Age: 50.0
Sex: F
Vaccine: COVID19
Symptoms: Thyroxine free, Ultrasound thyroid
Clinical narrative: This is a spontaneous report from a contactable consumer. A contactable consumer reported different events for different patients and different events for 29 patients. This is one of 29 reports. This is patient number 11. A 50-years-old female patient received BNT162B2 (PFIZER-BIONTECH COVID-19 VACCINE, Formulation: Solution for injection, Lot Number and Expiration date: was not reported) via unspecified route of administration on unspecified date as dose 2, single for COVID-19 immunization. Patient was pregnant: Unknown. The patient medical history was not reported (No PmHx). Patient received first dose of BNT162B2 (PFIZER-BIONTECH COVID-19 VACCINE, Formulation: Solution for injection, Lot Number and Expiration date: was not reported) via unspecified route of administration on unspecified date as dose 1, single for COVID-19 immunization. The patient's concomitant medications were not reported. On unspecified date patient experienced subacute thyroiditis, dysphagia/ difficulty swallowing, lymph node pain/ pain and significant lymph node swelling worsening over a week, lymphadenopathy/ significant lymph node swelling worsening over a week. The time of onset was 21 days. Covid19 vaccine - Thyroiditis subacute for MAH. The patient underwent lab tests and procedures which included antinuclear antibody: unknown results, anti-thyroid antibody: unknown results, blood thyroid stimulating hormone: unknown results, full blood count: unknown results, metabolic function test: unknown results, thyroxine free: unknown results, ultrasound thyroid: unknown results. Enquiry received in writing, therefore logged with limited information. The sender noted in their email: As the case reports described in this signal have been transmitted from a regulatory authority, we kindly request you not to resubmit them to the correspondent Regulatory Authority as this is where they originate from." Please note that the article refers to 29 cases that can be found in table 1 in the article. Up to 08Jun2021, a regulatory database contained 2,638,983 reports including a vaccine as suspected. Thirty-nine percent (n = 1,033,890) of those reports concern the COVID-19 vaccines. A safety signal following COVID-19 vaccination was observed via disproportionality analysis comparing the number of observed reports against the calculated number of expected Open Completed on Due Date 22Jul2021 13:29 PM 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 a regulatory database. Up to 08Jun2021, a regulatory research authority, contained 29 reports of (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. Cases reporting SAT were sent from nine countries. Countries contributing most reports were the country 1 (n=9), country 2 (n=6), and country 3 (n=4). Eighteen (62 percent) 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 percent). 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 percent) and five patients were male (17 percent). 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 disease. In the current case series, RAIU was performed in three cases confirming the diagnosis of SAT (cases 5, 23, and 26). In five reports (17 percent) cardiac reactions, such as tachycardia and palpitations, and in three cases (10 percent) hyperthyroidism were co-reported. Another eight cases contained non-specific reaction terms, such as pyrexia (n=7), neck pain (n=4), headache (n=3), and arthralgia (n=2). Information about the outcome was available in 22 cases. The outcome was reported as not recovered' at the time of reporting in 12 cases (41 percent), in eight cases it was reported as recovered and in the remaining two cases the outcome was unknown. In seven cases (24 percent) patients reportedly received pharmacotherapy. In six of the cases corticosteroids (prednisone or dexamethasone) were used to treat SAT and in the remaining case the patient was planned to start antibiotic therapy. Information about the outcome was available in five of these cases. In two cases the patients were reported to have recovered, in one case the patient was recovering at the time of reporting and in the remaining two cases the outcome was reported as not recovered at the time of reporting, but in one of those cases (case 16) the patient was reported to respond to prednisone treatment. Except for case 8, a second patient (case 2) was reported to have an underlying thyroid disorder (autoimmune thyroiditis). Furthermore, the patient in case 13 was reported to have complained about a swelling at the right side of her neck with pain radiating to the right ear for one month prior to vaccination. She was furthermore reported to have underlying normocytic anemia. However, an SAT was suspected and successfully treated with NSAIDs and corticosteroids. In a third case (case 23) the patient was found to have had a past COVID-19 infection (diagnosed via an antibody test) but an acute infection was excluded via antigen testing. Furthermore, in the recent scientific literature a series of case reports of patients developing SAT associated with COVID-19 infections was published 1421. Six of the eight published reports concern female patients 1416,1921. In most of the cases the onset of the SATs 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. 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 weeks. 