Introduction

Since the emergence of COVID-19 at the end of 2019, more than 426 million infections and 5,800,000 deaths have been documented due to this disease, as of 20 February 2022 [1]. While there is currently no confirmed curative treatment for the COVID-19, various types of vaccines have been developed including innovative technology-based vaccines (mRNA-based and virus-vector-based vaccines), which can induce high protection against severe forms of COVID-19. The World Health Organization (WHO) confirmed on November 15, 2021 that some mRNA-based vaccines (Moderna and Pfizer/BioNTech), viral vector-based vaccines (AstraZeneca/Oxford and Johnson and Johnson), and inactivated vaccines (Sinopharm, Sinovac, and Covaxin) are safe and effective [2, 3]. As of 20 February 2022, a total of more than 10.4 billion vaccine doses have been administered, globally [1]. The COVID-19 vaccines can confer protection through induction of the anti-spike (S) protein neutralizing antibodies [4]. The overall safety and efficacy of currently available COVID-19 vaccines have been indicated in multiple studies [5,6,7]. However, the occurrence of a few cases of post-vaccination complications, such as thyroid disorders, has been observed after administration of various types of COVID-19 vaccines [5].

Thyroid hormones influence almost all nucleated cells and play a fundamental role in the regulation of vital activities, such as metabolism, growth, haematopoiesis, and reproduction [8, 9]. Thyroid gland-derived hormones regulate the function of the majority of organs and maintain the body's internal homeostasis [10]. Thyroid disorders are frequent and have detrimental influences on the general health of all patients. Thyroid illnesses are diagnosed based on evidence of structural abnormalities in the gland as well as impaired secretory function [8, 10]. Based on the above explanation, in evaluating the safety of many drugs and vaccines, there is special attention to their impacts on thyroid function. This attention to the side effects of the COVID-19 vaccines on this gland was explored and reported in a few papers mainly as case reports/series. However, a summary review is needed to generate a comprehensive view to compare and combine their findings. Therefore, we reviewed the published papers to compile their results.

Methods

We conducted a review of the literature to identify all reports regarding thyroid dysfunction after COVID-19 vaccination by searching for indexed articles until 20 February 2022 in PubMed, PubMed Central, Web of Science, and Scopus. The following keywords were used: COVID-19, SARS-CoV-2, Vaccine, Vaccination, thyroid, thyroiditis, and Graves' disease (GD). Inclusion criteria were administration of the SARS-CoV-2 vaccine, case reports, and case series describing patients with the approved thyroid dysfunction. Articles that were not written in English were excluded from this analysis. Among 80 papers, 40 articles were suitable for inclusion in the analysis, and in a total, 83 patients with thyroid dysfunction were included.

Thyroid dysfunctions after COVID-19 vaccination

Thyroid disorders have been documented following the administration of all COVID-19 vaccine types. To characterize the COVID-19 vaccination-associated thyroid disorders, we categorized them based on the administered vaccine type (Table 1). Among 83 reported cases which were included in this review, the most frequent cases of thyroid abnormalities were observed after vaccination with mRNA-based vaccines [57/83 (68.7%)], followed by viral vector vaccines [13/83 (15.7%)] and 12/83 (14.5%) cases following inactivated vaccines. Moreover, SAT was the most common COVID-19 vaccination-related thyroid disease, accounting for 50/83 (60.2%) of all cases, followed by GD with 21/83 (25.3%). Moreover, some cases with focal painful thyroiditis [3/83 (3.6%)], silent thyroiditis [3/83 (3.6%)], and concurrent GD and SAT [2/83 (2.4%)] were also reported. Thyroid eye disease, overt hypothyroidism, atypical subacute thyroiditis, and painless thyroiditis with thyrotoxic periodic paralysis (TPP) were found with lower frequency [1/83 (1.2%) for each disorder] (Table 1).

