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

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

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

Age-dependent and sex-dependent disparity in mortality in patients with adrenal incidentalomas and autonomous cortisol secretion: an international, retrospective, cohort study.

BACKGROUND The association between cortisol secretion and mortality in patients with adrenal incidentalomas is controversial. We aimed to assess all-cause mortality, prevalence of comorbidities, and occurrence of cardiovascular events in uniformly stratified patients with adrenal incidentalomas and cortisol autonomy (defined as non-suppressible serum cortisol on dexamethasone suppression testing). METHODS We conducted an international, retrospective, cohort study (NAPACA Outcome) at 30 centres in 16 countries. Eligible patients were aged 18 years or older with an adrenal incidentaloma (diameter ≥1 cm) detected between Jan 1, 1996, and Dec 31, 2015, and availability of a 1 mg dexamethasone suppression test result from the time of the initial diagnosis. Patients with clinically apparent hormone excess, active malignancy, or follow-up of less than 36 months were excluded. Patients were stratified according to the 0800-0900 h serum cortisol values after an overnight 1 mg dexamethasone suppression test; less than 50 nmol/L was classed as non-functioning adenoma, 50-138 nmol/L as possible autonomous cortisol secretion, and greater than 138 nmol/L as autonomous cortisol secretion. The primary endpoint was all-cause mortality. Secondary endpoints were the prevalence of cardiometabolic comorbidities, cardiovascular events, and cause-specific mortality. The primary and secondary endpoints were assessed in all study participants. FINDINGS Of 4374 potentially eligible patients, 3656 (2089 [57·1%] with non-functioning adenoma, 1320 [36·1%] with possible autonomous cortisol secretion, and 247 [6·8%] with autonomous cortisol secretion) were included in the study cohort for mortality analysis (2350 [64·3%] women and 1306 [35·7%] men; median age 61 years [IQR 53-68]; median follow-up 7·0 years [IQR 4·7-10·2]). During follow-up, 352 (9·6%) patients died. All-cause mortality (adjusted for age, sex, comorbidities, and previous cardiovascular events) was significantly increased in patients with possible autonomous cortisol secretion (HR 1·52, 95% CI 1·19-1·94) and autonomous cortisol secretion (1·77, 1·20-2·62) compared with patients with non-functioning adenoma. In women younger than 65 years, autonomous cortisol secretion was associated with higher all-cause mortality than non-functioning adenoma (HR 4·39, 95% CI 1·93-9·96), although this was not observed in men. Cardiometabolic comorbidities were significantly less frequent with non-functioning adenoma than with possible autonomous cortisol secretion and autonomous cortisol secretion (hypertension occurred in 1186 [58·6%] of 2024 patients with non-functioning adenoma, 944 [74·0%] of 1275 with possible autonomous cortisol secretion, and 179 [75·2%] of 238 with autonomous cortisol secretion; dyslipidaemia occurred in 724 [36·2%] of 1999 patients, 547 [43·8%] of 1250, and 123 [51·9%] of 237; and any diabetes occurred in 365 [18·2%] of 2002, 288 [23·0%] of 1250, and 62 [26·7%] of 232; all p values <0·001). INTERPRETATION Cortisol autonomy is associated with increased all-cause mortality, particularly in women younger than 65 years. However, until results from randomised interventional trials are available, a conservative therapeutic approach seems to be justified in most patients with adrenal incidentaloma. FUNDING Deutsche Forschungsgemeinschaft, Associazione Italiana per la Ricerca sul Cancro, Università di Torino