Patients With Autoimmune Thyroiditis Present Similar Immunological Response to COVID-19 BNT162b2 mRNA Vaccine With Healthy Subjects, While Vaccination May Affect Thyroid Function: A Clinical Study.

Background: This is the first study, that aimed: a) to compare immune response, namely the kinetics of neutralizing antibodies (Nabs), after vaccination with BNT162b2 mRNA vaccine (Comirnaty, Pfizer/BioNTech) between patients with autoimmune thyroiditis and controls, and b) to investigate changes in thyroid function in healthy subjects with no history of thyroid dysfunction before and after vaccination with BNT162b2 mRNA vaccine (Comirnaty, Pfizer/BioNTech). Methods: The entire study consisted of two sub-studies. In the first sub-study, NAbs levels after BNT162b2 mRNA vaccination were compared between 56 patients with autoimmune thyroiditis and 56 age and gender-matched healthy controls from the day of the first dose until a period of up to three months after the second dose. In the second sub-study, thyroid hormones (T3, T4, TSH) and thyroid auto-antibodies levels (anti-TG, anti-TPO) of 72 healthy subjects with no history of thyroid disease were examined before (D1) and one month after completion of the second dose (D50). Results: Among patients with autoimmune thyroiditis, the median neutralizing inhibition on D22, immediately before second dose, was 62.5%. One month later (D50), values increased to 96.7%, while three months after the second dose NAbs titers remained almost the same (94.5%). In the healthy group, median NAbs levels at D22 were 53.6%. On D50 the median inhibition values increased to 95.1%, while after three months they were 89.2%. The statistical analysis did not show significant differences between two groups (p-values 0.164, 0.390, 0.105 for D22, D50 and three months). Regarding changes in thyroid function, the mean value for T4 before vaccination was 89.797 nmol/L and one month after the second dose was 89.11 nmol/L (p-value=0.649). On D1 the mean T3 value was 1.464 nmol/L, which dropped to 1.389 nmol/L on D50 (p-value = 0.004). For TSH, mean levels were 2.064 mIU/ml on D1 and fell to 1.840 mIU/ml one month after the second dose (p-value=0.037). Despite decrease, all thyroid hormone levels remained within the normal range. No changes were found for anti-TPO or anti-TG. Conclusions: This study provided evidence that patients with autoimmune thyroiditis present similar immunological response to COVID-19 BNT162b2 mRNA vaccine (Comirnaty, Pfizer/BioNTech) with healthy subjects, while vaccination may affect thyroid function.

The Independent Association of TSH and Free Triiodothyronine Levels With Lymphocyte Counts Among COVID-19 Patients.

Background: Both lymphopenia and thyroid dysfunction are commonly observed among COVID-19 patients. Whether thyroid function independently correlates with lymphocyte counts (LYM) remains to be elucidated. Methods: We included consecutive adults without known thyroid disorder admitted to Queen Mary Hospital for COVID-19 from July 2020 to April 2021 who had thyroid-stimulating hormone (TSH), free thyroxine (fT4), free triiodothyronine (fT3) and LYM measured on admission. Results: A total of 541 patients were included. Median LYM was 1.22 x 109/L, with 36.0% of the cohort lymphopenic. 83 patients (15.4%) had abnormal thyroid function tests (TFTs), mostly non-thyroidal illness syndrome (NTIS). Patients with lymphopenia had lower TSH, fT4 and fT3 levels than those without. Multivariable stepwise linear regression analysis revealed that both TSH (standardized beta 0.160, p<0.001) and fT3 (standardized beta 0.094, p=0.023), but not fT4, remained independently correlated with LYM, in addition to age, SARS-CoV-2 viral load, C-reactive protein levels, coagulation profile, sodium levels and more severe clinical presentations. Among the 40 patients who had reassessment of TFTs and LYM after discharge, at a median of 9 days from admission, there were significant increases in TSH (p=0.031), fT3 (p<0.001) and LYM (p<0.001). Furthermore, patients who had both lymphopenia and NTIS were more likely to deteriorate compared to those who only had either one alone, and those without lymphopenia or NTIS (p for trend <0.001). Conclusion: TSH and fT3 levels showed independent positive correlations with LYM among COVID-19 patients, supporting the interaction between the hypothalamic-pituitary-thyroid axis and immune system in COVID-19.