Table 1 Distribution of the thyroid disorders after COVID-19 vaccination according to the vaccine type
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Subacute thyroiditis after COVID-19 vaccination

Subacute thyroiditis (SAT), also known as granulomatous thyroiditis or de Quervain’s thyroiditis, is a self-limiting inflammatory illness that is caused by viral infections or postviral inflammatory reactions [11, 12]. A recent viral infection (around 2–6 weeks prior) is thought to be a triggering agent in genetically susceptible individuals [12]. The pathogenesis of SAT has been associated with some viral infections, such as measles, mumps, coxsackie, rubella, and adenovirus, either directly or through an inflammatory reaction to the virus [12]. SARS-CoV-2 infection can also operate as a trigger factor for the development of SAT [11]. Some HLA haplotypes, such as HLA-Bw35, HLA-B67, HLA-B35, HLA-DRB1*08, HLA-DRB1*01, HLA-B*18:01, HLA-DRB1*01, and HLA-C*04:01, have been linked to SAT [13,14,15].

The most prevalent symptom of SAT is anterior neck pain; however, some cases of SAT without any neck pain are also documented [12, 16, 17]. The clinical course of SAT often consists of three sequential phases: thyrotoxicosis in the first months, hypothyroidism for about 3 months, and ultimately euthyroidism [17, 18].

Table 2 summarizes the main characteristics of the 50 COVID-19 vaccination-related SAT cases reported as of February 20, 2022. According to vaccine type, the distribution of SAT cases was: 31/50 (62.0%) after vaccination with mRNA-based vaccines, 12/50 (24.0%) after vaccination with inactivated vaccines, and 6/50 (12.0%) after vaccination with vector-based vaccines (Tables 1 and 2). Vaccine type and brand were not reported for one case with SAT [19] (Table 2).

Table 2 Characteristics of cases presenting with subacute thyroiditis following COVID-19 vaccination
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According to vaccine brand, 25/50 (50.0%) of SAT cases were reported after Pfizer vaccination, 11/50 (22.0%) of cases after Sinovac (Life Sciences, Beijing) vaccination, 6/50 (12.0%) of cases after AstraZeneca vaccination, 6/50 (12.0%) of cases after Moderna vaccination, and 1/50 (2.0%) of cases after Covaxin (Bharat Biotech, India) vaccination.

The frequency of the SAT is highest in middle-aged women, and females account for 75.0–80.0% of patients [20, 21]. According to the gender of patients, 36/50 (72.0%) of SAT cases were women, while 14/50 (28.0%) were men, and the women/men ratio was about 2.57:1. The median age was 39.5 years (ranged: 26–73 years) for SAT women and was 45.5 years (ranged: 26–75 years) for SAT men. In 19/36 (52.8%) of women and in 10/14 (71.4%) of men, the onset of SAT symptoms occurred following the first vaccine dose with a median of 10.0 days (ranged: 3–21 days) and 10 days (ranged: 3–15 days) after vaccination, respectively (Table 3). In 16/36 (44.4%) of women and in 4/14 (28.6%) of men, the onset of SAT symptoms occurred following the second vaccine dose with a median of 6.5 days (ranged: 0.5–30 days) and 18.5 days (ranged: 7–37 days) after vaccination, respectively. Overall, in 29/50 (58.0%) of patients, the onset of SAT symptoms occurred following the first vaccine dose with a median of 10.0 days (ranged: 3–21 days) after vaccination, whereas 20/50 (40.0%) of patients developed the symptoms after the second dose with a median of 10.5 days (ranged: 0.5–37 days) after vaccination. The onset time of symptoms was not reported in one SAT woman. The reported SAT cases were from 11 countries, including Germany, USA, Greece, Spain, Turkey, UK, Cyprus, Iran, South Korea, Ireland, and Brazil (Table 2).

