2022 Volume 69 Issue 12 Pages 1431-1435
Mass immunization has led to a decrease in the transmission of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) worldwide. At the same time, awareness regarding possible adverse effects of newly developed vaccines is critical. The present study was undertaken to report the cases of Graves’ disease occurring after administration of viral vector vaccine (ChAdox1nCoV-19) and describe the clinical profile, response to treatment, and effect of administration of a second dose in patients developing Graves’ disease. Four cases of Graves’ disease after administration of the vaccine were noted. Two of these had a mild thyroid eye disease. Three cases were female and had a family/self-history of autoimmune disease. All cases responded well to treatment and became euthyroid within two to four months. Two patients exhibited worsening thyrotoxicosis after receiving a second dose of the vaccine. We propose that the temporal relationship between administration of the vaccine and the onset of symptoms establishes Graves’ disease as an adverse event after the SARS-CoV-2 viral vector vaccine. Close follow-up is advisable in individuals developing Graves’ disease after SARS-CoV-2 vaccination.
THE COVID-19 PANDEMIC caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has cost >5 million lives worldwide as of July 2022 [1]. The rapid development of vaccines against SARS-CoV-2 and mass immunization has led to a decrease in transmission of the virus and the severity of disease. Different types of vaccines available for SARS Covid-19 include inactivated whole virus vaccine, protein subunit vaccine, viral vector vaccine, and mRNA vaccine. ChAdox1nCoV-19 is a viral vector vaccine with a replication-deficient chimpanzee adenovirus vector (ChAdox1) encoding a SARS-CoV-2 surface glycoprotein antigen (Spike protein, nCoV-19) [2].
Autoimmune thyroid disorders, including Graves’ disease, are characterized by the development of an autoimmune response to thyroid antigens in a genetically predisposed individual. This autoimmune response can be influenced by exposure to environmental factors [3]. Various environmental factors triggering Graves’ disease include smoking, stress, and infection. Several infectious agents including hepatitis C virus, enterovirus and reovirus have been postulated to trigger Graves’ disease through molecular mimicry [3].
Adjuvants are molecules added to vaccines to enhance their immunogenicity. Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) syndrome refers to diverse autoimmune conditions induced by exposure to adjuvants used in vaccines [4]. The term ASIA syndrome was introduced by Schonfield and Agmon-Levin in 2011 [4] and has been described with the use of influenza vaccine, hepatitis B virus (HBV) vaccine, human papillomavirus (HPV) vaccine, and silicone implants [5]. Various endocrinological manifestations so far described as ASIA syndrome include subacute thyroiditis, Hashimoto’s thyroiditis, primary ovarian insufficiency, type1 diabetes mellitus, and autoimmune adrenal insufficiency [6].
Both Graves’ disease and subacute thyroiditis (SAT) have been reported after SARS-CoV-2 infection [7, 8]. Also, there have been case reports of SAT and Graves’ disease following the administration of the vaccine against SARS-CoV-2 [9-13]. Here, we report four cases of Graves’ disease with onset of symptoms after administration of the viral vector vaccine ChAdox1nCoV-19 (COVISHIELD) from a tertiary care institute in India. Two out of four patients reported, had a mild thyroid eye disease.
Four cases of Graves’ disease following administration of viral vector vaccine presented to our center between July 2021 and November 2021.
Case 120-year-old male, non-smoker, non-alcoholic, without previous history of thyroid disease presented with weight loss, tremors, and bulging of the left eyeball for six weeks. The patient started having symptoms one week after vaccination (ChAdox1nCoV-19; COVISHIELD); bulging of the eyeball was noticed two weeks after onset of symptoms. There was no history of autoimmune disease or thyroid disorder in the family. Upon examination, the patient had a pulse rate of 100 beats/min and a blood pressure (BP) of 128/80 mm Hg. Tremors were present and there was no goiter. Mild proptosis, lid lag, and lid retraction were present in the left eye. Clinical activity score (CAS) was 2/7 in the left eye and 0/7 in the right eye. There was no thyroid dermopathy or thyroid acropachy. Liver function tests (LFT), hemogram, and renal function tests (RFT) were normal. Thyroid function test (TFT) was suggestive of thyrotoxicosis with a raised titer of thyrotropin receptor antibody (TRAb) (Table 1) substantiating the diagnosis of Graves’ disease with mild thyroid eye disease (TED) [14]. The patient was started on carbimazole [20 mg once daily (OD)] and propranolol. Upon follow-up, symptoms were relieved, TED remained stable and TFT became normal after 4 months. The patient received a second dose of vaccine after normalization of T4 levels and there was no further worsening of TFT or TED.