Assessment of thyroid function of newly diagnosed SARS-CoV-2 infected patients in Nigeria.

INTRODUCTION: the outbreak and rapid spread of the novel SARS-CoV-2, the causative agent of the coronavirus disease 2019 (COVID-19), has evolved into an unprecedented global pandemic. The infection impairs several human organs and systems, however, it is not clear how it affects thyroid function. The study therefore aimed at measuring plasma levels of thyroid hormones and Hs-CRP in COVID-19 patients and apparently healthy uninfected controls to assess the possible effect of SAR-CoV-2 infection on thyroid function. METHODS: in this cross-sectional study carried out between May-August 2020, 90 consenting participants comprising 45 COVID-19 patients and 45 apparently healthy uninfected controls were recruited. Plasma FT3, FT4, TSH and Hs-CRP were measured using Enzyme Linked Immunosorbent Assay (ELISA) method. Data was analysed using SPSS version 20 and statistical significance set at p < 0.05. RESULTS: the mean plasma FT3 and TSH concentrations were significantly higher in COVID-19 patients compared to controls (p < 0.001, p < 0.001 respectively). Euthyroidism was observed in all uninfected controls, whereas 35 (77.8%) COVID-19 patients were euthyroid. Sick euthyroid and subclinical hypothyroidism was observed in 7 (15.6%) and 3 (6.7%) COVID-19 patients, respectively. CONCLUSION: though there was a preponderance of euthyroidism among COVID-19 patients, significantly higher mean plasma levels of TSH and FT3, sick euthyroid syndrome and subclinical hypothyroidism observed among some COVID-19 patients may be indicative of disease-related thyroid function changes. Hence, there is need to pay attention to thyroid function during and after treatment of COVID-19.

Association of hypothyroidism with acute COVID-19: a systematic review.

OBJECTIVE: There is an increasing body of literature on the impact of COVID-19 on the pituitary-thyroid axis. Therefore, we conducted a systematic review to assess the prevalence of hypothyroidism in patients with COVID-19. METHODS: A literature review was conducted using LitCOVID for study selection in PubMed and MEDLINE till May 2021. All relevant original articles evaluating thyroid dysfunction were included and information regarding the prevalence of hypothyroid disease in COVID-19 was retrieved from the eligible articles. RESULTS: Out of 32 articles, six articles qualified for the final analysis which included 1160 patients. There was significant heterogeneity among the included articles. Most of the patients had lower mean triiodothyronine (T3) and normal or low thyroid-stimulating hormone (TSH). Increased TSH ranged from 5.1% to 8% while low T3 was present in up to 28% of the patients. In these studies, the prevalence of altered thyroid hormones was significantly more in COVID-19 patients as compared to control groups. A positive correlation between low mean T3 and clinical severity of COVID-19 was reported. CONCLUSION: This systematic review reveals a significant proportion of hypothyroidism associated with COVID-19. Therefore, routine assessment of thyroid function is warranted in hospitalized COVID-19 patients.

Thyroid Hormone Levels During Hospital Admission Inform Disease Severity and Mortality in COVID-19 Patients.

