Bentham Science Logo

New Emirates Medical Journal

Volume 3, 2 Issues, 2022
ISSN: 0250-6882 (Online)
This journal supports open access

Open Access Article

A Systematic Review of Subacute Thyroiditis Related to COVID-19



Mohammad AlShatnawi1, *, Mohammad Sunoqrot1, Basil AlBakri1, Mohammad AlOqaily1, Saif Aldeen AlRyalat1
1 School of Medicine, University of Jordan, Amman, Jordan

Abstract

Background:

The novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which belongs to the family Coronaviridae, is the cause of COVID-19 infection. Its outbreak was declared a pandemic on March 11, 2020. COVID-19 does not involve the respiratory system solely, but other systems were also noted to be affected, including the endocrine, cardiovascular, and gastrointestinal systems. Several case reports and series have been published regarding SAT related to COVID-19 infection, yet management and clinical outcomes of the disease have not been discussed in detail.

Methods:

This is a systematic review of cases that have been reported to have subacute thyroiditis induced by COVID-19 infection. A systematic search was conducted throughout multiple databases, including PubMed, Google Scholar, and MeSH network.

Results:

The total number of reported subacute thyroiditis cases attributed to COVID-19 is 24. There was a female predominance (18 females and 6 males) with a female to male ratio of 3:1. Ages ranged from 18 to 69 years (mean = 38.67). Twenty-four symptoms related to thyroiditis were reported, the most common of which being neck pain (95.83%, n=23), palpitations (79.17%, n=19), and fever (66.67%, n=16). The outcome was complete resolution in 70% of cases.

Conclusion:

The endocrine complications of COVID-19 and their management have been disregarded by most as they are rare. Our knowledge of COVID-19 and its complications is growing rapidly. More favourable outcomes were linked with the use of corticosteroid therapy. Until larger studies can be conducted, the management of SAT caused by COVID-19 remains to be based on each individual case. However, the treatment regimen should include corticosteroid therapy.

Keywords: COVID-19, De Quervain’s thyroiditis, SARS-CoV-2, Subacute thyroiditis, Thyroiditis, Viral thyroiditis.


Article Information


Identifiers and Pagination:

Year: 2022
Volume: 3
Issue: 1
First Page: 35
Last Page: 41
Publisher Id: nemj-3-35
DOI: 10.2174/02666211213151545

Article History:

Received Date: 30/5/2021
Revision Received Date: 15/8/2021
Acceptance Date: 27/9/2021
Electronic publication date: 21/01/2022
Collection year: 2022

© 2022 AlShatnawi et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the School of Medicine, University of Jordan, Queen Rania St., Amman, Jordan; Tel: +962776340778; E-mail: mohem93@gmail.com




1. INTRODUCTION

The novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which belongs to the family Coronaviridae, is the cause of COVID-19 infection. Its outbreak was declared a pandemic on March 11, 2020 [1]. COVID-19 causes a wide spectrum of symptoms ranging from a completely asymptomatic carrier of the virus to severe life-threatening manifestations such as respiratory failure, kidney failure, and even death [2]. COVID-19 does not involve the respiratory system solely, but other systems were also noted to be affected, including the endocrine, cardiovascular, and gastrointestinal systems [3].

Subacute thyroiditis (SAT), also referred to as de Quervain thyroiditis, is an acute, immune-mediated inflammatory disease that affects the thyroid gland and is usually related to viral infection [4]. It is self-limiting with symptoms including neck pain, diffuse goitre, and sometimes episodes of hyperthyroidism followed by either hypothyroidism or euthyroidism [5].

Several case reports and series have been published regarding SAT related to COVID-19 infection, yet management and clinical outcomes of the disease have not been discussed in detail. Thus in order to help in diagnosing this disease and characterizing its clinical signs, symptoms, biochemical changes, and clinical outcomes, which generally guide the treatment, we have conducted this literature review on the case reports and series of “subacute thyroiditis related to COVID-19”. We have reviewed patients’ characteristics, clinical presentations, disease course, hormonal changes induced by SAT, and the outcome of patients in all case reports and series we have found, reported up to the date of writing this manuscript.

