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Carsote, M.; Popescu, M.; , .; Vasile, C.; Ghenea, A.E. Subacute Thyroiditis and the COVID-19. Encyclopedia. Available online: https://encyclopedia.pub/entry/22347 (accessed on 23 June 2024).
Carsote M, Popescu M,  , Vasile C, Ghenea AE. Subacute Thyroiditis and the COVID-19. Encyclopedia. Available at: https://encyclopedia.pub/entry/22347. Accessed June 23, 2024.
Carsote, Mara, Mihaela Popescu,  , Corina Vasile, Alice Elena Ghenea. "Subacute Thyroiditis and the COVID-19" Encyclopedia, https://encyclopedia.pub/entry/22347 (accessed June 23, 2024).
Carsote, M., Popescu, M., , ., Vasile, C., & Ghenea, A.E. (2022, April 27). Subacute Thyroiditis and the COVID-19. In Encyclopedia. https://encyclopedia.pub/entry/22347
Carsote, Mara, et al. "Subacute Thyroiditis and the COVID-19." Encyclopedia. Web. 27 April, 2022.
Subacute Thyroiditis and the COVID-19
Edit

Subacute thyroiditis (SAT), also known as De Quervain or granulomatous thyroiditis, is caused by a viral infection, especially (but not exclusively) of the upper respiratory tract or by post-viral inflammation. Since 2020, the entity has been listed in association with the coronavirus disease 2019 (COVID-19) infection, and since 2021 it has been related to the vaccine against the virus.

subacute thyroiditis COVID-19 infection

1. Subacute Thyroiditis Induced by COVID-19 Infection

SAT might occur simultaneously with COVID-19 infection (the viral form) or it might occur within days or weeks after infection (usually within 6 to 8 weeks, although up to 6 months have been reported); the term “post-viral thyroiditis” seems more appropriate for this form [1][2]. Knowing that non-coronavirus thyroiditis follows the infection, concomitant thyroid inflammation with the triggering infection represents a particular aspect of this new entity.
The clinical picture may be associated with the typical signs and symptoms underlying hyperthyroidism and thyroid inflammation and/or various COVID-19 infection presentations (from asymptomatic forms to complicated, severe presentations including COVID-19 pneumonia and others) [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40].
Some authors suggest the presence of more intense neck pain, a higher incidence of fever, and more frequent hypothyroidism at 3 months, which is opposite to other forms of SAT not associated with COVID infection [3]. However, not all the data sustain these assertions. Based on the analysis, the youngest patient was 18 years old and the oldest was 85 years old, and typical patients were middle-aged adult females [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40]. The previous medical histories of affected individuals did not indicate any particular risk factors; a few cases with prior diagnosis of autoimmune thyroiditis or thyroid nodules/cancers were reported, but thyroid comorbidities were not associated with a higher risk of SAT in coronavirus-positive patients.
The real incidence of SAT among subjects infected with SARS-CoV-2 virus is currently unknown. The severity of COVID-19 infection that is complicated with SAT varies from severe presentations requiring hospitalization and admission to intensive care units to completely asymptomatic cases. There is one report of an 85-year-old male with postmortem diagnosis of SAT [40]. As expected, post-viral forms were less severe than viral SAT.
Based on the published data, two types of SAT-associated clinical spectra were considered. One pattern involves patients heavily affected by the COVID-19 infection and the other involves patients that develop a mildly symptomatic (or completely asymptomatic) form. Both of them may be under-diagnosed concerning SAT, for different reasons. It has been suggested that in cases with severe COVID-19 disease, SAT is difficult to recognize since multiple other manifestations of infection are present and mask thyroid inflammation, which otherwise should be listed among the extra-pulmonary spreading of the coronavirus infection [6][7]. Some authors have suggested that 20% of severe coronavirus infections have various thyroid involvements. Concerning the general COVID-19 picture of viral SAT in severe infections, the most affected organ is the lung, while the most important complication of SAT-related thyroid anomalies involves cardiac function. No relationship between hospitalization length and SAT was identified. The less severe aspects were cases of SAT as single manifestations of coronavirus infection or as first manifestation of a mild infection or associated with a clinical picture dominated by SAT rather than COVID-19 infection. Most post-viral forms also expressed this pattern. Recently, it was suggested that SAT represents an exponent of the post-COVID-19 recovery period [8][9]. Some authors have explained that post-COVID-19 fatigue induced by hypothyroidism is due to SAT after developing transitory (and probably unrecognized) hyperthyroidism [10].