Table 3 Age of subjects and the onset time of thyroid disorder-related symptoms following COVID-19 vaccination according to the gender of patients
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Regarding the characteristics of SAT, the inflammatory indicators such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels are virtually increased [22]. The ultrasonography features of SAT include hypoechoic and heterogeneous patches with blurred borders, as well as weak vascularization [23, 24]. In examined cases, the thyroid ultrasonography or scintigraphy imaging was consistent with SAT characteristics. COVID-19 vaccination-associated SAT mainly presented with the clinical characteristics of neck pain, thyrotoxicosis-related thyroid function tests (TFTs) (low TSH along with high free T4), and confirmatory ultrasonography and scintigraphy findings. Regarding the therapeutic and outcome aspects, steroidal and non-steroidal anti‐inflammatory drugs (NSAIDs) were effective for the improvement of symptoms, thyrotoxicosis resolution, and inflammatory marker normalization.

Graves’ disease after COVID-19 vaccination

Graves' disease (GD) as an autoimmune disease is caused by agonist autoantibodies to the thyroid-stimulating hormone receptor (TSHR), inducing hyperthyroidism, independent of pituitary regulation [50]. The binding of thyroid-stimulating antibodies (TSAb) to thyrocyte TSHR induces cell proliferation, thyroid growth, and hyper-secretion of T4 and T3 hormones [51]. Anti-TSHR, anti-TPO, and anti-TG antibodies are found in 90.0, 80.0, and 50.0–60.0% of GD patients, respectively [52].

A combination of environmental and genetic parameters can contribute to the development of GD. The association of GD susceptibility with certain HLA genes, such as HLA-A*68, HLA-B*08, HLA-DRB1*03, DQB1*02, and DQA1*0501, has been reported [53, 54]. Due to molecular mimicry between thyroid molecules and infectious agents, some bacterial infections (such as Yersinia enterocolitica and Helicobacter pylori) and viral infections (hepatitis C and congenital rubella) can induce GD by inducing cross-reactive antibodies [53]. Moreover, influenza B virus, Foamy viruses, Parvovirus B19, and Epstein–Barr virus can also contribute to GD development [51]. The association of GD with COVID-19 was also indicated which mainly affected females about 30–60 days from the day of COVID-19 beginning. COVID-19-related hyper-inflammatory responses can trigger the GD development [53].

Table 4 summarizes the main characteristics of the 21 COVID-19 vaccination-related GD cases reported on February 20, 2022. In reported GD cases, the primary clinical symptoms, TFTs, and thyroid ultrasonography or scintigraphy imaging were consistent with GD characteristics. GD is the second COVID-19 vaccination-related thyroid disease, accounting for 31.6% of all cases. According to vaccine type, the distribution of GD cases was: 16/21 (76.2%) after vaccination with mRNA-based vaccines, and 5/21 (23.8%) after vaccination with vector-based vaccines. According to vaccine brand, the distribution of GD patients was: 14/21 (66.7%) of cases after vaccination with the Pfizer vaccine, 4/21 (19.0%) of cases after vaccination with the AstraZeneca vaccine, 2/21 (9.5%) of cases after vaccination with the Moderna vaccine, and 1/21 (4.8%) of cases after vaccination with the Janssen vaccine (Table 4).

Table 4 Characteristics of cases presenting with Graves’ disease following COVID-19 vaccination
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GD affects people of all ages, although it is more prevalent among women of reproductive age, with a female-to-male ratio of 5–10:1 [50, 51]. According to the gender of patients, 16/21 (76.2%) of GD cases were women, while 5/21 (23.8%) were men, and the women/men ratio was 3.2:1 (Table 3). The median age was 44 years (ranged: 28–73 years) for GD women and was 46 years (ranged: 30–70 years) for GD men. In 11/16 (68.8%) of women and in 2/5 (40.0%) of men, the onset of GD symptoms occurred following the first vaccine dose, with a median of 7 days (ranged: 1–60 days), and 14.5 days (range: 14–15 days) after vaccination, respectively. In 5/16 (31.2%) of women and in 3/5 (60.0%) of men, the onset of GD symptoms occurred following the second vaccine dose with a median of 14 days (ranged: 5–35 days), and 28 days (ranged: 2–28 days) after vaccination, respectively. Overall, in 13/21 (61.9%) of patients, the onset of GD symptoms occurred following the first vaccine dose with a median of 10 days (ranged: 1–60 days) after vaccination, whereas 8/21 (38.1%) of patients developed the symptoms after the second dose with a median of 14 days (ranged: 2–35 days) after vaccination (Table 3). Previous thyroid abnormalities were observed in two GD cases (Table 4). The reported GD cases were from ten countries, including Spain, Austria, Australia, Mexico, South Korea, China, USA, Thailand, Italy, and Belgium (Table 4).