Background: Illness severity in patients infected with COVID-19 is variable. Methods: Here, we conducted an observational, longitudinal, and prospective cohort study to investigate serum thyroid hormone (TH) levels in adult COVID-19 patients, admitted between June and August 2020, and to determine whether they reflect the severity or mortality associated with the disease. Results: Two hundred forty-five patients [median age: 62 (49-75) years] were stratified into non-critical (181) and critically ill (64) groups. Fifty-eight patients (23.6%) were admitted to the intensive care unit, and 41 (16.7%) died. Sixteen (6.5%) exhibited isolated low levels of free triiodothyronine (fT3). fT3 levels were lower in critically ill compared with non-critical patients [fT3: 2.82 (2.46-3.29) pg/mL vs. 3.09 (2.67-3.63) pg/mL, p = 0.007]. Serum reverse triiodothyronine (rT3) was mostly elevated but less so in critically ill compared with non-critical patients [rT3: 0.36 (0.28-0.56) ng/mL vs. 0.51 (0.31-0.67) ng/mL, p = 0.001]. The univariate logistic regression revealed correlation between in-hospital mortality and serum fT3 levels (odds ratio [OR]: 0.47; 95% confidence interval [CI 0.29-0.74]; p = 0.0019), rT3 levels (OR: 0.09; [CI 0.01-0.49]; p = 0.006) and the product fT3 × rT3 (OR: 0.47; [CI 0.28-0.74]; p = 0.0026). Serum thyrotropin, free thyroxine, and fT3/rT3 values were not significantly associated with mortality and severity of the disease. A serum cutoff level of fT3 (≤2.6 pg/mL) and rT3 (≤0.38 ng/mL) was associated with 3.46 and 5.94 OR of mortality, respectively. We found three COVID-19 mortality predictors using the area under the receiver operating characteristic (ROC) curve (AUC score): serum fT3 (AUC = 0.66), rT3 (AUC = 0.64), and the product of serum fT3 × rT3 (AUC = 0.70). Non-thyroidal illness syndrome (fT3 < 2.0 pg/mL) was associated with a 7.05 OR of mortality ([CI 1.78-28.3], p = 0.005) and the product rT3 × fT3 ≤ 1.29 with an 8.08 OR of mortality ([CI 3.14-24.2], p < 0.0001). Conclusions: This prospective study reports data on the largest number of hospitalized moderate-to-severe COVID-19 patients and correlates serum TH levels with illness severity, mortality, and other biomarkers to critical illness. The data revealed the importance of early assessment of thyroid function in hospitalized patients with COVID-19, given the good prognostic value of serum fT3, rT3, and fT3 × rT3 product. Further studies are necessary to confirm these observations.

Normal Adrenal and Thyroid Function in Patients Who Survive COVID-19 Infection.

CONTEXT: The COVID-19 pandemic continues to exert an immense burden on global health services. Moreover, up to 63% of patients experience persistent symptoms, including fatigue, after acute illness. Endocrine systems are vulnerable to the effects of COVID-19 as many glands express the ACE2 receptor, used by the SARS-CoV-2 virion for cellular access. However, the effects of COVID-19 on adrenal and thyroid gland function after acute COVID-19 remain unknown. OBJECTIVE: Our objectives were to evaluate adrenal and thyroid gland function in COVID-19 survivors. METHODS: A prospective, observational study was undertaken at the Clinical Research Facility, Imperial College NHS Healthcare Trust, including 70 patients ≥18 years of age, at least 3 months after diagnosis of COVID-19. Participants attended a research study visit (8:00-9:30 am), during which a short Synacthen test (250 µg IV bolus) and thyroid function assessments were performed. RESULTS: All patients had a peak cortisol ≥450 nmol/L after Synacthen, consistent with adequate adrenal reserve. Basal and peak serum cortisol did not differ according to disease severity or history of dexamethasone treatment during COVID-19. There was no difference in baseline or peak cortisol after Synacthen or in thyroid function tests, or thyroid status, in patients with fatigue (n = 44) compared to those without (n = 26). CONCLUSION: Adrenal and thyroid function ≥3 months after presentation with COVID-19 was preserved. While a significant proportion of patients experienced persistent fatigue, their symptoms were not accounted for by alterations in adrenal or thyroid function. These findings have important implications for the clinical care of patients after COVID-19.

Physiological Role and Use of Thyroid Hormone Metabolites - Potential Utility in COVID-19 Patients.

