Insights into SARS-CoV-2-associated subacute thyroiditis: from infection to vaccine

The exact pathophysiology of COVID-19-associated SAT has not been completely deciphered (Fig. 1). However, as mentioned above, direct molecular analysis of surgical samples of thyroid tissues has demonstrated the expression of ACE2 and TMPRSS2 on the thyroid follicular cells making the thyroid gland susceptible to the development of injury during COVID-19 infection either via direct viral toxicity or via an indirect way due to immune-mediated injury or activation of the hypothalamo-pituitary axis by inflammatory cascades [7]. Moreover, another hypothesis regarding the internalization of SARS-CoV-2 into host cells focuses on the role of integrin ανβ3, which recognizes and binds Arg-Gly-Asp (RGD) and Lys-Gly-Asp (KGD), molecular motifs, which are localized in the ACE2 and the spike protein of SARS-CoV-2. Thus, it is hypothesized that integrin ανβ3 may serve as an alternative entrance gate for COVID-19 into host cells [8]. Matters appear to be further complicated by the fact that increased thyroxine concentrations—commonly seen in SAT—induce enhanced expression of integrins, potentially facilitating the entry of the virus into the host cells [1]. Moreover, as it is known, the initial stage of the disease—with its flu-like manifestations and possible transition to pneumonia—is followed by the second stage, characterized by pulmonary and systemic inflammation. Indeed, this phase of the disease commonly coexists with innate immune activation and excessive release of pro-inflammatory cytokines, for example, tumor necrosis factor α, interleukin (IL) 1β, IL-6, and adaptive T-cell-mediated immune responses [7].

Finally, it should be mentioned that genetic predisposition—especially regarding various haplotypes of human leukocyte antigen (HLA)—seems to play a pivotal role in the pathogenesis of SAT [9] via stimulation of aberrant human leukocyte antigen DR isotype expression and the activation of toll-like receptors [10]. The first correlation of SAT with HLA and specifically with HLA-B35 was carried out by Nyulassy almost 50 years ago [11], a native that was verified in a multitude of publications in the years that followed [9]. In the meantime, it is well documented that 70% of patients with SAT are carriers of HLA-B35, while for the remaining 30%, the genetic background is not determined [12]. This observation raises the question if patients who are negative for HLA-B35 have another unknown genetic predisposition. Indeed, further studies have shown that other HLA haplotypes, for example, HLA-B67, HLA-B15/62, HLA-Bw35, and HLA-Drw8, could be additionally implicated in the pathogenesis of SAT [13]. Lastly, a recent, large healthy Polish cohort of Stasiak et al. (2020) highlighted that HLA-B*18:01 and HLA-DRB1*01 represent independent SAT risk alleles and that carriers of HLA-B*35 and HLA-C*04:01 are genetically susceptible to its development [9].

In the vast majority of cases, SAT is a self-limited inflammatory disease that—although not exclusively—is caused by viral infections [14]. It is presumed to occur either simultaneously with SARS-CoV-2 infection due to direct viral toxicity or to represent a post-viral complication of COVID-19 infection, frequently within 6–8 weeks [6]. Similar to SAT caused by other viruses, COVID-19-associated SAT shows a predilection for middle age female patients [15]. Patients with SARS-CoV-2-induced SAT present classical signs and symptoms caused by thyroid inflammation, including neck tenderness and pain, and symptoms associated with the underlying hyperthyroidism (e.g., fever, palpitations, anxiety, agitation, tremor, heat intolerance, insomnia, weight loss, and excessive perspiration) [15]. However, compared to SAT induced by other infections, some studies have highlighted a stronger intensity of neck pain, a higher incidence of fever, and a higher probability of hypothyroidism at three months of the disease onset [6]. Until March 2022—and two years after the first described case of COVID-19-associated SAT [2, 6]—only 81 cases of SAT related to SARS-CoV-2 infection had been published. This observation raises the suspicion that the described low incidence rate may have been underestimated when the high expression of ACE2 and TMPRSS2 in the thyroid gland is taken into account. Indeed, as mentioned above, neck tenderness and pain constitute the main findings and diagnostic criteria of painful SAT [15]. However, in patients with COVID-19 infection, there is a significant possibility that these signs and symptoms may be either masked by the respiratory symptoms of the disease or modified by therapeutic interventions (e.g., by dexamethasone- and heparin application), leading to atypical forms of SAT and, as such, easily escaping physicians’ attention. Indeed, despite the initial skepticism about corticosteroid administration, almost half of the patients with COVID-19 have been treated with some type of corticosteroid [16]. Moreover, SAT and COVID-19 often present common symptoms (e.g., fever, asthenia, and neck pain), which can lead to misinterpretation of the contemporary presence of thyroiditis [16].

A further diagnostic pitfall in the context of corticosteroid administration is the fact that even low doses of corticosteroid administration can affect TSH levels in humans due to their direct inhibitory effect on pituitary thyrotrope cells and inhibition of the hypothalamic release of TRH. Furthermore, acute glucocorticoid administration results in a decrease in circulating T3 to T4, indicating that these agents hinder the conversion of T4 to T3 [16]. Additionally, in critically ill patients with COVID-19 admitted to high-intensity care units, low levels of TSH and free T3 have been demonstrated in the study of Muller et al. [17]. Moreover, regarding the clinical findings for this specific patients population, the authors described an atypical subtle form of SAT characterized by lymphopenia and not leucocytosis, formulating the hypothesis that the presence of lymphopenia inhibits the pathognomic infiltration of giant cells and, consequently, the appearance of classic symptoms of the disease.