Expert opinions indicate a high rate of suboptimal diagnosis of SAT since the condition is more frequent than people know. Routine COVID-19 tests are useful in each new case of SAT in the COVID-19 pandemic. Post-viral forms are more clearly identified and adequately recognized in the absence of other viral infections [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35]. However, pre-pandemic versus pandemic studies analyzing SAT incidence in areas with increased incidence of COVID-19 infection did not report a higher rate but this is still an open issue [4].
Nowadays, COVID-19 infection correlates with a new entity of SAT, which is traditionally known to be associated with various viral infections (Coxsackie, influenza, mumps, adenoviruses, measles, rubella virus, etc.) [41]. The data people have from other etiologies concerning potential predisposition seem applicable to coronavirus infection; in particular, HLA (human leukocyte antigen) configuration and also female sex are more frequently affected [11][12][13]. The clear differences among other forms of SAT are yet to be established since the current amount of statistical evidence is low and thus a general conclusion is premature [14][15][16].
The pathogenesis of thyroid involvement includes virus-induced direct damage of follicular cells followed by fibrosis (mostly found in destructive thyroiditis) due to the coronavirus targeting angiotensin converting enzyme 2, which is abundant in the thyroid; immune anomalies; either increased or suppressed immune response, especially during severe infections; cytokine imbalances (for instance, TNF suppression causes increased IFN-alpha as a promotor of thyroid inflammation); thyroid inflammation may also be caused by the host immune response to coronavirus (including a post-viral reaction), not only by direct invasion [13][14][15][16].
Inflammation assays are positive in the majority of SAT cases. Based on the current data, there is no clear correlation between the clinical presentation of SAT during/after COVID-19 infection and inflammatory markers, nor was a highly suggestive marker of potential thyroid involvement identified in a patient developing coronavirus infection (except for what people already know about HLA susceptibility). IL-6 seems to be correlated with the severity of thyrotoxicosis. Thyroid hormone imbalance (low TSH, high FT4) might display the pitfall of FT3 levels (which are low in non-thyroidal illness syndrome and high in typical SAT).
The traditional evaluation based on thyroid ultrasound is also very practical and it should be routinely performed in each case of SAT considering the limits of the pandemic-related digital medicine era [17][18][19][20][21][22]. Fine-needle aspiration biopsy at the thyroid level, despite not being routinely indicated in other etiologies of De Quervain thyroiditis, in this case might become a very useful tool (and are an original feature of COVID-19-associated SAT), especially in poorly symptomatic cases, in post-viral circumstances, and in situations when differential diagnosis is difficult to establish unless a cytological report is provided [15][16].
It is important to be aware of this particular complication of the COVID-19 infection and to differentiate it from other acute complications such as pneumonia or thromboembolism as some complications require investigations where iodine contrast is used for computer tomography. Such investigations might aggravate thyroid hormone anomalies, such as, for instance, in cases with primary hyperthyroidism [5]. Also, once SAT is recognized, specific anti-thyroid drugs are unnecessary since beta-blockers and non-steroidal anti-inflammatory drugs usually control the disease; glucocorticoids should be used as a last resort for cases with severe local symptoms [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40]. Some reported cases were already under glucocorticoid medication therapy due to COVID-19 evolution, possibly delaying the diagnosis of SAT [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38].