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 behavior due to the COVID-19 pandemic have been described and could have an impact the reported outcomes. The patients characteristics in the analyzed 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 field. 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 thyroid ACE 2 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-induced SAT. Since the vaccines included in the analyzed case series do not contain the virus itself in any form (neither live attenuated or 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 (case 18) reported a viral thyroiditis without further specification. The only available information was that the patient was not tested positive for COVID-19. Another two cases may represent confounders: the patient in case 16 was reported to receive concomitant eculizumab treatment in course of a clinical trial. Eculizumab potentially increases the risk for infections favouring the occurrence of SAT. In case 28 the patient was reported to receive tamoxifen concomitantly. Tamoxifen is known to be able to cause increased T4 serum levels potentially confounding the SAT diagnosis in this case. Another possible mechanism could be related to autoimmune reactions. In association with vaccines the concept of the autoimmune or inflammatory syndrome induced by adjuvants, known as ASIA syndrome comes to mind. A literature review conducted by (unlisted name) and colleagues in 2017 investigated the potential correlation between (country 4) and thyroidal autoimmune conditions. The authors included a series of case reports of patients developing autoimmune thyroid conditions (SAT, multinuclear giant cell granulomas, and thyrotoxicosis) following immunization with various vaccines (in two cases seasonal influenza vaccine, and H1N1 influenza vaccination in the remaining case). The Pfizer/BioNTech vaccine that was reported as suspected in the majority of the cases in the current case series, does not contain any classical adjuvant. However, the nanoparticles used as delivery system of the mRNA were discussed to either code liver or themselves to act as adjuvants. Nevertheless, the role of country 4 as a potential mechanism is undermined by lacking evidence. Another hypothesis could be the induction of autoimmune reactions by molecular mimicry. Even though its relevance for the development of autoimmune thyroid diseases was questioned, results from an in-silico study suggested that it might play a role. Furthermore, limitations of the analyzed data (e.g. underreporting of concomitant medication or underlying conditions due to technical constraints in some reporting systems) must be considered. Summary: Subacute thyroiditis (SAT) is a typically painful inflammatory condition of the thyroid, potentially causing hyperthyroidism-like symptoms such as tachycardia, agitation, tremor, and hyperhidrosis. It is often associated with viral infections, such as mumps, measles, coxsackie, adenovirus, and influenza A and B infection. A safety signal of subacute thyroiditis following vaccination with the novel mRNA- and vector-based COVID-19 vaccines was found during a screening of regulatory databases of individual case safety reports on 21Apr2021. By 08Jun2021 there were 29 databases reporting SAT following the immunization with COVID-19 vaccines entered in a regulatory research site. 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 SATs 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: As of 08Jun2021, globally 16 vaccines have been authorized to prevent infections with the coronavirus SARS-CoV-2, known as COVID-19. The authorized vaccines use different, and sometimes new, vaccine platforms. The vaccination campaign started worldwide at the end of 2020, with a total of 2,220,425,093 doses administered globally up to today (08Jun2021). 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 in (country 1) with a higher incidence in females than males (19.1 vs 4.1 cases/ 100,000 person years) between 1970 and 1971. However, no recent information about SATs incidence is available. Furthermore, SAT was observed to occur more commonly during young adulthood and in middle-aged patients. 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 disorders. Therapeutic options are the administration of non-steroidal anti-inflammatory drugs (NSAIDs) for pain relief but in some cases corticosteroid treatment can be necessary. SAT was added to a regulatory database of COVID-19 adverse events of special interest (AESI) in January 20215. 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 percent 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 a regulatory database. Up to 08Jun2021, regulatory databases 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, a database 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 nine countries. Countries contributing most reports were the country 1 (n=9), country 2 (n=6), and country 3 (n=4). Eighteen (62 percent) 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 percent). 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 percent). 