Similar to infections, vaccination can potentially induce immunologic reactions resulting in autoimmune diseases. The pathophysiological mechanisms are complex and include molecular mimicry, polyclonal activation, epitope spreading, and presentation of cryptic antigenic components [19]. In this context, the development of subacute thyroiditis after vaccination is well established and has been previously described as a consequence of influenza [20], hepatitis B [21], and human papillomavirus vaccinations [22].
Although no curative treatment against SARS-CoV-2 currently exists, various types of vaccines have been developed [3, 23], whose safety and efficacy have been adequately tested in a significant number of clinical studies [19]. Regardless, however, of the provable safety of the vaccines, several types of post-vaccination side effects have been highlighted. The most frequently observed side effect refers to mild reactions, including pain and swelling at the injection site, fever, headaches, chills, muscle/joint aches, and tiredness [24]. However, rare complications, such as thyroid diseases, including SAT, may also occur [19].
There is mounting evidence from case reports, case series, and retrospective, prospective, and longitudinal studies indicating that SAT is a rare adverse effect that has been observed after vaccination with different types of SARS-CoV-2 vaccines (Table 1, Fig. 2) [25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72]. Even though post-vaccination SAT represents an uncommon complication, given the intensity of vaccinations against COVID-19—until March 2022, a total of almost 11 billion vaccine doses had been globally administered [3]—physicians should be aware of this side effect, which should not influence immunization strategies in any case.
Illustration of the number of studies per country examining post-vaccine SAT
Pathophysiology
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].
Diagnosis and differential diagnosis
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].