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• Response to "Persistent COVID-19 related anosmia in patients with chronic autoimmune thyroiditis: What’s behind hypothyroidism?"
  Paraskevi C. Fragkou, Sotirios Tsiodras and Georgios Tsivgoulis
  Published on: 30 August 2021
• Persistent COVID-19 related anosmia in patients with chronic autoimmune thyroiditis: What’s behind hypothyroidism?
  Mario Rotondi, Francesca Coperchini, Fernando de Castro, Laura Croce, Antonio Oliviero and Luca Chiovato
  Published on: 16 July 2021

• Published on: 30 August 2021

  Response to "Persistent COVID-19 related anosmia in patients with chronic autoimmune thyroiditis: What’s behind hypothyroidism?"

  • Paraskevi C. Fragkou, Internal Medicine Consultant Fourth Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens
  • Other Contributors:
    • Sotirios Tsiodras, Professor of Internal Medicine and Infectious Diseases
    • Georgios Tsivgoulis, Professor of Neurology

  We recently published our preliminary case-control study showing that a medical history of hypothyroidism was more prevalent among COVID-19 patients with persistent olfactory dysfunction compared to controls (50% vs 8%; p=0.009) and that hypothyroidism was independently (p=0.021) associated with higher likelihood of persistent hyposmia/anosmia among patients with COVID-19 (OR: 21.1; 95%CI: 2.0 to 219.4) after adjusting for age and sex (1). As previously stated, our results are not -by any means- confirmatory of an etiologic association between hypothyroidism (or preferably chronic autoimmune thyroiditis, CAT, as aptly suggested by Rotondi et al.) and the development of persistent anosmia in COVID-19 patients (1). However, the suggetsed mechanism by Rotondi et al. strengthens our observations by proposing a possible biomolecular explanation behind our clinical observations. Indeed, chemokines that are induced by SARS-CoV-2 infection, and especially CXCL10, could act as effectors of demyelination of the central nervous system (CNS) - including the olfactory apparatus - through attraction and recruitment of T-lymphocytes (2,3). Although the proposed pathogenetic mechanism by Rotondi et al. needs further investigation and laboratory confirmation through experimental studies in COVID-19 patients with persistent olfactory dysfunction, it certainly invigorates our preliminary clinical results and sets the grounds for further research in a clinically significant post-COVID-9 seque...

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  We recently published our preliminary case-control study showing that a medical history of hypothyroidism was more prevalent among COVID-19 patients with persistent olfactory dysfunction compared to controls (50% vs 8%; p=0.009) and that hypothyroidism was independently (p=0.021) associated with higher likelihood of persistent hyposmia/anosmia among patients with COVID-19 (OR: 21.1; 95%CI: 2.0 to 219.4) after adjusting for age and sex (1). As previously stated, our results are not -by any means- confirmatory of an etiologic association between hypothyroidism (or preferably chronic autoimmune thyroiditis, CAT, as aptly suggested by Rotondi et al.) and the development of persistent anosmia in COVID-19 patients (1). However, the suggetsed mechanism by Rotondi et al. strengthens our observations by proposing a possible biomolecular explanation behind our clinical observations. Indeed, chemokines that are induced by SARS-CoV-2 infection, and especially CXCL10, could act as effectors of demyelination of the central nervous system (CNS) - including the olfactory apparatus - through attraction and recruitment of T-lymphocytes (2,3). Although the proposed pathogenetic mechanism by Rotondi et al. needs further investigation and laboratory confirmation through experimental studies in COVID-19 patients with persistent olfactory dysfunction, it certainly invigorates our preliminary clinical results and sets the grounds for further research in a clinically significant post-COVID-9 sequela. Therefore, we are highly grateful to Rotondi and colleagues for their insightful and constructive comments in our study.