| Patient 1 | Patient 2 | Patient 3 | Patient 4 | |
|---|---|---|---|---|
| Age (years) | 20 | 46 | 19 | 37 |
| Gender | Male | Female | Female | Female |
| Clinical presentation | Tremor, weight loss, bulging of left eye | Weight loss, heaviness both eyes | Hair loss, palpitation, weight loss | Weight loss, palpitation, increased frequency of stool |
| Time to onset of symptoms after vaccination (days) | 7 | 10 | 28 | 14 |
| History of autoimmune disease (self) | No | No | No | Yes |
| Family history of autoimmune disease | No | Yes | Yes | Yes |
| Goiter | No | No | No | No |
| Thyroid eye disease | Yes | Yes | No | No |
| Worsening after 2nd dose | No | Yes | No | Yes |
| T3 (ng/mL) (0.70–2.04) | 2.50 | 2.70 | 1.62 | 2.10 |
| T4 (μg/dL) (5.74–13.03) | 18.69 | 21.10 | 14.59 | 17.28 |
| TSH (μIU/mL) (0.34–5.60) | 0.002 | <0.01 | <0.01 | <0.01 |
| TRAb (IU/L) (<1.22) | 2.60 | >40 | 7.32 | 4.37 |
| Anti-TPO (U/mL) (<60) | Not done | 417 | 703 | 116 |
| Carbimazole initial dose (mg) | 20 | 30 | 10 | 20 |
| Follow up T3 (ng/mL) (0.70–2.04) | 1.1 (4 months) | 1.71 (2 months) | 1.09 (2 months) | 1.92 (3 months) |
| Follow up T4 (μg/dL) (5.74–13.03) | 6.79 (4 months) | 11.9 (2 months) | 6.6 (2 months) | 11.83 (3 months) |
| Follow up TSH (μIU/mL) (0.34–5.60) | 0.349 (4 months) | 0.15 (2 months) | 0.02 (2 months) | <0.01 (3 months) |
T3 - Triiodo thyronine, T4 - Thyroxine, TSH - Thyroid stimulating hormone, TRAb - Thyrotropin receptor antibody, Anti-TPO - Anti-Thyroid peroxidase
46-year-old female, non-smoker, non-alcoholic, with no previous personal history of thyroid/autoimmune disease presented with weight loss and heaviness of both eyes for two months. The patient started having symptoms 10 days after vaccination. There was a history of autoimmune hypothyroidism in the patient’s son. On examination, she had tremors, no goiter, a pulse rate of 90 beats/min, and a BP of 138/75 mmHg. She had TED with CAS of 2/7 and mild proptosis in both eyes. There was no thyroid dermopathy or thyroid acropachy. LFT was suggestive of transaminitis. Hemogram and RFT were normal. TFT was suggestive of thyrotoxicosis with a raised titer of TRAb (Table 1). The patient was started on carbimazole (30 mg OD) and propranolol. Upon follow-up, symptoms were relieved, TED remained stable and TFT became normal after two months. After receiving a second dose of the vaccine, symptoms of thyrotoxicosis reappeared along with worsening of TFT (T3, 1.70 ng/mL; T4, 21.3 μg/dL; TSH, <0.1 μIU/mL). There was no worsening of TED. Carbimazole dose was up titrated, and the patient became euthyroid in two months (T3, 0.95 ng/mL; T4, 9.01 μg/dL; TSH, 1.66 μIU/mL).
Case 319-year-old female, non-smoker, non-alcoholic; presented with hair loss, palpitation, and weight loss for one month. The patient started having symptoms four weeks after vaccination. There was a family history of autoimmune hypothyroidism in the mother and Graves’ disease in the father. On examination, pulse rate was 104 beats/min and BP was 124/70 mmHg. She didn’t have goiter and tremors. There was no TED, thyroid dermopathy or thyroid acropachy. LFT, RFT and hemogram were normal. TFT was suggestive of thyrotoxicosis with a raised titer of TRAb (Table 1). The patient was managed with carbimazole (10 mg OD) and propranolol. Symptoms improved and TFT normalized after two months. She received a second dose of the vaccine after normalization of TFT and there was no further worsening.
Case 437-year-old female, non-smoker, non-alcoholic presented with weight loss, palpitation, and increased frequency of defecation for four months. Symptoms started two weeks after receiving a first dose of Covid-19 vaccination but were ignored. The patient received a second dose 12 weeks later and had an increase in palpitation. She first sought medical consultation two weeks after her second dose. The patient had a history of autoimmune hypothyroidism for which she was treated from 2008–2011. A TFT done in January 2021 was normal. There was a family history of autoimmune hypothyroidism in the mother. Upon examination, her pulse rate was 100 beats/min and BP was 130/72 mmHg. She had tremors and there was no goiter. There was no TED, thyroid dermopathy or thyroid acropachy. LFT, RFT and hemogram were normal. TFT was suggestive of thyrotoxicosis with a raised titer of TRAb (Table 1). The patient was started on carbimazole (20 mg OD) along with propranolol and her TFT normalized after three months.
Mass immunization is a key strategy in the fight against COVID-19 to decrease viral transmission and disease severity. Although vaccines used against SARS-CoV-2 are safe in most cases, it’s critical to be aware of adverse effects, especially when they are used on a global scale. Our case series describes four cases of Graves’ disease that developed after administration of viral vector vaccine (ChAdox1nCoV-19) and the effect of administration of a second dose of vaccine in them.
