Subacute thyroiditis after SARS‐CoV‐2 vaccination: A case report

Key Clinical Message Subacute thyroiditis which is typically characterized by cervical pain and fever is caused by viral infection and is seen after SARS‐CoV‐2 vaccination. Here we report a post‐vaccination subacute thyroiditis after SARS‐CoV‐2 vaccination. Abstract Subacute thyroiditis (SAT) is possibly caused by a viral infection and is typically characterized by cervical pain and fever. SAT associated with SARS‐CoV‐2 infection or SARS‐CoV‐2 vaccination has been reported, albeit in limited numbers. A 34‐year‐old woman was referred to our clinic with typical SAT symptoms. The diagnosis was confirmed through thyroid scintigraphy after receiving the SARS‐CoV‐2 vaccination, despite testing negative for COVID‐19 via RT‐PCR. There is a theoretical correlation between SARS‐CoV‐2 vaccination and SAT. Vaccination may have a direct or indirect impact on the thyroid, but further studies are required to confirm this relationship. A systematic review of the literature of similar cases was performed for comparison. Ultimately, the overall benefits of SARS‐CoV‐2 vaccination outweigh the potential adverse effects. Therefore, these types of reports should not divert attention from the actual reality.

or 99m Tc-pertechnetate uptake and distribution, which is expected to be markedly reduced in SAT. 4,5AT could play a role as a component of the COVID-19 presentation with the signs mentioned above. 6In addition, SAT has been rarely reported after SARS-CoV-2 vaccination in some case reports. 1,7It is suggested that SARS-CoV-2 vaccination may trigger autoimmune reactions of which SAT is the most prevalent example of it.Autoimmune/inflammatory syndrome induced by adjuvants (ASIA syndrome) is the other suggested reason behind SAT after vaccination due to the exposure to adjuvants.[10] We report a case of SAT following SARS-CoV-2 vaccination along with a literature review.

| CASE HISTORY
A 34-year-old woman presented to our clinic with fatigue, sweating, anterior cervical pain, and fever lasting for 8 days.The patient mentioned receiving a SARS-CoV-2 vaccination 4 weeks ago, specifically the first dose of the BBIBP-CorV (Sinopharm, Beijing CNBG (inactivated virus vaccine)) vaccine.She has a medical history of gastroesophageal reflux disease (GERD) and had a previous episode of COVID-19 about 7 months ago, for which she did not require antiviral or corticosteroid therapy or hospitalization.She did not report any personal or familial history of thyroid diseases before, and she had no symptoms related to upper respiratory tract infections during these days.A physical examination was conducted, revealing an oral temperature of 38.5°C and tenderness in the anterior cervical-thyroid anatomical area without any erythema.

| METHODS
The nasopharyngeal swab polymerase chain reaction (PCR) test was negative for SARS-CoV-2.abratoryL studies, including CBC, inflammatory markers, thyroid function tests, and thyroid scintigraphy, shown in the table and figure below, were consistent with SAT probably associated with the preceding vaccine.Ultrasonography reported an upper limit of normal thyroid size with regular margins, decreased echogenicity, heterogeneous echotexture with hypoechoic areas, and normal vascularity in both lobes without nodules or cervical lymphadenopathy.

| OUTCOME AND RESULTS
The treatment with 12.5 mg/day of prednisolone was initiated for the patient.During the follow-up visit after 2 weeks, the primary symptoms had resolved, so the corticosteroid dose was gradually tapered.

| SAT after vaccination
Several cases have been reported as subacute thyroiditis after COVID-19 infection and SARS-CoV-2 vaccination which some of them are enlisted in Table 1 to facilitate any comparison.Now, subacute thyroiditis is a known complication or clinical manifestation of COVID-19 with several reports from all over the world.SARS-CoV-2 could affect thyroid cells directly through ACE2 receptors (angiotensin-converting enzyme) and the following inflammation. 11hyroid disorders following viral infections or vaccinations have been discussed in the past decades.After the COVID-19 pandemic and the production of vaccines with different structures and their injection, thyroid-related disorders were seen. 12Studies have shown that these disorders have occurred with the injection of almost all types of COVID-19 vaccines, although the highest rate has occurred with mRNA-based vaccines, followed by viral vectors, and less in inactive vaccines.These disorders include subacute thyroiditis, Graves' disease, focal painful thyroiditis, and finally silent thyroiditis. 13Of course, in some cases, concurrent Graves' disease and SAT have been reported, too. 14ubacute thyroiditis, which is also referred to as granulomatous or de Quervain's thyroiditis, is a self-limiting autoimmune condition that occurs in response to a viral infection or the resulting inflammatory state.It usually presents with fever, neck pain, and palpitations; however, in some cases, patients do not develop any significant symptoms. 12Typical SAT has three sequential phases, which include thyrotoxicosis, hypothyroidism, and euthyroidism.It is believed that this condition occurs after a recent viral infection in genetically predisposed patients, and the relationship between numerous HLAs (such as HLA-Bw35, HLA-B67, HLA-B35, HLA-DRB108, HLA-DRB101, HLA-B18:01, HLA-DRB101, and HLA-C*04:01) and SAT has been established. 15,16AT mostly affects middle-aged women, and as we mentioned earlier, it is common after receiving viral vaccinations.Jafarzadeh et al. 13 gathered data on 50 SAT cases, of which 62% occurred following mRNA-based vaccines, 24% with inactivated vaccines, and 12% with viral vector vaccines.In one patient, there was no data about the type of vaccine.They also stated that most patients were female, with a mean age of 39.5 years, and 58% of patients experienced SAT after the first vaccine injection.Similar to our study, the patient was a 34-year-old woman who had a history of receiving the first dose of an inactivated viral vaccine before developing SAT.
The diagnosis of SAT is based on laboratory findings, ultrasonography (US), and scintigraphy features.Elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), as well as abnormal thyroid function tests, are seen in patients.In the US, hypoechoic and heterogeneous pieces with obscure borders and feeble vascularization are characteristic features.In line with our study, as shown in Table 2, our patient had high levels of ESR, CRP, T3, T4, and low TSH.On US evaluation, there was an upper limit-sized thyroid with regular margins and decreased echogenicity, heterogeneous echotexture with hypoechoic areas. 17The thyroid scintigraphy usually shows a low or absent uptake, similar to our case, Figure 1, Scintigraphy (99mTc scan) demonstrates poor radiotracer uptake of both lobes with increased background and salivary gland uptake consistent with SAT. 18teroids and non-steroidal anti-inflammatory drugs (NSAIDs) are mostly effective in treating the symptoms and normalizing the laboratory markers of SAT. 19In our study, after diagnosing SAT, we prescribed prednisolone (12.5 mg daily) for the patient, and in a 2-week follow-up, her condition improved.

