patterns as consistent with NTIS, thyrotoxicosis and hypothyroidism. Results: A NTIS pattern was encountered in 60% of ICU and 36% of ward patients, with similar frequencies between SARS-CoV-2 positive and negative patients (46.0% vs 46.8%, P = NS). A thyrotoxicosis pattern was observed in 14.6% SARS-CoV-2 ICU patients vs 7.7% in ICU negative (P = NS) and, overall in 8.8% of SARS-CoV-2 positive vs 7.4% of neg ative patients. In these patients, thyroglobulin levels were similar to those with normal thyroid function or NTIS. The hypothyroidism pattern was rare. Conclusions: NTIS pattern is common and relates to the severity of disease rather than SARS-CoV-2 infection. A thyrotoxicosis pattern is less frequently observed with similar frequency between patients with and without COVID-19. It is suggested that thyroid hormone monitoring in COVID-19 should not differ from other crit ically ill patients

Investigation of serial metabolic alterations in sepsis and septic shock

We have shown for the first time that adiponectin increases and resistin decreases during the course of prolonged sepsis. These changes were most evident in patients who recovered from the critical state and were associated with the reduction of the inflammatory response, as this was assessed by the levels of proinflammatory cytokines. Adiponectin levels correlated with growth hormone levels, suggesting a positive effect of growth hormone in adiponectin secretion. Resistin levels mainly related to the severity of sepsis and the degree of the inflammatory response suggesting that the main role of resistin in humans is that of an acute phase protein. We also characterized the changes of crucial stress hormones during prolonged sepsis. Patients with the worst prognosis had significantly higher cortisol levels, both basal and post ACTH stimulation, higher growth hormone levels and lower DHEA-S levels. We also observed a gradual increase of ACTH and DHEA concentrations in the course of sepsis; this finding has not been described previously. In conclusion, diverse endocrine and metabolic adaptations occur in critical illness. Characterizing these changes opens the way for planning better treatments for these patients, aiming at improving survival and accelerate recovery. Towards this direction further studies are needed to delineate the underlying pathophysiological mechanisms and to clarify which of these changes are beneficial and which maladaptive in order to design clinical trials aiming to modify those changes that are harmful. For example an early increase of adiponectin and a reduction of resistin theoretically could have a beneficial effect in reducing the inflammatory response and the marked insulin resistance. However, the production of biosynthetic adiponectin for exogenous administration has significant limitations as the molecule is subject to several post-translational modifications. Furthermore it circulates at very high plasma concentrations (5-30 mg /ml) and has a relatively short half-life so that high amounts of recombinant protein and frequent administration would be required. An alternative approach would be to increase endogenous adiponectin. The administration PPAR-γ agonists has the advantage of increasing the adiponectin and simultaneously reduce the levels of resistin. Existing PPAR-γ agonists, thiazolidinediones, have several side effects such as fluid retention resulting in peripheral edema and heart failure, and therefore they are not suitable for use in ICU patients. Possibly newer more selective PPAR-γ agonists may prove useful in the future.Στην παρούσα μελέτη δείξαμε για πρώτη φορά ότι η αδιπονεκτίνη αυξάνεται και η ρεζιστίνη μειώνεται στη διάρκεια της παρατεινόμενης σήψης. Οι μεταβολές αυτές ήταν πιο εμφανείς στους ασθενείς που τελικά εξήλθαν από την κρίσιμη κατάσταση και σχετίζονταν με την μείωση της φλεγμονώδους απάντησης όπως αυτή αξιολογήθηκε από τα επίπεδα των προφλεγμονωδών κυτταροκινών. Τα επίπεδα της αδιπονεκτίνης παρουσίασαν θετική συσχέτιση με τα επίπεδα της αυξητικής ορμόνης, υποδηλώνοντας ενδεχομένως θετική επίδραση της αυξητικής ορμόνης στην έκκρισή της. Τα επίπεδα της ρεζιστίνης σχετίσθηκαν κυρίως με τη βαρύτητα της σήψης και το βαθμό της φλεγμονώδους απάντησης υποδηλώνοντας ότι ο κύριος ρόλος της ρεζιστίνης στον άνθρωπο είναι αυτός της πρωτεΐνης οξείας φάσης. Επίσης καταγράψαμε και τις μεταβολές σημαντικών ορμονών κατά τη διάρκεια της παρατεινόμενης σήψης. Οι ασθενείς με τη χειρότερη πρόγνωση είχαν σημαντικά υψηλότερα επίπεδα κορτιζόλης, τόσο βασικά όσο και μετά από διέγερση, υψηλότερα επίπεδα αυξητικής ορμόνης και χαμηλότερα επίπεδα DHEA-S. Παρατηρήσαμε επίσης μία σταδιακή αύξηση της ACTH και της DHEA στην πορεία της σήψης, κάτι που δεν έχει περιγραφεί προηγουμένως. Συμπερασματικά, οι προσαρμογές που παρατηρούνται στους βαρέως πάσχοντες αφορούν όλο το φάσμα του ενδοκρινικού συστήματος. Η κατανόηση αυτών των διαταραχών ανοίγει το δρόμο για καλύτερη θεραπευτική αντιμετώπιση αυτών των ασθενών με στόχο την επιβίωση και την επιτάχυνση της ανάρρωσής τους. Προς αυτήν την κατεύθυνση χρειάζονται επιπλέον μελέτες κατανόησης των υποκείμενων παθοφυσιολογικών μηχανισμών και αποσαφήνισης του ποιες από αυτές τις μεταβολές είναι ευεργετικές και ποιες δυσπροσαρμοστικές με στόχο να σχεδιαστούν κλινικές μελέτες τροποποίησης εκείνων των μεταβολών που θεωρούνται επιβλαβείς. Για παράδειγμα η έγκαιρη αύξηση της αδιπονεκτίνης και η μείωση της ρεζιστίνης θεωρητικά θα είχε ευεργετικό αποτέλεσμα ως προς τη μείωση της εκσεσημασμένης φλεγμονώδους αντίδρασης και της αντίστασης στην ινσουλίνη. Εντούτοις η παραγωγή βιοσυνθετικής αδιπονεκτίνης για εξωγενή χορήγηση έχει σημαντικούς περιορισμούς καθώς το μόριο της υπόκειται σε αρκετές μετα-μεταφραστικές τροποποιήσεις. Επιπλέον κυκλοφορεί σε πολύ μεγάλες συγκεντρώσεις στο πλάσμα (5–30 mg/ml) και έχει σχετικά βραχύ χρόνο ημίσειας ζωής γεγονός που καθιστά δυσχερή τη χορήγησή της καθώς θα απαιτούνταν υψηλές ποσότητες ανασυνδυασμένης πρωτεΐνης και συχνή χορήγηση160. Η αύξηση της ενδογενούς αδιπονεκτίνης θεωρητικά αποτελεί εναλλακτική προσέγγιση. Η χορήγηση PPAR-γ αγωνιστών έχει το πλεονέκτημα ότι αυξάνει την αδιπονεκτίνη και ταυτόχρονα μειώνει τα επίπεδα της ρεζιστίνης. Οι υπάρχοντες PPAR-γ αγωνιστές, οι θειαζολιδινεδιόνες, έχουν αρκετές παρενέργειες όπως κατακράτηση υγρών με περιφερικά οιδήματα και καρδιακή ανεπάρκεια και γι’ αυτό δεν είναι κατάλληλοι για χορήγηση σε ασθενείς της ΜΕΘ. Ενδεχομένως οι νεότεροι εκλεκτικοί αγωνιστές του PPAR-γ να αποδειχθούν χρησιμότεροι. Συνοψίζοντας οι μεταβολικές και ενδοκρινικές μεταβολές σε βαρέως πάσχοντες αποτελούν ένα ιδιαίτερα ευρύ και ενδιαφέρον πεδίο έρευνας με υποσχόμενα αποτελέσματα ως προς την βέλτιστη αντιμετώπιση αυτών των ασθενών

