|Year : 2020 | Volume
| Issue : 2 | Page : 62-69
Management of thyroid diseases during pandemic: A narrative review
Mathew John1, Vimal Mavila Veetil2
1 Providence Endocrine and Diabetes Specialty Centre, Thiruvananthapuram, Kerala, India
2 Department of Endocrinology & Diabetes, Aster MIMS, Kozhikode, Kerala, India
|Date of Submission||08-May-2020|
|Date of Acceptance||25-May-2020|
|Date of Web Publication||01-Jul-2020|
Dr. Mathew John
Providence Endocrine and Diabetes Specialty Centre, Prasanth Nagar, Ulloor, Thiruvananthapuram - 695 011, Kerala
Source of Support: None, Conflict of Interest: None
The COVID-19 pandemic caused by the novel coronavirus (SARS-CoV-2) has caused significant morbidity and mortality across the globe. It has resulted in compromised care for patients with chronic diseases. Thyroid diseases are highly prevalent in the world, both in iodine-deficient and -sufficient areas. Viruses can cause thyroid diseases by the direct invasion of the gland, by triggering immune mechanisms, and by the effects of antiviral drugs on the gland. Although there is no signal of a pathogenic mechanism of thyroid diseases by SARS-CoV-2 to date, the high prevalence of thyroid diseases in people affected by this pandemic makes it prudent to study the association between these diseases and to formulate a management plan in the resource-limited setting. In this brief review, we have tried to discuss the relationship between the virus and diseases of the thyroid gland and the management challenges in patients with hypothyroidism, hyperthyroidism, Graves' orbitopathy, and thyroid nodules including cancer. We have also tried to incorporate the advantages and limitations of telemedicine for thyroid disease in the era of a pandemic.
Keywords: COVID-19, Graves' orbitopathy, hyperthyroidism, hypothyroidism, thyroid, thyroid neoplasm
|How to cite this article:|
John M, Veetil VM. Management of thyroid diseases during pandemic: A narrative review. Thyroid Res Pract 2020;17:62-9
| Introduction|| |
Diseases of the thyroid gland are one of the most prevalent endocrine diseases. Studies done from various parts of India highlight the high prevalence of various forms of thyroid disease including thyroid cancer. In NHANES III, hypothyroidism was found in 4.6% of the US population, hyperthyroidism in 1.3%, positive thyroglobulin antibodies in 10.4%, and thyroid peroxidase antibody in 11.3%. With the increasing use of high-resolution sonography, 19%–68% of people may have thyroid nodules.
COVID-19 caused by the novel coronavirus (SARS-CoV-2) is a worldwide pandemic, which has affected more than 3,500,000 individuals and causing more than 247,000 deaths. COVID-19 has resulted in new challenges to the health sector, resulting in major restructuring of priorities to care of people affected by the pandemic, leading to compromised care for people with chronic diseases such as diabetes mellitus, hypertension, cancers, and cardiovascular diseases. Professional bodies have responded to these challenges by formulating guidelines which seek to maintain essential standards of care, while balancing the potential risks associated with the pandemic, and the challenges posed by the limited mobility of people, while maintaining safety to all stakeholders., Although the proportion of people with thyroid disease is not increased in the case series of COVID-19, the sheer volume of people living with thyroid disease makes it a major concern for physicians. Recommendations from professional societies have provided important inputs to solve many of the issues.,, This narrative review expands on these recommendations and suggests pragmatic solutions for many case scenarios.
| Search Strategy|| |
We systematically searched PubMed database till April 2020 using various keywords related to thyroid diseases (thyroid, hypothyroidism, hyperthyroidism, thyroid nodules, thyroid cancers, orbitopathy, differentiated thyroid cancers, thyroxine, antithyroid drugs [ATD] and radioactive iodine [RAI]) and keywords related to viral diseases (SARS, coronavirus, SARS-CoV-2, COVID-19, and ACE2). We searched professional association websites in the field of thyroidology, endocrinology, and endocrine surgery for guidance on the management of various thyroid diseases. We formulated possible scenarios in clinical thyroidology, and relevant literatures from these searches were used to answer the questions. In the absence of significant data on COVID-19 and thyroid, we used literature on SARS pandemic for decision-making.