It can be identified a single, prospective study from 2022 which included 64 patients, with 18.8% of them diagnosed with coronavirus-related SAT (3 out of 12 patients had thyroid involvement as the first sign of COVID-19 infection) and 9.3% of all (n = 6) diagnosed with vaccine-induced thyroiditis; the clinical presentation, laboratory assessments and therapies were similar among patients with COVID-19 versus non-COVID-19 etiologies, while SAT after immunization had statistically significantly fewer severe symptoms [38].
Overall, delaying or missing the diagnosis of SAT has at least four practical consequences. In severe forms of COVID-19 infection, thyroid disease aggravates the general status, with particular concerns being tachycardia/arrhythmias, cardiac insufficiency, and ischemic events. At the other end of the spectrum, a patient with SAT as the single manifestation of the infection may be an unrecognized case of COVID-19 and spread the disease amid the pandemic. On the other hand, there were situations involving misdiagnosis, where high levels of thyroid hormones were unnecessarily treated with anti-thyroid drugs or where fever of unknown cause, with or without local neck pain, was treated with antibiotics. Also, a newly detected case of hypothyroidism during the pandemic requires differential diagnosis with virus-induced low levels of thyroid hormones, including post-SAT hypothyroidism.
Once recognized, SAT does not seem to require a particular approach when compared with non-COVID-19 cases. A complete resolution of thyroid hormone anomalies and inflammation is expected; except for a small percentage of individuals with permanent hypothyroidism (the rate of which seems similar to non-COVID SAT). The current level of statistical evidence is expected to change in the next period of time.

2. Subacute Thyroiditis following Vaccine against COVID-19 Infection

SAT as a result of an immune response caused by COVID-19 vaccination represents a new topic in the medical literature due to the novelty of the vaccine [42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79]. The thyroid’s reaction is either that of SAT, with the traditional clinical presentation characterized by local anterior cervical discomfort/pain, fever, hyperthyroidism-related signs, or silent thyroiditis (the asymptomatic pattern), which is diagnosed based on blood and ultrasound assays and/or histological/cytological reports [43].
The thyroid’s involvement appears after vaccination, within a period ranging between a few hours and a few weeks (no particular pattern related to the first or second vaccine dose has been identified so far) [44]. A differential diagnosis is mandatory in order to exclude alternative causes of thyroiditis—not only concurrent COVID-19 infection itself but also influenza, cytomegalic infection, Epstein-Barr infection, measles, rubella, or even mumps [44].
The pathogenesis of vaccine-induced thyroiditis includes anomalies of immuneoinflammatory response, as similarly described in viral and post-viral forms. Immune system over-activation and molecular mimicry between the thyroid (such as thyroid peroxidase peptide sequences) and vaccine components (especially spike protein) represent the most important mechanism. Another hypothesis includes ASIA syndrome (autoimmune/auto inflammatory syndrome induced by adjuvants), suggesting that the vaccination acts as a trigger of autoimmune thyroid response, but this is yet to be determined [42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79]. An alternative theory to the vaccine-induced immune/autoimmune response is represented by vaccine-induced higher viscosity status, which may cause an abnormal increase in thyroid hormone levels due to their excessive release from the thyroid, particularly in patients displaying a higher risk for coagulation anomalies [45][46].
In vaccine-induced thyroiditis, neck pain and general changes due to inflammation may require general glucocorticoid therapy but only in selected cases and not as a general rule; hyperthyroidism–related tachycardia may be controlled with beta-blockers such as propranolol [44].
Despite these reports, vaccination against COVID-19 is encouraged since SAT is extremely rare and is typically associated with good clinical evolution and good long-term outcomes due to the condition being self-limiting [47][48].
From what people know so far concerning the risk factors, a prior episode of SAT with non-COVID 19 etiology is not associated with a higher risk of vaccine-related thyroiditis, nor is a previous history of coronavirus infection itself. Similarly, an SAT episode after the first dose of the vaccine does not restrict immunization protocols.