All four cases in this case series had a temporal relationship between administration of the vaccine and onset of symptoms. Three out of four patients were female. Three patients (Patient 2, Patient 3, and Patient 4) had a self/family history of autoimmune disorder. Cases of Graves’ disease after SARS-CoV-2 vaccination have been described from all over the world. Thus, the development of Graves’ disease after SARS-CoV-2 vaccination doesn’t seem to be related to ethnicity or geography. However, similar to our study, female preponderance and history of autoimmunity have been frequently observed in previously reported cases. Hence, genetic predisposition and female gender can be considered important factors for the development of Graves’ disease after vaccination. While all cases in the present series had new-onset Graves’ disease after administration of the SARS-CoV-2 vaccine, relapse of Graves’ disease after SARS-CoV-2 vaccination has also been reported [15]. All patients responded well to medical treatment and became euthyroid after two to four months. Patient 2 and Patient 4 had worsening symptoms after receiving a second dose of the vaccine, an observation we first report here. This implies that subsequent vaccine administration may lead to amplification of an ongoing autoimmune response. It thus becomes pertinent to closely follow up individuals with existing Graves’ disease or individuals developing Graves’ disease after a first dose of the vaccine. In addition, there have been case reports of subacute thyroiditis following SARS-CoV-2 vaccination [8-10]. Since the symptomatic profiles of Graves’ disease and SAT are similar, early differentiation is important for timely initiation of appropriate treatment.
Patient 1 and Patient 2 had mild TED, which was one of the presenting complaints for both. Previously, to our knowledge, four cases of TED have been reported after SARS-CoV-2 vaccination [15, 16]. TED can precede, present concurrently, or follow hyperthyroidism. While both our patients had concurrent presentation of TED with hyperthyroidism, it’s plausible that TED could be the sole presenting complaint. Two out of four patients in our case series had TED. Taking into consideration cases reported so far, the frequency of TED was higher in our series. Three out of four cases reported worldwide of TED after SARS-CoV-2 vaccination are from Asia. A previous meta-analysis has shown the prevalence of TED to be highest in individuals of Asian ethnicity [17]. Hence, genetic predisposition of the population might be a reason for a higher frequency of mild TED observed in our study.
Adjuvants are added in the vaccine to enhance immunogenicity, but they may result in exaggerated or inadvertent immune response in genetically predisposed individuals resulting in ASIA syndrome. Adjuvants can lead to the development of ASIA syndrome either by induction of autoimmunity or unmasking of latent autoimmune disease. The exact pathophysiological mechanism of ASIA syndrome is not known. Since the recognition of ASIA syndrome in 2011, many endocrine manifestations have been reported after the administration of various vaccines. However, Graves’ disease as a manifestation of ASIA syndrome has only been reported after the administration of the vaccine against SARS-CoV-2.
Thyroid dysfunction, ranging from thyrotoxicosis to hypothyroidism, has been described after SARS-CoV-2 infection [18]. Molecular mimicry has been implicated as one of the pathophysiological mechanisms of SARS-CoV-2 for COVID-19-related manifestations in different organs [19]. In addition, molecular mimicry is the pathophysiological mechanism for triggering Graves’ disease by various infectious agents. The onset of Graves’ disease both after infection with SARS-CoV-2 and vaccine against SARS-CoV-2 points toward the potential role of spike protein in the induction or unmasking of autoimmunity in genetically predisposed individuals. Hence, it remains a matter of debate whether the onset of Graves’ disease after vaccination against SARS-CoV-2 is a result of the bystander effect of adjuvants or probable immunogenicity of spike protein itself. To the best of our knowledge, cases of Graves’ disease after administration of the SARS-CoV-2 vaccine have been observed only with mRNA and viral vector vaccine. In a case report by Sriphrapradang (2021) a patient received two doses of inactivated vaccine but developed Graves’ disease only after administration of a booster dose of viral vector vaccine [20]. Hence, the mode of antigen delivery seems to have a relationship with the development of Graves’ disease after SARS-CoV-2 vaccination. However, due to a lack of clear evidence, nothing can be conclusively postulated at present.
The benefits of mass immunization outweigh the minor risk of side effects in genetically susceptible populations and an ongoing immunization program is strongly endorsed. However, as recommendations for booster doses are updated, it becomes important to be aware of the new-onset Graves’ disease and worsening of the already existing disease after vaccination. The purpose of this case series is to make clinicians aware of the development of Graves’ disease following vaccination, so that onset of thyrotoxic symptoms with a temporal relationship to administration of the vaccine is not overlooked and treated timely. This is especially pertinent in individuals with a personal/family history of autoimmune disorder. In the light of the present case series, we purpose that in individuals with already existing or new-onset Graves’ disease after vaccination, euthyroidism should be ensured before the administration of a vaccine. In addition, these patients should be closely followed up after administration of the vaccine to look for the worsening of thyrotoxicosis.
None.
Written informed consent for publication of their clinical details was obtained from the patients.
