key: cord-0887055-8zgqddvr
authors: Yair, Schwarz; Ruth, Percik; Bernice, Oberman; Yaffe, Dana; Eyal, Zimlichman; Amir, Tirosh
title: Sick euthyroid syndrome on presentation of COVID-19 patients, a potential marker for disease severity
date: 2021-01-11
journal: Endocr Pract
DOI: 10.1016/j.eprac.2021.01.001
sha: 3eabd2d9758598ef54e2005a7b5f33658b80bb1c
doc_id: 887055
cord_uid: 8zgqddvr

OBJECTIVE: Precise risk stratification and triage of COVID-19 patients has become essential in the setting of an overwhelming pandemic burden. Clinical observation has shown a somewhat high prevalence of sick euthyroid syndrome among COVID-19 patients. The study objective was to evaluate the predictive value of free Triiodothyronine (FT3), at the clinical presentation of COVID-19 for disease severity and death. METHODS: This was a retrospective cohort study based on electronic medical records. The study was conducted at Sheba Medical Centre, a tertiary hospital in which several acute and chronic wards have been dedicated to the treatment of COVID-19 patients. The primary outcome measure was death during hospitalization; secondary outcomes included hospitalization in intensive care, mechanical ventilation and length of hospitalization. RESULTS: Of a total of 577 PCR positive COVID-19 patients hospitalized between 02.27.2020 and 07.30.2020, 90 had at least one measurement of TSH, FT4 and FT3 within 3 days of presentation. After excluding patients with pre-existing thyroid disease, exposure to possible interfering drugs prior to FT3 measurement, and patients admitted for rehabilitation, 54 patients were included in the study. Patients in the lowest tertile of FT3, had significantly higher rates of mortality (40%, 5.9%, 5.9% P=0.008), mechanical ventilation (45%, 29.4%, 0%; P=0.007) and ICU admission (55%, 29.4%, 5.9%, P=0.006). In multivariate analyses adjusted for age, Charlson index, creatinine, albumin and WBC count, FT3 remained a significant independent predictor for death. CONCLUSION: FT3 levels early in the presentation of COVID-19 can serve as a prognostic tool for disease severity.

Precise stratification and triage of COVID-19 patients early in the course of hospitalization has become essential in the setting of emergency departments and intensive care units overwhelmed by the pandemic burden (1). Age and pre-existing conditions, including obesity, diabetes, cardiovascular disease and hypertension, are associated with increased mortality (2) (3) . In addition, laboratory markers including D-dimer, ferritin and lymphocyte count have additional prognostic value (1). Clinical observations have revealed a relatively high prevalence (up to 64%) of Sick euthyroid syndrome (SES), among COVID-19 patients, with some patients exhibiting a profound decrease in thyroid hormone levels (4) ,although the prognostic significance of this observation is currently unknown. SES is a physiological adaptation to acute or chronic illness of the hypothalamic-pituitarythyroid-(peripheral tissues) axis characterized by a decrease in thyroid hormone levels and TSH, despite absent intrinsic thyroid dysfunction at baseline (5) . The available research on SES provides considerable knowledge on etiology, correlation with disease severity and its prognostic value in a variety of acute and chronic states (6) (7) (8) (9) (10) (11) (12) (13) (14) . Specifically, FT3 has been shown to be a robust predictor of ICU mortality. In a prospective trial involving 480 critically ill patients admitted to the ICU, FT3 levels served as an independent and powerful predictor of mortality (7) . The course of SES includes a decline of serum triiodothyronine (T3) levels as early as 24 hours after disease onset, accompanied by a reciprocal increase in reverse T3. Serum total thyroxine (TT4) levels decline as the acute illness progresses (15, 16) whereas free T4 (FT4) hormone levels remain normal (17) . The recovery phase is characterized by a gradual increase in serum thyroidstimulating-hormone (TSH) levels (16) and may be prolonged even by months following clinical recovery. Of all thyroid hormones, FT3 stands out as the denominator of SES, because it is the most dynamic hormone in the evolution of SES and is conventionally measurable, as opposed for example to RT3. (9, 18, 19) .

