Subacute thyroiditis (SAT) (also named De Quervain thyroiditis) is a self-limited thyroid disease caused by a viral or postviral inflammatory process [
64]. Neck pain is the hallmark of the clinical syndrome, that’s why another synonym is “painful subacute thyroiditis” [
64]. The clinical course of SAT usually shows three consecutive phases: first thyrotoxicosis during the first few months, followed by hypothyroidism for about three months and then by euthyroidism [
64]. Many viruses are known to be associated with the development of SAT, and evidence for infection can be based on epidemiological, serological (or circulating viral genome) or direct evidence data [
65]. Direct evidence of the presence of viruses or their components in the thyroid tissue is available only for few viruses [
65]. Virus infections could be responsible for thyroid diseases by liberating antigens (via necrosis or apoptosis), by forming altered antigens or causing molecular mimicry, by proinflammatory cytokine and chemokine secretion, by inducing aberrant HLA-DR expression and Toll-Like Receptor (TLR) activation [
65]. It was conceivable that also SARS-CoV-2 could be associated to SAT [
66]. Table
1 collects the main features of the nine COVID-19-related SAT cases that have been reported to date. Patients were all females except one, and age ranged from 18 to 69 years, as expected in general for SAT outside of the COVID-19 pandemic [
64]. Previous autoimmune thyroid disease or dysfunction was absent in all cases. Evidence of SARS-CoV-2 infection was demonstrated by the presence of viral RNA in oropharyngeal or nasopharyngeal swabs along with quantitative detection of serum specific IgG and IgM in three cases. Covid-19 manifestations were mild in eight of nine cases, while interstitial pneumonia affected the oldest patient with SAT (i.e. 69 years old). It is important to note that in six of nine patients (about 65%) SAT occurred after remission of COVID-19 (i.e. clinical disappearance and negative virus detection tests), with a time interval from COVID-19 ranging from 17 to 40 days. Conversely, in three cases [
38,
39,
41] SAT presented along with manifestations of SARS-CoV-2 infection, at admission or during the first days of hospitalization. It is noteworthy that in the patient with SARS-CoV-2-related pneumonia [
38] control swab test continued to be positive two months after the COVID-19 diagnosis. Neck pain (optionally radiated to the jaw and/or the ear) was present in eight of nine cases (about 90%), and it was missing only in the oldest patient with SARS-CoV-2-related pneumonia who was also on painkillers for previous back surgery [
38]. Moreover, fever accompanied neck pain in five cases (about 60%). The degree of biochemical thyrotoxicosis could range from mild to moderate: indeed, maximum serum free T4 (FT4) and free T3 (FT3) levels could be about two times the upper limit of the normal. TSH receptor antibodies (TRAb) and thyroperoxidase (TPOAb) antibodies were negative in all cases, while thyroglobulin antibodies (TgAb) were positive in two patients of whom one needed T4 for subsequent hypothyroidism [
36]. C-reactive protein (CRP) values were high in all cases and they could range from 8 to 122 mg/L. Manifestations of early-onset SAT could include different signs and symptoms such as goiter, fatigue, palpitations, inappetence, sweating, insomnia, anxiety, tremor, weight loss. Nevertheless, the 38-year-old female with no history of cardiovascular disease experienced atrial fibrillation [
36]. In the context of SAT thyrotoxicosis, atrial fibrillation is rarely described [
67], while this is one of the main arrhythmias resulting from the systemic inflammatory response and myocardial injury of COVID-19 [
68]. Thus, it is conceivable that in patients with thyrotoxicosis and COVID-19 (current or recent past infection with SARS-CoV-2) atrial fibrillation could be due to both the hormonal excess and the systemic inflammatory response [
36,
42]. In all cases, thyroid imaging (i.e. ultrasound or scintigraphy) features corresponded to that of classical SAT at the time of destructive thyrotoxicosis. Also as regards the therapeutical and outcome characteristics, COVID-19-related SAT was similar to SAT secondary to other viruses: in all cases, steroidal and non-steroidal anti‐inflammatory drugs (NSAIDs) were effective to obtain a quick resolution of thyrotoxicosis and normalization of inflammatory markers. Glucocorticoid use in patients with COVID-19 has been proven to be of benefit in selected cases [
69]. Considering the potential cardiovascular complications of both COVID-19 and SAT thyrotoxicosis, a low dose regimen of steroids to treat SAT thyrotoxicosis and neck pain could positively impact on the outcome of patients with COVID-19-related SAT. Hypothyroidism after SAT occurred in only two cases [
36], and relapse of COVID-19 (both clinically and at diagnostic tests) was excluded in six cases [
35,
36,
40].
