Sex: M
Vaccine: COVID19
Symptoms: Hyperthyroidism, Inflammation, Thyroiditis subacute, Ultrasound scan
Clinical narrative: Hyperthyroidism; Thyroiditis subacute; Inflammation; This is a spontaneous report from a Non-contactable consumer. The reporter had an overview of 29 cases reporting SAT (Subacute thyroiditis) after COVID-19 vaccination. This is one of the cases for a 42/M patient.    A 42-year-old male patient received BNT162B2 (Pfizer-BioNTech COVID-19 vaccine, formulation: solution for injection, Batch/Lot number were not reported), via an unspecified route of administration on an unspecified date in 2021 as dose 2, single for COVID-19 immunisation. No medical history and concomitant medications were reported. The patient previously received BNT162B2 (Pfizer-BioNTech COVID-19 vaccine, formulation: solution for injection, Batch/Lot number were not reported), via an unspecified route of administration on an unspecified date as dose 1, single for COVID-19 immunisation. On an unspecified date after dose 2, the patient experienced thyroiditis subacute, hyperthyroidism, and inflammation. The event hyperthyroidism was serious (medically significant). The Time-to-onset (TTO) was 1-month. It was reported that the patient had hyperinflammation and severe hyperthyroidism three weeks after vaccination (2nd dose) and was treated with prednisone. The patient underwent lab tests which included Ultrasound that showed nodules in the thyroid with dysregulated thyroid hormones, on an unspecified date. The patient received treatment for the events. The outcome of the events was unknown.  Summary of the report: The reporter had an overview of about 29 patients (Between age of 18 and 67years) who had reported SAT (Subacute thyroiditis) after COVID-19 vaccination. Reporter stated that patients experiencing SAT following vaccination were mainly female (n=24; 83%) and five patients were male (17%). Patients' age was reported in 28 cases resulting in a median age of 45 years (range 18 to 67 years). By 08Jun2021 there were 29 ICSRs reporting SAT following the immunization with COVID-19 vaccines entered in VigiBase. Most of the reports contained Pfizer/BioNTech's and Moderna's mRNA-based vaccines as suspected. Statistically significant disproportionate reporting was observed for these two vaccines. Eleven reports (38%) were classified as serious and in seven cases (24%) pharmacotherapy of SAT symptoms was reported. In five reports cardiac reactions, such as tachycardia and palpitations, and in three reports hyperthyroidism were co-reported. Since SAT's symptomatology can be confused with other painful oropharyngeal conditions (e.g.: odontalgia) but carries the risk of thyrotoxicosis and therefore the possibility of related cardiac, hepatic, and neuromuscular conditions, patients and health care professionals should be sensitized to consider the possibility of SAT following vaccination with the novel COVID-19 vaccines.  Introduction: Subacute thyroiditis (SAT) is an inflammatory disease of the thyroid caused by viral infections or autoimmune reactions. Its reported incidence was 12.1 cases/100,000 person years with a higher incidence in females than males (19.1 vs 4.1 cases/100,000 person years) between 1970 and 19971. However, no recent information about SATs incidence is available. Furthermore, SAT was observed to occur more commonly during young adulthood and in middle-aged patients2. Typical, but rather nonspecific symptoms include pain in the anterior neck and fever. Furthermore, hyperthyroidism-like symptoms, such as tachycardia, agitation, tremor, and hyperhidrosis can occur. Because of thyroid follicular cell destruction thyroglobulin is degraded leading to the uncontrolled liberation of triiodothyronine (T3) and thyroxine (T4). Due to increased levels of free T3 (FT3) and T4 (FT4) the release of thyroid-stimulating hormone (TSH) is reduced. These processes result in the clinical picture of hyperthyroidism carrying the risk for the development of thyrotoxicosis potentially increasing the occurrence of related cardiac, hepatic, or neuromuscular disorders3. Therapeutic options are the administration of non-steroidal anti-inflammatory drugs (NSAIDs) for pain relief but in some cases corticosteroid treatment can be necessary4. SAT was added to Research Organization's list of COVID-19 adverse events of special interest (AESI) in Jan2021. It was observed that SAT occurred primarily as a post-infectious condition with a delayed onset of several weeks after an acute COVID-19 infection5. A safety signal for SAT following COVID-19 vaccination was observed via disproportionality analysis comparing the number of observed reports against the calculated number of expected reports.Disproportionate reporting was observed to be statistically significant for the two mRNA-based vaccines of Pfizer/BioNTech (observed n=18, expected n=3) resulting in a lower 95% limit of the Information Component measure for disproportionality (IC025) of 1.5 and Moderna (observed n=5, expected n=1, IC025 = 0.1). The expected value is based on the total number of reports on the covid-19 vaccines and the proportion of reports that relate to SAT in the VigiBase.  