Subacute Thyroiditis in Active COVID-19 Infection: A Report of Two Cases With a Systematic Review of the Literature

Subacute thyroiditis (SAT) is a self-limiting inflammatory condition of the thyroid gland with distinct symptoms and a predictable outcome. During the current COVID-19 pandemic, there have been multiple isolated reports of SAT either during the active viral illness or following recovery. Here, we report two such cases of COVID-19 infection presenting with SAT. A 65-year-old male presented with a two-week history of anterior neck pain, odynophagia, high-grade fever (38.9°C), sweating, palpitations, and tremulousness. At physical examination, the patient presented with a slightly increased heart rate and a tender and enlarged thyroid on palpation. Laboratory examination showed high C-reactive protein levels, with elevated erythrocyte sedimentation rate, and thyroid function tests were suggestive of thyrotoxicosis. Ultrasonography showed a heterogeneous thyroid gland with ill-defined hypoechoic areas, and thyroid scintigraphy showed reduced uptake, confirming the diagnosis of SAT. In another case, a 52-year-old male presented with fever, cough, and myalgias, and was diagnosed with mild COVID-19 pneumonia, and managed conservatively. After two weeks, the patient had a recurrence of high-grade fever, odynophagia, palpitations, and tremors. Examination revealed tachycardia, hyperhidrosis, and a tender and enlarged thyroid on palpation. Thyroid function tests revealed low thyroid-stimulating hormone, with normal total T4 and total T3. Ultrasonography examination showed a heterogeneous thyroid gland with bilateral ill-defined hypoechoic areas. In our systematic review, including 103 SAT cases, it has been suggested that SAT should be recognized as an uncommon extra-pulmonary clinical manifestation of COVID-19 infection and clinicians need to be aware of the association. Pending larger multicentric studies, management of the condition has to be on a case-by-case basis.

A host of viral infections, including coxsackievirus [5], mumps [6], Epstein-Barr virus [7], cytomegalovirus [8], and influenza virus [1,[9][10][11][12], have been incriminated in the causation of SAT.Initially, it was thought that this disease is common in summers [13], but other studies have shown it to be equally distributed throughout the season [4,14].Over the last two years, during the unprecedented pandemic of coronavirus disease 2019 (COVID-19), a number of case reports of SAT have appeared suggesting that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection acts as a trigger of SAT, which may present either during the infection or after it has resolved [2].COVID-19 is a highly contagious disease caused by the SARS-CoV-2 [15], a positive-sense, single-stranded, enveloped RNA virus belonging to the beta-coronavirus family.SARS-CoV-2 is phylogenetically related to SARS-CoV-1, the virus that causes severe acute respiratory syndrome (SARS).During the SARS-CoV-1 outbreak, the histopathology of the thyroid gland of infected individuals demonstrated the destruction of epithelial cells, parafollicular cells, and follicular epithelial cells [16].The main mechanism proposed for this thyroid injury is extensive apoptosis of cells rather than cell necrosis or inflammatory infiltration.Although SARS-CoV-1 results in severe infection, its effect on thyroid is believed to be less severe than that of SARS-CoV-2 [16].Early in the current SARS-CoV-2 pandemic, several reports of SAT and cases of thyroid dysfunction were reported [17][18][19] and this led to a notion that SAT was an underestimated manifestation of COVID-19 [20][21][22][23][24].As per a recent systematic review, thyroid dysfunction in COVID-19 patients in intensive care units may partly be accounted for by non-thyroidal illness syndrome.Furthermore, several studies have shown that thyroid dysfunction does not increase the risk of SARS-CoV-2 infection and hence patients with thyroid dysfunction may not need any COVID-19-adapted follow-up [25].
We herewith report two cases of SAT temporally associated with acute COVID-19 infection.Besides, we have systematically reviewed the literature to describe clinical characteristics, treatment requirements, resolution rates, and outcomes of SAT in COVID-19 patients.