Pituitary–Adrenal Responses and Glucocorticoid Receptor Expression in Critically Ill Patients with COVID-19

The hypothalamus–pituitary–adrenal (HPA) axis was described as the principal component of the stress response 85 years ago, along with the acute-phase reaction, and the defense response at the tissue level. The orchestration of these processes is essential since systemic inflammation is a double-edged sword; whereas inflammation that is timely and of appropriate magnitude is beneficial, exuberant systemic inflammation incites tissue damage with potentially devastating consequences. Apart from its beneficial cardiovascular and metabolic effects, cortisol exerts a significant immunoregulatory role, a major attribute being that it restrains the excessive inflammatory reaction, thereby preventing unwanted tissue damage. In this review, we will discuss the role of the HPA axis in the normal stress response and in critical illness, especially in critically ill patients with coronavirus disease 2019 (COVID-19). Finally, a chapter will be dedicated to the findings from clinical studies in critical illness and COVID-19 on the expression of the mediator of glucocorticoid actions, the glucocorticoid receptor (GCR)

Endocrine Aspects of ICU-Hospitalized COVID-19 Patients

The unprecedented scale of the current SARS-CoV-2/COVID-19 pandemic has led to an extensive—yet fragmented—assessment of its endocrine repercussions; in many reports, the endocrine aspects of COVID-19 are lumped together in intensive care unit (ICU) patients and non-ICU patients. In this brief review, we aimed to present endocrine alterations in ICU-hospitalized patients with COVID-19. There are tangible endocrine disturbances that may provide fertile ground for COVID-19, such as preexisting diabetes. Other endocrine disturbances accompany the disease and more particularly its severe forms. Up to the time of writing, no isolated robust endocrine/hormonal biomarkers for the prognosis of COVID-19 have been presented. Among those which may be easily available are admission glycemia, thyroid hormones, and maybe (OH)25-vitamin D3. Their overlap among patients with severe and less severe forms of COVID-19 may be considerable, so their levels may be indicative only. We have shown that insulin-like growth factor 1 may have prognostic value, but this is not a routine measurement. Possibly, as our current knowledge is expanding, the inclusion of selected routine endocrine/hormonal measurements into artificial intelligence/machine learning models may provide further information

Glucocorticoid and mineralocorticoid receptor expression in critical illness: A narrative review.

