Malignant Pseudothyroiditis after COVID-19 Infection Revealing a Poor-Cellular Variant of a Thyroid Anaplastic Carcinoma (preprint)

ATC is a rare cancer with a slightly growing incidence and a poor prognosis determined by the delay of treatment, usually revealed by an enlarging goiter with compressive symptoms and, more rarely, by inflammatory and thyrotoxic symptoms, a clinic entity called malignant pseudothyroiditis (MPT) mimicking subacute thyroiditis (SAT). With the advent of COVID-19 pandemic, many cases of COVID-19 related SAT were described with the usual clinical presentation enriched by the COVID-19 symptoms, leading to the emergence of atypic clinical pictures. We present the case of a 60-year-old patient who developed, one month after a COVID 19 acute infection, a clinical presentation of SAT with atypical ultrasound features leading to the diagnosis of MPT; histological atypia was misleading, finally making precise diagnosis was difficult. To our best knowledge, this is the first ever reported case of MPT mimicking COVID-19 SAT. We reviewed thirty five cases published to date and discuss the mechanisms underlying MPT physiopathogenesis and the ultrasound and histological features. We point out the similarities between MPT and SAT and the role of ultrasound at clinical presentation workup. Finally there are two key points to remind: First, to perform neck ultrasound in any painful goiter and, in case of atypia, perform a US guided core-needle biopsy, a complementary CT-scan and quickly refer the patient to an expert center. Second, always think that COVID-19 infection is a recent entity and be aware that it can influence the clinical presentation of any disease.

Subacute thyroiditis and thyrotoxicosis after SARS-CoV-2 vaccine: report of 2 cases / Tiroiditis subaguda y tirotoxicosis posterior a vacuna contra SARS-CoV-2: reporte de 2 casos

La enfermedad por coronavirus SARS-CoV-2 que surgió en el año 2019 (COVID-19), ha obligado al rápido desarrollo de vacunas para prevenir su propagación e intentar controlar la pandemia. Dentro de las vacunas desarrolladas, las primeras en ser aprobadas con una tecnología nueva en el campo de la vacunación, fueron las vacunas basadas en ARNm (ácido ribonucleico mensajero), que lograron tasas de efectividad cercanas al 95 % para la prevención de la enfermedad COVID-19 grave. Los eventos adversos comunes son reacciones locales leves, pero ha habido varios informes de pacientes que desarrollaron tiroiditis subaguda y disfunción tiroidea después de recibir la vacuna contra SARS-CoV-2. Este artículo presenta dos casos de tiroiditis subaguda poco después de recibir la vacuna contra COVID-19

The SARS-CoV-2 coronavirus disease which emerged in 2019 (COVID-19), has forced the rapid development of vaccines to prevent the spread of infection and attempt to control the pandemic. Among the vaccines developed, one of the first to be approved with a new technology in the field of vaccination, was the mRNA (messenger ribonucleic acid) vaccine, with rates of effectiveness close to 95% for the prevention of severe COVID-19 disease. Common adverse events are mild local reactions, but there have been some reports of patients developing sub-acute thyroiditis and thyroid dysfunction after receiving the SARS-CoV-2 vaccine. This article presents two case reports of subacute thyroiditis shortly after receiving the COVID-19 vaccine

Concurrent Subacute Thyroiditis and Graves' Disease After COVID-19: A Case Report.

There are many reports of subacute thyroiditis (SAT) that occurred after the coronavirus disease 2019 (COVID-19), but no such case has been reported in Korea. Moreover, the simultaneous occurrence of SAT and Graves' disease (GD) is rare. Here, we describe a patient who developed SAT and GD after the second episode of COVID-19. A 27-year-old woman with no known history of thyroid disease presented with fever, upper respiratory tract symptoms, and painful neck swelling. Thyroid function tests revealed thyrotoxicosis, and thyroid ultrasound showed heterogeneous echogenicity of enlarged thyroid glands. Her initial clinical presentation was consistent with SAT after viral infection, with typical neck tenderness and spontaneous improvement of thyrotoxicosis without antithyroid drug use. However, this case had some atypical features, such as an elevated thyroid-stimulating immunoglobulin level, relapse of thyrotoxicosis in short-term follow-up, and increased Tc-99m pertechnetate uptake, suggesting the coexistence of GD. About two months after methimazole (15 mg/day) was prescribed, she was lost to follow up again. We report the first case of unusual co-occurrence of SAT and GD following COVID-19.