| Angiotensin-Converting Enzyme 2 and Thyroid|| |
SARS virus (SARS and SARS-CoV-2) gains entry into the target cells by attaching the viral structural spike(S) protein to the angiotensin-converting enzyme 2 (ACE2) receptor on the cell membrane. The high expression of ACE2 is found in the small intestine, testis, kidneys, heart, thyroid, and adipose tissue in addition to various other tissues such as lung, heart, and nervous system. The presence of ACE2 in these tissues is linked directly to consequences such as myocardial injury, pneumonia, and neuronal injury., Because thyroid injury has been documented in SARS infection and both viruses use the ACE2 as the cellular receptor, there is a high probability of thyroid involvement in COVID-19 infection. There is an increased expression of ACE2 in thyroid malignancies although the implications of this finding for pathogenesis, survival, or risk for COVID-19 are not clear.,
| Viruses and Thyroid|| |
Viral infections have been attributed as etiologies in autoimmune thyroid disease and subacute thyroiditis. Case clusters of subacute thyroiditis following viral respiratory tract infections and seasonal occurrence of these infections synchronizing with certain viral infections suggest possible viral etiology. Circulating antibodies to mumps virus and positive viral cultures of mumps were found in cases of subacute thyroiditis. There have been reports of cases where mumps virus were cultured from the thyroid of people with mumps. Other viruses such as coxsackie, adenovirus, CMV, and influenzae B and dengue fever have been found in association with subacute thyroiditis.,,
Infection is considered as a trigger for autoimmune disease. Infections and autoimmunity are interlinked by various mechanisms such as liberation of antigens (via cell destruction or apoptosis), formation of altered antigens, cytokine and chemokine secretion, molecular mimicry, induction of aberrant HLA-DR expression, and toll-like receptor activation. Hashimoto's thyroiditis has been associated with various viruses like HIV, HTLV1, congenital rubella, HCV, HBV, enterovirus infection during pregnancy, and MMR vaccination. Graves' disease (GD) has been associated with HTLV1, HIV, HFV, HIAP-1, HHV6, HHV7, parvovirus, enterovirus, HSV, and CMV.,
In an autopsy study on people with SARS infection, there was consistent destruction of the follicular epithelium, distortion of architecture, and exfoliation of epithelial cells into the follicle. There was no significant neutrophilic or lymphocytic infiltration. The terminal deoxynucleotidyl transferase-mediated (dUPT) nick end-labeling assay demonstrated many follicular cells undergoing apoptosis. In the absence of any significant data on how COVID-19 affects the thyroid, the data on SARS should alert clinicians on similar possibility. In a series of two autopsies in fatal cases of COVID-19, thyroid were grossly normal.
| Thyroid Function Tests|| |
Thyroid function test (TFT) forms an essential part of thyroid assessment. With the availability of immunochemistry analyzers, the testing is widespread in many parts of the world with a low turnaround time. Interference with TFT can be due to dysfunction of the hypothalamo–pituitary–thyroid axis, antibody or drug interference with assays, and drug interference with thyroid and nonthyroidal illnesses.
In an autopsy study of patients with SARS, the number and the immunoreactive intensity of TSH-positive cells in the anterior pituitary of people in the SARS group significantly decreased. This was reflected in low TSH seen in these people infected with SARS. Possible reasons include direct action of virus on TSH-secreting cells, hypoxemia, and the effect of exogenous glucocorticoids (GCs). Effects of increased somatostatin levels associated with stress may also contribute to reduced TSH-secreting cells. Low T3 and T4 levels in association with the findings of extensive thyroid follicular destruction point to thyroid involvement in SARS. In a study of survivors of SARS, transient subclinical thyrotoxicosis and central and primary hypothyroidism were documented.
