A case of subacute thyroiditis after influenza vaccination

Background

Subacute thyroiditis (SAT) is a self-limiting inflammatory disease characterized by fever, painful thyroid gland swelling, and thyrotoxicosis (1). It is commonly believed to be caused by a viral infection (2). The number of cases has recently increased following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (3). Furthermore, many cases of SAT have recently been reported following coronavirus disease 2019 (COVID-19) vaccination (4). By contrast, several cases of SAT after influenza vaccination have been reported (5, 6, 7, 8, 9, 10, 11, 12, 13).

In this report, we present a Japanese female case of SAT following influenza vaccination and two doses of COVID-19 vaccination.

Case presentation

We present the case of a 40-year-old Japanese woman who had no family or medical history of thyroid disease. She had been treated for bronchial asthma. On days −60 and −32, she received the first and second doses of the COVID-19 vaccine (COVID-19 vaccine Moderna intramuscular injection®, Takeda Pharmaceutical Company Ltd, Osaka, Japan/Moderna Biotech Ltd, Cambridge, MA, USA) with no adverse effects. She then received the seasonal influenza vaccine (Influenza HA Vaccine “KMB”^®, KM Biologics Ltd, Kumamoto, Japan) on day 0. After 2 days, a fever of 38.3℃ and palpitations appeared, and the fever persisted at night. On day 6, she was given antibiotics and non-steroidal anti-inflammatory drugs as prescribed by a general physician. However, the fever persisted. On day 12, the patient was referred to the outpatient rheumatology office at Sapporo City General Hospital because of a fever of unknown origin. No iodinated contrast media had been used prior to the first visit to our hospital, and no large doses of iodine had been ingested. Her heart rate was 90 beats per minute, and her body temperature was 36.9°C. She also complained of mild neck pain, excessive sweating, and anxiety but no weight loss. Palpation revealed an enlarged left lobe of the thyroid gland with mild tenderness. No finger tremor was observed. There was no proptosis nor eyelid swelling in her eyes, and no oculomotor disturbances were observed. She was diagnosed with SAT on day 15, and she was started on prednisolone at a dose of 15 mg/day on the same day.

Investigation

The following laboratory results were obtained during her first visit to our hospital on day 12: free T3 (FT3) was 5.42 pg/mL (reference range (RR): 2.3–4.0), free T4 (FT4) was 2.34 ng/dL (RR: 0.9–1.7), thyroid-stimulating hormone (TSH) was less than 0.01 μIU/mL (RR: 0.5–5.0), C-reactive protein (CRP) was 5.77 mg/dL (RR: < 0.3), anti-thyroglobulin antibody (TgAb) was positive at 897.5 IU/mL (RR: < 12), anti-thyroid peroxidase antibody (TPOAb) was positive at 34.7 IU/mL (RR: < 5.1), and TSH receptor antibody (TRAb, the third generation) was negative at 0.7 mIU/mL (RR: < 2.0). A polymerase chain reaction of a nasal swab was negative for SARS-CoV-2. On day 15, color Doppler ultrasonography revealed thyroid swelling in the left lobe with a tumor-like hypoechoic lesion and decreased vascularity (Fig. 1). The hypoechoic region coincided with the tender site.

Ultrasonography of the thyroid gland. Ultrasonography in horizontal view (A), color Doppler ultrasonography in horizontal view of the light lobe (B), and longitudinal view of the left lobe (C). In the left lobe, the majority of the thyroid gland is replaced by an irregular hypoechoic nodular lesion with decreased vascularity.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 1; 10.1530/EDM-22-0364

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Ultrasonography of the thyroid gland. Ultrasonography in horizontal view (A), color Doppler ultrasonography in horizontal view of the light lobe (B), and longitudinal view of the left lobe (C). In the left lobe, the majority of the thyroid gland is replaced by an irregular hypoechoic nodular lesion with decreased vascularity.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 1; 10.1530/EDM-22-0364

• Download Figure
• Download figure as PowerPoint slide

Ultrasonography of the thyroid gland. Ultrasonography in horizontal view (A), color Doppler ultrasonography in horizontal view of the light lobe (B), and longitudinal view of the left lobe (C). In the left lobe, the majority of the thyroid gland is replaced by an irregular hypoechoic nodular lesion with decreased vascularity.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 1; 10.1530/EDM-22-0364

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• Download figure as PowerPoint slide

The human leukocyte antigen (HLA) types identified for serum were A2, A11, B35, B51, DR4, and DR1403, and for DNA types, they were A*02:01/11:01, B*35:01/51:01, DRB1*04:03, and DRB1*04:03.