2. METHODS

This is a systematic review of cases that have been reported to have subacute thyroiditis induced by COVID-19 infection. A systematic search was conducted throughout multiple databases beginning with PubMed databases using its medical subject heading (MeSH) database, followed by a supplementary Google Scholar search. Database search was conducted from February 1, 2021 to April 23, 2021, using the following keywords: “COVID-19” AND “thyroiditis” OR “subacute thyroiditis” OR “endocrinopathies.” We followed the PRISMA guidelines [6], and we have presented the PRISMA flow chart in Fig. (1), showing the steps of our search process. We found and included 14 case reports and two case series, collectively comprising 24 cases. We included cases that were diagnosed with subacute thyroiditis and either tested positive for COVID-19 by PCR or tested positive for COVID-19 IgG antibodies, and no other cause for thyroiditis could be detected. Since the diagnosis of SAT could be established days or weeks after recovery from COVID-19, testing for COVID-19 IgG antibodies is utilized as evidence for a recently resolved infection. The criteria for diagnosis of SAT included having painful thyroid accompanied with elevated ESR, elevated free serum T4, decreased TSH, and at least one of the following imaging studies: 1) Ultrasonographic features of the thyroid showing hypoechoic areas in a normal-to-mildly enlarged thyroid. 2) Absent or reduced technetium-99m uptake on thyroid scintigraphy. 3) Decreased, absent, or heterogenous uptake of radioactive iodine [3]. We excluded cases that were diagnosed with thyroid diseases other than subacute thyroiditis. We also excluded cases with other identified possible causes of thyroiditis.

3. RESULTS

The total number of reported subacute thyroiditis cases attributed to COVID-19 was 24 patients, of whom 14 were in separate case reports and two case series that included four and six patients, respectively. There was a female predominance (18 females and 6 males) with a female to male ratio of 3:1. Ages ranged from 18 to 69 years (mean = 38.67). Symptoms of SAT appeared in a range of 5 to 49 days after resolution of COVID-19 symptoms (mean = 21.6 days), and the duration of SAT was variable, ranging from 7 to 75 days (mean = 31.4 days). The outcome was complete resolution in 70% of cases (N=17). Meanwhile, 16% of cases (N=4) went into a hypothyroid state, and the remaining 12.5% (N=3) were in a subclinical hypothyroid state in the last follow up (Table 1).

Fig. (1)
PRISMA flow chart demonstrating search steps and article included [6].

Neck ultrasound findings were consistent with the diagnosis of SAT by finding diffuse or patchy hypoechoic areas across all patients. Thyroid radioactive iodine intake mostly showed decreased uptake in patients who had it performed, while colour Doppler showed reduced blood flow to affected areas of the thyroid (Table 1).

In all cases that were reviewed, 24 symptoms related to thyroiditis were reported, the most common of which being neck pain (95.83%, n=23), palpitations (79.17%, n=19), fever (66.67%, n=16), and fatigue (54.17%, n=13). Other symptoms, as listed in Table 1, include pain radiation to the jaw and ears, thyroid enlargement and goitres, tremors, weight loss, insomnia, heat intolerance, and palpable lymph nodes (Table 1).

The medical management mostly consisted of corticosteroid therapy, i.e., prednisolone with different doses and tapering regimens. Three patients were treated with symptomatic treatment using aspirin, ibuprofen, and propranolol, and one patient opted to continue monitoring without the administration of therapy. It is worth noting that of the four patients who did not receive corticosteroid therapy, three (75%) of them developed a hypothyroid state, and they made up 50% of patients who developed this outcome while only 16.7% (N=3) of patients who received corticosteroid therapy developed a hypothyroid state.

Table 1
Patient demographics, clinical presentation, management and outcomes.

4. DISCUSSION

Our systematic review demonstrated many similarities across cited case reports. 75% of patients were female, with a mean age of 38.67 years. Corticosteroids were used in 83% of cases. Beta-blockers, NSAIDS, and other drugs were used as a symptomatic treatment in some patients. Ultrasound showed diffuse or patchy hypoechogenicity in the majority of cases. Complete resolution was achieved in 70% of all cases regardless of treatment, while 83.3% of patients who received corticosteroid treatment achieved complete resolution.

SARS-CoV-2 is an enveloped virus belonging to the family Coronaviridae with a single-stranded positive ribonucleic acid (RNA) at its core. Its primary route of infection is via the respiratory system, and transmission through direct contact with contaminated surfaces may also occur, causing the current COVID-19 pandemic that began spreading by the end of the year 2019 [1, 21]. It enters the cell through the Angiotensin-Converting Enzyme-2 (ACE-2) receptors which are expressed to a high degree on the respiratory epithelial cells. The binding of the SARS-CoV-2 virus to the ACE-2 receptors leads to the fusion of the cell and virus membranes [22]. After the fusion of the virus and host cell membranes, the viral RNA uses cells machinery for replication. The immune response plays a major role in the disease as it has been shown that innate response cytokines levels may be predictive of both the clinical presentation and clinical course [23]. Since no antiviral therapy has been proven to lower mortality, management of COVID-19 is supportive, focusing on treating symptoms and supporting the respiratory system. Dexamethasone is the only medication proven to lower mortality in severe and moderate cases [24].

