Subacute thyroiditis (SAT) is part of the large, heterogeneous endocrine picture described in relation to the COVID-19 infection. From an endocrinological point of view, a high risk of severe COVID-19 infection is related to the presence of diabetes mellitus, high blood pressure, obesity, Cushing’s syndrome, sleep apnea (associated with acromegaly or obesity), coagulation anomalies, glucocorticoid therapy for various conditions, etc. [80,81]. Hypocortisolemia may develop on immune grounds (in addition or not to primary/secondary hypothyroidism) due to direct or immune-mediated pituitary and adrenal lesions [82]. Recently, the potential involvement of adrenal dysfunction (following or not following prior infection-related glucocorticoid exposure) was connected with long COVID-19 syndrome [83,84]. Also, transitory impairment of spermatogenesis in males, relative and direct hypoparathyroidism, and the worsening of metabolic bone disease have also been reported in subjects experiencing SARS-CoV-2 infection [85,86,87].

Suspecting or confirming SAT in patients infected with coronavirus represents a small piece of an otherwise very complex puzzle of the thyroid’s involvement under these specific circumstances [88]. Generally, the patient with prior thyroid disease is not considered to be at a high risk of contracting COVID-19 infection, nor of developing SAT secondary to coronavirus infection or after vaccination against the virus. Recently, it was found that uncontrolled hypothyroidism rather than hyperthyroidism is more prone to developing a severe form of COVID-19 infection, especially when associated with older age (although not all authors agree), thus thyroid–COVID-19 interplay might be more complex [89,90].

It is already known that any kind of infection, including coronavirus infection, may trigger hyperthyroidism that can manifest in various ways, including severe forms like thyroid storm, and needs to be differentiated from SAT-related transitory hyperthyroidism [91,92]. The direct thyroid injury caused by the virus leads to destructive thyroiditis that is usually associated with severe circumstances such as increased cytokine pathway activation [93]. We did not include in this overview any cases with this particular type of thyroiditis. Low-T3 syndrome has been found in severely ill patients and represents a predictor for poor outcomes in individuals infected with the SARS-CoV-2 virus; SAT should be differentiated from euthyroid sick syndrome (a differential diagnosis which is easier to perform in the following weeks after coronavirus infection rather than during infection) [94,95]. On the other hand, some cases of COVID-19-related thyroiditis have been retrospectively diagnosed based on current low thyroid hormone status in patients without a prior thyroid history. It is therefore important to consider it not only as a new SAT entity but also as a new approach to the differential diagnosis of hypothyroidism amid the COVID-19 pandemic.

Some authors have suggested that the COVID-19 infection might trigger the autoimmune mechanisms underlying Hashimoto’s thyroiditis (which is traditionally connected to a large area of other endocrine and non-endocrine autoimmune diseases) [96,97,98]. Also, aggravating selenium deficiency through the infection may act as a precipitating element [99]. Currently, there is not enough statistical evidence to support this specific hypothesis despite the theoretical rationale [100,101]. Other autoimmune complications in COVID-19-positive patients also include thrombocytopenia, hemolytic anemia, Guillan-Barre syndrome, etc. [102,103,104].

The rate of hypothyroidism in coronavirus-positive patients varies from study to study by up to one-fifth, and the underlying mechanisms are mostly represented by low-T3 syndrome as well as hypophysitis-related hypothyroidism, destructive thyroiditis, primary autoimmune hypothyroidism, residual thyroid insufficiency after an episode of SAT, etc. [105]. The thyroid hormone profile in severe cases might be regarded as a surrogate prognosis tool in patients without prior thyroid conditions, according to some authors despite not being generally recognized [106,107,108]. We should also take note of patients on anti-thyroid drugs or treated with high doses of radioiodine therapy for differentiated thyroid cancer, who may find themselves in a situation with an increased risk for neutropenia and agranulocytosis, thus aggravating any type of infection; also, SAT-associated temporary excess of thyroid hormones should be differentiated from primary hyperthyroidism in order to avoid unnecessary exposure to anti-thyroid drugs [109,110]. More aggressive forms of thyroid cancer during the COVID-19 pandemic era have been suggested to be caused by the delays in evaluation and surgical treatment due to lockdown restrictions and pandemic regulations that have bottlenecked access to medical services [111,112]. The rate of thyroidectomy access for benign goiter was found by some authors to be reduced during periods where restrictions were in place [113,114]. Similarly, the extensive use of telemedicine amid the pandemic might delay the presentation of SAT. Patients with previous thyroid nodules do not appear to be at greater risk during COVID-19 infection, nor at greater risk of developing a subacute complication of the thyroid, according to what has been described so far in the literature, [115,116].

A highly debated topic in the scientific community relates to the potential events involving COVID-19 immunization, including endocrine elements. It has been suggested that vaccination might aggravate eye disease or primary hyperthyroidism in patients with a history of Basedow–Graves disease. However, the level of statistical evidence remains poor up to this moment, and currently, the most probable pathogenic link is post-vaccine increased immunogenicity (including autoimmunity exacerbation and molecular mimicry), probably in susceptible individuals, although this has yet to be determined [117,118,119]. Primary hyper functioning of the thyroid needs a clear differentiation from the transitory hyperthyroidism underlying a subacute inflammation of the gland in order to avoid anti-thyroid medication. Hypophysitis with the clinical and hormonal expression of hypopituitarism was also reported (the level of statistical evidence, however, is of case reports) [120]. Immune- and/or inflammatory-mediated endocrine elements that have developed after COVID-19 vaccination may be regarded as a part of ASIA syndrome (it has been discussed whether Graves disease is a part of the syndrome), and the risk of exacerbating the autoimmune response by the infection itself has previously been described [121,122].

Generally, we consider that vaccination against COVID-19 is not associated with particular risks in patients with prior diagnoses of different endocrine conditions. Some diseases like diabetes mellitus and adrenal insufficiency have a particular indication for vaccine prioritization due to the higher risk of infections and more severe SARS-CoV-2 evolution [123,124]. Whether SAT might follow vaccination is still an open issue; the level of current statistical evidence is low but, as many other conditions amid the pandemic, the importance of awareness comes first at this point.

Whether symptoms of SAT after a certain vaccine dose should delay the following vaccine administration is debatable and, for the moment, we not do have any particular concerns regarding protocols for immunization (but, of course, the vaccination started in 2021, so this is a limited period of time to be able to draw clear conclusions). There is only one longitudinal study, published in 2022, which included 15 cases with vaccine-associated thyroiditis of the subacute type, occurring a median of 11.5 days after immunization and a median remission time of 11.5 weeks; seven out of nine individuals were re-vaccinated and did not experience a relapse of subacute thyroiditis, while two out of nine individuals suffered an aggravation of SAT due to the second dose of the vaccine inoculation [72]. According to what we currently know, revaccination should not be restricted in patients who experienced SAT following any dose during immunization.

Overall, we recognize that the number of reported cases considering this new entity is low when compared with the millions of people that have had the coronavirus infection and received the vaccine, but many other unexpected novel clinical entities have been reported amid the pandemic at first with a low level of statistical evidence since the COVID-19 pandemic is an extraordinary, never-before-seen medical experience. This is why the lack of adequate recognition and diagnosis represents one more reason to spread the information and increase awareness in order to reduce disease-related burden if adequately recognized (including unnecessary investigations or medications) and to apply optimum health care for improved quality of life in affected patients. To our knowledge, this is the largest number of patients with either COVID-19-related or vaccine-associated SAT to date

 

 

 

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