Case Presentation
Case 1 AB, a 65-year-old male, presented with a two-week history of anterior neck pain, odynophagia, high-grade fever (38.9°C), sweating, palpitations, and tremulousness.In the preceding week, the patient had a history of cough, myalgias, fever, and fatigue.A rapid antigen test was positive for COVID-19 and family members exhibited a similar illness.The patient had received two doses of COVISHIELD (Oxford-AstraZeneca vaccine) and the last dose was given seven months back.On current examination, the patient was conscious and oriented with a heart rate of 100 per minute, blood pressure of 120/80mmHg, and BMI of 27.99 kg/m2.The thyroid gland was enlarged (WHO grade II) and tender, with no bruit.Laboratory tests on admission showed a high CRP level, with elevated ESR and thyroid function tests, suggestive of thyrotoxicosis (a low TSH, elevated total T4, and elevated total T3) (Table 1).Thyroid-peroxidase antibody (TPO-Ab) was negative and an ultrasound of the neck showed a heterogeneous thyroid gland (right lobe: 2.1 × 2.6 × 4.5 cm; left lobe: 2.2 × 2.6 × 4.2 cm) with ill-defined hypoechoic areas and small cervical lymph nodes (Figure 1).Radiography of the chest revealed bilateral ground glass opacities and the oxygen saturation was normal.
Thyroid scintigraphy showed reduced uptake, confirming the diagnosis of subacute thyroiditis.The patient was treated with ibuprofen 400 mg twice daily and propranolol 40 mg once a day for one week.Since the symptoms continued, the patient was put on prednisolone 60 mg daily for one week, followed by tapering of the dose over eight weeks.Although repeat thyroid function after six weeks revealed normal total T4 (10.43 μg/dl), total T3 (121.2ng/dl), and TSH (3.780 mIU/mL), the patient developed dysglycemia, which was managed with a combination of teneligliptin 20 mg and metformin 1 gm daily.

Case 2
XY, a 52-year-old male, presented with fever, cough, and myalgias with a similar illness in all the family members and was detected positive by real-time polymerase chain reaction (RT-PCR) on the nasopharyngeal swab for SARS-CoV-2.The patient had received two doses of COVISHIELD (Oxford-AstraZeneca vaccine) and the last dose was given on 22nd April 2021, three months before the index presentation.In view of chest X-ray findings (bilateral ground glass opacities), the patient was diagnosed with mild COVID-19 pneumonia and managed conservatively.Two weeks following this illness, the patient had a recurrence of high-grade fever, odynophagia, palpitations, and tremors.Examination revealed tachycardia (pulse rate = 102 beats/minute), hyperhidrosis grade II, and tender thyromegaly with no orbitopathy or dermopathy.Thyroid function tests revealed low TSH, with normal total T4 and total T3.CRP level was normal (Table 1).Ultrasonography examination showed a heterogeneous thyroid gland (right lobe: 45 × 31 mm; left lobe: 26 × 12mm) with bilateral ill-defined hypoechoic areas.The patient was treated with propranolol 40 mg once a day and prednisolone 50 mg daily for one week followed by tapering over four weeks.The symptoms resolved in six weeks and repeat thyroid function was normalized by then.