Thyroxine and triiodothyronine (T3) are classical thyroid hormones and with relatively well-understood actions. In contrast, the physiological role of thyroid hormone metabolites, also circulating in the blood, is less well characterized. These molecules, namely, reverse triiodothyronine, 3,5-diiodothyronine, 3-iodothyronamine, tetraiodoacetic acid and triiodoacetic acid, mediate both agonistic (thyromimetic) and antagonistic actions additional to the effects of the classical thyroid hormones. Here, we provide an overview of the main factors influencing thyroid hormone action, and then go on to describe the main effects of the metabolites and their potential use in medicine. One section addresses thyroid hormone levels in corona virus disease 19 (COVID-19). It appears that i) the more potently-acting molecules T3 and triiodoacetic acid have shorter half-lives than the less potent antagonists 3-iodothyronamine and tetraiodoacetic acid; ii) reverse T3 and 3,5-diiodothyronine may serve as indicators for metabolic dysregulation and disease, and iii) Nanotetrac may be a promising candidate for treating cancer, and resmetirom and VK2809 for steatohepatitis. Further, the use of L-T3 in the treatment of severely ill COVID-19 patients is critically discussed.

Two Cases of Graves' Disease Following SARS-CoV-2 Vaccination: An Autoimmune/Inflammatory Syndrome Induced by Adjuvants.

Background: The autoimmune/inflammatory syndrome induced by adjuvants (ASIA) comprises four entities, including the postvaccination phenomenon, which appears after being exposed to adjuvants in vaccines that increase the immune response. There is limited information about autoimmune endocrine diseases and ASIA after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. Patient's Findings: Two female health care workers received a SARS-CoV-2 vaccine, and three days later developed clinical manifestations of thyroid hyperactivity, with increased thyroid hormone levels on thyroid function tests, suppressed thyroid-stimulating hormone, and elevated antithyroid antibodies. Summary: Vaccines have been shown to trigger an immune response that leads to a broad spectrum of autoimmune diseases, including autoimmune thyroid disease. Our patients met the diagnostic criteria for ASIA; they were exposed to an adjuvant (vaccine), and they developed clinical manifestations of thyroid hyperfunction within a few days, with the appearance of antithyroid antibodies, despite being healthy before vaccination. Conclusion: Graves' disease can occur after SARS-CoV-2 vaccination.

A prospective, observational clinical trial on the impact of COVID-19-related national lockdown on thyroid hormone in young males.

Trying to manage the dramatic coronavirus disease 2019 (COVID-19) infection spread, many countries imposed national lockdown, radically changing the routinely life of humans worldwide. We hypothesized that both the pandemic per se and the consequent socio-psychological sequelae could constitute stressors for Italian population, potentially affecting the endocrine system. This study was designed to describe the effect of lockdown-related stress on the hypothalamic-pituitary-thyroid (HPT) axis in a cohort of young men. A prospective, observational clinical trial was carried out, including patients attending the male infertility outpatient clinic before and after the national lockdown for COVID-19 pandemic. The study provided a baseline visit performed before and a follow-up visit after the lockdown in 2020. During the follow-up visit, hormonal measurements, lifestyle habits and work management were recorded. Thirty-one male subjects were enrolled (mean age: 31.6 ± 6.0 years). TSH significantly decreased after lockdown (p = 0.015), whereas no significant changes were observed in the testosterone, luteinising hormone, follicle-stimulating hormone, estradiol and prolactin serum levels. No patient showed TSH serum levels above or below reference ranges, neither before nor after lockdown. Interestingly, TSH variation after lockdown was dependent on the working habit change during lockdown (p = 0.042). We described for the first time a TSH reduction after a stressful event in a prospective way, evaluating the HPT axis in the same population, before and after the national lockdown. This result reinforces the possible interconnection between psychological consequences of a stressful event and the endocrine regulation.

The Association of TSH and Thyroid Hormones With Lymphopenia in Bacterial Sepsis and COVID-19.

