To our knowledge, this is the first study to develop a prediction score for abnormal thyroid function in COVID-19 to guide the need to check TFTs on admission for COVID-19 patients. As routine thyroid function testing in each COVID-19 patient on admission may not be cost-effective, we developed this prediction score (ThyroCOVID) consisting of five readily available clinical parameters for potential clinical application.

ThyroCOVID consisted of malaise, IHD/CHF, C-reactive protein, lymphocyte count and SARS-CoV-2 Ct values. These clinical features are players in the relationship between COVID-19 and the thyroid. COVID-19 impacts on the thyroid causing thyroid dysfunction, both directly and indirectly. SARS-CoV-2 uses ACE2 combined with the transmembrane protease serine 2 (TMPRSS2) as the key molecular complex to enter and infect the host cells. Furthermore, as ACE2 and TMPRSS2 expression levels are higher in the thyroid gland than in the lungs, this provides a mechanistic link for the direct thyroid damage causing thyroid dysfunction amongst COVID-19 patients [15]. SARS-CoV-2 has been shown in the thyroid tissues in an autopsy study [9]. Studies have specifically demonstrated the expression of ACE2 mRNA in thyroid cells [10, 11]. The finding of expression of mRNA encoding for the ACE2 receptor in thyroid follicular cells makes them a potential target for SARS-COV-2 entry, providing a clue to the possible direct viral effect of SARS-CoV-2 on thyroid leading to thyroiditis [10]. This may explain why SARS-CoV-2 Ct value can predict the occurrence of biochemical picture of thyroiditis amongst the abnormal TFTs. COVID-19 can also indirectly impact on the thyroid through immune-inflammatory responses to SARS-CoV-2 [15]. The immune response pathway in COVID-19 includes a range of cytokine release, where in severe form of COVID-19 may lead to cytokine storm. The pro-inflammatory cytokine release contributes to the picture of NTIS [28]. Thus, SARS-CoV-2 Ct value can predict the occurrence of NTIS, another main category of abnormal TFTs in acute COVID-19. In COVID-19 patients who developed thyroiditis, CRP elevation was commonly observed [29]. Higher CRP levels in the context of COVID-19 also correlated with the occurrence of NTIS [30]. Thus, CRP levels contribute significantly to our prediction score. Moreover, COVID-19 patients typically present with malaise [31], which is a common manifestation of viral infection and inflammation, and therefore, is included in ThyroCOVID. Lymphopenia is a common haematological finding in COVID-19, postulated to be related to the direct effect of SARS-CoV-2 on lymphocyte apoptosis, bone marrow impairment and thymic suppression, and cytokine-induced apoptosis of lymphocytes [32]. Thus, lymphopenia, a marker of extra-pulmonary involvement of COVID-19, may predict thyroid dysfunction in COVID-19. Interestingly, recent studies have demonstrated the associations between lymphopenia and abnormal TFTs [33, 34], suggesting potential interactions between the hypothalamic–pituitary–thyroid axis and the immune system. Hence, lymphopenia may reflect disturbances in the hypothalamic–pituitary–thyroid axis and predict the occurrence of abnormal TFTs. Last but not least, cardiovascular comorbidities have been shown to carry significant prognostic implications in COVID-19 [35]. Specifically, IHD/CHF is an important medical comorbidity in COVID-19 patients [36]. Therefore, patients with IHD/CHF may be prone to thyroid dysfunction including NTIS by virtue of worse premorbid status. Furthermore, sensitivity analyses in our study demonstrated the ability of ThyroCOVID in the prediction of abnormal TFTs suggestive of NTIS and abnormal TFTs suggestive of thyroiditis respectively.

We did not observe any influence of gender on abnormal TFTs, such that gender is not included in ThyroCOVID. Interestingly, it has been reported in an Italian cohort of patients admitted to high intensity of care units that SARS-CoV-2 atypical thyroiditis was predominantly observed amongst men [8]. In contrast, our cohort comprised predominantly patients with non-severe COVID-19. The difference in the spectrum of disease severity, along with the fact that gender does not influence on the occurrence of NTIS, may explain the lack of gender effect on abnormal TFTs in our study.

Earlier in the COVID-19 pandemic, WHO did not recommend routine thyroid function testing in COVID-19 patients [14, 15], which is reasonable as the prevalence of abnormal TFTs has been estimated to be around 20–30% in general [37]. Nonetheless, the prevalence of abnormal TFTs increases with worsening severity of COVID-19 [37], such that abnormal TFTs has been reported to occur in up to 60% of the cohort with more severe illness [38]. Furthermore, SARS-CoV-2-related atypical thyroiditis has been reported to be more frequent amongst COVID-19 patients requiring intensive care [8]. Hence, it has been suggested that COVID-19 patients requiring high-intensity care may benefit from thyroid function testing [8]. However, it remains to be determined regarding COVID-19 patients in non-intensive care settings who are at risk of thyroid dysfunction and may benefit from thyroid function testing given the clinical and prognostic implications of the spectrum of thyroid dysfunction in COVID-19. Our current prediction score, ThyroCOVID, addressed this knowledge gap.

Application of ThyroCOVID can help to identify patients with abnormal TFTs suggestive of thyroiditis who can benefit from interval monitoring of TFTs for possible evolution to hypothyroid phase [39]. On the other hand, whilst identifying patients with more severe disease who undergo a non-thyroid illness alteration of TFTs provides prognostic information, whether interventions such as triiodothyronine replacement in NTIS offer benefits to these patients remain to be evaluated [40,41,42].

The strengths of the current study include a well-characterised cohort of COVID-19 patients consecutively recruited in a major COVID-19 treatment centre, demonstrated to be a representative cohort of the territory [17]. Moreover, the results are likely generalisable to COVID-19 patients at large as our cohort consists of mostly non-severe COVID-19 patients [31]. However, certain limitations exist in this study. First, as the cohort comprised mainly patients with non-severe COVID-19, the prevalence of abnormal TFTs was only 15%. A larger sample size may improve the power of the prediction score. Second, due to the relatively small number of abnormal TFTs, the construction of prediction scores for specific types of abnormal TFTs is not feasible. Nonetheless, we have demonstrated the potential utility of the prediction score in NTIS and thyroiditis in the sensitivity analyses. Last but not least, our prediction score requires external validation in independent populations to confirm our findings.