Other thyroid disorders after COVID-19 vaccination

Table 5 summarizes the main characteristics of 12 cases who expressed focal painful thyroiditis, silent thyroiditis, concurrent GD and SAT, thyroid eye disease, overt hypothyroidism, atypical subacute thyroiditis, and painless thyroiditis with thyrotoxic periodic paralysis after COVID-19 vaccination. Focal painful thyroiditis was reported in 3 women with a median age of 38.0 years (ranged: 35–59 years) after vaccination with the Pfizer vaccine. Painless or silent thyroiditis is caused by the destruction of thyroid follicles by inflammation, which results in the release of preformed T3 and T4, causing transitory thyrotoxicosis. Patients display thyrotoxicosis symptoms, but unlike the SAT, they have no pain or tenderness in their thyroid. In 2–12 weeks, the thyrotoxic status recovers spontaneously, and the patients either return to euthyroid condition or pass through a temporary hypothyroid stage [64]. Moreover, 3 patients (2 women and 1 man) with a median age of 32.0 years (ranged: 29–34 years) exhibited silent thyroiditis after receiving the first dose of the mRNA-based vaccines (Pfizer and Moderna). Two patients (1 woman and 1 man with 69 and 39 years old, respectively) also displayed concurrent GD and SAT after receiving the first dose of the Pfizer or Janssen vaccines.

Table 5 Characteristics of cases presenting other thyroid disorders following COVID-19 vaccination
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Thyroid eye disease (TED), also known as Graves' eye disease or Graves’ ophthalmopathy, is a self-limiting orbital inflammatory disorder, that can be sight disfiguring and debilitating. TED is more prevalent among women, and the women/men is about 5.5:1 [65, 66]. The majority of TED patients exhibit biochemical indicators of GD. However, TED can be developed in individuals with hypothyroidism or euthyroidism [65]. The activation of fibroblasts by anti-TSHR and anti-insulin-like growth factor-1 (IGF-1) antibodies contributes to the development of TED. Th1 cells, B cells, macrophages, and mast cells are also infiltrated [67]. Inflammation of the extraocular muscles leads to proptosis and reduced eye movements. The compression of the optic nerve results in optic neuropathy and irreversible eyesight loss [65]. A 50 year old American woman with controlled GD expressed TED at 3 days after vaccination with the 2nd dose of the Pfizer-BioNTech vaccine [68]. The characteristics of 3 other cases from Italy, Spain, and South Korea who expressed overt hypothyroidism, atypical SAT, and painless thyroiditis with thyrotoxic periodic paralysis (TPP) were also exhibited in Table 5.