CONTEXT: Lymphopenia is a key feature of immune dysfunction in patients with bacterial sepsis and coronavirus disease 2019 (COVID-19) and is associated with poor clinical outcomes, but the cause is largely unknown. Severely ill patients may present with thyroid function abnormalities, so-called nonthyroidal illness syndrome, and several studies have linked thyrotropin (thyroid stimulating hormone, TSH) and the thyroid hormones thyroxine (T4) and 3,5,3'-triiodothyronine (T3) to homeostatic regulation and function of lymphocyte populations. OBJECTIVE: This work aimed to test the hypothesis that abnormal thyroid function correlates with lymphopenia in patients with severe infections. METHODS: A retrospective analysis of absolute lymphocyte counts, circulating TSH, T4, free T4 (FT4), T3, albumin, and inflammatory biomarkers was performed in 2 independent hospitalized study populations: bacterial sepsis (n = 224) and COVID-19 patients (n = 161). A subgroup analysis was performed in patients with severe lymphopenia and normal lymphocyte counts. RESULTS: Only T3 significantly correlated (ρ = 0.252) with lymphocyte counts in patients with bacterial sepsis, and lower concentrations were found in severe lymphopenic compared to nonlymphopenic patients (n = 56 per group). Severe lymphopenic COVID-19 patients (n = 17) showed significantly lower plasma concentrations of TSH, T4, FT4, and T3 compared to patients without lymphopenia (n = 18), and demonstrated significantly increased values of the inflammatory markers interleukin-6, C-reactive protein, and ferritin. Remarkably, after 1 week of follow-up, the majority (12 of 15) of COVID-19 patients showed quantitative recovery of their lymphocyte numbers, whereas TSH and thyroid hormones remained mainly disturbed. CONCLUSION: Abnormal thyroid function correlates with lymphopenia in patients with severe infections, like bacterial sepsis and COVID-19, but future studies need to establish whether a causal relationship is involved.

Thyroid Function Abnormalities in COVID-19 Patients.

Purpose: The novel coronavirus COVID-19, has caused a worldwide pandemic, impairing several human organs and systems. Whether COVID-19 affects human thyroid function remains unknown. Methods: Eighty-four hospitalized COVID-19 patients in the First Affiliated Hospital, Zhejiang University School of Medicine (Hangzhou, China) were retrospectively enrolled in this study, among which 22 cases had complete records of thyroid hormones. In addition, 91 other patients with pneumonia and 807 healthy subjects were included as controls. Results: We found that levels of total triiodothyronine (TT3) and thyroid stimulating hormone (TSH) were lower in COVID-19 patients than healthy group (p < 0.001). Besides, TSH level in COVID-19 patients was obviously lower than non-COVID-19 patients (p < 0.001). Within the group of COVID-19, 61.9% (52/84) patients presented with thyroid function abnormalities and the proportion of thyroid dysfunction was higher in severe cases than mild/moderate cases (74.6 vs. 23.8%, p < 0.001). Patients with thyroid dysfunction tended to have longer viral nucleic acid cleaning time (14.1 ± 9.4 vs. 10.6 ± 8.3 days, p = 0.088). To note, thyroid dysfunction was also associated with decreased lymphocytes (p < 0.001) and increased CRP (p = 0.002). The correlation between TT3 and TSH level seemed to be positive rather than negative in the early stage, and gradually turned to be negatively related over time. Conclusion: Thyroid function abnormalities are common in COVID-19 patients, especially in severe cases. This might be partially explained by nonthyroidal illness syndrome.

Thyroid Hormone Changes in Early Pregnancy Along With the COVID-19 Pandemic.