Reports in VigiBase: Up to 08Jun2021, VigiBase, the WHO database of individual case safety reports (ICSRs), contained 29 reports of SAT (MedDRA preferred term (PT): thyroiditis subacute) following immunization with the novel COVID-19 vaccines. Furthermore, VigiBase comprised 50 cases reporting the PT autoimmune thyroiditis and another 50 cases reporting the PT thyroiditis following COVID-19 vaccination up to 08Jun2021. In 30 of the 50 cases reporting the PT autoimmune thyroiditis patients were described to suffer underlying Hashimoto's thyroiditis flaring up after the vaccination. The following analysis will focus on the cases reporting the MedDRA PT thyroiditis subacute as it was the only PT found to be disproportionately reported. In-depth analysis of the other mentioned PTs can be made available on demand. Cases reporting SAT were sent from a number of countries. Contributing most reports amounted to (n=9), (n=6), and (n=4). Eighteen (62%) of the 29 reports were for the Pfizer/BioNTech mRNA vaccine, five for the Moderna mRNA vaccine, and six for the AstraZeneca adenovirus vector-based vaccine. Cases were mostly classified as non-serious (62%). In the 11 serious cases, two reported caused or prolonged hospitalization and the other nine medically important conditions as the seriousness criteria. Information on the dose number was available in 19 cases. In 11 cases the SAT occurred after administration of the first dose and in nine cases after the second dose. Time-to-onset (TTO) was observed to be in median three days after the second dose (ranging from 0 to 60 days) compared to a median TTO of six days after the first dose (ranging from 0 to 26 days). In one case (case 8), reporting the SAT onset after the second dose, it was mentioned that the patient experienced SAT already after the first dose and that symptoms recurred with the second (positive rechallenge). TTO in this case was reported as one day after vaccination with the second dose. Furthermore, this patient seemed to have an underlying thyroid disorder. It was reported that the symptoms of SAT resolved when she stopped her "thyroid medication". Since it was not specified what kind of medication the patient was taking, it is not possible to conclude whether it was underlying hyper- or hypothyroidism. Patients experiencing SAT following vaccination were mainly female (n=24; 83%) and five patients were male (17%). Patients' age was reported in 28 cases resulting in a median age of 45 years (range 18 to 67 years). The most frequently co-reported terms were pyrexia (n=7), lymphadenopathy and neck pain (each n=4), and blood TSH decreased, headache, hyperthyroidism, iodine uptake decreased, tachycardia, and thyroxine free decreased (each n=3). The radioactive iodine uptake (RAIU) test is a reliable test to differentiate between causes of hyperthyroidism. Low uptake suggests thyroiditis and high uptake suggests Grave's disease6.   Literature and labelling: SAT is not labelled as a potential adverse reaction in the three included vaccines' Summaries of Product Characteristics (SmPCs)79. However, SAT was included in the Research Organizations's priority list of COVID-19 adverse events of special interest in the quarterly update of Dec2020. Cases of SAT following immunization with other vaccines are very rare. Only four published case reports were found in the scientific literature. Two of the cases reported the occurrence of SAT in young female patients (25 and 28 years old) following seasonal influenza vaccination10,11. A third case described a middle aged male patient suffering from underlying autoimmune conditions who also developed SAT after seasonal influenza vaccination12. The fourth case report described a previously healthy 36-year-old female patient who presented with clinical symptoms of thyrotoxicosis after having received H1N1 influenza vaccination one month prior to presentation13.Furthermore, in the recent scientific literature a series of case reports of patients developing SAT associated with COVID-19 infections was published14-21. Six of the eight published reports concern female patients14-16,19-21. In most of the cases the onset of the SAT's symptoms (such as anterior neck pain) was reported around two weeks to one month after COVID-19 infection and the condition usually responded well to corticosteroid treatment.  