Subacute Thyroiditis after COVID-19: A Literature Review

ABSTRACT. Subacute thyroiditis (SAT), potentially caused by severe acute respiratory syndrome coronavirus 2 infection, has been reported as a complication of COVID-19 since 2020. The clinical characteristics and outcomes of SAT after COVID-19 remain incompletely defined. Therefore, we aimed to collect and survey case reports of SAT after COVID-19. We performed a systematic search of PubMed/MEDLINE, Web of Science, and Google Scholar. The keywords and MeSH terms used for the searches were “subacute thyroiditis” and “COVID-19.” A total of 38 patients from 26 case reports, case series, and letters on SAT associated with COVID-19 were included and analyzed. The most frequent SAT symptom was neck pain (27 cases), followed by fever (22 cases). Of the 25 cases with information on the duration between onset of COVID-19 symptoms and onset of SAT symptoms, the shortest was simultaneous occurrence, and the longest was 4 months. In most cases, patients developed SAT at several days or weeks after the onset of COVID-19. All patients with SAT recovered with no severe complications or sequelae. Clinicians should be aware of the possibility of SAT development in patients with neck pain and fever following COVID-19. Further research is necessary to determine the relationship between SAT and COVID-19.


INTRODUCTION
The COVID-19 pandemic, caused by SARS-CoV-2, has devastated the world since its emergence in 2019. 1 Although the leading cause of death associated with COVID-19 is acute respiratory distress syndrome, 2 other complications associated with COVID-19 have been reported, including acute kidney injury, pulmonary embolism, acute myocarditis, and septic shock. 3 Currently, subacute thyroiditis (SAT), potentially invoked by SARS-CoV-2 infection, has been reported as a possible complication associated with COVID-19. 4,5 SAT can be caused by multiple triggers, including viral infection, postinflammatory processes, and autoimmunity. 6,7 Patients with SAT exhibit fever, neck pain, and a tender diffuse goiter as well as abnormalities in serum thyroid hormones. The clinical characteristics and outcomes of SAT after COVID-19 remain incompletely defined.
In the present study, we gathered information on SAT after COVID-19 from case reports available in digital databases and described its clinical practice patterns, clinical symptoms, and outcomes. We aimed to examine the collected data on SAT after COVID-19 to further understand the relationship between SAT and COVID-19.

METHODS
Oversight and search strategy. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement, 8 we conducted a systematic search of PubMed/MEDLINE, Web of Science, and Google Scholar. References in the selected articles were reviewed manually and crosschecked for other relevant reports. The search of PubMed/MEDLINE was performed with the following MeSH terms: "COVID-19" and "Thyroiditis, Subacute." The searches in Web of Science and Google Scholar were carried out with the following terms: "COVID-19" and "Subacute thyroiditis." The full search terms were "COVID-19" [MeSH] AND "Thyroiditis, Subacute" [MeSH] and "COVID-19" AND "Subacute thyroiditis" in PubMed/MEDLINE; (covid) AND (subacute thyroiditis) in Web of Science; and (COVID-19) AND (subacute thyroiditis) AND (case report) in Google Scholar. The quality of the included articles was assessed using the CARE guidelines. 9 Selection of case reports. The inclusion criteria for the case reports were as follows: 1) SARS-CoV-2 infection confirmed in the context, 2) diagnosis of SAT confirmed in the context, 3) article written in English, and 4) article published from 2020 to 2021. Cases were excluded if they had too little information, such as conference abstracts or autopsy reports only, or if they were duplicated. When results from a case were reported more than twice, the most recent case report was used. All case reports identified in the databases were screened for eligibility on title and abstract.
Extraction of clinical information. Y. A. conducted the extraction of clinical information from the literature with the assistance of Y. O. Data extracted for the cases included sex, age, past medical history of thyroid disease, race, onset date of COVID-19 symptoms, duration of COVID-19 symptoms, duration between onset of COVID-19 symptoms and onset of SAT symptoms, COVID-19 management, SAT management, steroid usage, information on recovery, and prognosis (died or survived).