Subacute thyroiditis is an uncommon disease of the thyroid. It is thought to be a viral disease since a significant number of patients develop the disease during or after an episode of upper respiratory tract infection [25]. Many viral diseases have been associated with SAT, including influenza, mumps, measles, coxsackievirus, adenovirus, enterovirus, HIV, and hepatitis E. Some studies reported variable seasonal peaks of SAT related to influenza, coxsackievirus, and echoviruses [26, 27]. In addition, several cases of thyroid dysfunction were reported in patients during the SARS pandemic in 2002 [28].

Although several cases of SAT after COVID-19 were reported in the literature, demonstrating a causal relationship is difficult since cases are rare and often solitary. Nevertheless, it is important for physicians to be aware of COVID-19 as a possible cause for developing SAT. All reviewed cases either tested positive for COVID-19 by performing PCR or were positive for COVID-19 IgM and IgG. However, three cases did not present with COVID-19 symptoms, and SAT was their first presentation, delaying performing proper isolation procedures. Further suspicion of COVID-19 as a trigger for SAT can be made after testing negative for other possible viral aetiologies.

Recent studies that have described the pathophysiology of COVID-19 infection suggested the mechanism of SAT related to SARS-CoV-2, raising the suspicion of a causal relationship. Hoffman et al. have demonstrated the interaction between SARS-CoV-2 and ACE-2 receptors and the subsequent cellular entry of the virus [22]. Besides the lungs, many other organs express ACE-2 receptors. Higher levels than the lungs were reported in the thyroid, small intestines, testis, heart, and kidneys, and medium levels in the colon, liver, bladder, and adrenal glands, explaining the extrapulmonary symptoms that were described in many COVID-19 patients. Nevertheless, the fact that transmission of the virus is primarily through the respiratory tract explains why the respiratory system is the most affected [29, 30].

SAT is more common in females (2-6:1 female-to-male ratio). The reason for female predominance could be due to the higher degree of expression of ACE-2 receptors in follicular thyroid cells, which, as mentioned earlier, appears to be playing an important role in the pathogenesis of SAT related to COVID-19 [2]. SAT occurs mostly in the third or fourth decade of life with an average age of 35.2 +/-11.2 years [26]. Clinical signs and symptoms are variable; however, neck pain and tenderness are nearly universal in all patients, distinguishing this condition from other thyroid conditions such as Graves’ disease, Hashimoto’s thyroiditis, and painless thyroiditis [27]. Other signs and symptoms related to hyperthyroidism include palpitations, fatigue, fever, and weight loss, which usually persist for three to six weeks after initial complaint [26, 31]. Genetic predisposition to SAT was suggested based on the familial occurrence of the disease, and individuals with the human leukocyte antigen (HLA) B35 were particularly predisposed [25]. The clinical outcome of SAT is complete recovery in 90-95% of patients, although transient hypothyroidism may occur, which could last from weeks to months with a recurrence rate of SAT in around 7% [25]. Rare yet serious side effects have been reported, such as thyroid storm and ventricular tachycardia [32, 33].

Clinical features of thyroid inflammation (pain and tenderness over the thyroid), accompanied by laboratory findings suggestive of hyperthyroidism, are usually adequate to diagnose SAT [27]. In the acute phase of inflammation, WBCs count, ESR, and CRP are usually elevated, and patients are in a hyperthyroid state due to thyroid follicular destruction, which leads to high free T3 and T4 with a low T3:T4 ratio. Laboratory findings also may show low or undetectable levels of antithyroglobulin antibodies and antithyroid peroxidase. In case of uncertainty, thyroid ultrasonography usually shows hypoechoic areas on a normal-to-mildly enlarged thyroid. In addition, radioiodine imaging studies help in diagnosing SAT by showing low or heterogeneous uptake of iodine [25, 27]. The most important differential diagnoses of SAT include acute suppurative thyroiditis, Graves’ thyroiditis, Hashimoto’s thyroiditis, painless thyroiditis, and drug-associated thyroiditis [31]. Since SAT is a self-limiting disease, treatment should focus on the management of symptoms. Patients with mild to moderate pain can be given NSAIDs or salicylates and corticosteroids for severe pain. High dosing of prednisone (30-60 mg/d daily), tapered over 4-6 weeks, is usually effective in relieving pain. Beta-blockers should also be administered to treat symptoms of hyperthyroidism [25, 27].

