Endocrinology in the time of COVID-19

N/A.


Introduction
On March 11 th 2020, the World Health Organisation (WHO) declared infection by the corona (SARS-CoV-2) virus causing COVID-19 disease a global pandemic 1 . Most countries have implemented local and national crisis management plans to try and cope with the most severe and overwhelming health crisis in a century. Most healthcare practitioners have been re-deployed to frontline services and other areas which are most in need and routine medical care and elective procedures have been postponed.
Additionally, with more than a third of the world population in lockdown, patients face difficulties accessing facilities for clinic review as well as diagnostic and therapeutic procedures.
Hypo-and hyperthyroidism are chronic conditions which are usually treated in an outpatient setting and their management is heavily reliant on biochemical testing, imaging and nuclear medicine procedures. Moreover, some of the commonly used therapies may pose diagnostic and therapeutic challenges for health care practitioners and patients. This manuscript aims to provide consensus advice for safe management of patients during a resource limited crisis and may need to be adapted to local practice and available infrastructure.
The authors screened the available literature and included search terms like "thyroid and COVID-19/SARS/Corona", "thyroid and influence" and "thyroid and ACE-receptor". Since no obvious evidence was found on how to handle patients with thyroid dysfunction during the COVID-19 pandemic, the authors decided to join efforts for an expert-based recommendation. Our key messages are summarised in Table 1.

How will COVID-19 and thyroid dysfunction impact each other?
 Effect of thyroid autoimmunity on COVID-19 infection: Both hyper-and hypothyroidism are usually caused by autoimmune conditions. Around 80% of the pathogenesis of Graves' disease and Hashimoto thyroiditis is determined by genetic factors with environmental factors accounting for 20%. Viral infections including those with parvo-, Epstein Barr and Hepatitis C viruses have been proposed as potential environmental triggers 2 but there is no evidence that patients with existing autoimmune thyroid disease are more susceptible to contracting viral illnesses including infection with SARS-CoV-2, nor that they are at risk of developing more severe COVID-19 disease. Certain subsets of patients, such as those with Graves' ophthalmopathy who are actively undergoing immunosuppressive therapy, are likely to be at increased risk of developing severe corona virus infection.
 Effect of antithyroid drugs (ATDs) on COVID-19: ATDs are not known to increase the risk of infection, and we do not consider patients on ATDs to be at higher risk of contracting COVID-19 or of developing more severe disease in the event of contracting the infection.
 Effects of COVID-19 on hypothalamic-pituitary-thyroid axis: Systemic diseases are known to be associated with low-T3 syndrome or non-thyroidal-illness 3 . Severe COVID-19 is expected to generate such condition especially when the infection is associated with fever and lower respiratory tract involvement. Additionally, SARS-CoV-2 infection has been reported to affect the nervous system with involvement of cranial nerves for olfaction and taste commonly affected 4 . Future studies are required to evaluate the risk of hypothalamitis potentially leading to central hypothyroidism in COVID-19 patients after remission 5, 6 . Nonetheless we advise against routine screening for thyroid dysfunction in acutely ill patients unless there is a strong suspicion that thyroid disease is contributing to the clinical presentation.
 Effect of thyroid function control on COVID-19: There is no evidence that those with poorly controlled thyroid disease are more likely to contract viral infections. However, it is plausible that patients with uncontrolled thyroid dysfunction, especially those with thyrotoxicosis may be at higher risk of complications (e.g. thyroid storm) from any infection 7 . We strongly recommend that patients with thyroid dysfunction continue taking their thyroid medication(s) to reduce this risk. Emergency thyroid surgery or 131-I administration may be considered in life-threatening cases of uncontrolled hyperthyroidism, although the administration of radioiodine has been suspended in many countries. identify the underlying diagnosis 8,9 . This is particularly important since most centres have suspended the use of diagnostic isotope scanning during the COVID-19 crisis in view of staff and resource unavailability and in order to reduce footfall in hospitals. Thyroid ultrasonography may aid in defining the underlying aetiology 8 , although with a reduction in the availability of hospital appointments, and since treatment options for hyperthyroidism are limited regardless of the underlying aetiology, the role of this imaging modality is likely to be limited. Determination of malignancy risk associated with palpable thyroid nodules can usually be postponed, unless particular characteristics (rapid growth, highly suspicious features at palpation or imaging) indicate a high-risk thyroid cancer.
 Regimens for treatment of thyrotoxicosis: Patients whose hyperthyroidism is well controlled with a titration or block-and-replace regimen (BRR) should continue their treatment without changes. However, since over the coming weeks to months, it may become difficult to undertake biochemical monitoring of thyrotoxicosis, BRRs should be considered as initial treatment, especially in patients presenting with new or relapsed hyperthyroidism. BRRs generally have similar efficacy and long-term cure rates as titration regimens but usually reduce the amount of thyroid function testing that is required and allow euthyroidism to be achieved and maintained in the majority of patients with hyperthyroidism, irrespective of aetiology. 9, 10 Suggested BBRs for adults and children are outlined in Figure 1 and   Radioiodine administration for hyperthyroidism: Elective radioiodine administration with 131-I has been postponed in most countries both for benign and for malignant thyroid diseases. This is based on prioritisation of delivery of emergency care with re-location of healthcare staff and resources as well as anticipated difficulties with patients being unable to adhere to radiation protection guidance during the COVID-19 pandemic. We feel confident that, in most cases, there will be no long-term adverse effects from postponing 131-I therapy.
Importantly it is crucial to identify those patients who have undergone 131-I treatment for hyperthyroidism in the months before the COVID pandemic, and to adopt a low threshold for commencing levothyroxine therapy if hypothyroid symptoms develop. In patients with Graves' disease, when 131-I treatment is urgently required, prophylactic steroid treatment should be given when indicated 15 .