In general, the female sex is more prone to developing any type of SAT or autoimmune condition. Among the few reported cases, a series showed two sisters developing SAT symptoms after immunization. A specific genetic background is difficult to consider at this point (except for HLA susceptibility in non-coronavirus SAT) [49][50]. Moreover, one reported case had a previous diagnosis of Hashimoto’s thyroiditis, which traditionally does not increase the risk of subacute thyroid inflammation [49][50]. Another female subject also had a prior diagnosis of anti-thyroid antibody–induced chronic thyroiditis as well as a confirmation of papillary thyroid carcinoma which had not been treated with radioiodine therapy at the time the vaccination-induced thyroiditis was detected [51].
Here also mention a reported case of (what most likely was) acute thyroiditis in association with bilateral optic neuritis after vaccination (noting that isolated optic neuritis after COVID-19 infection has also been described) [52][53].
It can be concluded that vaccine-related SAT is typically less symptomatic than other types and variably follows either the first or second dose within an average of 2 weeks. The diagnosis should be established in the absence of other well-known etiologies. The pathogenic mechanisms are less understood; people do not know any individual, new risk factors. Complete remission is found in all cases without specific requirements other than what people already know for SAT.
Practitioners should be aware of post-vaccine SAT, which does not represent at all a restriction for vaccination as it appears as an exceptional event based on the current level of evidence [54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79]. It can be clearly stated that the benefits of vaccines against coronavirus far outweigh any transient issues concerning the thyroid gland (Table 1).
Table 1. Evidence of subacute thyroiditis following vaccination against COVID-19 infection (the name of the vaccine as used by authors of the original studies is provided).
Number First Author/Reference Number Year Type of Study Number of Patients Type of Vaccine Others Observations
1. Siolos A. [43] 2021 Case series 2 1. Pfizer-BioNTech 1. SAT (after 2 w)
2. AstraZeneca 2. SAT (after 3 w)
2. Kyriacou A. [44] 2021 Case report 1 Pfizer-BioNTech SAT (after 12 h)
3. Soltanpoor P [47] 2021 Case report 1 COVAXIN (The Bharat BiotechCOVID-19 Vaccine) SAT (after 5 d)
4. Saygılı ES. [48] 2021 Case report 1 CoronaVac SAT (after 2 w)
5. Chatzi S. [49] 2021 Case series 2 1. Pfizer-BioNTech 1. SAT (after 12 d) *
2. Pfizer-BioNTech 2. SAT (after 4 d) **
6. Sigstad E. [51] 2021 Case report 1 Pfizer-BioNTech SAT (after 6 d) ***
7. Patel KR. [54] 2021 Case report 1 NA SAT (after 7 d)
8. Bornemann C. [55] 2021 Case series 2 1. Spikevax (Moderna Biotech) 1. SAT (after 7 d) ****
2. Vaxzevria (AstraZeneca) 2. ST (after 3 d) ****
9. Oyibo SO. [56] 2021 Case report 1 ChAdOx1 nCoV-19 vaccine, (AstraZeneca) SAT (after 7 d)
10. Şahin-Tekin SM. [57] 2021 Case report 1 CoronaVac SAT (after 17 d)
11. İremli BG. [58] 2021 Case series 3 CoronaVac SAT (after 4 to 7 d) *****
12. Schimmel J. [59] 2021 Case series 3 BNT162B2 SAT (after 24 h)
13. Ratnayake GM. [60] 2021 Case report 1 ChAdOx1, Vaxzevria (AstraZeneca) SAT (after 2 w)