Mechanisms of COVID-19 vaccination-induced thyroid dysfunctions

The results of this study indicate the occurrence of thyroid disorders following COVID-19 vaccination. The occurrence of the SAT was also reported after vaccination with influenza [72,73,74,75], human papillomavirus [76, 77], and hepatitis B [78] vaccines. In 8 cases of SAT reported after influenza vaccination, the symptoms have occurred during 2–60 days following the administration of vaccine [72,73,74,75, 79]. All cases were successfully treated and completely recovered [79]. Thyroid cells express the SARS-CoV-2 receptor named angiotensin-converting enzyme 2 (ACE2) as well as transmembrane protease, serine 2 (TMPRSS2) facilitating the virus infectivity [80]. Thus, SARS-CoV-2 can directly attack the thyroid tissue, leading to gland dysfunction during and after COVID-19. SARS-CoV-2 can be considered as a driver of SAT, GD, and Hashimoto’s thyroiditis [80]. The results from a systematic review indicated that 13–64% of COVID-19 patients display thyroid dysfunction, and a positive correlation was also found between the COVID-19-related clinical severity and gland abnormalities [81]. The SARS-CoV-2-related SAT mainly occurred in COVID-19 patients with ages 18–63 years and women accounting for 73.6% of the cases [80].

However, the etiology of thyroid abnormalities remains to be proven in future investigations. Just like infections, vaccines can play a role in the development of autoimmune diseases through various mechanisms, such as molecular mimicry, epitope spreading, polyclonal activation, bystander activation, and presentation of cryptic antigenic determinants [5]. If the antigenic content of a vaccine shares structural similarities with autoantigens, then the immune response to the vaccine antigen could extend to host cells exhibiting the similar self-antigen. In genetically susceptible people, the molecular mimicry between the vaccination antigen and thyroid proteins might trigger an autoimmune response [82]. A cross-reactive immune response against the thyroid cells can result from immune responses to SARS-CoV-2-related proteins. It has been indicated that antibody against SARS-CoV-2 S protein potently reacts with TPO [83]. These antibodies may have a role in initiating the autoimmunity via molecular mimicry in susceptible individuals [84]. SARS-CoV-2 S protein, nucleoprotein, and membrane protein, all cross-react with TPO. According to BLAST matching, a number of TPO-related gene sequences exhibit similarity with gene sequences in multiple SARS-CoV-2 proteins. As a result, antibodies generated against SARS-CoV-2 may contribute to the development of autoimmune thyroiditis. As there is a high similarity between genomic sequences of SARS-CoV and SARS-CoV-2, patients with SARS may also exhibit destruction of thyroid follicular cells [82]. Cross-reactivity of SARS-CoV-2 with thyroid proteins might result in the emergence of autoimmune thyroiditis after COVID-19 vaccination. It should be noted that the existence of molecular similarity does not necessarily lead to autoimmunity. In addition to molecular mimicry, other factors, such as tissue injury, prolonged inflammatory reaction, and genetically predisposed background, may be necessary to cause autoimmune disease. For instance, a Lyme disease vaccine consists an antigenic determinant of Borrelia burgdorferi outer surface protein A, which has high similarity to human lymphocyte function-associated antigen-1, a member of leukocyte adhesion molecules [85]. Despite this similarity raised concern about the safety of this vaccine, there was no indication of the elevated risk of arthritis in people who received the Lyme vaccination [86, 87].

If thyroid autoimmunity is triggered by molecular mimicry between COVID-19 vaccines and thyroid antigens, particularly TPO, it remains to explain why a rise in Hashimoto's thyroiditis has not been reported following vaccination. This is likely due to lack of investigation and under-estimating, because SAT and GD are characterized by a rapid onset of clinical symptoms that facilitate their diagnosis. However, Hashimoto's thyroiditis has a chronic and slow course, and usually, hypothyroidism (and thus symptoms) occurs years after the appearance of thyroid-related autoantibodies [52]. To establish whether there is an increase also in Hashimoto's thyroiditis occurrence following SARS-CoV-2 vaccination, prospective studies measuring thyroid-related autoantibodies before and after vaccination as well as comparison with an unvaccinated control group should be conducted.