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 disease. In the current case series, a regulatory study was performed in three cases confirming the diagnosis of SAT (cases 5, 23, and 26). In five reports (17 percent) cardiac reactions, such as tachycardia and palpitations, and in three cases (10 percent) hyperthyroidism were co-reported. Another eight cases contained non-specific reaction terms, such as pyrexia (n=7), neck pain (n=4), headache (n=3), and arthralgia (n=2). Information about the outcome was available in 22 cases. The outcome was reported as not recovered' at the time of reporting in 12 cases (41 percent), in eight cases it was reported as recovered' and in the remaining two cases the outcome was unknown. In seven cases (24 percent) patients reportedly received pharmacotherapy. In six of the cases corticosteroids (prednisone or dexamethasone) were used to treat SAT and in the remaining case the patient was planned to start antibiotic therapy. Information about the outcome was available in five of these cases. In two cases the patients were reported to have recovered, in one case the patient was recovering at the time of reporting and in the remaining two cases the outcome was reported as not recovered at the time of reporting, but in one of those cases (case 16) the patient was reported to respond to prednisone treatment. Except for case 8, a second patient (case 2) was reported to have an underlying thyroid disorder (autoimmune thyroiditis). Furthermore, the patient in case 13 was reported to have complained about a swelling at the right side of her neck with pain radiating to the right ear for one month prior to vaccination. She was furthermore reported to have underlying normocytic anemia. However, an SAT was suspected and successfully treated with NSAIDs and corticosteroids. In a third case (case 23) the patient was found to have had a past COVID-19 infection (diagnosed via an antibody test) but an acute infection was excluded via antigen testing. Literature and labelling: SAT is not labelled as a potential adverse reaction in the three included a regulatory study. However, SAT was included in a regulatory authority 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 vaccination. A third case described a middle aged male patient suffering from underlying autoimmune conditions who also developed SAT after seasonal influenza vaccination. 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 presentation. Six of the eight published reports concern female patients. 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 weeks. 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 described and could have an impact the reported outcomes. The patients' characteristics in the analyzed 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 field. 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 thyroid ACE 2 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 induced SAT20. Since the vaccines included in the analyzed case series do not contain the virus itself in any form (neither live attenuated or 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 (case 18) reported a viral thyroiditis without further specification. The only available information was that the patient was not tested positive for COVID-19. Another two cases may represent confounders: the patient in case 16 was reported to receive concomitant eculizumab treatment in course of a clinical trial. Eculizumab potentially increases the risk for infections favouring the occurrence of SAT. In case 28 the patient was reported to receive tamoxifen concomitantly. Tamoxifen is known to be able to cause increased T4 serum levels potentially confounding the SAT diagnosis in this case. Another possible mechanism could be related to autoimmune reactions. In association with vaccines the concept of the autoimmune or inflammatory syndrome induced by adjuvants, known as country 4 syndrome comes to mind. A literature review conducted in 2017 investigated the potential correlation between (country 4) and thyroidal autoimmune conditions. The authors included a series of case reports of patients developing autoimmune thyroid conditions (SAT, multinuclear giant cell granulomas, and thyrotoxicosis) following immunization with various vaccines (in two cases seasonal influenza vaccine, and H1N1 influenza vaccination in the remaining case)26. The Pfizer/BioNTech vaccine that was reported as suspected in the majority of the cases in the current case series, does not contain any "classical" adjuvant. However, the nanoparticles used as delivery system of the mRNA were discussed to either co-deliver or themselves to act as adjuvants. Nevertheless, the role of (country 4) as a potential mechanism is undermined by lacking evidence. Another hypothesis could be the induction of autoimmune reactions by molecular mimicry. Even though its relevance for the development of autoimmune thyroid diseases was questioned, results from a study suggested that it might play a role. Furthermore, limitations of the analysed data (e.g. underreporting of concomitant medication or underlying conditions due to technical constraints in some reporting systems) must be considered. Conclusion: SAT is a painful inflammatory condition of the thyroid. Since SATs 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 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. Seriousness criteria reported as intervention/medically important and hospitalization prolonged. Outcome of the event subacute thyroiditis was recovered on an unspecified date, and all other events not recovered. No follow-up attempts are possible; information about lot/batch number cannot be obtained. No further information is expected.