| A relation behind the vaccine injection and thyroid diseases
As stated in the studies, thyroid cells produce the SARS-CoV-2 receptor called angiotensin-converting enzyme 2 (ACE2) and the transmembrane protease serine 2 (TMPRSS2).Therefore, SARS-CoV-2 can assault thyroid tissue, leading to thyroid dysfunction during and after COVID-19 infection.Antibodies against SARS-CoV-2S protein have been reported to react with thyroid peroxidase (TPO) and can directly bind to ACE2-expressing thyroid cells.These antibodies may play a role in initiating autoimmunity through molecular mimicry in susceptible individuals.Additionally, studies have reported a positive relationship between clinical severity associated with COVID-19 and thyroid dysfunction. 13,17,20accines, like infections, may play a role in the development of autoimmune conditions through different mechanisms, such as molecular mimicry, epitope spreading, polyclonal activation, and the presentation of enigmatic antigenic determinants.Molecular mimicry between vaccine antigens and thyroid proteins can trigger an autoimmune response.Several factors, such as tissue damage, prolonged inflammatory response, and genetic background, can also cause autoimmune diseases. 13ased on the above explanations, patients infected with SARS-CoV-2 or vaccinated may be at risk for thyroid dysfunction, especially those with a prolonged inflammatory response and a genetic background.
However, it was observed by Clarke et al. 21that thyroid and adrenal function were found to be preserved ≥3 months after the onset of COVID-19.Although a considerable number of individuals had chronic fatigue, changes in thyroid or adrenal function could not explain their symptoms.In addition, Goyal et al. 22 conducted longitudinal cohort research in which subjects examined at a short time (<1 year) after a primarily mild and asymptomatic SARS-CoV-2 infection did not show signs of thyroid autoimmune or dysfunction progressing.In our opinion, the risk of subacute thyroiditis due to SARS-CoV-2 infection or vaccination is different for each person and occurs rarely.However, according to the history of autoimmune disorders and the specific conditions of each person, therapeutic and preventive protocols should be undertaken in susceptible people.
The cases presented, including those outlined in Table 1, occurred following SARS-CoV-2 vaccination.This occurrence is considered coincidental, and the theories discussed represent potential pathways rather than established causation.Further investigations are essential to provide a more comprehensive understanding of this potential correlation.
It is important to emphasize that SARS-CoV-2 vaccination has resulted in a substantial reduction in mortality and disease severity among the general population.The occasionally reported adverse events should not undermine the significant benefits associated with vaccination. 23

| CONCLUSION
Despite numerous studies, it is still impossible to definitively determine the effect of being infected with COVID-19 or receiving a SARS-CoV-2 vaccine on the occurrence of autoimmune thyroid disease.This issue has become more complicated, especially considering several factors, including the different types of vaccines administered to different individuals.We hereby present a documented instance of SAT following SARS-CoV-2 vaccination, accompanied by a thorough a brief review concerning COVID-associated and post-vaccination cases of SAT.We have organized the relevant data in Table 1    Abbreviations: TSH: ↓ 0.01-0.2μIU/mL, ↓↓ <0.01 μIU/mL.T3, FT3, T4, FT4, WBC, CRP and etc.: → within normal; ↑, increased; ↓, decreased; ↑↑, 1.5 times more than normal upper limit; ↓↓, 1.5 times lower than normal lower limit; TSH, thyroid-stimulating hormone; (F)T3, (free) triiodothyronine; (F)T4, thyroxine; anti-TPO, thyroid peroxidase Antibody; WBC, white blood cell; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; Anti-Tg, anti-thyroglobulin antibody; TRAB, thyroid receptor antibodies; N/A, not assessed.T A B L E 2 Laboratory results of the patient on admission date and follow-up.
to facilitate comparisons.T A B L E 1