The COVID-19 pandemic burden requires accurate triage based on early identification of individuals at risk to develop severe disease. The aim of this study was to prognostically evaluate thyroid hormone levels specifically FT3 at COVID 19 presentation.

This was a retrospective study conducted at Sheba Medical Centre, a tertiary academic hospital in Israel. During the 2020 pandemic, several acute and chronic wards among them internal medicine, intensive care, obstetric, paediatric, psychiatric and rehabilitation wards, were dedicated for the treatment of COVID-19 patients.

The study included patients aged 18 and above with documented PCR positive COVID-19 infection.

Exclusion criteria included background thyroid disease based on diagnosis or chronic medications, treatment with drugs which may interfere with thyroid function including amiodarone, interferon and glucocorticoids (other than chronic treatment with a low dose glucocorticoid) or exposure to an iodine containing contrast medium before thyroid hormone measurement, and admission for rehabilitation after initial recovery from an acute COVID-19 infection. Medical records of PCR positive COVID-19 patients hospitalized between February 27 th -July 30 th 2020 were retrieved and searched using MDClone (mdclone.com), a query tool that provides a wide range of patient data during a predefined time frame around an index event (20) , and electronic medical records (Chameleon, version 5.12.2.43395, Elad-Health). The index event was defined as hospitalization with a COVID-19 diagnosis in patients over 18 years of age.

Patient data queried included demographic data, medical history, laboratory parameters related to the index event, hospitalization, transfer between wards, mechanical ventilation, discharge or death.

Thyroid function tests were performed in the hospital's core laboratory using immunoassay (UniCel Dxl 800, Backman Coulter Diagnostics, normal reference ranges: TSH 0.4-4.0 mIU/l; FT4 7-16 pmol/l, FT3 3.3-7.2 pmol/l, inter-assay coefficients of variation below or equal to 5%, 8.8% and 8% respectively and intra-assay coefficients of variation below or equal to 2%, 4.4%, 6.6% respectively).

The Charlson Score was calculated for each patient. The Charlson comorbidity index, developed by Charlson (21) in 1987, is based on 19 conditions found to significantly influence survival and is a reflection of the number and severity of the comorbidities that the patient has. The comorbidities present in a patient are weighted and summed to give the final score, taking into account the persons age.

The primary outcome of the study was death during hospitalization; secondary outcomes included hospitalization in the ICU, mechanical ventilation and length of hospitalization.

Demographic, clinical and laboratory variables were compared between FT3 tertiles and between the groups of survivors and non-survivors. Continuous variables that were normally distributed were compared between groups using t-tests or ANOVA as indicated, adjusting if necessary, for inequality of variances. Continuous variables that were not normally distributed were compared using the Kruskal-Wallis rank sum test. Categorical variables were compared using Chi-squared tests or Fishers Exact test according to sample size.

Univariate logistic regression was carried out to determine risk factors for mortality. Significant variables resulting from the univariate logistic regression were entered into multivariate logistic regression models. Models were compared using a Pseudo R2 (Nagelkerkes). A ROC analysis enabled evaluation of the predictive ability of FT3 with respect to mortality; the best cutoff point was determined using the Youden index. A Kaplan-Meier analysis assessed the probability of survival in the different FT3 groups, which were compared using the Logrank Test. All analyses were performed using R (22). The study was approved by the Sheba Medical Center Institutional Review Board.

A total of 577 adult patients were diagnosed with COVID-19 and hospitalized in dedicated wards between February 27 th and July 30 th 2020 (Fig. 1) . Patients without an initialFT3 measurement (n=395) or with prior thyroid disease (n=52) or undergoing hospitalization for rehabilitation (n=11) J o u r n a l P r e -p r o o f were excluded. Of the remaining 119 individuals, 47 patients were excluded for not having an FT3 measurement within 3 days of presentation (defined as the time window for COVID-19 presentation).An additional 16 patients who had received treatment with glucocorticoids before their first FT3 measurement (other than 1 subject on 5 mg prednisone for renal transplantation) were excluded, and 2 patients who had been exposed to iodinated contrast material prior to their thyroid hormone measurements were also not included in the analysis. None of the remaining patients in the cohort were treated with amiodarone.