Subacute thyroiditis following COVID-19: A systematic review.

Background: Subacute thyroiditis (SAT) is a self-limiting thyroid inflammatory disease occurring specifically after upper respiratory tract infections. Since COVID-19 is a respiratory disease leading to multi-organ involvements, we aimed to systematically review the literature regarding SAT secondary to COVID-19. Methods: We searched Scopus, PubMed/MEDLINE, Cochrane, Web of Science, ProQuest, and LitCovid databases using the terms "subacute thyroiditis" and "COVID-19" and their synonyms from inception to November 3, 2022. We included the original articles of the patients with SAT secondary to COVID-19. Studies reporting SAT secondary to COVID-19 vaccination or SAT symptoms' manifestation before the COVID-19 infection were not included. Results: Totally, 820 articles were retained. Having removed the duplicates, 250 articles remained, out of which 43 articles (40 case reports and three case series) with a total of 100 patients, were eventually selected. The patients aged 18-85 years (Mean: 42.70, SD: 11.85) and 68 (68%) were women. The time from the onset of COVID-19 to the onset of SAT symptoms varied from zero to 168 days (Mean: 28.31, SD: 36.92). The most common symptoms of SAT were neck pain in 69 patients (69%), fever in 54 (54%), fatigue and weakness in 34 (34%), and persistent palpitations in 31 (31%). The most common ultrasonographic findings were hypoechoic regions in 73 (79%), enlarged thyroid in 46 (50%), and changes in thyroid vascularity in 14 (15%). Thirty-one patients (31%) were hospitalized, and 68 (68%) were treated as outpatients. Corticosteroids were the preferred treatment in both the inpatient and outpatient settings (25 inpatients (81%) and 44 outpatients (65%)). Other preferred treatments were nonsteroidal anti-inflammatory drugs (nine inpatients (29%) and 17 outpatients (25%)) and beta-blockers (four inpatients (13%) and seven outpatients (10%)). After a mean duration of 61.59 days (SD: 67.07), 21 patients (23%) developed hypothyroidism and thus, levothyroxine-based treatment was used in six of these patients and the rest of these patients did not receive levothyroxine. Conclusion: SAT secondary to COVID-19 seems to manifest almost similarly to the conventional SAT. However, except for the case reports and case series, lack of studies has limited the quality of the data at hand.

HLA typing of patients who developed subacute thyroiditis and Graves' disease after SARS-CoV-2 vaccination: a case report.

BACKGROUND: Cases of subacute thyroiditis (SAT) after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination have been reported. A human leukocyte antigen (HLA) allele, HLA-B*35, appears to be involved in the pathogenesis of SAT. CASE PRESENTATION: We conducted HLA typing of one patient with SAT and another with both SAT and Graves' disease (GD), which developed after SARS-CoV-2 vaccination. Patient 1, a 58-year-old Japanese man, was inoculated with a SARS-CoV-2 vaccine (BNT162b2; Pfizer, New York, NY, USA). He developed fever (38 °C), cervical pain, palpitations, and fatigue on day 10 after vaccination. Blood chemistry tests revealed thyrotoxicosis and elevated serum C-reactive protein (CRP) and slightly increased serum antithyroid-stimulating antibody (TSAb) levels. Thyroid ultrasonography revealed the characteristic findings of SAT. Patient 2, a 36-year-old Japanese woman, was inoculated twice with a SARS-CoV-2 vaccine (mRNA-1273; Moderna, Cambridge, MA, USA). She developed fever (37.8 °C) and thyroid gland pain on day 3 after the second vaccination. Blood chemistry tests revealed thyrotoxicosis and elevated serum CRP, TSAb, and antithyroid-stimulating hormone receptor antibody levels. Fever and thyroid gland pain persisted. Thyroid ultrasonography revealed the characteristic findings of SAT (i.e., slight swelling and a focal hypoechoic area with decreased blood flow). Prednisolone treatment was effective for SAT. However, thyrotoxicosis causing palpitations relapsed thereafter, for which thyroid scintigraphy with 99mtechnetium pertechnetate was conducted, and the patient was diagnosed with GD. Thiamazole treatment was then initiated, which led to improvement in symptoms. CONCLUSION: HLA typing revealed that both patients had the HLA-B*35:01, -C*04:01, and -DPB1*05:01 alleles. Only patient 2 had the HLA-DRB1*11:01 and HLA-DQB1*03:01 alleles. The HLA-B*35:01 and HLA-C*04:01 alleles appeared to be involved in the pathogenesis of SAT after SARS-CoV-2 vaccination, and the HLA-DRB1*11:01 and HLA-DQB1*03:01 alleles were speculated to be involved in the postvaccination pathogenesis of GD.