Treatment

On day 15, the patient was given prednisolone at a dose of 15 mg/day. Prednisolone dosage was reduced by 5 mg every 2 weeks for 6 weeks before being discontinued.

Outcome and follow-up

Table 1 summarizes the patient’s clinical course. On day 12, she came to our outpatient’s office. On day 15, the patient was diagnosed with SAT and was started on prednisolone at a dose of 15 mg/day on the same day. The fever subsided the following day. On day 42, the prednisolone dosage was reduced by 5 mg every 2 weeks and discontinued after 6 weeks. On day 22, FT3 and FT4 levels were estimated to be normal. On day 34, low FT3 and FT4 levels as well as high TSH levels were observed. On day 48, FT3, FT4, and TSH levels had returned to normal. On day 174, TPOAb was negative at 3.5 IU/L, but TgAb was still positive at 37.8 IU/L.

Discussion

In our patient, there were no preceding cold-like symptoms and the fever persisted 2 days after receiving a seasonal influenza vaccine. The patient had received the second inoculation of the Moderna vaccine for COVID-19 32 days prior to receiving the influenza vaccine. On her first visit to our hospital, fever, anterior neck pain, thyroid gland tenderness, mild thyrotoxicosis, and elevated CRP levels were present, as well as a negative TRAb. Ultrasonography revealed a hypoechoic lesion with low vascularity in the left lobe of the thyroid gland. Glucocorticoid administration markedly reduced fever and inflammation. Thyroid function returned to normal after transient hypothyroidism. On the basis of the preceding course, the patient was diagnosed with SAT. Although SAT developed 34 days after the second dose of the COVID-19 vaccine, the patient received the influenza vaccine 2 days before the onset of SAT. Therefore, it is reasonable to assume that the influenza vaccine triggered the onset of SAT.

Currently, there have been nine cases of influenza vaccine-induced SAT (5, 6, 7, 8, 9, 10, 11, 12, 13). Table 2 presents an outline of the SAT after influenza vaccination in 10 cases, including the present case. The patients’ ages ranged from 25 to 58 years, with 70% of them being female. The interval between vaccination and the onset of SAT was 2 or 3 days in four patients, 14 days in three, and more than 30 days in two. The primary symptoms were neck pain in six patients, fever in four, and palpitation in four. Glucocorticoids were given to six patients. These clinical features are comparable to those in patients with classical SAT.

In the study that examined the incidence of SAT caused by COVID-19 vaccines using the European pharmacovigilance database, virus vaccines other than COVID-19 were used as references, and the reporting odds ratios of mRNA vaccines for COVID-19, namely, BNT162b2 and mRNA-1273, were 3.58 (95% confidence interval (CI): 1.92–6.66) and 3.44 (95% CI: 1.71–6.45), respectively. When influenza vaccines were used as references, the reporting odds ratios of mRNA vaccines for COVID-19, namely, BNT162b2 and mRNA-1273, were 1.81 (95% CI: 0.74–4.43) and 1.74 (95% CI: 0.67–4.51), respectively. In this report, the incidences of SAT after influenza vaccines, BNT162b2, and mRNA-1273 were 5:52 842, 103:602 891, and 27:164 320 (cases with SAT: cases without SAT), respectively. There were no differences in the incidence of SAT following vaccination between influenza and COVID-19 vaccines (14).

The mechanism of developing SAT after influenza vaccination is unclear. Genetic factors may play a role in the development of SAT, and HLA-B35 is present in up to 70% of patients with classical SAT (2). Four patients with SAT after influenza vaccination had their HLA type tested, and all of them had HLA-B35. Except for one patient who had no HLA type examined other than HLA-B35, all three patients had HLA-A2. In vitro experiments revealed that HLA-A1, A2, B8, and B35 enhanced influenza A virus-specific cytotoxic T-lymphocyte responses, with HLA-A2 having the strongest effect (15). The existence of both HLA-A2 and HLA-B35 may be involved in the development of SAT following influenza vaccination. Further investigations into a larger number of cases are required.

Currently, the influence of two doses of COVID-19 vaccination prior to influenza vaccination is unclear. However, when influenza vaccination is given after COVID-19 vaccination, the risk of SAT development should be considered.

We conclude that SAT may occur after influenza and COVID-19 vaccinations. SAT after influenza vaccination may be overlooked. For patients with SAT, it is necessary to obtain information regarding their vaccination history.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This study did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Patient consent

Written informed consent for publication of their clinical details and clinical images was obtained from the patient.

Author contribution statement

All authors participated in the patient’s treatment, data collection, data interpretation, and manuscript writing. All authors read and approved the final manuscript.