The remaining 54 patients included in the statistical analysis, were divided into tertiles according to their FT3 levels (2.4-4 pmol/l, 4.1-4.8 pmol/l and 4.9-7.4 pmol/l respectively). Patients in the lowest tertile included patients with an FT3 value below the reference range or in the lower part of the reference range; this group of patients included amongst them the patients with SES. Demographic, clinical and characteristics were compared between the FT3 tertiles and are shown in Table 1 .

Participants in the lowest FT3 tertile were significantly older compared to the higher tertiles (68.7, 56.7 and 48.9 years, respectively; P=0.006), had a higher Charlson index score (5.0, 2.47 and 1.65 respectively; P<0.001) and a higher prevalence of diabetes mellitus (55%, 23.5% and 17.6% respectively; P=0.033). No significant differences were found with respect to BMI, gender, hypertension, ischemic heart disease, congestive heart failure, autoimmune disease or diagnosis of cognitive decline. Patients in the lowest FT3 tertile had a significantly lower mean room air oxygen saturation on presentation (81%, 92.7% and 93.7% respectively; P=0.006), and only patients in the lowest tertile required mechanical ventilation in the emergency department (5 patients compared to 0 in both the higher tertiles; P=0.009, data not shown). Patients in the lowest tertile had a higher creatinine on presentation (1.3 compared with 0.9 and 0.67 mg/dl; P=0.001), a higher CRP (154. dimer was not significantly different between the tertiles. No significant differences in TSH or FT4 at presentation were found between the groups, but patients in the lowest FT3 tertile at presentation with COVID-19 reached a significantly lower TSH and FT4 nadir during the course of the disease (TSH; 1.3, 1.6, 2.8 mIU/l; respectively; P=0.039 and FT4; 9.2, 11.1, 12.6 pmol/l respectively; P=0.011).

Patients in the lowest FT3 tertile had a significantly higher mortality rate (40% compared to 5.9% in both the second and third tertiles, ; P=0.008), more mechanical ventilation (45% compared to 29.4% in the second tertile and 0% in the third tertile; P=0.007) and ICU hospitalization (55% compared to 29.4% and 5.9% in the higher tertiles;P=0.006). The average length of hospitalization was not significantly different between the groups. A Kaplan-Meier 90-day survival analysis between the tertiles (Figure 2 ) demonstrates the significant survival disadvantage of the lowest FT3 tertile (Logrank p=0.032). Study outcomes are shown in Table 1 and Figure 3 . A full comparison of survivors with non-survivors is presented in Table 2 .

Of the 54 patients in our cohort there were 10 deaths, eight of them among patients in the lowest tertile of FT3.These patients had an average FT3 on presentation which was significantly lower (3.45 vs 4.65 pmol/l; P<0.001). Patients who died were significantly older (74.9 years vs 55.0 years; P=0.03) and had a higher Charlson index score (6.1 vs 2.48; P<0.001). There were no significant differences regarding BMI and pre-existing comorbidities. Heart rate, mean room air saturation, respiratory rate, temperature and blood pressure were not significantly different at presentation. Laboratory markers that were significantly different between non-survivors and survivors included white blood cell count (14.6 vs 7.5 K/microL; P=0.001), absolute neutrophile count (12.8 vs 5.5 K/microL; P=0.001) and albumin (2.79 vs 3.70 g/dL; P<0.001). Several markers for severe disease J o u r n a l P r e -p r o o f including creatinine, LDH and D-dimer were borderline significant between the two groups. In a univariate analysis, baseline characteristics that were significantly associated with higher risk of death included older age (Odds ratio (OR) 1.07, 95%CI 1.02-1.12) and a higher Charlson index (OR 1.7, 1.22-2.37). When analysing the association of thyroid hormones at presentation and death, lower FT3 was significantly associated with death but neither TSH or FT4 were significant for mortality (OR for FT3; 0.17, 0.05-0.54). Other laboratory markers significantly associated with death were low albumin (OR 0.02, 0.00-0.25), white blood cell count (WBC) (OR 1.34, 1.11-1.63) and neutrophile count (OR 1.37, 1.12-1.67). The ORs for FT3 and albumin are low since unlike other variables associated with death a higher FT3 and a higher albumin are associated with a decreased risk for death. values) had a markedly higher disease severity and increased mortality (40% mortality rate) compared with patients with a higher FT3 (in the higher tertiles (5% mortality rate)). Low FT3 at presentation remained a robust predictor of mortality in multivariate analyses which included all other significant predictors: age, Charlson index, albumin, WBC and neutrophiles. The FT3 ROC curve proved that FT3 is an excellent predictor for mortality (AUC 0.84), superior to age (AUC 0.79), and only slightly inferior to albumin (AUC 0.89) and Charlson index (AUC 0.86).