Which patient groups are at particular risk form COVID-19 infection?
 Patients with thyroid eye disease on immuno-suppressive medication: Patients with thyroid eye disease who are undergoing treatment with immunosuppressive agents are considered to be extremely vulnerable and at very high risk of severe illness from coronavirus  and should be advised to self-isolate for at least 12 weeks 18 . This includes patients on glucocorticoids at immunosuppressive doses as well as those on other immunosuppressive agents such as mycophenolate, azathioprine and biological agents including teprotumumab, rituximab and tocilizumab 19 . It is particularly important to reduce the risk of progression of ophthalmopathy during this pandemic: advice including the discontinuation of cigarette smoking and/or selenium supplementation should be reinforced 15   Face to face appointments: Patients with new-onset or worsening thyroid eye disease, those with enlarging goitres causing symptoms of obstruction and patients who are not responding to standard treatment measures as expected may require appointments in person for a thorough clinical assessment. We anticipate that this is only required in a minority of patients.
 Satellite blood-testing services: The management of thyroid dysfunction is heavily reliant on biochemical testing. Many centres have established peripheral "pods" for blood taking and tests required for managing thyroid dysfunction do not require specific handling making such facilities ideal for these particular patients.

What might be the longer-term consequences for service provision?
 Patients with thyroid dysfunction will not be managed as closely as would be ideal in noncrisis situations. Patients with severe hyper-and hypothyroidism should be prioritised. The underlying aetiology of those with hyperthyroidism will not be identified in a significant number of patients and those with toxic nodular hyperthyroidism will not receive the most appropriate treatment, namely 131-I treatment or thyroid surgery. In addition, there will be a significant back-log of patients who have not received timely appointments and who will need to be reviewed in person or remotely depending on the duration of the crisis and the clinical needs.
 It seems plausible that the experience with remote and virtual follow-up of patients will translate into a number of systems that can be continued and maintained following the COVID-19 pandemic, resulting in more efficient management of patients with thyroid dysfunction.