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 the existing thyroid dysfunction are more at risk of developing more severe COVID-19 disease [7]. In our study, the pre-existing thyroid disease was not associated with increased risk of COVID-19 related worse outcomes in hospitalised patients, including death, which is in agreement with the published literature so far [8, 9]. In a retrospective study conducted by van Gerwen M et al., hypothyroidism was not associated with an increased risk of hospitalisation, mechanical ventilation nor death [10]. Similar to previous findings, in our patient’s cohort, 88.8% had no history of pre-existing thyroid disorder, and of those with previous thyroid disorder 10.5% had hypothyroidism and 0.7% reported hyperthyroidism.
In our study, lower/suppressed TSH level during hospitalisation for COVID-19 was associated with worse short-term outcomes, including admission to the ICU, mechanical ventilation and death. In addition, patients with lower TSH were more frequently treated with corticosteroids. Non-thyroidal illness (NTI) is a well-known phenomenon reported in critically ill patients and in many diseases. It is characterised by decreased free triiodothyronine (FT3) levels and low or normal TSH and high, normal or low FT4 levels [11, 12]. One of the shortcomings of this study was that FT3 and FT4 were not assessed at admission, owing to the retrospective nature of the study. 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. NTI is considered the most frequent thyroid-related problem in the COVID-19 care, particularly in hospitalised patients and in intensive care units [7]. In a retrospective study by Chen M et al. 56% of patients, hospitalised for COVID-19 infection, had significantly lower-than-normal values of TSH 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 the thyroid function [13]. In our patients we did not see the differences in laboratory parameters associated with severity of viral disease (such as CRP, IL-6, procalcitonin, D-dimer) and TSH level. Moreover, we did not see any difference between the duration of hospital stay according to patients’ TSH level. Khoo et al. aimed to detail the acute effects of COVID-19 on the thyroid function. In 50 patients included in the study, 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 [14]. We observed that patients who had lower TSH during hospitalisation, were the patients in whom TSH rose more significantly in the post-COVID period.
On the other hand, post-mortem studies suggest morphological and pathological changes of endocrine glands, including the thyroid, in people affected by the coronavirus family not previously diagnosed with the thyroid disease [15, 16]. 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 [9]. In our patient cohort we only had FT4 levels determined for 72 patients, and in 56.9% of cases it was normal, while 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 or 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 [17–20]. 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 medical literature lacks data about the potential thyroid influence on non-specific symptoms often described during the post-COVID period which negatively influence patients' quality of life and recovery. Due to the retrospective nature of the study, we could not investigate non-specific symptoms that patients had reported. Therefore, we aimed to investigate if there is an association between objective changes in lung parenchyma (seen on chest MSCT after hospitalisation) 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 the recovery after lung injury [21]. 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 [21, 23]. In our study, those patients that had lower TSH during hospitalisation, also had worse long-term outcomes and more pulmonary parenchyma affected by COVID. As already mentioned, those were the patients with a more significant increase of TSH in the post-COVID period. It would be interesting to see if those are the patients that had low FT3, and more research is needed to answer this question. Currently, a phase 2 clinical trial (NCT 04115514) is being conducted, investigating liothyronine as a treatment for ARDS in humans, including that associated with COVID-19 [24].
One of the main shortcomings of this study, owing to the retrospective analysis, was that FT3 and FT4 were not assessed at admission. In addition, the serum TSH was tested while patients were receiving glucocorticoids. Furthermore, the patients included in this study were hospitalised patients with moderate to severe disease. Thus, we lack data from patients with milder disease. 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 pulmonary involvement. The results of our research may indicate that lower TSH might be a predictor of worse outcomes.
In conclusion, although sick euthyroidism is the most frequent thyroid-related problem encountered in COVID-19 patients, especially those with more severe disease, other thyroid disorders have also been reported. Physicians should be aware of possible connections between SARS CoV-2 and the thyroid. Further prospective studies including FT3 and FT4 are needed to investigate the impact of COVID-19 on hypothalamic-pituitary-thyroid axis and vice versa, as well as the impact of thyroid changes on outcomes of patients with COVID-19.