Despite the fact that SAT is mainly a clinical diagnosis, laboratory and ultrasound findings can support its diagnosis further, particularly in atypical manifestations of the disease. Typically, laboratory findings include thyroid function disturbances and elevated inflammatory markers, whereas thyroid ultrasound frequently reveals a voluminous and inhomogenous thyroid gland [6].

Although, to date, no causal treatment for SAT exists, corticosteroids appear to be effective in controlling symptoms even within the first 24 h. In order to avoid the detrimental effects of long-term steroid use, some authors recommend the combined use of steroids/celecoxib. In the case of patients with mild to moderate disease severity, starting with a low dose of prednisolone is encouraged, whereas, for more severe cases, it seems that higher doses cannot be avoided [18].

As previously mentioned, the pathogenesis of vaccine-induced-SAT is mediated by various pathophysiological mechanisms, for example, molecular mimicry, polyclonal and bystanding activation, epitope spreading, and presentation of cryptic antigen determinants [19]. However, the main pathogenetic mechanisms include molecular mimicry between thyroid components (e.g., thyroid peroxidase peptide sequences) and vaccine antigens—particularly the spike protein—and immune system hyperstimulation [6].

The vast majority of vaccines against COVID-19 encode the S protein of the virus, leading to the production of antibodies, which could potentially play a role in initiating autoimmunity via molecular mimicry mechanisms [35]. Moreover, accumulating data indicate that if the vaccine contains antigenic epitopes, which are structurally similar to autoantigens, then the immune reaction to the vaccination antigen can extend to host cells’ antigens, especially in genetically susceptible individuals [73, 74]. Concerning thyroid tissue antigens, recent research highlights that thyroid peroxidase sequences share structural similarities with SARS-CoV-2-related proteins [35], potently contributing to a cross-reactive immune reaction between the spike protein of the virus and the thyroid antigens [73, 74].

The second major hypothesis regarding the pathophysiology of post-vaccination SAT refers to an autoimmune/autoinflammatory syndrome induced by adjuvants, that is, the ASIA syndrome, according to which the vaccination against SARS-CoV-2 can trigger an autoimmune thyroid response [6]. Indeed, it has been proposed that vaccine adjuvants, used to enhance the immunogenicity of the vaccine, are potential triggers of adverse immune reactions [75]. However, this last hypothesis requires further and in-depth investigation as a number of studies failed to show a causal relationship between vaccine adjuvants and autoimmune pathologic entities [19].

Additionally, it should be mentioned that vaccine-related S protein may directly interact with thyroid cells expressing ACE2 and thus result in thyroid dysfunction [19]. Finally, vaccine-associated enhanced viscosity-status may lead to a pathological release of thyroid hormones from the thyroid, especially in patients with abnormal coagulation status [76].

Post-vaccination SAT literally refers to a painful thyroid inflammation following vaccination [77]. Consistent with previous studies of SAT of other etiologies [78], recent systematic reviews demonstrate a clear gender preference, with middle-aged women being more affected than men, with a gender ratio of about 2.57:1 [79]. The patient’s age at presentation ranges from 26 to 73 years old [79], while the timeline between vaccination and onset of SAT symptoms lies between a few hours to a few weeks (12 h to 60 days) [77].

Similarly to classic forms of SAT, the most frequently reported signs and symptoms of post-vaccination SAT include anterior neck pain, commonly radiating to the jaw and the ear, neck swelling, headaches, nausea, concentration difficulties, fever, asthenia, fatigue, emotional lability, and signs of thyrotoxicosis (e.g., palpitations, hypertension, weight loss, hyper-defecation, anxiety, and sweating) [79]. It should be noted, however, that in some patients, symptoms caused by post-vaccination SAT may have been underestimated and falsely identified as common vaccination side effects leading to an overlook of the diagnosis of SAT induced by the SARS-CoV-2 vaccine.

Regarding the biochemical characteristics of patients with post-vaccination SAT, thyroid function tests are almost universally consistent with thyrotoxicosis (i.e., suppressed TSH and elevated free T4), with some patients additionally revealing enhanced levels of free T3. Antithyroid antibodies are typically negative, while inflammation markers, such as erythrocyte sedimentation rate (ESR) and C-reactive protein, are typically elevated [51, 79].

Ultrasonographic findings of the disease, when available, include a voluminous, hypoechoic thyroid gland with heterogeneous echo-structure and suppressed vascularization, similar to SAT of other etiologies [77].

A differential diagnosis is of decisive importance for the prognosis of the patients and should include alternative causes of thyrotoxicosis and thyroiditis, such as SARS-CoV-2-associated SAT, as well as causes related to other infectious, for example, Epstein-Barr, cytomegalovirus, influenza, measles, rubella, and mumps [80].