Medicina | Free Full-Text | Thyroid Stimulating Hormone as a Possible Additional COVID-19 Outcome Marker

Medicina | Free Full-Text | Thyroid Stimulating Hormone as a Possible Additional COVID-19 Outcome Marker

1. Introduction

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), continues to pose a threat to global health. According to the World Health Organization, until December 2023, there were 772,838,745 confirmed cases of COVID-19 worldwide with 6,988,679 confirmed deaths [1].
The pathogenesis of COVID-19 involves SARS-CoV-2 entering the respiratory system. When the angiotensin-converting enzyme 2 (ACE2) on the surface of pneumocytes binds to the spike protein of the virus, it facilitates the entry of the virus into cells [2,3]. Numerous organs, including endocrine glands, express ACE2, potentially leading to the extrapulmonary and multiorgan spread of SARS-CoV-2 [4,5].
In March 2020, the European Society of Endocrinology issued a statement to raise awareness within the entire endocrine community regarding the role and responsibilities of endocrinologists worldwide during the ongoing COVID-19 outbreak. Individuals with diabetes were identified among those at high risk for serious illness, along with people with obesity, malnutrition, and adrenal insufficiency [6]. An update in April 2021 described an emerging endocrine phenotype of COVID-19, emphasizing the significance of thyroid aspects in the context of COVID-19 [7].

It is crucial to gain a deeper understanding of the pathophysiology of the disease and promptly identify the phenotypes of vulnerable patients who are at the highest risk of immediate and prolonged unfavorable outcomes.

Our study aims to investigate the predictive value of serum Thyroid Stimulating Hormone (TSH) in patients with no known thyroid disorder concerning short-term and middle-term COVID-19 outcomes.

