Subacute thyroiditis (ST) is an inflammatory condition of the thyroid gland that can potentially cause symptoms similar to hyperthyroidism: tachycardia, agitation, tremor, and hyperhidrosis. It is often associated with viral infections such as mumps, measles, Coxsackie, influenza A and B, and adenovirus infections.
Signal of the development of subacute thyroiditis after vaccination with new mRNA and vector vaccines against COVID-19. From 21 April to 8 June 2021, 29 individual safety reports were received in the WHO Global Database, VigiBase. In most of the recorded cases, the suspected medicinal products were the Pfizer/BioNTech and Moderna mRNA vaccines. Eleven reports (38%) were classified as serious; in seven cases (24%), treatment of the symptoms of subacute thyroiditis was described. In five cases, cardiovascular disorders such as tachycardia and palpitations were described, and in three cases, hyperthyroidism.
The symptoms of PT can be confused with, for example, odontalgia; it should be taken into account that it can lead to thyrotoxicosis and concomitant cardiac, hepatic and neuromuscular disorders. In this regard, patients and doctors should be informed about the possibility of developing PT after vaccination with COVID-19 vaccines.
Reports from VigiBase
As of 8 June 2021, VigiBase contained 29 PT reports (MedDRA preferred term (PT): Subacute thyroiditis) following immunization with the new COVID-19 vaccines. VigiBase also contains 50 individual safety reports of autoimmune thyroiditis PT (PT: autoimmune thyroiditis) and 50 cases of thyroiditis PT (PT: thyroiditis). In 30 of 50 cases reporting patients with autoimmune thyroiditis, a concomitant disorder – Hashimoto’s thyroiditis, which developed after vaccination – was also reported. The subsequent analysis will focus on cases of subacute thyroiditis, as such reports had a high disproportionality score.
Eighteen (62%) of 29 reports concerned the Pfizer/BioNTech vaccine, five – Moderna, and six – AstraZeneca. Cases were mostly classified as non-serious (62%). In two of 11 serious cases, PT led to prolonged hospitalization, and in the other nine, the seriousness criteria were defined as a medically important condition.
In 11 cases, thrombocytopenia developed after the first dose of the vaccine, and in 9 after the second. The mean time to onset of the adverse event after the second dose was 3 days (range 0 to 60 days), and after the first dose, 6 days (range 0 to 26 days).
The vast majority of PT cases were recorded among vaccinated females (n = 24; 83%), five were male (17%). The patient’s age averaged 45 years (from 18 to 67 years). The following concomitant conditions were reported most often: pyrexia (n = 7), lymphadenopathy and neck pain (each n = 4), decreased blood TSH level, headache, hyperthyroidism, decreased iodine uptake, tachycardia and decreased free thyroxine level (each n = 3 ).
The radioactive iodine uptake test (RAIU) is a reliable test for differentiating the causes of hyperthyroidism. Low uptake indicates thyroiditis, and high uptake indicates Graves’ disease. In the current case series, RAIU was performed in three cases, which confirmed the diagnosis of PT. In five cases (17%), cardiac reactions such as tachycardia and palpitations were reported, and in three (10%), hyperthyroidism. Eight more cases contained information on nonspecific reactions such as pyrexia (n = 7), neck pain (n = 4), headache (n = 3) and arthralgia (n = 2). Information on the outcome of the adverse event was available in 22 cases. At the time of the report submission, in 12 cases the outcome was defined as “unchanged” (41%), in 8 as “recovered”, and in two cases as “unknown”.
Labeling and literature
PT is not included in the “Adverse reactions” section of the instructions for medical use of the three above-mentioned vaccines. Cases of PT after immunization with other vaccines are very rare. Only four published reports were found in the scientific literature. Two cases reported the development of PT in young patients (25 and 28 years old) after seasonal influenza vaccination. The third case was recorded in a middle-aged male patient who suffered from autoimmune diseases and who also developed PT after seasonal influenza vaccination. The fourth describes a previously healthy female patient aged 36 years in whom clinical symptoms of thyrotoxicosis were detected after vaccination against H1N1 influenza.
In addition, a series of reports has been published in the scientific literature on patients who developed PT associated with COVID-19. Eight published reports concerned female patients who developed PT between two weeks and a month after infection, which responded well to treatment with corticosteroids.
Discussion and conclusions
In the series of reports reviewed, the suspected medicinal products were 3 of the 16 authorized COVID-19 vaccines. The reports were submitted from nine countries.
It was noted that the difference in the average time to onset of the adverse event is quite large: from zero to 26 days after the first dose and from zero to 60 days after the second dose. This interval is similar to the onset of PT after natural infection (from two to eight weeks). However, when interpreting the data presented, it should be taken into account that the diagnosis of PT requires medical evaluation and an appropriate examination.
In one case, viral thyroiditis was reported without further details. The only available information was that the patient did not have a positive test for COVID-19. In two other cases, a factor complicating the assessment of the causal relationship between the development of PT and the use of the vaccine was concomitant treatment with eculizumab during a clinical trial. Eculizumab potentially increases the risk of infections that contribute to the onset of PT.
In one case, the patient was receiving concomitant treatment with tamoxifen. Tamoxifen is known to increase serum T4 levels, which could potentially interfere with the diagnosis of thyroid storm in this case.
Another possible mechanism may be related to autoimmune reactions (autoimmune/inflammatory syndrome induced by adjuvants). A literature review conducted by Watad and colleagues in 2017 investigated the potential correlation between autoimmune/inflammatory syndrome induced by adjuvants (ASIA) and autoimmune thyroid diseases. The authors included a series of case reports in which patients developed autoimmune thyroid diseases after immunization with various vaccines (in two cases, the seasonal influenza vaccine and the H1N1 influenza vaccine). The Pfizer/BioNTech vaccine, reported as the suspect medicinal product in most cases, does not contain any “classical” adjuvant. However, the nanoparticles used as the mRNA delivery system have been discussed as possibly acting as adjuvants. Nevertheless, the role of ASIA as a potential mechanism for the development of thyroid disorders is not sufficiently convincing due to the lack of evidence.
Molecular mimicry is another hypothesis of the induction of autoimmune reactions.
Given that the symptoms of PT can be confused with other manifestations of oropharyngeal diseases (for example, odontalgia), and that it carries a risk of developing thyrotoxicosis and, consequently, the likelihood of cardiac, hepatobiliary, nervous and muscular manifestations, healthcare professionals should be informed and take into account the possibility of developing PT after vaccination with the new vaccines against COVID-19.
However, the mechanisms of development of SAT are currently unconfirmed, and further research is needed. This signal is aimed at raising awareness among patients and healthcare professionals about the possibility of subacute thyroiditis developing after vaccination against COVID-19. It is believed that the potential benefit of COVID-19 vaccines outweighs the possible associated risk of subacute thyroiditis.
Source of information: Signal assessment report “COVID-19 vaccine – Subacute thyroiditis”, Annette Rudolph, Uppsala Monitoring Centre, August 2021, based on data from the WHO Global Database – VigiBase
