Serum TSH level in hospitalized patients with moderate-to-severe COVID-19

Introduction

Nowadays, SARS-CoV-2 (COVID-19) infection is a serious problem for global health. COVID-19 causes significant damage to many organ systems, especially the respiratory system [1]. At the same time, SARS-CoV-2 may provoke a negative effect on the endocrine system, in particular on the hypothalamic-pituitary-thyroid axis, but the pathogenetic aspects remain unclear [2]. A number of authors describe immuno-mediated thyroid gland (thyroid gland) damage due to the development of hyperinflammatory syndrome associated with an increase in cytokine levels and the formation of the phenomena of multiple organ failure [3][4]. To date, it has not been possible to determine the presence of SARS-CoV-2 in the thyroid and pituitary gland by means of using studies concerning light microscopy, immunohistochemistry, electron microscopy, and quantitative RT-PCR [5]. However, in academic literature, there are indications of the possibility of the direct cytotoxic effect of SARS-CoV-2 on thyrocytes and thyrotrophs through interaction with the receptor apparatus: angiotensin-converting enzyme 2 (ACE-2), transmembrane protease serine-2 (TMPRSS2), integrin avß3, and neuropilin-1 [6-10].

The results of previous studies have shown that at different time intervals after a new coronavirus infection, the incidence of thyroid pathology increases, including Graves' disease, Hashimoto's thyroiditis, subacute, pain-free and postpartum thyroiditis associated with the development of both hypothyroidism and thyrotoxic syndrome [11]. There are also data in academic literature on an isolated decrease in thyroid-stimulating hormone (TSH) and low T3 syndrome (euthyroid pathology syndrome) during the outbreak of SARS-CoV in 2002 [12][13].

Taking into account the well-known role of thyroid dysfunction in worsening the course of major diseases, for example, cardiovascular pathology, the relevance of studying thyroid pathology associated with COVID-19 is beyond doubt.

The aim of this particular study was to assess the level of TSH in dynamics in patients with moderate and severe course of new coronavirus infection in the acute period of the disease.

Materials and methods

A retrospective analysis of the data obtained from the qMS medical information system on the basis of the Almazov National Medical Research Centre of the Ministry of Health of the Russian Federation (St. Petersburg) was performed. The study included patients who were on inpatient treatment for a new coronavirus infection in the period from December 2020 to February 2021. The inclusion criteria were the patient's age (18 years and older) and the diagnosis of moderate and severe COVID-19 confirmed by the polymerase chain reaction test (PCR) test. The exclusion criterion was the presence of a history of thyroid diseases. While analyzing the data, clinical data were taken into account (age, gender, body mass index, concomitant diseases, the day of illness on which hospitalization was performed and the duration of hospitalization, as well as the outcome); laboratory results (TSH level on the 1^st-2^nd and 9^th-10^th days of hospitalization, 25(OH)D, C-reactive protein (CRP), ferritin, lactate dehydrogenase (LDH) at the time of hospitalization); results of instrumental studies (volume and degree of lung damage according to the results of multislice spiral computed tomography), as well as therapy with glucocorticosteroids.

The level of TSH, CRP, and LDH was measured on an automatic biochemical analyzer Cobas C411 Roche (Switzerland), reference ranges – 0.27–4.2 mMU/l, 0–6 mg/l, 133–225 units/l, respectively. The levels of 25(OH)D and ferritin in blood serum were determined by means of an Abbott Architect c8000 analyzer (USA) using calibrators and control serums from the manufacturer; the reference range was 9.4–52.4 ng/ml and 30.00–400.00 ng/ml, respectively.

The degree of lung tissue damage was established in accordance with the temporary methodological recommendations of the Ministry of Health of the Russian Federation version 13.1 of 17.11.2021: CT-1 (minimum) – lesion volume < 25%; CT-2 (average) – lesion volume 25–50%; CT-3 (significant) – lesion volume 50–75%, CT-4 (subtotal) – lesion volume > 75%.

Statistical analysis was performed in the Jamovi program, version 1.6.23 (Jamovi project, 2021). The data are represented by the median and interquartile range (25; 75 percentiles). In order to assess the statistical significance of the differences between the two independent groups, the Mann-Whitney T-test was used, and the Wilcoxon W-test was used for paired measurements. Fisher's criterion was used for the analysis of variance, and Spearman's correlation criterion was taken for correlation analysis. In order to assess the statistical significance of the results obtained, the probability of a random error of less than 5% (p <0.05) was chosen.

Results

The study included 133 patients with a confirmed diagnosis of COVID-19 in the above-mentioned period. Among these patients, 63 were women (47.7%) and 69 were men (52.3%). The median age of women was 62 years [ 55, 69] (from 29 to 86 years); the median age of men was 58 years [ 48, 68] (from 32 to 81 years). The general characteristics of the patients included in the study are presented in Table 1.

As can be seen from the presented data, the average age of patients was 59 [ 52; 68] years, the median body mass index of patients was 29.6 kg/m² [ 25.7, 32.9] (from 18.2 and up to 48.1 kg/m²). It was found that obesity was characteristic of 55 patients (41.7%), and type 2 diabetes mellitus – for 43 (32.6%) patients. As for cardiovascular diseases, hypertension was present in 96 (72.2%) patients, and coronary heart disease – in 31 (23.3%) patients.

Additionally, the authors of this study assessed the day of illness on which hospitalization occurred, on average it was 8 days [ 6.10], and the number of bed days spent by patients on inpatient treatment was 17 days [ 14.22]. Except for one case, the hospitalization of the remaining 132 (99.2%) patients ended with discharge.

