Thyroid Function During and After COVID-19 Infection: A Review

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to multiorgan dysfunction through pulmonary and systemic inflammation. Infection also affects the thyroid gland directly via cytopathological effects of the virus or indirectly through cytokines, complement systems and coagulation mechanisms. The thyroid gland regulates innate and adaptive immune systems by genomic and nongenomic pathways. During or after SARS-CoV-2 infection, Graves' disease and subacute thyroiditis might be triggered resulting in hyperthyroidism; alternatively, the effect of the virus on the hypophyseal.hypothalamic axis might cause central hypothyroidism. Severe cases of coronavirus disease 2019 (COVID-19) can present with hypoxia, which requires the use of dexamethasone. This can depress basal serum concentrations of 3,5,3'-triiodothyronine. Thyroid function should be monitored when using dexamethasone in patients with COVID-19. This article briefly reviews the direct and indirect effects of SARS-CoV-2 on the thyroid gland and function.

Thailand, on 13 January 2020. 1 From the start of the pandemic to 11  The pathogenesis of COVID-19 may affect multiple human organ systems in several ways.
In particular, severe COVID-19 is characterized by organ dysfunction, hypercytokinemia and lymphopenia. The direct cytopathological damage of host cells and the dysregulated immune response caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is assumed to be the primary underlying mechanisms of COVID-19. 3 SARS-CoV-2 enters the lungs and into the lung parenchyma through the respiratory system.
Eventually, spike proteins of the virus attach to angiotensin-converting enzyme 2 (ACE2), which is expressed at the surface of pneumocytes. 4,5 ACE2 binds to the spike proteins of SARS-CoV-2 and acts as a receptor, mediating the entry of the virus to the host cells. This virus mechanism is also used to gain entry to other cell types of the human body. Many endocrine system organs have ACE2-expressing cells, such as the pancreas, testis, ovary, adrenal gland, pituitary gland and thyroid gland. 6,7 The testis has the highest level of ACE2 expression, followed by the thyroid, whereas the hypothalamus has the lowest level. 6 The pituitary-thyroid axis should be regarded as a vulnerable target of SARS-CoV-2, and pituitary damage, whether direct or indirect, has been recognized as a determining factor of secondary hypothyroidism (functional or organic). 8 As 3,5,3′-triiodothyronine (T3) and thyroxine (T4) are positively correlated with serum ACE levels, the ACE level could be used as a marker to investigate the action of peripheral thyroid hormones. 9 A study by Rotondi et al. also proposed the thyroid as a potential target for SARS-CoV-2, as thyroid follicular cells encode the messenger RNA for ACE2 receptors. 10 After entering the body, SARS-CoV-2 may cause numerous clinical symptoms, SARS and multisystem organ failure by causing both direct and indirect injury to the body. The direct effect is due to the cytotoxic effect of the virus on the target cell, and the indirect effect is caused by the aberrant immune inflammatory responses, which include cytokine, complement systems and coagulation. 6,7,9,11 Innate and adaptive immune responses are regulated by thyroid hormones via genomic and nongenomic pathways. 12 Cytokine production and release are triggered by T4 and T3; this results in a "cytokine storm", which usually accompanies systemic viral infections. 13,14 Furthermore, thyroid hormones can enhance the antiviral activity of interferon-γ, thus explaining why some immune system pathways, such as cytokine and T helper 1 cell hyperactivation, occur in response to virus infections in thyroid disorders. 12 It is also worth noting that T4 is capable of touchREVIEWS in Endocrinology activating human platelets, which lead to pathological clotting, which is a complication of virus infection. 15 This article reviews up-to-date clinical   information about the interactions between the thyroid gland and   COVID-19, including thyroid pathology, thyroid function, drug interactions, cytotoxic effect and thyroid diseases.
Two reviewers independently undertook a two-step selection, with studies screened via titles and abstracts followed by a full-text review.
Data were extracted from the articles' text, tables and figures. Data were collected, analysed and discussed to answer the following clinical questions: • Can COVID-19 have a negative impact on thyroid function?
• Is the COVID-19 prognosis worse with concomitant or previous thyroid disease?
• Could the clinical course of COVID-19 be altered by the treatment of thyroid diseases?
This review discusses the relationship between COVID-19 and thyroid gland/thyroid-related diseases, including the direct cytological effects of the virus, the autoimmune-related effects, the hypothyroidism-related effects, the relationship to non-thyroidal illness syndrome (NTIS) and drug-related connections.