RESULTS
We identified 1,379 articles in our digital searches. After reviewing the titles and abstracts and excluding duplicates, we identified 38 cases in 26 articles published up to the end of December 2021. 4,5,10-33 A flow chart of the article selection process is shown in Figure 1, and an overview of the 38 cases included in the study is provided in Table 1. The quality of the 15 case reports, four case series, six (scientific) letters, and one brief report was assessed and scored using the CARE guideline checklist (Supplemental Table 1). 9 All 26 articles contained patient demographic information and diagnosis of SAT after COVID-19.
Of the 38 patients with SAT after COVID-19, 25 were women. In the four case reports that described patient race, two patients were Caucasian and two were Asian. Among the total patients, two had past medical history of thyroid disease, described as nontoxic goiter. We confirmed SARS-CoV-2 infection in the context from a swab or laboratory examination in 20 cases. COVID-19 symptoms were confirmed for 32 cases. The most frequent COVID-19 symptom was fever (22 cases). Three cases were described as asymptomatic. Three case reports did not describe the COVID-19 symptoms. On the basis of the living guidance for clinical management of COVID-19 provided by the WHO, 34 23 cases were categorized as mild, seven cases as moderate, and two as severe.
All reports for the 38 cases described SAT symptoms. The most frequent SAT symptom was neck pain (27 cases), followed by fever (22 cases). Of the 25 cases with information on the duration between onset of COVID-19 symptoms and onset of SAT symptoms, as mentioned in the text or able to be calculated, the shortest was simultaneous occurrence (0 days) and the longest was 4 months. In most cases, patients developed SAT at several days or weeks after the onset of COVID-19.
We confirmed that the thyroid state was described for 22 cases. Enlarged thyroid was the most common state (11 cases), followed by any tenderness (nine cases). We further confirmed that 37 patients had thyrotoxicosis, evaluated by detection of free T4, free T3, or thyroid-stimulating hormone. One article did not mention the actual serum levels of thyroid hormones, but we concluded that the patient experienced SAT from the following text: "Thyroid function tests were consistent with subclinical hypothyroidism." 4 The states for thyroglobulin, thyroglobulin antibody, antithyroid peroxidase antibody, and thyroid-stimulating hormone receptor antibody were mentioned in 27 cases. We further extracted the results of biological examinations reported for 35 cases. Of these 35 cases, 31 cases had increased Creactive protein, and 30 cases had confirmed elevation of erythrocyte sedimentation rate. Interleukin-6 was measured in only one case and was found to be elevated. 31 Ultrasound analysis of the thyroid was carried out in 14 cases and revealed hypoechoic areas in an enlarged thyroid in most cases. These findings were consistent with SAT.
Management of SAT was reported for 30 cases. Twentyfive patients were treated with corticosteroids such as prednisone. All patients recovered from both COVID-19 and SAT, although four patients suffered from hypothyroidism after SAT. 20,22,23,29

DISCUSSION
In this study, we analyzed 38 cases of SAT after COVID-19. Most patients developed SAT at several days or weeks after the onset of COVID-19. However, some cases had onset of SAT at several months after the onset of COVID-19. In most SAT cases, the severity of COVID-19 was categorized as mild. The symptoms associated with SAT were similar to those previously reported for typical SAT cases. 35,36 Although four patients suffered from hypothyroidism after SAT, none of the patients died of SAT.
We found that the clinical characteristics of SAT after COVID-19 were similar to those of typical SAT. In general, young female adults are commonly affected by SAT, 36,37 and the cases in the present study were consistent with this trend. The present study also demonstrated that the biological data for SAT after COVID-19 resembled those for typical SAT. These similarities suggest that SAT associated with COVID-19 may occur with the same pathophysiology as typical SAT, including viral infection, post-inflammatory processes, and autoimmunity. To date, the incidence rate of  (continued)   Our study showed that SAT can develop regardless of the severity of COVID-19. Previous reports indicated the importance of IL-6 in the cytokine storm associated with COVID-19. 38,39 Direct damage to the thyroid gland was also hypothesized. 40 However, in most SAT patients, the severity of COVID-19 was categorized as mild or moderate.
Most patients with SAT were treated with steroids, followed by gradual tapering over several months. It is noteworthy that all the patients in our study became asymptomatic within several months. Previous reports described that some patients with COVID-19 had sequelae, such as fatigue, dyspnea, chest pain, and cough. 41,42 Patients with COVID-19 can also have psychological or cognitive symptoms. 43,44 In our study, all patients with SAT following COVID-19 had no remarkable sequelae after their recovery.
Thyroid and COVID-19. Currently, several reports have suggested an underlying relationship between the thyroid and COVID-19. Expression of angiotensin-converting enzyme 2 receptor was detected in the thyroid, 45,46 leading to a hypothesis that SARS-CoV-2 directly infects the thyroid tissue. 47 This may arise because angiotensin-converting enzyme 2 receptor and cellular protease TMPRSS2 are the SARS-CoV-2 entry requirements for infection. 48,49 Some researchers mentioned the anatomical location of the thyroid, being near the front of the airway and lying against and around the front of the larynx and trachea. 47,50 Specifically, this anatomical location can provide an easy entry point for the virus.
Strengths and limitations. The strength of our study is the relatively large number of cases compared with previous studies because we accumulated cases until the end of December 2021. In addition, the WHO staging was applied. 34 Our study showed that SAT can occur regardless of the severity of COVID-19, thus alerting physicians that SAT can develop under COVID-19 therapy.
The present study has some limitations. First, the number of cases collected was too small to reach a conclusion on the relationship between SAT and COVID-19. Second, the descriptive quality of the case reports was heterogeneous, which made it difficult to review the reports comprehensively. Because the effect of publication bias was strong and statistical analysis will result in low generalizability, we refrained from conducting statistical analyses. Third, publication bias could be inevitable in this research because there are likely unpublished cases of SAT after COVID-19. This may arise because SAT is not always critical and may be overlooked by physicians. Finally, bias arising from the database or language choices may have affected the case selection.
Nevertheless, given the increasing numbers of COVID-19 cases worldwide, it is estimated that the number of cases with SAT after COVID-19 infection will increase. The present research enables physicians to consider certain clinical implications, such as when to suspect SAT in COVID-19 patients or when to prescribe agents. In addition, we suggest the importance of monitoring serum levels of thyroid hormones in COVID-19 patients.
Conclusion. In conclusion, SAT may develop days or weeks after the onset of COVID-19. The clinical features of SAT after COVID-19 were similar to those of typical SAT, and in most cases, the patients achieved complete remission using steroids without sequelae. Clinicians should be aware of the possibility of SAT in patients with neck pain and fever after COVID-19.