  References
  1. Tsivgoulis G, Fragkou PC, Karofylakis E, Paneta M, Papathanasiou K, Palaiodimou L, Psarros C, Papathanasiou M, Lachanis S, Sfikakis PP, Tsiodras S. Hypothyroidism is associated with prolonged COVID-19-induced anosmia: a case-control study. J Neurol Neurosurg Psychiatry. 2021.
  2. Oliviero A, de Castro F, Coperchini F, Chiovato L, Rotondi M. COVID-19 Pulmonary and Olfactory Dysfunctions: Is the Chemokine CXCL10 the Common Denominator? Neuroscientist. 2020:1073858420939033.
  3. Rotondi M, Chiovato L, Romagnani S, Serio M, Romagnani P. Role of chemokines in endocrine autoimmune diseases. Endocr Rev. 2007;28(5):492-520.

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  Conflict of Interest:
  None declared.

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• Published on: 16 July 2021

  Persistent COVID-19 related anosmia in patients with chronic autoimmune thyroiditis: What’s behind hypothyroidism?

  • Mario Rotondi, Endocrinologist Istituti Clinici Scientifici Maugeri IRCCS, Unit of Internal Medicine and Endocrinology, Lab. for Endocrine Disruptors, Pavia
  • Other Contributors:
    • Francesca Coperchini, Biologist
    • Fernando de Castro, Neurologist
    • Laura Croce, Endocrinologist
    • Antonio Oliviero, Neurologist
    • Luca Chiovato, Endocrinologist

  Thyroid hormones play a role in the development and function of virtually all human cells, including maturation of olfactory neurons. The clinical observation that patients with hypothyroidism can experience disturbances in their sense of smell was first reported more than 60 years ago, and it was subsequently confirmed in both humans and animal models. In vivo animal studies clearly demonstrated that hypothyroidism induced by anti-thyroid drugs administration in mice was associated to variable degrees of anosmia, which however promptly reverted following restoration of euthyroidism by levothyroxine replacement therapy (1).
  This latter finding was regarded as the proof that thyroxine, besides its role for correct development of the nervous system would also be involved in the genesis of new olfactory receptor neurons, a process demonstrated to be maintained also in adulthood.
  Since the early phase of the ongoing Sars-CoV-2 pandemic, anosmia was identified as a peculiar clinical symptom of COVID-19 being experienced by nearly 80% of the affected patients (2). It is now known that, at least in some cases, COVID-19 course may encompass protracted olfactory dysfunction and development of olphactory bulb atrophy (3). Thus, attention was paid to potential risk factors predicting this long-term sequela. Interestingly, Tsivgoulis et al., recently performed a prospective case–control study aimed at evaluating whether hypothyroidism could be associated to prolonged COVID...