Discussion
A systematic review of the literature was performed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist guidelines [26] and was prospectively registered on the International Prospective Register of Systematic Reviews (PROSPERO; CRD42022310160  2).The finally selected 37 articles included 32 case reports, one case series (11 SAT cases), one cross-sectional study (18 SAT cases), one prospective observational study (12 SAT cases), one retrospective observational study (five SAT cases), and one retrospective-prospective cohort (11 SAT cases).The quality of all selected studies/reports was assessed by two independent reviewers using the Joanna Briggs Institute's (JBI) Critical Appraisal Checklist for Studies, including the risk of bias in studies/reports [27].The percentage of "yes" scores ranged from 50% to 100% in all of the articles included in the study, indicating a low to moderate risk of bias.SAT: subacute thyroiditis.
A total of 103 cases of COVID-19 with SAT were identified, and the number of cases in the studies ranged from one to 18. Table 2 summarizes the key demographic and clinical characteristics of each enrolled patient.The age of the patients ranged from 18 to 73 years with a median of 41 years (IQR: 34-52), and out of the described 103 patients, 79 were females (76.7%).Of the included 37 studies that were published from 17 countries, eight (21.6%) were from the United States of America, five (13.5%) from Italy, four (10.8%) from Spain, three (8.1%) each from Turkey and India, and two (5.4%) each from Iran and Mexico.The cases were reported from Europe (n = 47, 45.6%), Asia (n = 43, 41.7%), North America (n = 10, 9.7%), and South America (n = 3, 2.9%).The true prevalence of thyroid disease and thyroid function abnormalities in COVID-19 is largely unknown.Given the fact that only a few reports of SAT have appeared against the backdrop of more than 500 million reported cases of COVID-19 worldwide, SAT seems to be a rather rare manifestation of COVID-19 infection.
The probable reason may be either SAT is being misdiagnosed with COVID-19 symptoms, or there is masking of SAT symptoms due to routine use of corticosteroids and NSAIDs during COVID-19 management.According to Trimboli et al. [25], SAT cannot be considered a direct or frequent complication of SARS-CoV-2.A study comparing SAT cases during the COVID-19 pandemic to those observed in the previous years reported that the COVID-19 pandemic influenced the severity of the disease, leading to more severe forms of the disease, although COVID-19 was not associated with a rise in the overall number of SAT cases in 2020 compared to the previous years [34].The thyroid gland may be vulnerable to COVID-19 infection due to the abundance of angiotensin-converting enzyme 2 (ACE2) receptors in the thyroid parenchyma, which might affect thyroid function.Serum levels of TSH, T3, and T4 in COVID-19 patients were found to be significantly lower than those in the control group, and a positive correlation between the severity of SARS and T3 levels was reported [61][62][63].
After the first report of SAT with COVID-19 infection in an 18-year-old female in Italy by Brancatella et al. [35], several such cases have been reported worldwide.These reports suggest that SARS-CoV-2 infection may serve as a probable trigger for the development of SAT, either during the active infection or even after the acute illness has resolved.To date, only three systematic studies on a similar topic have been conducted, with 27 (17 case reports and two case series) [25], 21 (11 case reports and two case series) [64], and 17 cases [65] with SAT.Among these, the latest systematic review retrieved studies until 20th April 2021.In these reviews, only case reports and case series were available, and the number and quality of published data on SAT in COVID-19 patients were rather inadequate.We have conducted the most comprehensive and up-todate systematic review of the published literature and have included all reported cases till the date of review, identifying 103 SAT cases in 37 included articles with a more detailed presentation of data.Our review demonstrates that SAT is an uncommon association of SARS-CoV-2 viral illness, which may occur either concomitant with the illness or even after recovery from the primary viral illness, presents with mild to moderate symptoms, and generally responds to conservative medical therapy.Studies have reported that SAT is more prevalent in females than males (4:1 ratio) and most often occurs at 40 to 50 years of age [37].We observed that reported cases were more common in females (female-to-male ratio of 3:1) with a median age of 41 years at presentation.The incidence of SAT is higher in females compared to males (19.1 vs. 4.1 per 100,000/year, respectively) [14].This can partly be explained by greater levels of ACE-2 and TMPRSS2 expression in women [66][67][68].These circumstances may explain why SARS-CoV-2 causes SAT more commonly in women [66].Men, on the other hand, are more vulnerable to COVID-19 than women and have a poorer prognosis [69].
In a prospective study, the clinical features of COVID-19-associated SAT patients were similar to those of classical SAT [28].Our systematic review demonstrates that clinical characteristics, laboratory results, and therapy characteristics of SAT with COVID-19 are similar to those described in classical SAT.Temporally, SAT developed following the COVID-19 infection in most cases, and concurrently only in a few, with clinical symptoms such as neck pain, fever, palpitations, and tremors.According to the most recent systematic review [25], the time between COVID-19 and the onset of SAT symptoms ranged from three to 60 days, and patients included in our review had a median onset time of 28 (IQR: 12-36) days.Wang et al. [70] reported that T3, T4, and TSH levels among patients with SARS-CoV-2 were than those in the control group but here low or undetectable TSH and high T3 and T4 that may differentiate it from the sick euthyroid syndrome or non-thyroidal illness (NTI).Anti-TPO-antibody (reported negative in 48% of the patients), thyroid USG (revealing classic findings of hypoechoic glands), and thyroid scintigraphy (showing absent or reduced uptake) may serve to differentiate it from NTI of COVID-19 in some cases.
The course of SAT is usually self-limiting.The American Thyroid Association's (ATA) recommendations propose that therapy of SAT be guided by the severity of the condition, with steroids indicated for moderate to severe cases and NSAIDs for mild ones [71].Accordingly, the cases have been managed variously with steroids and NSAIDS as the mainstay of treatment.Among the described cases, the majority achieved resolution of symptoms, i.e., 72% (95% CI: 62% to 80%); nevertheless, 25 patients (24%) had subclinical hypothyroidism at follow-up.Although the majority of cases return to euthyroidism, thyroid function needs to be closely monitored for at least six months after the resolution of symptoms.
Since the incidence and diversity of SAT in COVID-19 patients are undetermined, increased numbers of cases would be required to show its causation and relationship to the virus.Due to the rarity of cases, the causal relationship between SAT and COVID-19 cannot be established.However, recurrence of SAT may need longer follow-up since the rate of SAT recurrence has been found to be significantly higher in genetically susceptible people (especially with HLA-B18 and HLA-B35 haplotypes) [57].Therefore, it may be worthwhile to observe if COVID-19 patients who develop SAT also have these HLA-B35 and HLA-B18 antigens.
With the drop in global occurrence of COVID-19 infection cases, we attempted to collate all the reported SAT and COVID-19 cases in addition to two of our cases till May 5, 2022.The aim is to have an updated description of all the data for understanding various aspects of the association.There are certain limitations in this study.First, this study largely included case reports and was thus vulnerable to selection bias.Second, it is likely that only clinically challenging cases were reported and published, therefore the propensity for publication bias.Third, it is quite possible that symptoms of SAT were misdiagnosed in severe COVID-19 disease or concealed, modulated/ameliorated by the routine administration of high-dose corticosteroids.Fourth, many cases have not given details on whether steroids were used as the first line of treatment, and some of the cases lacked details on clinical characteristics, laboratory results, and diagnostic parameters.