Emerging trends and hot spots in subacute thyroiditis research from 2001 to 2022: A bibliometric analysis.

Background: Subacute thyroiditis (SAT) is the most prevalent self-limiting thyroid disease that causes pain, accounting for about 5% of all clinical thyroid disorders. Numerous clinically noteworthy results have been published in this area over the last 20 years. However, no article has comprehensively assessed the relevant literature yet. We conducted a bibliometric analysis of SAT to provide light on the dynamic nature of scientific advancement and aid researchers in gaining a global perspective while examining research core themes and hotspots. Methods: SAT-related articles and reviews from 2001 to 2022 were retrieved from the Science Citation Index-Expanded of Web of Science Core Collection (WoSCC). We analyzed current research trends and hotspots in this area using CiteSpace and Vosviewer. Results: A total of 568 studies associated with SAT research were published in 282 academic journals by 2,473 authors in 900 institutions from 61 countries/regions. The United States was a crucial link in inter-country/region collaboration and was the most frequently involved country in international cooperation. The University of Missouri System was the top organization, and Braley-Mullen H. was the most productive researcher. Thyroid published the most papers, with 36 publications. The most co-cited article was "Clinical features and outcome of subacute thyroiditis in an incidence cohort: Olmsted County, Minnesota, study" (by Fatourechi V., 2003). The clustered network and timeline view of keywords showed that the prevalence, diagnosis, and treatment of SAT were the research core themes during the past 20 years. Analysis of keyword bursts indicated that the clinical characteristic and the influence of COVID-19 on SAT appeared to be the current research hotspots. Conclusion: This bibliometric analysis conducted a thorough review of the SAT research. The clinical characteristics and the genetic background of SAT under the influence of COVID-19 are current research hotspots. However, there is still a need for further study and global collaboration. Our findings can aid researchers in understanding the current status of SAT research and immediately pinpoint new directions for further investigation.

Evaluation of the diagnostic features and clinical course of COVID-19 vaccine-associated subacute thyroiditis.

OBJECTIVE: This study aimed to identify cases of coronavirus disease 2019 (COVID-19) vaccine-associated subacute thyroiditis (SAT) during the active vaccination period of the pandemic, analyze the characteristics of these cases, and compare them with cases of non-vaccine associated SAT diagnosed in the same period. METHODS: A total of 55 patients diagnosed with SAT in our outpatient clinic between February and October, 2021, were included in this retrospective single-center study. RESULTS: Of the study population, 16 (29.1%) were diagnosed with COVID-19 vaccine-associated SAT (10 with CoronaVac® and six with Pfizer-BioNTech® vaccine), with a median time to onset of symptoms after vaccination of 6.5 (range, 2-20) days. There was no statistically significant difference between the vaccine-associated (VA) and non-vaccine associated (NVA) groups in terms of age, gender, time to diagnosis, thyroid volumes, thyroid function tests, and acute phase reactants. Seven (43.8%) and 25 (64.1%) patients were treated with methylprednisolone in the VA group and NVA group, respectively (p = 0.16). Follow-up data of 45 patients (16/16 for VA and 29/39 for NVA) were available. The mean follow-up of these patients was 47.4 ± 19.4 days, and the follow-up periods of the VA group and NVA group were comparable (p = 0.24). There was no difference between the two groups in terms of the frequency of euthyroidism at the follow-up visit (12/16 vs.14/29, p = 0.08). CONCLUSION: With the increase in COVID-19 vaccination rates during the current pandemic, VA SAT cases are seen more frequently. The present study demonstrated that these cases have similar diagnostic features and clinical course to that of classic forms of SAT. In addition, most patients with VA SAT had a mild clinical course that improved with non-steroidal anti-inflammatory drugs.

Subacute Thyroiditis after COVID-19: A Literature Review.

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.

Incidence of Subacute Thyroiditis During the COVID-19 Pandemic in South Korea Using the National Health Insurance Service Database.