14. Das L. [61] 2021 Case report 1 ChAdOx1 nCoV-19 (Astra Zeneca) SAT (after 2 w)
15. Jeeyavudeen MS. [62] 2021 Case report 1 COVID-19 mRNA vaccine BNT162b2 (Pfizer-BioNTech) SAT (2 w after second dose)
16. Plaza-Enriquez L. [63] 2021 Case report 1 Moderna mRNA COVID-19 vaccine SAT (6 d after second dose)
17. Pujol A. [64] 2021 Case series 1 out of 3 cases Moderna mRNA COVID-19 vaccine SAT (8 d after first dose)
18. Sözen M. [65] 2021 Case series 4 COVID-19 mRNA vaccine (Pfizer/BioNTech®) SAT onset:
1. 1 d after first dose
2. 6 d after second dose
3. 4 d after first dose
4. 20 d after second dose
5. progressive onset after first dose and exacerbation after second dose
19. González López J. [66] 2021 Case series 2 1. Comirnaty© SAT was identified:
1. 3 d after second dose
2. 2 w after first dose
2. Vaxzevria©
20. Khan F. [67] 2021 Case report 1 Pfizer-BioNTech SAT (4 d after second dose)
21. Pandya M. [68] 2021 Case series 3 1,2. Pfizer Bio-NTech SAT onset:
1. 10 d after first dose
3. Moderna COVID-19 mRNA vaccine 2. 20 d after second dose
3. 15 d after first dose
22. Vasileiou V. [69] 2021 Case report 1 SARS-CoV-2 mRNA vaccine Comirnaty (Pfizer/BioNTech) SAT (10 d after first dose)
23. Pla Peris B. [70] 2021 Case series 3 out of 8 cases Moderna® SAT (10 to 14 d)
24. Bahçecioğlu AB. [38] ****** 2022 Prospective study 6 out of 64 cases n = 4 with 2 doses of Sinovac-CoronaVac®
n = 2 with single dose of Pfizer-BioNtech®
SAT (1 to 12 w after vaccine)
25. Bostan H. [71] 2022 Case series 2 1. Pfizer-BioNTech® 1. SAT after 3 d
2. CoronaVac® 2. SAT after 6 d
26. Oğuz SH. [72] 2022 Longitudinal study 15 Pfizer-BioNTech COVID-19 vaccine (BNT162b2) SAT (after a median of 11.5 d (median time of remission 11.4 w))
27. Jhon M. [73] 2022 Case report 1 RNA-1273 (Moderna) vaccination SAT (5 d after first dose)
28. Yorulmaz G. [74] 2022 Case series 11 6/11 with BNT162b2 Pfizer/BioNTech COVID-19 mRNA vaccine®
4/11 with Coronavac inactivated SARS-CoV-2 vaccine®
1/11 with first dose of BNT162b2 after two doses of Coronavac
SAT (after an average time of 22 d (15 to 73 d))
29. Pipitone G. [75] 2022 Case report 1 Comirnaty by Pfizer Inc. (New York, USA) SAT (1 w after first dose)
30. Stasiak M. [76] 2022 Case series 2 Pfizer-BioNTech 1. SAT a few days after second dose
2. SAT 3 w after second dose
31. Bennet WM. [77] 2022 Case report 1 COVID-19 vaccine AstraZeneca SAT (1 w after first dose)
32. Kishimoto M. [78] 2022 Case series 2 COVID-19 mRNA vaccine One SAT case with masive liver dysfunction
33. Huo J. [79] 2022 Case report 1 COVID-19 vaccination SAT (after 1 w)
Abbreviations: SAT = subacute thyroiditis; SL = silent thyroiditis; w = week; d = days; h = hour; NA = not available. * After the first dose (the patient had a prior diagnosis of Hashimoto’s thyroiditis). ** After the second dose; the patients were sisters. *** The diagnosis was established as a post-operative pathological diagnosis. **** Also confirmation based on fine-needle aspiration cytology. ***** Two of the three females were in the breastfeeding period. ****** The study is also mentioned in previous content since it includes both types of subacute thyroiditis (vaccine-induced and virus-induced).

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