Bimodal distribution of thyroid dysfunction triggered by COVID-19 Infection: An experience from a single endocrine center—a case series and literature review

Background: COVID-19 infection has been spreading across the globe since the end of 2019, and it continues to cause chronic multi-system sequelae, of which thyroid dysfunction appears to be the major one. We have discussed here 10 cases of thyroid dysfunction after COVID-19 infection. Methods: Case series report. From October 2020 to July 2021, a series of 10 cases of thyroid dysfunction after COVID-19 infection were recorded and managed in a single outpatient endocrine center in Doha, Qatar. Cases presentation: We have reported 5 cases of Graves's hyperthyroidism, 2 of chronic primary hypothyroidism (including one with Grave's disease [GD]) who was treated through radioactive iodine (RAI) therapy, one case of subacute thyroiditis, one case with “Sick euthyroid disease,” and one case of central hypothyroidism. Presently, patients with GD are being treated with carbimazole and those with hypothyroidism are being treated with levothyroxine. The remaining patients had recovered with euthyroid. Conclusion: This is the largest case series reported from a single center to date. The findings of this series indicate a bimodal distribution of thyroid dysfunction in patients with COVID-19 infection. A review of the literature and discussion of potential pathophysiological mechanisms has been presented. We have emphasized the importance of screening for thyroid dysfunction in “post-COVID-19” cases, considering that the prevalence may be underestimated.

Keywords: Hyperthyroidism, Thyroiditis, hypothyroidism, COVID-19, Case Series BACKGROUND For over 2 years, the world has been battling with the health impact stemming from Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), also known as COVID-19 (coronavirus disease 2019), which was first reported in Wuhan in the winter of 2019/2020. The virus classically presents with respiratory symptoms but could well be asymptomatic or may even present with an atypical presentation with non-pulmonary complications that include neurological disorders, cardiac abnormalities, renal failure, liver disease, rhabdomyolysis, coagulopathy, thrombosis, and endocrine dysfunctions. 1 SARS-CoV-2 uses angiotensin-converting enzyme-2 (ACE-2) receptor and transmembrane protease serine 2 (TMPRSS2), as well as cathpesin to gain access and infect the human cells. 2 Infection or entry of this virus triggers a cascade of virus replication and the release of the virus, resulting in cell damage. This process is called pyroptosis, an abrupt form of programmed cell death, 3 with a subsequent cascade of events including the release of an array of cytokines (e.g. interleukins, tumor necrosis factor [TNF], and interferon [IFN]-g), in addition to intracellular molecules such as adenosine triphosphate (ATP), nucleic acids, and pathogen-associated molecular patterns. The proinflammatory cytokines (such as interlukin [IL]-b, TNFa, IFN-g) may lead to immune response hyperactivity and uncontrolled systemic inflammatory response. 3 Enhanced T-helper (Th1/Th17) immune responses and cytokine pathways involved in severe acute respiratory syndrome (SARS) resemble the immune activation occurring in immune-mediated thyroid diseases. 4 ACE-2 and transmembrane protease serine 2 (TMPRSS2) expression are extremely high in the thyroid more than that in the lungs. 5 The uptake by host cells of SARS-COVID-2 is believed to be mediated by other cellular proteases and molecules. One main group of a cellular membrane proteins involved was found to be integrins, and ACE2 has been reported to bind to integrins to modulate the downstream signal transduction. Thyroxine (T4) regulates the expression of genes for the monomeric protein that constitutes integrins. 5 Thyroid hormones regulate genes for the monomeric protein that constitute integrins and are believed to promote the internalization of integrins. 7,8 Notably, olfactory receptors (ORs) are co-expressed with ACE2 and TMPRSS2. ORs are widely expressed in the thyroid. 9 Impairment of the cellular function at the neuroepithelium of the olfactory bulb constitutes the molecular mechanism that underlies the anosmia observed in COVID-19 victims. 10 The damage to ORs is postulated to contribute to the impairment of other organs expressing OR, not excluding the thyroid. 9 Viruses have been well recognized to trigger thyroid autoimmunity. 11 Thyroid disease in the context of COVID-19 infection was demonstrated in a recent systematic review and meta-analysis was associated with a poor outcome. 12 However, the relationship between the two has been described as bidirectional. 13 In this short report, we have presented 10 cases of thyroid dysfunction associated with COVID-19 infection that was diagnosed and managed at a single endocrine center in Qatar. We have also reviewed the relevant literature to support the case report.