Bystander activation is an antigen non-specific process that results in the activation of autoreactive T cells [5, 88]. In bystander activation, host tissue damage due to immunopathologic responses or infection leads to the releasing of sequestered autoantigens, activating antigen-presenting cells (APCs) and autoreactive Th cells. After that, activated macrophages and autoreactive T cells produce cytokines, which result in the recruitment of more Th cells promoting local inflammation [5, 88]. Abnormal cytokine and chemokine production can lead to aberrant expression of major histocompatibility complex (MHC) class II molecules, contributing to the pathogenesis of viral diseases, probably through the presentation of autoantigens [84]. Imbalances in various T-cell subsets have been related to some thyroid disorders [89, 90].

Furthermore, COVID-19 vaccine-derived S protein can directly bind to ACE2-expressing thyroid cells, leading to thyroid dysfunction. This possible alternative mechanism may explain the occurrence of thyroid dysfunction following vaccination with all types of SARS-CoV-2 vaccines. In addition to the protective target antigen, vaccines may contain other components, such as adjuvants that potentiate the immune response to the antigen, stabilizers, and preservatives, and sometimes traces of antibiotics to avoid bacterial or/and fungal contaminations during the manufacturing process [5]. The vaccine adjuvants (such as aluminum and thimerosal) were linked to autoantibody levels, such as increased anticardiolipin antibodies after influenza vaccination in lupus patients, as well as anti-thyroid and anti-ovarian antibodies after HPV vaccination [86]. The findings presented here indicate that most cases of thyroid abnormalities, including SAT and GD, were observed after vaccination with mRNA-based vaccines. While the novel mRNA-based vaccines of COVID-19 do not contain adjuvants, the mRNA could act as an adjuvant due to its intrinsic immunostimulatory properties [91]. Indeed, the possible recognition of mRNA by endosomal Toll-like receptors (such as TLR7 and TLR8) and cytoplasmic sensors such as retinoic acid-inducible gene I (RIG-I) [92, 93] potentiate the inflammatory reactions that amplify the autoimmune responses in genetically susceptible people.

The post-vaccination SAT and GD occurred with a greater rate in women compared to men. Like most autoimmune diseases, these observations can be attributed to the immunological effects of sex hormones. For example, testosterone promotes, while estrogen reduces the regulatory T (Treg)-cell-related activity [94]. The association of the vaccine-induced autoimmunity and human leukocyte antigen (HLA) gene has been also indicated. Furthermore, genetic polymorphisms in the cytokine genes may cause overexpression of cytokines and hyper-inflammatory responses, resulting in unfavorable consequences [86, 95, 96].

Conclusion

The reports concerning the incidence rate of vaccination-induced autoimmune responses may be under-estimated [86]. Because an effective monitoring system is missing, and the vaccination status of the majority of patients with newly diagnosed thyroid dysfunction is not checked. The world is currently undertaking the greatest mass vaccination, and cases of thyroid abnormalities will undoubtedly arise, either as a result of the vaccine-associated and/or vaccine-independent processes. Thus, prospective studies using vaccinated and unvaccinated groups should be conducted to establish a valid risk/benefit assessment and reliable figures of thyroid disorders. Fortunately, a favorable outcome was observed in nearly all cases of COVID-19 vaccination-associated thyroid dysfunction after treatment.

Globally, there is no exact information regarding the coverage of each type of COVID-19 vaccine. As of February 22, 2022, the numbers of administered doses based on the vaccine type in European countries are as follows: Pfizer: 592.37 million doses, Moderna: 143.35 million doses, AstraZeneca: 67.39 million doses, Johnson & Johnson: 18.5 million doses, Sinopharm: 2.29 million doses, and Sputnik V: 1.85 million doses [97]. Therefore, the increased incidence of thyroid disorders after vaccination with a particular vaccine may be attributed to the higher coverage of that vaccine. In addition, post-vaccination thyroid complications may be more monitored in some countries. It should be noted that reports of thyroid disorders following vaccination do not prove causality. More longitudinal studies using control groups are necessary to paint a clearer picture of the subject. Physicians should be knowledgeable about the typical and atypical clinical manifestations of these thyroid disorders to diagnose and manage possible cases and mitigate adverse events.