5. LIMITATIONS

Since this study reviewed case reports and series, it is vulnerable to selection bias, in addition to the inability to establish a causal relationship between COVID-19 and SAT since cases are rare. Many reported cases lacked certain information regarding clinical features and diagnostic procedures, such as thyroid radioisotope scans.

CONCLUSION

Due to our current situation, our knowledge of COVID-19 and its complications is growing rapidly. Despite that, many questions remain unanswered, and there are many areas to be explored. The endocrine complications of COVID-19 and their management have been disregarded by most as they are rare, yet they remain a significant cause for morbidity and possibly mortality in many patients. In our article, more favourable outcomes were linked with the use of corticosteroid therapy. Until larger studies can be conducted, the management of SAT caused by COVID-19 remains to be based on each individual case. However, the treatment regimen should include corticosteroid therapy.

CONSENT FOR PUBLICATION

Not applicable.

FUNDING

None.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Declared none.

REFERENCES

[1] Parasher A. COVID-19: Current understanding of its pathophysiology, clinical presentation and treatment. Postgrad Med J 2020; 138577. http://pmj.bmj.com/
[2] Caron P. Thyroiditis and SARS-CoV-2 pandemic: A review 2021; 1-6.
[http://dx.doi.org/10.1007/s12020-021-02689-y]
[3] Khatri A, Charlap E, Kim A. Subacute thyroiditis from COVID-19 infection: A Case report and review of literature. Eur Thyroid J 2021; 9(6): 324-8.https://www.karger.com/Article/FullText/511872
[http://dx.doi.org/10.1159/000511872] [PMID: 33708634]
[4] Subacute Thyroiditis: Practice Essentials, Pathophysiology, Etiology. Available from: https://emedicine.medscape.com/article/125648-overview
[5] Campos-Barrera E, Alvarez-Cisneros T, Davalos-Fuentes M. Subacute thyroiditis associated with COVID-19. Case Rep Endocrinol 2020; 2020: 8891539.
[http://dx.doi.org/10.1155/2020/8891539] [PMID: 33005461]
[6] Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviewsThe BMJ 2021; 372
[http://dx.doi.org/10.1136/bmj.n71]
[7] Álvarez Martín MC, del Peso Gilsanz C, Hernández López A. Subacute De Quervain thyroiditis after SARS-CoV-2 infection. Endocrinol Diabetes y Nutr 2020. pmc/articles/PMC7709717
[8] Asfuroglu Kalkan E, Ates I. A case of subacute thyroiditis associated with Covid-19 infectionournal of Endocrinological Investigation 2020; 1173-4.
[http://dx.doi.org/10.1007/s40618-020-01316-3]
[9] Brancatella A, Ricci D, Viola N, Sgrò D, Santini F, Latrofa F. Subacute thyroiditis after Sars-COV-2 infection. J Clin Endocrinol Metab 2020; 105(7): 2367-70.
[10] Chakraborty U, Ghosh S, Chandra A, Ray AK. Subacute thyroiditis as a presenting manifestation of COVID-19: A report of an exceedingly rare clinical entity. BMJ Case Rep 2020; 13(12): 239953. http://casereports.bmj.com/
[http://dx.doi.org/10.1136/bcr-2020-239953] [PMID: 33370933]
[11] Chong WH, Shkolnik B, Saha B, Beegle S. Subacute thyroiditis in the setting of coronavirus disease American J Med Sci 2021; 361: 400-2.
[12] Davoodi L, Oladi Z, Jafarpour H, Zakariaei Z, Soleymani E, Razavi A. A 33-year-old man with COVID-19 presented with subacute thyroiditis: A rare case report and literature review. New Microbes New Infect 2021; : 100871.
[13] De San Juan MJ, Florencio MQ V, Joven MH. Subacute thyroiditis in a patient with coronavirus disease 2019. AACE Clin Case Reports 2019; 6(6): e361-4.
[14] Ippolito S, Dentali F, Tanda ML. SARS-CoV-2: a potential trigger for subacute thyroiditis? Insights from a case reportJournal of Endocrinological Investigation 2020; 1171-2.