CASE PRESENTATIONS
. The thyroid uptake scan revealed normal morphology and function, except for a cold nodule in the postero-inferior part of the right lobe. After a discussion with the patient, it was decided to adopt the wait-and-see policy. TFT repeated after 6 weeks showed that the TSH value had risen to 61 mIU/L and FT to 4 pmol/L. He was accordingly started on levothyroxine (100 mcg, daily), and his TFT normalized after 6 weeks. . Case 2: A 50-year-old Filipino male, with a medical history of asthma and hypertension, presented with respiratory symptoms and tested positive for COVID-19 infection. His chest X-ray showed bilateral lung infiltrates. He was treated for COVID-19 pneumonia and as per the hospital protocol (azithromycin: 500 mg daily, ceftriaxone 2 mg IV once daily, hydroxychloroquine 400 mg daily, lopinavir/ ritonavir 200/50 mg bid, ribavirin, and oseltamivir 150 mg bid). His hospital course was complicated by acute respiratory distress syndrome requiring intensive care unit (ICU) admission. He accordingly received tociluzimab and methylprednisolone, but did not require endotracheal intubation or mechanical ventilation. TFTs were conducted because of persistent tachycardia, which showed TSH of 0.08 mu/L, FT3 of 3.4 pmol/L (NRR 3-6), and FT4 of 23 pmol/L. When TFT was repeated after 6 weeks, it showed resolution of the thyroid dysfunction with a TSH of 0.47 mIU/L and FT4 of 18.8 pmol/L, suggesting "thyroxine thyrotoxicosis" due to COVID-19-related thyroiditis. Subsequent follow-up over 6 months revealed no further abnormality. . Case 3: A 32-year-old Sudanese female patient had hypothyroidism during her adolescence, for which she was treated with levothyroxine until the age of 16 years. She has been an euthyroid since then. She also presented with a history of thyroid nodules in 2016, which was not followed up later. In September 2020, she was diagnosed with COVID-19 following a mild respiratory illness. She made an uneventful recovery, but, after 3 months, in December 2020, she presented with the symptoms of tiredness, fatigue, bilateral hand tremors, palpitations, increased sweating, shortness of breath, and irregular periods. Her physical examination was consistent with a hyperthyroid state, with a small diffuse goiter. TFTs revealed TSH , 0.01 mIU/L, FT4: 72.3 pmol/L, and TRAb 28 U/L (normal ,0.75). A thyroid nuclear uptake scan with technetium revealed an enlarged thyroid, with an overall picture suggestive of diffuse Grave's disease (GD). She was accordingly started on carbimazole 30 mg, daily, along with propranolol (40 mg bid) and she improved. Repeated TFT after 2 months revealed TSH , 0.01 mIU/L, FT3: 7.6 pmol/L, and FT4: 24.0 pmol/L. Subsequent TFTs showed a normal level. She was followed up at the Endocrinology Clinic for her GD, and the latest TFTs conducted in January 2022 showed persistent remission with carbimazole. .