The glucocorticoid receptor (GCR) and the mineralocorticoid receptor (MR) are members of the steroid receptor superfamily of hormone-dependent transcription factors. The receptors are structurally and functionally related. They are localized in the cytosol and translocate into the nucleus after ligand binding. GCRs and MRs can be co-expressed within the same cell, and it is believed that the balance in GCR and MR expression is crucial for homeostasis and plays a key role in normal adaptation. In critical illness, the hypothalamic-pituitary-adrenal axis is activated, and as a consequence, serum cortisol concentrations are high. However, a number of patients exhibit relatively low cortisol levels for the degree of illness severity. Glucocorticoid (GC) actions are facilitated by GCR, whose dysfunction leads to GC tissue resistance. The MR is unique in this family in that it binds to both aldosterone and cortisol. Endogenous GCs play a critical role in controlling inflammatory responses in critical illness. Intracellular GC concentrations can differ greatly from blood levels due to the action of the two 11β-hydroxysteroid dehydrogenase isozymes, type 1 and type 2. 11β-hydroxysteroid dehydrogenases interconvert endogenous active cortisol and intrinsically inert cortisone. The degree of expression of the two isozymes has the potential to dramatically influence local GC availability within cells and tissues. In this review, we will explore the clinical studies that aimed to elucidate the role of MR and GCR expression in the inflammatory response seen in critical illness

Adipose Tissue Lactate Clearance but Not Blood Lactate Clearance Is Associated with Clinical Outcome in Sepsis or Septic Shock during the Post-Resuscitation Period

No study has directly measured tissue lactate clearance in patients with sepsis during the post-resuscitation period. In this study we aimed to assess in ICU patients with sepsis (n = 32) or septic shock (n = 79)—during the post-resuscitation phase—the relative kinetics of blood/tissue lactate clearances and to examine whether these are associated with outcome. We measured serially—over a 48-h period—blood and adipose tissue interstitial fluid lactate levels (with microdialysis) and we calculated lactate clearance. Statistics included mixed model analysis, Friedman’s analysis of variance, Wilcoxon’s test, Mann-Whitney’s test, receiver operating characteristics curves and logistic regression. Forty patients died (28-day mortality rate = 28%). Tissue lactate clearance was higher compared to blood lactate clearance at 0–8, 0–12, 0–16, 0–20 and 0–24 h (all p < 0.05). Tissue lactate clearance was higher in survivors compared to non-survivors at 0–12, 0–20 and 0–24 h (all p = 0.02). APACHE II along with tissue lactate clearance <30% at 0–12, 0–20 and 0–24 h were independent outcome predictors. We did not find blood lactate clearance to be related to survival. Thus, in critically ill septic patients, elevated tissue (but not blood) lactate clearance, was associated with a favorable clinical outcome

Adipose Tissue Lactate Clearance but Not Blood Lactate Clearance Is Associated with Clinical Outcome in Sepsis or Septic Shock during the Post-Resuscitation Period

No study has directly measured tissue lactate clearance in patients with sepsis during the post-resuscitation period. In this study we aimed to assess in ICU patients with sepsis (n = 32) or septic shock (n = 79)-during the post-resuscitation phase-the relative kinetics of blood/tissue lactate clearances and to examine whether these are associated with outcome. We measured serially-over a 48-h period-blood and adipose tissue interstitial fluid lactate levels (with microdialysis) and we calculated lactate clearance. Statistics included mixed model analysis, Friedman’s analysis of variance, Wilcoxon’s test, Mann-Whitney’s test, receiver operating characteristics curves and logistic regression. Forty patients died (28-day mortality rate = 28%). Tissue lactate clearance was higher compared to blood lactate clearance at 0-8, 0-12, 0-16, 0-20 and 0-24 h (all p < 0.05). Tissue lactate clearance was higher in survivors compared to non-survivors at 0-12, 0-20 and 0-24 h (all p = 0.02). APACHE II along with tissue lactate clearance <30% at 0-12, 0-20 and 0-24 h were independent outcome predictors. We did not find blood lactate clearance to be related to survival. Thus, in critically ill septic patients, elevated tissue (but not blood) lactate clearance, was associated with a favorable clinical outcome