Background: Subacute thyroiditis (SAT) is a thyroid disease initiated by viral infection. Whether severe acute respiratory syndrome coronavirus 2 infection can cause SAT is unclear. This study investigated changes in the nationwide incidence of SAT during the coronavirus disease 2019 (COVID-19) pandemic. Methods: This is a retrospective, cross-sectional population-based study. Data regarding SAT and related viral diseases, including COVID-19, from 2017 to 2020 were collected from the National Health Insurance Service and Korea Disease Control and Prevention Agency databases. Results: In a total of 15,447 patients, 2484 men and 12,963 women diagnosed with SAT from 2017 to 2020 were included in this study. The incidence of SAT was significantly higher in 2020 than in 2017-2019 (8.30 vs. 7.27 per 100,000 persons, p < 0.001), while the incidence of SAT-related respiratory viral diseases, except for COVID-19, markedly decreased in 2020. The peak age of SAT incidence in 2020 was 50-59 years, and the women-to-men ratio was 5.4 (similar to that in 2017-2019). Corticosteroids were prescribed more often (72% vs. 58%, p < 0.001), and the prescription rate exceeding 1 month was significantly higher (45% vs. 40%, p < 0.01) in 2020 than in 2017-2019. Conclusions: The incidence of SAT increased in 2020 in association with COVID-19. A diagnostic approach to COVID-19 needs to be considered in patients with SAT during the COVID-19 pandemic.

Subacute thyroiditis after the third dose of the COVID-19 mRNA vaccine. Case report.

Subacute thyroiditis (SAT) is a thyroid inflammatory disease, whose pathogenesis is still unclear. We report a 52-year-old female with SAT after the third dose of COVID-19 mRNA vaccine BNT162b2 (Pfizer-BioNTech). This case was documented with laboratory tests and ultrasound examination. She needed therapy during the acute phase and subsequently thyroxine supplementation.

Subacute thyroiditis after SARS-Cov2 vaccination: A review of the cases being described and personal experience.

Objective. The present study evaluates the occurrence of subacute thyroiditis in temporal connection with SARS-Cov2 vaccinations described in the literature last year and confirmed by our clinical routine. Methods. Systematic literature search in Medline for studies reporting diagnosis of subacute thyroiditis in temporal connection with vaccinations against Covid 19. Results. The literature search yielded 24 relevant references out of which 22 were "case reports" and two "Letters to the Editor" and encompassed 37 patient cases, in total. They had received a SARS-Cov2 vaccination shortly before the diagnosis (median interval to vaccination six days). In none of these cases, infection of the upper respiratory tract had previously been identified as a classic trigger of the disease. Newly occurring hyperthyroidism and increased laboratory signs of inflammation were described in 78% and 74% of cases, respectively. Atypical clinical pictures (asymptomatic, euthyroid, no inflammation marks) have been observed in both the literature and our patients suspected of thyroid cancer referred to surgery. Conclusions. In times of pandemics and the resulting vaccination, new rapidly occurring sonographic changes in the thyroid gland should be revaluated after 2-3 weeks, or recommended to undergo a fine-needle biopsy, in order to avoid unnecessary surgical interventions.

Thyroid Inconveniences With Vaccination Against SARS-CoV-2: The Size of the Matter. A Systematic Review.

After the beginning of COVID-19 vaccination campaigns, several reports of thyroid disease possibly related to the COVID-19 vaccination progressively appeared in the literature, raising the question of whether the thyroid disorder might be a SARS-CoV-2 vaccine complication. The aim of this study was to analyze the data about COVID-19 vaccination and thyroid disease, evaluate the size and quality of related literature, assess the type of these events, and investigate their timing of onset with respect the vaccination. Pubmed/MEDLINE and Cochrane were systematically reviewed until February 2022 to retrieve the largest number of original papers, case reports, and case series articles reporting thyroid disease after SARS-CoV-2 vaccination. Forty-six articles were included with a total of 99 patients aged from 26 to 73 years were described, of whom 74.75% female. Regarding the vaccination received, 49.49% of patients received Comirnaty (Pfizer/BioNTech), 14.14% CoronaVac (Sinovac), 12.12% Vaxzevria (Oxford/Astrazeneca), 11.11% Spikevax (Moderna), 3.03% Ad26.COV2.S (Janssen, Johnson & Johnson), one patient Covaxin (Bharat Biotech) and one patient Convidecia (Cansino). In 7 cases the thyroid disorder developed after the third dose with a combination of different vaccines. Regarding the type of thyroid disorder, 59 were subacute thyroiditis (SAT), 29 Graves' disease (GD), 2 co-occurrence of SAT and GD, 6 painless thyroiditis (PT), and single cases of thyroid eye disease and hypothyroidism associated with mixedema. The timeline between vaccination and thyroid disorder ranged between 0.5 to 60 days, with an average of 10.96 days. Considering the limited follow-up time, a complete remission was reported in most of SAT and PT cases while a persistence was observed in GD. In conclusion, both size and quality of published data about thyroid inconveniences after COVID-19 vaccination are limited; thyroid disorders may occur within 2 months after COVID-19 vaccination; among all thyroid diseases after COVID-19 vaccination, GD and SAT seem to be more frequent.

