COVID-19 is the most rapidly progressing and lethal infectious disease since the Spanish Flu of 1818-1820 (4). The disease has its main clinical manifestation in the respiratory system, causing a flu-like syndrome in most cases, which can evolve to interstitial pneumonia. It also has the potential to infect other organs and systems, such as the neurological, cardiovascular, gastrointestinal and endocrine systems (3, 4, 13).
The virus invades the cells through the spike protein, which binds to angiotensin-converting enzyme-2 (ACE2) receptors, which regulate the renin-angiotensin-aldosterone (RAAS) system, presented in large profusion on the surface of human epithelial cells (3, 4, 12, 14). ACE2 receptors (genetically susceptible to infection by SARS-CoV-2) are abundant, particularly in the follicular cells of the parenchyma of the thyroid gland (4). Injury to the endocrine system can occur directly due to the cytopathological toxicity of the virus in the gland or indirect injury through the involvement of the hypothalamic-pituitary axis by systemic inflammation from the secretion of chemokines and cytokines, induced autoimmune injury and/or vascular injury (3). In a study performed analyzing necropsies of patients infected with SARSCov carried out in 2007, histological analysis revealed severe lesion of the follicular cells with destruction of the follicular epithelium, spoliation of epithelial cells, capillary congestion of the connective tissue between the follicles, as well as interstitial fibrosis (15). Studies have shown a reduction in TSH and a relationship between thyroid dysfunction and COVID-19 severity (3). Lania et al. (16) verified an inverse relationship between TSH and interleukin 6 (IL-6) levels, confirmed in multivariate analyses, and an increase in hospital mortality in patients with thyrotoxicosis and TSH <0.1 mU/L. Gao et al. (17) observed that free T3 levels were negatively correlated with CRP (C-reactive protein), IL-6 and tumor necrosis factor (TNF) alpha.
Subacute or de Quervain's thyroiditis is a granulomatous and nonsuppurative inflammatory disease of the thyroid that manifests as pain in the topography of the gland and is associated with systemic manifestations such as fever, fatigue, and myalgia (10, 18). SAT is an infrequent thyroid disorder; however, it is the most common cause of thyroid gland pain (6, 11). Fatourechi et al. (19), in a study carried out in a Minnesota county (USA), estimated the prevalence of TSA to be 4.9/100,000 per population. It can also manifest with symptoms of thyrotoxicosis, resulting from the extravasation of thyroid hormones secondary to injury to the gland, and even hypothyroidism in cases where the injury results in permanent gland damage (18, 20). Ohsako et al. (21) observed that although there is production of antibodies against the thyroid gland in SAT, it is a transient phenomenon and results from the leaking of antigens after the destruction of thyroid follicles and therefore does not represent a true autoimmune disease. Furthermore, a genetic predisposition to SAT was associated with the presence of the human leukocyte antigen (HLA) Bw35 (12, 21). SAT is more prevalent in females, with a ratio of 3-7:1 in relation to males, ages 20 to 60 years, and is considered rare in children and elderly individuals (18).
The pathophysiology of the disease involves an inflammatory reaction secondary to a previous viral infection of the upper airway, and many viruses have been associated with SAT (5, 18). The histological changes in the initial phase are in accordance with the hyperthyroid state, caused by gland destruction, colloid and hormone leakage and neutrophilic invasion with the development of microabscesses. In the transition from acute to subacute inflammation, there is lymphocytic and histiocytic invasion, and the presence of multinucleated giant cells infiltrated in the colloid is noticeable (18). The late phase is distinguished by interfollicular fibrosis and corresponds to the hypothyroidism phase. Fine needle aspiration (FNA) may vary depending on the stage of the disease, and it may show a mixture of multinucleated giant cells, epithelial granulomas and inflammatory residues in the middle of the colloid. Multinucleated cells are the “thyroiditis giant cells” and are the hallmark of the disease. However, they can be found in other conditions, such as sarcoidosis and infections (by fungi and mycobacteria), and are a nonspecific finding of papillary thyroid carcinoma (18).
Generally, the disease develops within two to eight weeks after viral infection and may evolve with a fluctuating pattern between 3 and 6 weeks, with gradual or sudden onset (11, 18). The patient in this report presented a painful goiter earlier than usual (eight days) and a relatively abrupt onset associated with mild symptoms of thyroiditis. She also presented TSH suppression, an increase in T4 and T4 L values, and a marked increase in inflammatory markers. One of the first cases of SAT associated with COVID-19 was reported by Brancatella et al. (6) in an 18-year-old woman with fever, neck pain and palpitations 15 days after having tested positive for SARS-CoV-2 and mild symptoms of COVID-19. Brancatella et al. (20) also published a series of four cases in patients with mild manifestations of SARS-CoV-2 infection. Two patients had severe gland pain, all patients had symptoms of thyroiditis, and one developed atrial fibrillation requiring electrical cardioversion. Two patients developed subclinical hypothyroidism after treatment. Echographic thyroid alterations were also described in all patients, but no description of nodules mimicking a thyroid tumor was found. It is important to highlight that thyroiditis and thyrotoxicosis were present in critically ill patients, also as painless manifestations, probably due to the use of pain killers (3, 16).
The thyroid gland may also present with symmetrical or asymmetrical enlargement and stiffness. Thyroid ultrasonography changes are common in thyroiditis and may have a polymorphic presentation. Although the applicable methodology is to perform ultrasonography, it also depends on the examiner's interpretation, which makes it susceptible to variations in the exam description. Thyroid nodules (TNs) are increasingly common findings in clinical practice, surpassing Graves' disease. The prevalence of TN in the adult population in clinical evaluation is estimated at 3-7%, and with ultrasound, it increases to 13-67% (18). There are several causes for the formation of TN, including iodine consumption, exposure to radiation, tobacco consumption and mainly chronic inflammation; further, a positive association has been found between TN and Helicobacter pylori infection (22).
Our patient had an ultrasound examination suggestive of a malignant nodule, classified as TIRADS-4. Three months later, on ultrasound to guide fine needle aspiration, the nodule was remitted and assumed to be an inflammatory pseudonodule. Inflammatory pseudonodules are rare, but thyroid ultrasound changes secondary to TSA can sometimes be suggestive of this finding (18, 23). Prajapati et al. (18) evaluated a patient with SAT and a 9x7 mm nodule, classified as TIRADS 6 and Bethesda category 6. She underwent a total thyroidectomy, and in the histopathological analysis, the findings were typical of thyroiditis, with no signs of malignancy. Most likely, in our case report, the time elapsed between ultrasonography assessments (which was approximately three months) associated with correct SAT clinical management enabled nodule remission, thus preventing more invasive procedures and iatrogenic measures. Li et al. (23), in 2014, published a case in which the SAT presented a painful nodule measuring 1.5x0.8 cm as the only clinical finding of thyroiditis, showing that laboratory alterations are not always present. It is also possible that SAT manifests without pain, especially in critically ill patients (18, 23).
The treatment of SAT is based on observational studies and aims to reduce inflammation and control symptoms of hyperthyroidism. It is usually performed with the administration of nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids in refractory cases. The prognosis is good, but SAT is a risk factor for developing hypothyroidism and permanent thyroid dysfunction, which requires follow-up. In addition, it is rare but possible to have disease recurrence years after the initial presentation (18). It is important to emphasize that patients with thyroid disorders may have a worse SARS-CoV-2 infection outcome, especially those at high risk of developing severe manifestations (4, 13).