SES is recognized as a non-specific adaptive mechanism for illness and an indirect marker of disease severity in various conditions including acute coronary syndrome (10), hospitalization in the critical care setting (7), cancer (23), burns (9) and brain surgery (8) . The underlying mechanisms for SES include multiple and complex alterations in iodothyronine deiodinases, thyroid-stimulating hormone (TSH) secretion, thyroid hormone binding to plasma proteins, thyroid hormone transport and activity in peripheral tissues, and expression of thyrotropin-releasing hormone in the J o u r n a l P r e -p r o o f hypothalamus (24). Cytokines are central mediators of endocrine changes related to systemic illness, with specific effects on the thyroid gland. They have been shown to inhibit thyroid iodide uptake (25), inhibit iodine organification (26-28), suppress thyroglobulin synthesis (29, 30) and decrease thyroid hormone secretion (15, (31) (32) (33) (34) (35) . Administration of thyroid hormone to restore normal serum thyroid hormone levels is controversial and currently available data do not provide clear evidence of a benefit (38) (39) (40) .

The course and severity of COVID-19 are closely linked to the action of several cytokines and the presence of a "cytokine storm" induced by the virus. Pro-inflammatory cytokines, including IL-6 and TNF-alpha which are known to interact with thyroid function, as described above, lead to Acute respiratory distress syndrome (ARDS) aggravation and widespread tissue damage resulting in multiorgan failure (36, 37) . The rise in inflammatory cytokines occurs before the clinical deterioration in COVID-19 patients, thus, suppression of FT3 may serve as a simple indicator of a clinically significant increase in cytokines. Besides, the rise in cortisol in the setting of acute infection, may also exert a suppressive effect on TSH secretion, FT4 to FT3 conversion and an increase in the conversion of FT4 to RT3. Low FT3 is likely to be an integrative marker for the host response to COVID-19 infection.

This study has several limitations. Due to the retrospective data collection, thyroid function tests were not available for all patients on admission. This might reflect diverse policies of laboratory assessment in different wards or a decision of medical staff to perform a more thorough initial laboratory work-up when assessing the patient. The study population is relatively small due to the meticulous cohort selection performed in order to evaluate FT3 as a predictor for mortality early in the course of hospitalization and without potential confounders such as glucocorticoid treatment which is very common among these patients. This stringent selection method limited cohort size but was necessary for the clarity and significance of the results. We measured FT3 by a conventional automated clinical method rather than by equilibrium dialysis which could overcome potential interference in the laboratory assay due to alterations in thyroid hormone-binding capacity. Given J o u r n a l P r e -p r o o f the scarce availability of these methods in most medical centers, and the availability of FT3 immunoassay, the latter is a more feasible biomarker for COVID-19 risk stratification.

In conclusion, our findings suggest that FT3 provides strong prognostic value, which can serve as a valuable stratification tool for newly diagnosed COVID-19 patients. 

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* Excluded patients who were excluded from the study and study cohort

Cerebrovascular accident; IHD, Ischemic heart disease

Congestive heart failure; PVD, Peripheral vascular disease; Hb, Hemoglobin; WBC, White blood cells

Length of stay