Autoimmune and inflammatory thyroid diseases following vaccination with SARS-CoV-2 vaccines: from etiopathogenesis to clinical management.

Since the Covid-19 pandemic emerged in 2019, several adenoviral-vectored, mRNA-based and inactivated whole-virus vaccines have been developed. A massive vaccination campaign has been undertaken around the world, and an increasing number of SARS-CoV-2 vaccine-induced thyroid diseases have been described in the literature. Subacute thyroiditis has been reported in 52 patients, mean age 45.5 ± 1.8 years, mainly in women (n = 39). Graves' disease is more frequent in women (n = 22) than in men (n = 10), mean age 46.2 ± 2.6 years, reported as new onset, recurrent or exacerbation of well-controlled hyperthyroidism. The mean time to symptoms onset is 9.0 ± 0.8 days in subacute thyroiditis, and 15.1 ± 2.6 days in Graves' patients. Rare patients (n = 6) present silent or painless autoimmune thyroiditis. Thyroid function and autoimmune tests, inflammatory markers, thyroid echography with colour flow Doppler, radio-activity uptake on thyroid scan, medical treatment and follow-up are described and compared in patients with SARS-CoV-2 vaccine-induced thyroid diseases. The underlying pathogenic mechanisms of vaccine-induced thyroid diseases, molecular mimicry (various SARS-CoV-2 proteins sharing a genetic homology with a large heptapeptide human protein) or autoimmune/inflammatory syndrome induced by adjuvants (ASIA) are discussed in the context of predisposition or genetic susceptibility. The benefits of SARS-CoV-2 vaccination far outweigh the potential vaccine-induced adverse effects, but clinicians should be aware of possible autoimmune and inflammatory thyroid diseases, and can advise patients to seek medical assistance when experiencing anterior neck pain, fever or palpitations following SARS-CoV-2 vaccines. Further studies are warranted to investigate the etiopathogenesis and to clarify the factors which predispose patients to SARS-CoV-2 vaccine-induced thyroid diseases.

Subacute thyroiditis and COVID-19 vaccines: a case/non-case study.

PURPOSE: Some case reports have suggested a possible association between COVID-19 vaccines and subacute thyroiditis (SAT), however, to our knowledge, no study has analyzed this possible relationship. This study aimed to analyze whether a disproportionate number of cases of SAT were reported in the EudraVigilance database for four COVID-19 vaccines (BNT162b2, mRNA-1273 ChAdOx1-S or Ad26.COV2.S). METHODS: A case/non-case study was conducted to assess the association between SAT and COVID-19 vaccines, calculating the reporting odds ratios (RORs) up to December 2, 2021. Cases were selected using the preferred term 'subacute thyroiditis'. First, cases involving COVID-19 vaccines were compared with those involving all other drugs. Secondly, the RORs for COVID-19 vaccines compared with other viral vaccines (overall and influenza vaccines only) were obtained. RESULTS: Until December 2, 2021, of 1,221,582 spontaneous cases of adverse reactions with the four vaccines, we found 162 SAT cases: BNT162b2 (n = 103), mRNA-1273 (n = 27), ChAdOx1-S (n = 31) and Ad26.COV2.S (n = 1). SAT cases were found to be reported more frequently in association with BNT162b2, mRNA-1273, and ChAdOx1-S vaccines than with other drugs. Moreover, we found a signal of disproportionate reporting for SAT with BNT162b2 and mRNA-1273 vaccines comparing with other viral vaccines (BNT162b2 ROR 3.58, 95% CI 1.92-6.66; mRNA-1273 ROR 3.44, 95% CI 1.71-6.94). However, this association was absent when these COVID-19 vaccines were compared with influenza vaccines. CONCLUSIONS: In EudraVigilance, SAT is relatively more frequently reported in association with mRNA COVID-19 vaccines than with other viral vaccines. Well designed observational studies are needed to confirm these results.