Purpose: COVID-19 (Coronavirus Disease 2019) was first reported in December 2019 and quickly swept across China and around the world. Levels of anxiety and depression were increased among pregnant women during this infectious pandemic. Thyroid function is altered during stressful experiences, and any abnormality during early pregnancy may significantly affect fetal development and pregnancy outcomes. This study aimed to determine whether the COVID-19 pandemic induces thyroid hormone changes in early pregnant women. Methods: This study comprised two groups of pregnant women in Shanghai in their first trimester - those pregnant women before the COVID-19 outbreak from January 20, 2019, to March 31, 2019 (Group 1) and those pregnant during the COVID-19 outbreak from January 20, 2020, to March 31, 2020 (Group 2). All women were included if they had early pregnancy thyrotropin (TSH), free triiodothyronine (FT3), free thyroxine (FT4), total triiodothyronine (TT3), and total thyroxine (TT4) concentrations, thyroid peroxidase (TPO) antibody or thyroglobulin antibody (TgAb) available and did not have a history of thyroid diseases or received thyroid treatment before or during pregnancy. We used propensity score matching to form a cohort in which patients had similar baseline characteristics. Results: Among 3338 eligible pregnant women, 727 women in Group 1 and 727 in Group 2 had similar propensity scores and were included in the analyses. Pregnant women in Group 2 had significantly higher FT3 (5.7 vs. 5.2 pmol/L, P<0.001) and lower FT4 (12.8 vs. 13.2 pmol/L, P<0.001) concentrations compared with those in Group 1. Pregnant women in Group 2 were more likely to develop isolated hypothyroxinemia (11.6% vs. 6.9%, OR, 1.75 [95% CI, 1.20-2.53], P=0.003) than those in Group 1 but had a significantly lower risk of TgAb positivity (12.0% vs. 19.0%, OR, 0.58 [95% CI, 0.43-0.78], P<0.001). Conclusion: Pregnant women in their first trimester in Shanghai during the COVID-19 outbreak were at an increased risk of having higher FT3 concentrations, lower FT4 concentrations, and isolated hypothyroxinemia. The association between thyroid hormones, pregnancy outcomes, and the COVID-19 outbreak should be explored further.

Thyroid hormone concentrations in severely or critically ill patients with COVID-19.

OBJECTIVE: COVID-19 is a new coronavirus infectious disease. We aimed to study the characteristics of thyroid hormone levels in patients with COVID-19 and to explore whether thyroid hormone predicts all-cause mortality of severely or critically ill patients. METHODS: The clinical data of 100 patients with COVID-19, who were admitted to Wuhan Tongji Hospital from February 8 to March 8, 2020, were analyzed in this retrospective study. The patients were followed up for 6-41 days. Patients were grouped into non-severe illness and severe or critical illness, which included survivors and non-survivors. Multivariate Cox proportional hazards analysis was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality in association with continuous and the lower two quartiles of thyroid hormone concentrations in severely or critically ill patients. RESULTS: The means of free T3 (FT3) were 4.40, 3.73 and 2.76 pmol/L in non-severely ill patients, survivors and non-survivors, respectively. The lower (versus upper) two quartiles of FT3 was associated with all-cause mortality HR (95% CI) of 9.23 (2.01, 42.28). The HR (95% CI) for all-cause mortality in association with continuous FT3 concentration was 0.41 (0.21, 0.81). In the multivariate-adjusted models, free T4 (FT4), TSH and FT3/FT4 were not significantly related to all-cause mortality. Patients with FT3 less than 3.10 pmol/L had increased all-cause mortality. CONCLUSION: FT3 concentration was significantly lower in patients with severe COVID-19 than in non-severely ill patients. Reduced FT3 independently predicted all-cause mortality of patients with severe COVID-19.

Thyroid disorders and SARS-CoV-2 infection: From pathophysiological mechanism to patient management.

The World Health Organization (WHO) declared the COVID-19 epidemic to be a global pandemic in March 2020. COVID-19 is an infection caused by SARS-CoV-2, a coronavirus that utilizes the angiotensin-2 converting enzyme to penetrate thyroid and pituitary cells, and may result in a "cytokine storm". Based on the pathophysiological involvement of the pituitary-thyroid axis, the current review discusses the diagnosis of abnormal thyroid function test, and the management of patients presenting with thyrotoxicosis, thyroid-associated orbitopathy and hypothyroidism in the context of SARS-CoV-2 infection.