Conclusions
SAT is a self-limited thyroid disease caused by a viral or post-viral SARS-CoV-2 infection.SAT can be considered another, although rare, extra-pulmonary clinical manifestation of COVID-19 infection, and its timely early detection and anti-inflammatory therapy can help the successful management of the disease.The index of suspicion of COVID-19-induced SAT should be elevated amongst clinicians, and treatment must be done on a case-by-case basis; however, corticosteroid therapy should be included in the treatment plan.

FIGURE 1 :
FIGURE 1: Ultrasonographic images of thyroid lobes.A and B: Enlarged isthmus, right and left lobe of the thyroid gland with coarse heterogeneous echo texture.C. Enlarged cervical lymph nodes with maintained fatty hilum.

FIGURE 2 :
FIGURE 2: Flow chart to illustrate the process by which articles were selected or rejected for inclusion in the study.
(7)les and abstracts of 999 studies were screened and a total of 734 records were excluded.The remaining 265 articles met the criteria for full-text review.The criteria for inclusion of the published studies of any design (including case reports) were COVID-19-associated SAT, and the exclusion criteria were: (1) studies not related to SAT; (2) studies not providing sufficient data; (3) studies without results; (4) commentaries, guidelines, editorials, book chapters, reviews, and meta-analysis; (5) animal studies; (6) COVID-19-negative SAT cases;(7)studies without any SAT case/patient.After applying exclusion criteria, out of 265 full texts, 228 were excluded and 37 articles were included for final qualitative analysis.The selection process of the studies is displayed in the flow diagram (Figure ).A comprehensive literature search was carried out in seven different databases until May 5, 2022, for articles reporting SAT in COVID-19 patients using broad key terms: (COVID OR COVID-19 OR SARS-CoV-2 OR coronavirus OR COVID-19 vaccination) and (thyroiditis OR subacute thyroiditis OR thyrotoxicosis).In all, there were 1,531 citations: 689 from PubMed, 620 from ScienceDirect, 143 from the WHO COVID-19 database, 37 from Scopus, 25 from Embase, and 17 from The Cochrane Library, and among these 532 duplicate cases were removed.

TABLE 2 : Demographics and clinical presentation of COVID-19-associated subacute thyroiditis.
In 72 patients (69.9%),COVID-19 was diagnosed using RT-PCR and no information regarding testing was available in 21.4% of patients.COVID-19 was asymptomatic in seven cases (6.8%), with mild to moderate respiratory symptoms in 80 cases (77.7%), and severe in 11 cases (10.7%).Nineteen percent (20 cases) reported the presence of goiter prior to the onset of the symptoms.The onset of the timing of SAT diagnosis in relation to COVID-19 was mentioned only in 83 patients.Among the subjects where the information was available, the time interval between the start of COVID-19 illness and the appearance of SAT symptoms ranged from four to 168 days (median: 28, IQR: 12-36) in 73 (70.8%) cases.SAT occurred concurrently with COVID-19 among eight (7.8%) cases.Overall, 92.2% of patients had some symptoms suggestive of SAT with the most common ones as neck pain, fever, palpitations, and tremors.Neck pain was experienced by 86 (83.5%) patients, fever by 71 (68.9%), palpitations by 50 (48.5%),and tremors by 25 (24.3%)patients.Other clinical features included anxiety, agitation, insomnia, weight loss, excessive sweating, asthenia, and malaise.Hyperadrenergic symptoms (52.4%) were commoner than goiter (19%) and neck tenderness (49.5%).

Table 5
gives the overall summary of the findings of this systematic review.