DISCUSSION
COVID-19 infection continues to ravage the world population, and its effect proved to be diverse with multi-system consequences. Covid-induced thyroid dysfunction is emerging as a well-established and common aftermath of the disease. 4 As demonstrated by our case reports, the clinician in endocrine practice could face diverse presentations. Five of our 10 cases presented with immune-mediated hyperthyroidism, and 4 had virus-induced destructive thyroiditis, which proved to be transient in 2 cases, and had a permanent effect in the other two. One patient had central hypothyroidism. Triggering of various autoimmune diseases in general by Covid-19 has been recognized, and includes anti-phospholipid syndrome, autoimmune thrombocytopenia, hemolytic anemia, and Guillain-Barre syndrome, among others. 14 This may persist long after the resolution of COVID-19.
The literature shows that non-thyroidal illness (NTI) is the most common abnormality observed in COVID-19 patients. Up to 30% of COVID-19 patients may suffer the syndrome of low TSH with low or normal T4 and low T3. 15 NTI may occur at all spectra of the illness. It commonly occurs with the "Cytokine Storm," also known as Cytokine Release Syndrome. 16,17 The degree of reduction of TSH and FT3 is proportional to the severity of COVID-19 infection. 18 Those with low  25 or during the few weeks to months following its resolution, as noted in our patients and those reported by Brancatella et al. 32 Neck pain is the hallmark of this disease in SAT. The classical course includes an initial phase of hyperthyroidism followed by hypothyroidism and then euthyroidism, which unfolds over 6 months. The outcome is either complete resolution 31,33 or the development of permanent hypothyroidism. 32 Our series included 2 patients with SAT, one of them, a young girl, recovered completely, while the second one developed permanent hypothyroidism that required replacement thyroxine therapy. A variant of subacute thyroiditis, which occurred in 15% as a form of 'SAT' without neck pain, is thought to be attributable to lymphopenia, 34 which was first recognized in critically ill patients admitted to the ICU. 35 40 While central hypothyroidism was spontaneously remitted in the 3 patients with central hypothyroidism after 3-9 months, most patients with primary hypothyroidism generally required permanent T4 therapy. 40 However, our experience with 1 patient implies that the outcome may not be predictable and that therapy can be required for managing symptoms and treating persistent biochemical hypothyroidism. The thyroid may be indirectly damaged from hyperactivity of the Th1/Th17 40 and the surge of "Cytokine Storm," which possibly triggers and perpetuates the thyroid gland inflammation. 3 Lania et al. reported an inverse relationship between TSH and the level of IL-6 in their cohort of 287 patients. 25 This finding suggested the role of cytokines in perpetuating thyroid dysfunction. On the other hand, an extensive injury to the "follicular and parafollicular" cells caused by the virus has been reported by some studies. 41 This result may facilitate the comprehension of the increased risk of osteonecrosis in COVID-19 patients. 42,43 Postulated mechanisms of the trigger of Graves' hyperthyroidism were reviewed by Murugan & Alzahrani. 40 . The possible role of COVID-19 in triggering thyroid autoimmunity is supported by several reports of thyroid dysfunction triggered by vaccines developed from these viruses 45 -47 or the worsening of pre-existing Graves following vaccination. 48 The phenotypic expression of thyroid autoimmunity has been attributed to the balance between Th1 and Th2. A predominant Th1-mediated immune response is likely to trigger an apoptotic pathway in the thyroid follicular cells, destroying thyroid cells. Th2 immune-mediated activity is likely to activate antigen-specific B lymphocytes to make TSH-Rab, resulting in the proliferation of thyroid cells and the hyperactivity of the gland. 40 A major limitation of this study is that it is a case series of 10 cases selected from our outpatient clinic. Detailed observation and follow-up of the patients with COVID-19 infection and thyroid illness should be conducted in the future to establish the connection suggested by the present findings.

CONCLUSIONS
In conclusion, the evidence for COVID-19 leading to thyroid dysfunction is gradually accumulating, indicating a bimodal distribution and occurring along with an acute infection as well as during the recovery period. Our report provides further support to this notion. Thus, screening during the follow-up period is highly recommended in patients who have recovered from COVID-19 infection, especially among those with a history of thyroid autoimmunity.

DECLARATIONS Ethical Approval and Consent to participate
The case series report was approved by the Medical Research center, Hamad Medical Corporation, Doha, Qatar, MRC 04-21-409. A waiver of informed consent was obtained as the report does not contain any identifiers of patients involved.

Consent for publication
Consent for publication was approved by the Medical Research center, Hamad Medical Corporation, Doha, Qatar.

Availability of supporting data
The data that support the findings of this study are available from Cerner at Hamad Medical Corporation but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of Hamad Medical Corporation Medical research center.