The TSH level on Days 1–2 was assessed in all 133 patients, and its median was 1.15 mme/ml [ 0.760; 1.80] (reference value – from 0.05 to 4.49 mme/ml). Comparative characteristics of patients according to the TSH level on the 1^st–2^nd day of hospitalization (1 point) are presented in Table 2. It was found that seven patients had TSH levels <0.4. The authors of this study did not find statistically significant differences in the studied parameters between patients with TSH levels <0.4 mcME/ml (n=7) and patients with TSH = 0.4–4.5 microns/ml (n=125).

Repeated analysis of TSH on the 9^th–10^th day of hospitalization (2^nd point) was performed in 77 patients; its median was 1.04 mme/ml [ 0.70; 1.78] (from 0.25 to 7.14 mme/ml). The comparative characteristics of patients in accordance with the TSH level on the 9^th–10^th day of hospitalization (2^nd point) are shown in Table 3.

Depending on the TSH level, the patients were divided into three groups: I – TSH was less than 0.4 mme/ml; II – TSH was 0.4–4.5 mme/ml; III – TSH was more than 4.5 mme/ml. Four patients initially had a TSH level <0.4 mme/m, and then their number doubled by the 9^th–10^th day of hospitalization and amounted to 9 (11.7%) people. Also, by the 9^th–10^th day of hospitalization, an increase in TSH of more than 4.5 microns/ml was detected in four patients (4.2%). Thus, 13 out of 77 patients on the 9^th–10^th day of hospitalization had deviations in TSH values. In the present study, there was no association of the outcome of hospitalization with the level of TSH on the 1^st–2^nd or 9^th–10^th day.

While assessing markers of systemic inflammation identified in the first days of hospitalization, it was noted: CRP – 50.14 mg/l [ 19.27;107.73]; ferritin – 530.6 mcg/l [ 237.5;940.6]; LDH – 342 units/l [ 265;493]. The values of markers of systemic inflammation were compared with the values of TSH on the 1^st–2^nd day of hospitalization; however, no statistically significant correlation was obtained (r <0.1, p >0.05).

The median volume of lung tissue lesion averaged 35% [25;45] (from 0 to 85%). Lung tissue damage according to the results of CT of the 0^th degree was noted in 5.3% of patients, 1^st degree — in 22%, 2^nd degree – in 56.8%, 3^rd degree – 12.1%, 4^th degree – in 3.8%. There was no statistically significant correlation between the level of TSH on Days 1–2/9–10 and the severity of lung tissue damage (r=0.059, p=0.499); (r=–0.110, p=0.348).

Therefore, 104 patients received glucocorticoids in the form of dexamethasone, 25 patients – prednisone, 10 – methylprednisolone (some patients received different glucocorticoid preparations during hospitalization) of the 133 patients included in the study. The average TSH level on the 9^th–10^th day of hospitalization when prescribing dexamethasone was statistically lower than when using other drugs of the glucocorticosteroid group (p=0.001). No statistically significant differences were obtained for prednisolone and methylprednisolone (p = 0.962, p = 0.898).

Discussion

Currently, data are accumulating indicating a thyroid lesion associated with a previous infection caused by SARS-CoV-2 (COVID-19). The aim of this study was to assess the level of TSH in dynamics in patients without previously known thyroid diseases in the acute period of COVID-19.

Speaking about the time frame of the occurrence of thyroid diseases after a new coronavirus infection (Fig. 1), the literature review by Inaba et al. focuses readers' attention on the possibility of delayed (in 4–8 weeks) occurrence of thyroid diseases after confirmation of COVID-19 [11].

Considering the fact that patients were hospitalized on the 8^th day on average from the moment of the first symptoms of the disease and were in the hospital for about 17 days, it can be assumed that the change in TSH levels detected during hospitalization in 13 patients (16.9%) is associated with the presence or development of Hashimoto's thyroiditis. However, a longer follow-up period is required to more accurately determine the function of the thyroid gland in patients who have undergone COVID-19. Also, the detected changes in TSH levels both above and below the reference range without peripheral hormone data and antibody levels do not allow talking about the primary or secondary nature of the lesion, and also to attribute these changes with confidence to the influence of COVID-19. The lack of information about the values of TSH and the state of the thyroid gland prior to hospitalization, the level of thyroid hormones, markers of autoimmune thyroid damage, as well as the results of ultrasound of the thyroid gland, are the limitation of this analysis and require a further study of the problem and long-term examination of patients in the post-COVID period.

It is important to note that the literature describes the possibility of the effect of drugs used to treat COVID-19 on thyroid function, in particular glucocorticosteroid drugs. These data are to some extent confirmed by the results obtained, which showed a lower value of the average TSH level on the 9^th–10^th day of hospitalization with dexamethasone compared with the value of TSH against the background of the use of other glucocorticosteroids. It is important to take into account that the use of glucocorticosteroid medicines, as well as medicines of other groups, for example, low molecular weight heparins, can lead to changes in the level of TSH and thyroid hormones¹.

Conclusion

In patients with moderate and severe COVID-19 in the acute period of the disease, the TSH level can be both lower and higher than the reference. However, these changes cannot be unambiguously attributed to the influence of SARS-CoV-2 on the thyroid tissue or the hypolamo-pituitary system. In order to understand the etiopathogenesis of thyroid dysfunction, it is necessary to take into account the relevant anamnesis, conduct clarifying studies, and monitor thyroid function in the post-COVID period. For the correct interpretation of laboratory parameters, it is also important to remember the possibility of the influence of medicines used to treat COVID-19 on the hypothalamic-pituitary-thyroid axis. Additionally, the probability of delayed thyroid pathology development at the outpatient stage of treatment and rehabilitation should be taken into account.

Thus, the relevance of the problem of thyroid lesions associated with COVID-19 is beyond doubt and requires further research in this area.