[http://dx.doi.org/10.1007/s40618-020-01312-7]
[15] Mattar SAM, Koh SJQ, Rama Chandran S, Cherng BPZ. Subacute thyroiditis associated with COVID-19. BMJ Case Rep 2020; 13(8): 237336.
[http://dx.doi.org/10.1136/bcr-2020-237336] [PMID: 32843467]
[16] Mehmood MA, Bapna M, Arshad M. A case of post-COVID-19 subacute thyroiditis. Cureus 2020; 12(12)
[17] Ruano R, Zorzano-Martinez M, Campos A, Rius F, Hernández M. Subacute thyroiditis might be a complication triggered by SARS-CoV-2. Endocrinol Diabetes y Nutr 2020.
[18] Ruggeri RM, Campennì A, Siracusa M, Frazzetto G, Gullo D. Subacute thyroiditis in a patient infected with SARS-COV-2: an endocrine complication linked to the COVID-19 pandemic 2021; 20: 219-21.
[http://dx.doi.org/10.1007/s40618-020-01312-7]
[19] Brancatella A, Ricci D, Cappellani D, Viola N, Sgrò D, Santini F, et al. Is subacute thyroiditis an underestimated manifestation of SARS-CoV-2 infection? insights from a case series. J Clin Endocrinol Metab 2020; 105(10): 1-5.
[20] Sohrabpour S, Heidari F, Karimi E, Ansari R, Tajdini A, Heidari F. Subacute thyroiditis in COVID-19 patients. Eur Thyroid J 2021; 9(6): 321-3.
[http://dx.doi.org/10.1159/000511707] [PMID: 33708633]
[21] Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): A review. J Am Med Assoc 2020; 782-93.
[22] Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor Cell 2020; 181(2): 271-80.
[23] Chowdhury MA, Hossain N, Kashem MA, Shahid MA, Alam A. Immune response in COVID-19: A review.J Infec Public Health 2020; 1619-29.
[24] Majumder J, Minko T. Recent Developments on Therapeutic and Diagnostic Approaches for COVID-19AAPS Journal 2021; 23
[25] Yotsapon T, Sirinate K, Siriwan B, Soontaree N, Thep H. Clinical features and outcomes of subacute thyroiditis in Thai patients. J ASEAN Fed Endocr Soc 2015; 30(2): 125-8.
[http://dx.doi.org/10.15605/jafes.030.02.03]
[26] Alfadda AA, Sallam RM, Elawad GE, Aldhukair H, Alyahya MM. Subacute thyroiditis: Clinical presentation and long term outcome. Int J Endocrinol 2014; 794943.
[27] Fatourechi V, Aniszewski JP, Fatourechi GZE, Atkinson EJ, Jacobsen SJ. Clinical features and outcome of subacute thyroiditis in an incidence cohort: Olmsted County, Minnesota, study. J Clin Endocrinol Metab 2003; 88(5): 2100-5.
[http://dx.doi.org/10.1210/jc.2002-021799] [PMID: 12727961]
[28] Wei L, Sun S, Xu C hong, Zhang J, Xu Y, Zhu H. Pathology of the thyroid in severe acute respiratory syndrome. Hum Pathol 2007; 38(1): 95-102.
[29] Rotondi M, Coperchini F, Ricci G, et al. Detection of SARS-COV-2 receptor ACE-2 mRNA in thyroid cells: A clue for COVID-19-related subacute thyroiditis. J Endocrinol Invest 2021; 44(5): 1085-90.
[30] Li MY, Li L, Zhang Y, Wang XS. Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues. Infect Dis Poverty 2020; 9(1): 45.
[31] Hennessey J V. Subacute thyroiditis Endotext 2000. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25905310
[32] Alper AT, Hasdemir H, Akyol A, Çakmak N. Incessant ventricular tachycardia due to subacute thyroiditis. Int J Cardiol 2007; 116(1): e22-4.https://pubmed.ncbi.nlm.nih.gov/17134771/
[http://dx.doi.org/10.1016/j.ijcard.2006.08.068] [PMID: 17134771]
[33] Sherman SI, Ladenson PW. Subacute thyroiditis causing thyroid storm. Thyroid 2007; 17(3): 283.
[http://dx.doi.org/10.1089/thy.2007.0070] [PMID: 17381366]

Editor-in-Chief

Abdullah Shehab
Emirates Cardiac Society
Emirates Medical Association
Dubai
(United Arab Emirates)
Biography
View Full Editorial Board

Annual Journal Metrics

Speed

Acceptance rate = 40%

Average review speed: 45 days average

18 days from acceptance to publication



Webmaster Contact: info@benthamscience.net