Table 1
Analysis of cases of COVID-19-related subacute thyroiditis (SAT) reported in the literature to date
Sex | F | F | F | F | F | F | F | F | M |
Age (yr) | 18 | 38 | 29 | 29 | 46 | 69 | 41 | 43 | 34 |
Thyroid disease before Covid-19 | no | no | no | no | no | nodules | no | no | no |
Covid-19 test | swab | swab | swab, sIg | swab, sIg | swab | swab | swab | swab, sIg | swab |
Covid-19 manifestations | mild | mild | mild | mild | mild | pneumonia | mild | mild | mild |
Time from Covid-19 to SAT onset (days) | 17 | 16 | 30 | 36 | 20 | during Covid-19 | during Covid-19 | 40 | during Covid-19 |
Doctor’s visit | outpatient, in-person | outpatient, in-person | outpatient, in-person | outpatient, in-person | outpatient, in-person | inpatient | inpatient | outpatient, in-person | inpatient |
SAT manifestations | typical, neck pain, fever (37.5 °C) | typical, neck pain, fever (38.5 °C), AF | typical, neck pain | typical, neck pain | typical, neck pain, fever (37.2 °C) | typical, no neck pain | typical, neck pain, fever (38.5 °C) | typical, neck pain, fever (37.5 °C) | typical, neck pain |
Biochemical profile | TSH 0.004 FT4 27.2 FT3 8.7 TgAb+ TPOAb- TRAb- | TSH 0.1 FT4 29.3 FT3 8.0 TgAb- TPOAb- TRAb- | TSH 0.01 FT4 31.8 FT3 8.9 TgAb+ TPOAb- TRAb- | N.A. | TSH 0.01 FT4 27.8 FT3 6.9 TRAb- | TSH 0.08 FT4 31.6 FT3 7.0 TgAb- TPOAb- TRAb- | TSH 0.08 FT4 25.7 FT3 7.7 TgAb- TPOAb- TRAb- | TSH 0.006 FT4 34.6 FT3 9.0 TgAb- TPOAb- TRAb- | TSH 0.01 FT4 41.8 FT3 13.4 TPOAb- TRAb- |
Inflammatory markers | WBC 11.2, CRP 6.9 | CRP 11.2 | CRP 7.9 | N.A. | CRP 8 | N.A. | WBC 15.6, CRP 101 | WBC 6.6, CRP 8.8 | WBC 11.6, CRP 122 |
Thyroid US features | typical | typical | typical | typical | typical | typical | typical | typical | typical |
Thyroid scintigraphy uptake | N.A. | N.A. | absent | N.A. | N.A. | absent | N.A. | markedly reduced | N.A. |
Resolutive therapy | prednisone | prednisone | prednisone, propanolol | ibuprofen | prednisone | prednisone | prednisolone | prednisone | prednisolone, atenolol |
Thyroid function after SAT | normal | normal | hypothyroidism | hypothyroidism | normal | N.A. | N.A. | normal | normal |
Relapse of Covid-19 | no | no | no | no | no | swab+ | N.A. | no | N.A. |
In the study by Lania et al. [
42] a high number of patients (58/287, 20.2%) hospitalized for COVID-19 in non-intensive care units was found to be affected by thyrotoxicosis in absence of neck pain, likely identifying patients with COVID-19-related painless (silent) thyroiditis (or more roughly destructive thyroiditis cases without neck pain). Overt thyrotoxicosis (i.e. defined as low TSH values with FT3 and/or FT4 above the reference ranges) was diagnosed in 31 of 58 patients with thyrotoxicosis (53.4%) and an inverse and robust relationship between serum TSH and IL-6 levels was recorded, supporting the hypothesis of an inflammatory-mediated damage to the thyroid gland [
42]. The absence of neck pain and the TPOAb positivity are two main features of painless thyroiditis, which help distinguish it from subacute thyroiditis [
64]. In the study by Lania et al. [
42] all thyrotoxic patients did not have neck pain, but unfortunately, thyroid autoantibodies profile (i.e. TPOAb, TgAb and TRAb) was available in only nine patients and resulted negative. In hospitalized COVID-19 patients with clinical and radiological signs of pneumonia (i.e. patients enrolled in the study by Lania et al. [
42]), neck pain associated with destructive thyrotoxicosis could missing because of the leucopenia. The low count of lymphocytes characterizing hospitalized COVID-19 patients could preclude the formation of giant cells (congregates of lymphocytes, histiocytes, and colloid) at the thyroid level with consequent absence of stretching of thyroid capsule and neck pain [
44].
Also, it is important to note that 32% and 16% of overt thyrotoxic patients with COVID-19 also developed atrial fibrillation and thromboembolic events, respectively [
42]. Moreover, it was noted that in thyrotoxic patients in-hospital mortality was higher and the duration of hospitalization was longer as compared to COVID-19 patients with normal thyroid function [
42]. Therefore, thyrotoxicosis appears to be clinically relevant in COVID-19 patients, negatively impacting on their outcomes. One meta-analysis was published regarding the severity of COVID-19 in patients with pre-existing thyroid disease and it concluded that the presence of thyroid disease conferred a more severe degree of infection to COVID-19 [
76]. However, some relevant limitations of the study do not allow us to generalize this finding: four of the eight included studies were published on “MedRxiv” (an online platform of non-peer-reviewed articles whose results should not be used for clinical medicine); one other included study was published in 2016 (so before the COVID-19 outbreak); it was not specified which kind of thyroid disorders was included in the term “thyroid disease” (i.e. hyperthyroidism, hypothyroidism, cancer) [
76].