Discussion: In the current case series, three of the 16 authorized COVID-19 vaccines were reported as suspected. The reports included in the analysed case series were sent from nine countries from different geographic regions fulfilling the criterion of consistency. The stages of vaccine rollout in different countries as well as the availability of the vaccines in various geographic regions should be kept in mind when interpreting the presented results. An apparent difference in the TTO between the first and the second dose was observed. However, the variation in TTO was observed to be quite large with 0-26 days following the first dose and even 0-60 days following the second dose. This time span is similar when compared to SAT onset following a natural infection, which was observed to be two to eight weeks22. However, when interpreting the presented data, it must be considered that SAT diagnosis requires medical consultation and examination. In the current case series, several cases (e.g. cases 3, 4, and 12) suggested a delay of diagnosis of days or even months after symptom onset. Therefore, onset of SAT could be even shorter. Furthermore, alterations of patient's health care seeking behaviour due to the COVID-19 pandemic have been described29 and could have an impact the reported outcomes. The patients' characteristics in the analysed case series are in line with epidemiological findings for SAT. However, interpreting the current analysis, the vaccinated population must be kept in mind. In many countries, health care workers were the first to be vaccinated. It is likely that young and middle-aged women are over-represented in this professional field23. Though there is not much evidence of SAT following immunization in general, a series of case reports on patients developing SAT in association with COVID-19 infection can be found in the recent scientific literature. Inflammatory response, apoptosis, and local damage, direct viral replication, interaction with thyroidal ACE2 receptors, and a potential central mechanism with low TSH level possibly secondary to hypothalamus-pituitary dysfunction have been discussed as potential mechanisms for COVID-19. Since the vaccines included in the analysed case series do not contain the virus itself in any form (neither live attenuated nor inactivated), but only its genetic material, the hypotheses related to direct viral or post-viral damage seem rather improbable in the current context. However, one case reported a viral thyroiditis without further specification. The only available information was that the patient was not tested positive for COVID-19.   Conclusion: The reporter given the Conclusion for the event SAT that included: SAT was a painful inflammatory condition of the thyroid. Since SAT's symptomatology can be confused with other painful oropharyngeal conditions (e.g.: odontalgia) but carries the risk of thyrotoxicosis and therefore the possibility of related cardiac, hepatic, and neuromuscular conditions, as observed in several cases in the analysed case series, patients and health care professionals should be sensitized to consider the possibility of SAT following vaccination with the novel COVID-19 vaccines. A calculated Time-to-onset (TTO) with a median of six days after dose one and three days after dose two suggests a possible dose-response and temporal relationship between SAT onset and vaccination. Most cases in the analysed case series were classified as non-serious. However, serious cases requiring hospitalization and/or corticosteroid and other pharmacotherapy were observed. Furthermore, the case series contained five reports co-reporting cardiac reactions, such as palpitations and tachycardia. Published case reports suggest that an autoimmune mechanism could be the cause for SAT following COVID-19 immunization. However, this mechanism is not confirmed at the current time point and will require further investigation. The presented signal is aimed to increase patients' and healthcare professionals' awareness of the will be necessary. The potential benefit of the COVID-19 vaccines is considered to outweigh the possible associated risk of subacute thyroiditis.  No follow-up attempts are possible; information about lot/batch number cannot be obtained. No further information is expected.; Sender's Comments: Linked Report(s) : US-PFIZER INC-202100974883