4. Discussion

The interaction between SARS-CoV-2 and thyroid function is bidirectional and complex, and it is not yet fully understood. There is no clear evidence that patients with existing thyroid dysfunction are at risk of developing more severe COVID-19 disease [10,11,12,13]. Data related to thyroid disturbances during COVID-19 in individuals without pre-existing thyroid disorders are even more inconclusive. Therefore, this study contributes to the understanding of TSH as a potential prognostic marker for COVID-19 patients.
In our study, lower/suppressed TSH level during hospitalization for COVID-19 was associated with worse short-term outcomes, including admission to the ICU, and the need for higher oxygen supplementation via HFOT, or mechanical ventilation. Moreover, patients with lower/suppressed TSH more often died. On the other hand, higher TSH values correlated with better blood oxygen saturation and tended to be more frequent findings among COVID-19 survivors. Non-thyroidal illness (NTI) is a well-known phenomenon reported in critically ill patients in several diseases. It is characterized by decreased free triiodothyronine (fT3) levels and low or normal TSH and high, normal, or low fT4 levels [14,15]. One of the shortcomings of this study was that fT3 and fT4 were not assessed routinely during hospitalization, owing to the retrospective nature of the study, so we can not differentiate patients with NTI and hyperthyroidism. Furthermore, TSH was tested while most patients were treated with glucocorticoids, an additional factor affecting the pituitary–thyroid axis. Therefore, it is difficult to exclude the effect of corticosteroids and systemic inflammation on the pituitary–thyroid axis, leading to a possible misdiagnosis of thyroid dysfunction in severe cases of COVID-19. Nevertheless, our results suggest significantly lower TSH levels in female patients on corticosteroid therapy, but it did not affect their survival. NTI is considered the most frequent thyroid-related problem in COVID-19 care, particularly in hospitalized patients and in intensive care units [10]. In a retrospective study by Chen M et al., patients hospitalized for COVID-19 infection had significantly lower values of TSH than normal compared with healthy controls and non-COVID-19 pneumonia patients with a similar degree of severity. After recovery, the levels of all thyroid hormones returned to the normal value, with no significant differences in thyroid function [16]. In our patients, we did not see a strong association between the laboratory parameters associated with the severity of viral disease (such as IL-6 and D-dimer) with TSH. However, CRP and procalcitonin did show a weak correlation with TSH, which might be cautiously interpreted as the relation of TSH and disease severity. Khoo et al. aimed to detail the acute effects of COVID-19 on thyroid function. In their study of 50 patients, significant differences in TSH were found comparing baseline vs. admission and admission vs. follow-up values. On the contrary, there was no significant difference between baseline vs. follow-up values [17]. In our patient cohort, we observed the rise in TSH levels in 75% of cases during the post-COVID-19 follow-up. Whether this can be a possible explanation for the non-specific complaints some patients have during the post-COVID-19 follow-up is debatable. Low TSH during hospitalization was, besides being a predictor of worse short-term outcomes, also a significant predictor for persistent lung involvement measured by chest MSCT 6 to 8 weeks during post-COVID, whereas we found no correlations between post-COVID-19 TSH and post-COVID-19 lung involvement.
On the other hand, post-mortem studies suggest morphological and pathological changes in endocrine glands, including the thyroid, in people affected by the coronavirus family not previously diagnosed with thyroid disease [18,19]. In the study of Muller et al. patients treated in high-intensity care units (HICU) due to COVID-19 showed lower TSH levels than SARS-CoV-2-negative patients admitted to the same HICU. Furthermore, serum fT4 levels showed no difference between the groups, while the fT3 levels were low in both groups [12]. In our patient cohort, we only had fT4 levels determined for 72 patients, as a secondary level analysis in case of abnormal TSH findings, and in 56.9% of cases it was normal, while slightly elevated fT4 was detected in 41.7% of patients ). Unfortunately, fT3 was not determined. Therefore, due to the small sample size and the absence of fT3, we cannot interpret the findings and differentiate between NTI syndrome and hyperthyroidism due to other causes.
The cases of subacute thyroiditis with a possibility of clinically manifest hyperthyroidism, as well as the cases of autoimmune thyroiditis or Graves’ disease triggered by the “cytokine storm” induced by SARS-CoV-2 infection, have been described so far [20,21,22,23]. As mentioned earlier, we did not detect the correlation between cytokine levels (specifically IL-6) and TSH levels.
There is limited knowledge of thyroid function in patients who have recovered from COVID-19 and the medical literature lacks data about the potential thyroid influence on non-specific symptoms often described during the post-COVID-19 period, which negatively influences patients’ quality of life and recovery. Due to the retrospective nature of the study, we can not investigate non-specific symptoms that patients reported. Therefore, we aimed to investigate whether there is an association between objective changes in lung parenchyma (seen on chest MSCT after hospitalization) and serum TSH. It is known that the T3 receptor is present in the lung in the alveolar type II cells that are believed to be involved in recovery after lung injury [24]. Furthermore, studies in rats showed that hypothyroid rats are less able to clear fluid from their lungs, and fluid clearance can be ameliorated by liothyronine administration [25,26]. In our study, those patients who had lower TSH during hospitalization also had worse middle-term outcomes and more pulmonary parenchyma affected by COVID-19. It might be interesting to see whether those are the patients that had low fT3. In the study conducted by Ahn J. and colleagues on 119 Korean patients hospitalized due to COVID-19 infection, TSH and T3 levels were significantly lower in patients who died from COVID-19, as well as in those with severe and critical forms of the disease, compared to those with milder forms. Additionally, patients in the lowest tertile of TSH were more frequently mechanically ventilated than those in the middle or highest tertile of TSH levels. While the degree of reduction in TSH and T3 levels demonstrated a significant correlation with the severity of COVID-19, low T3 levels were identified as having prognostic significance [27]. Pappa and colleagues, in their study on 128 Greek patients, also demonstrated an association between low serum TSH levels and adverse outcomes in hospitalized COVID-19 patients. The authors therefore suggested integrating TSH levels into multivariable machine learning classification algorithms, as it shows promise for outcome prediction with high accuracy [28]. The study by Guven suggested fT3 as a potential predictor of the severity of COVID-19 [29]. The same conclusion was also reached by Dabas and colleagues who found a connection between low fT3 and elevated IL-6 (p = 0.021) and death risk (p = 0.031) in COVID-19 patients but no association on the other hand between TSH and COVID-19 outcomes [30]. Similar findings were reported by Dincer Yazan C. and collaborators in their work on 205 patients with COVID-19 in Turkey, demonstrating that patients with lower TSH and fT3 levels were more often admitted to the ICU and had a higher mortality rate from COVID-19 compared to euthyroid patients [31]. Currently, a phase 2 clinical trial (NCT 04115514) is being conducted that is investigating liothyronine as a treatment for ARDS in humans, including that associated with COVID-19 [32].

One of the main shortcomings of this study, owing to the retrospective analysis, was that fT3 and fT4 were not assessed during the hospitalization. In addition, the serum TSH was tested while patients were receiving glucocorticoids. Furthermore, the patients included in this study were hospitalized patients with moderate–severe disease. Thus, we lack data from patients with milder disease forms. In addition, chest MSCT was not available both during hospitalization and in the post-COVID-19 follow-up for all patients. Nevertheless, to our knowledge, this is the first study investigating the serum TSH and the COVID-19-associated outcomes of patients in a population drawn from the first and largest COVID-19 hospital in Croatia, with a follow-up to assess post-COVID-19 pulmonary involvement. The results of our research may indicate that lower TSH might be a predictor of worse immediate and middle-term outcomes.

Other considerations and limitations requiring clinicians’ attention are related to high sensitivity and low specificity associated with the cut-off value of TSH 0.5 mIU/L. The set specific threshold exhibits a predisposition toward yielding positives and false positives, emphasizing the importance of identifying patients at risk and the potential need for mechanical ventilation. Lower specificity implies a compromised ability of the test to accurately discern patients devoid of risk. However, in our opinion, designating a patient as at risk and providing additional observation is probably less harmful as opposed to the converse scenario. It is imperative to emphasize that TSH provides only supplementary laboratory aid, which should be utilized with caution and only in an adjunct to established standard procedures employed for evaluating the severity of the condition. As there is no current gold-standard test identifying COVID-19 patients at risk for worse outcomes at an early stage of the disease, any additional cheap and easily available tool, such as TSH, might be useful.

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