Direct cytological effects
Patients infected with SARS-CoV-2 may present with various symptoms that may be related to an ongoing thyroid pathology or present variations in markers related to thyroid function.
According to a subgroup analysis of patients with COVID-19 conducted by Chen et al., levels of thyroid-stimulating hormone (TSH) and total T3 (TT3) depression positively correlated with the prognosis of the disease. 16 This means that TSH and TT3 levels decline as the infection proceeds.
Similar outcomes have been reported in two further studies. 17 20 We know that cytokine storms characterized by the uncontrolled and excessive release of inflammatory mediators and resulting in overwhelming systemic inflammation and even multiple organ dysfunction are very common in patients with COVID-19, especially in severe cases. 21 Zou et al. reported that more than 25% of patients with COVID-19 were diagnosed with ESS. 22 ESS is an independent risk factor for disease severity in patients with COVID-19. Patients with COVID-19 with ESS had stronger inflammatory responses and showed higher levels of C-reactive protein and erythrocyte sedimentation rate and a positive rate of procalcitonin. 22 Therefore, direct virus effect and inflammation in COVID-19 seem to be responsible for ESS.
The other hypothesis explains the decreased serum TSH levels in patients infected by SARS-CoV-2 through a distorted hypothalamicpituitary-thyroid axis. 23 A critical function of serum TSH is the inverse proportional association with interleukin-6 (IL-6) levels, which identifies inflammatory response to SARS-CoV-2. 23  It is known that Graves' disease is the most frequent hyperthyroidism aetiology. 28

Coagulopathy
Coagulation is a complex response of the body to damaged endothelial cells and involves many inflammatory cytokines and chemokines, such as tumour necrosis factor-α, IL-1, IL-6 and IL-8. 55

Baricitinib
Baricitinib is a proinflammatory pathway inhibitor acting as a selective and reversible Janus kinase 1 (JAK1) and 2 (JAK2) inhibitor. Baricitinib is usually used for treating rheumatoid arthritis to prevent inflammatory damage to the joints. 61 Baricitinib was approved in February 2017 by the EU as a therapeutic option for rheumatoid arthritis. 61 The effects of baricitinib on JAK1 and JAK2 enzymes were also observed in patients with COVID-19 suffering from moderate-to-severe inflammatory responses. 56 Baricitinib has been approved for use by the FDA EUA. NIH treatment guidelines recommend that the use and dosage of baricitinib in patients with COVID-19 be determined based on the estimated glomerular filtration rate. 56 The use of baricitinib might cause adverse events in patients with rheumatoid arthritis or COVID-19. However, there are no reliable touchREVIEWS in Endocrinology data on any interactions between baricitinib and thyroid drugs used for both hypothyroiditic and hyperthyroiditic states. Furthermore, the use of baricitinib has no notable effect on patients suffering from thyroid-related complications besides its adverse effects shown by prior research. 62,63 Baricitinib, administered for atopic dermatitis, did not induce adverse thyroid events; 62,63 however, it remains unclear whether the possible onset of thyroid autoimmunity could be attributable to an underlying autoimmune condition rather than the consequence of an adverse event. 63 Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patients with COVID-19, notably those receiving high-flow oxygen or noninvasive ventilation. 62 The combination was associated with fewer serious adverse events. 62

Tocilizumab
Tocilizumab is another drug used for rheumatological disorders, such as giant cell arteritis, rheumatoid arthritis and systemic juvenile idiopathic arthritis. Tocilizumab acts as an antibody IL-6 receptor inhibitor, resulting in a reduction in undesired inflammatory and autoimmune activities in IL-6, which may negatively impact on patients suffering from SARSCoV-2. 64 The progression of COVID-19 involves inflammatory processes related to the IL-6 mechanism. 64 As an IL-6 receptor inhibitor, tocilizumab appeared to be a beneficial drug to use in some COVID-19 cases and was suggested by the NIH COVID-19 Treatment Guidelines Panel. 51 In the same guideline, another IL-6 inhibitor, sarilumab, is also suggested if tocilizumab is not available. 56 Autoimmune inflammatory responses triggering IL-6 mechanisms might be prevented by tocilizumab; however, the interaction of the drug with the human autoimmune system may result in some adverse effects.