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  Thyroid hormones play a role in the development and function of virtually all human cells, including maturation of olfactory neurons. The clinical observation that patients with hypothyroidism can experience disturbances in their sense of smell was first reported more than 60 years ago, and it was subsequently confirmed in both humans and animal models. In vivo animal studies clearly demonstrated that hypothyroidism induced by anti-thyroid drugs administration in mice was associated to variable degrees of anosmia, which however promptly reverted following restoration of euthyroidism by levothyroxine replacement therapy (1).
  This latter finding was regarded as the proof that thyroxine, besides its role for correct development of the nervous system would also be involved in the genesis of new olfactory receptor neurons, a process demonstrated to be maintained also in adulthood.
  Since the early phase of the ongoing Sars-CoV-2 pandemic, anosmia was identified as a peculiar clinical symptom of COVID-19 being experienced by nearly 80% of the affected patients (2). It is now known that, at least in some cases, COVID-19 course may encompass protracted olfactory dysfunction and development of olphactory bulb atrophy (3). Thus, attention was paid to potential risk factors predicting this long-term sequela. Interestingly, Tsivgoulis et al., recently performed a prospective case–control study aimed at evaluating whether hypothyroidism could be associated to prolonged COVID19-induced hyposmia/anosmia(3). Olfactory function and anosmia were objectively evaluated by the validated Quick Smell Identification Test. Briefly, among patients with a >40days duration of anosmia in the presence of a negative PCR for Sars-CoV-2, a strikingly higher prevalence of hypothyroidism (50% vs 8%; p=0.009) was observed in cases as compared to controls.
  More interestingly, hypothyroidism was identified to be significantly and independently associated with higher risk for persistent olfactory dysfunction among patients with COVID-19, even after adjusting for potential confounders such as age and sex. This latter is a relevant point in that it is known that autoimmune thyroid diseases display a strong female gender prevalence, thus the correction for sex further strengthen the findings.
  Although the above results were obtained in a rather limited study group, their potential clinical significance should not be neglected in view of their potential utility in the clinical care of the so called “post-COVID-19” syndrome”. However, some considerations should be drawn. Indeed, all of the patients studied by Tsivgoulis et al. were affected by chronic autoimmune thyroiditis (CAT) and were receiving levothyroxine replacement therapy with restoration of euthyroidism as assessed by normal thyroid function tests at study entry.
  Thus, a direct role for thyroid hormones on the persistency of olfactory dysfunction would be difficult to be envisaged in these patients. On the other hand, the observation by Tsivgoulis et al. appears to be worth to be further investigated in view of the following aspects.
  CAT is the most prevalent human autoimmune disease being the major cause of primary hypothyroidism. Interestingly, among several immune-active molecules, CXCL10 a Th1-oriented chemokine, was identified to play a crucial role in the recruitment and maintenance of lymphocytes sustaining chronic autoimmune inflammation (4). More specifically, patients with CAT either in the hypothyroid phase and in the euthyroid patients under LT4 phase display significantly higher circulating levels of CXCL10 as compared to both healthy controls and non-autoimmune hypothyroid patients (4). As far as COVID-19 is concerned, CXCL10 is currently regarded as a main actor in the so called “immune signature” of COVID-19, which is characterized by increased levels of soluble biomarkers (cytokine and chemokines) involved in the recruitment and activation of several immune cell types (5). Of note, we have previously reported how CXCL10 would play a crucial role in the genesis of olfactory dysfunction in COVID-19 infections. Briefly, following Sars-CoV-2 entrance in the upper respiratory tract, it enters nerve cells, promoting the secretion of CXCL10, which, in turn, recruits immune cells expressing the CXCL10-receptor CXCR3 (2). CXCL10-dependent attraction of T lymphocytes within the CNS would ultimately contribute to the demyelination of the olfactory pathway. Indeed, CXCL10 is a strongly involved chemokine in T cells recruitment within the CNS and T-lymphocytes are crucial effectors in the demyelination process (2). Taking together the above evidences, while highlighting the interesting findings reported by Tsivgoulis et al., we would strongly support the concept that the elevated circulating concentrations of CXCL10 observed in several human autoimmune condition and in particular CAT, rather than hypothyroidism (unless when left untreated) would be the cause of a more prolonged anosmia in COVID-19 patients.

  REFERENCES

  1. Beard MD, Mackay-Sim A. Loss of sense of smell in adult, hypothyroid mice. Brain Res. 1987;433(2):181-189.
  2. Oliviero A, de Castro F, Coperchini F, Chiovato L, Rotondi M. COVID-19 Pulmonary and Olfactory Dysfunctions: Is the Chemokine CXCL10 the Common Denominator? Neuroscientist. 2020:1073858420939033.
  3. Tsivgoulis G, Fragkou PC, Karofylakis E, Paneta M, Papathanasiou K, Palaiodimou L, Psarros C, Papathanasiou M, Lachanis S, Sfikakis PP, Tsiodras S. Hypothyroidism is associated with prolonged COVID-19-induced anosmia: a case-control study. J Neurol Neurosurg Psychiatry. 2021.
  4. Rotondi M, Chiovato L, Romagnani S, Serio M, Romagnani P. Role of chemokines in endocrine autoimmune diseases. Endocr Rev. 2007;28(5):492-520.
  5. Coperchini F, Chiovato L, Ricci G, Croce L, Magri F, Rotondi M. The cytokine storm in COVID-19: Further advances in our understanding the role of specific chemokines involved. Cytokine Growth Factor Rev. 2021.

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  Conflict of Interest:
  None declared.

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