Immunoassays can have interference from high levels of antibodies. It is well known that heterophile antibodies can interfere with hormone immunoassays. These antibodies can lead to false high values in TSH, T4, and T3 assays. Heterophile antibodies are common with EBV infection. In a person with EBV infection and thyroiditis, autoantibody interference leading to spuriously high total T3 was demonstrated. Whether COVID-19 antibodies or treatment with convalescent plasma will lead to such an interference is unknown. Presence of discordant TFT values in people affected by COVID-19 should alert the clinician of this possibility.
Various drugs used in the management of COVID-19, especially in the intensive care unit (ICU), can interfere with TFTs. Lopinavir/ritonavir is proposed as a treatment for people with SARS-CoV-2 infection. Increased TSH levels were found in people with hypothyroidism on ritonavir related to increased uridine diphosphate glucuronosyltransferase induction of thyroxine metabolism. In a series of 138 patients from China, 26% required intensive care, of which 61% developed ARDS and 30.6% developed shock. GCs and vasopressors are commonly used to treat people with ARDS and shock.
Abnormalities of the hypothalamo–pituitary–thyroid axis in critically ill individuals follow the pattern of nonthyroidal illness. This is characterized by low T3 in its initial stage followed by low total T4 as the severity and duration of the illness progresses. TSH stays normal or gets suppressed as the disease progresses and increases as the disease recovers. GCs and vasopressors can lead to inhibition of TSH release from the pituitary and subsequent low TSH levels.
Interferons are considered in the treatment combinations used to treat people with SARS-CoV-2. Various new trials for IFN alpha-2β (NCT04293887), IFN-β1a (NCT04350671), pegylated IFN-λ (NCT04343976), and IFN-5α (NCT01121731) alone or in various combinations are currently in progress. Various types of thyroid dysfunction such as destructive thyroiditis, hypothyroidism, and hyperthyroidism are described with the use of interferons alone or in combination with other antivirals such as ribavirin in people with hepatitis C infection.,
An increased risk of arrhythmias has been described with COVID-19. Nearly 17% of all hospitalized people and 44% out of 36 patients admitted in the ICU had arrhythmias. Various factors which predispose to arrhythmia include viral myocarditis, hypoxia, electrolyte imbalances, fever, stress, and use of various antiviral drugs. Drugs such as hydroxychloroquine, azithromycin, ritonavir, lopinavir, and remdesivir (especially in combinations) may prolong QTc via various precipitate arrhythmias. Amiodarone may be used in intensive care settings for life-threatening ventricular fibrillation and atrial fibrillation. Further, amiodarone is being studied in ongoing clinical trials for treating people with COVID infection (ReCOVery-SIRIO, NCT04351763). Amiodarone may be associated with a spectrum of thyroid function abnormalities including low T3, high T4, and high TSH. People with COVID infection may require iodine-based radiocontrast procedure for lung imaging. Thyroid function abnormalities related to this are not uncommon and may confuse the thyroid function in the ICU.
Various drugs and other interfering substances such as antibodies or nonthyroidal illness may affect TFTs in people with COVID-19 infection. Beyond the thyroid dysfunction due to the viral infection, these interferences can affect the interpretations of TFT.
| Hypothyroidism|| |
Destruction of the thyroid follicular epithelium and apoptosis of thyrocytes are seen in people with severe SARS infection. However, the long-term effects of respiratory viral infections such as SARS or COVID-19 on thyroid structure or function are not clear.
Periodic monitoring of TFTs is one of the most common follow-up strategies with primary hypothyroidism. During pandemics, access to thyroid function may be restricted due to issues with social distancing including travel for thyroid tests. In most stable adults with primary hypothyroidism, annual monitoring of thyroid functions is recommended. In a population-based study involving 2125 patients, the outcomes of 18-month follow-up for thyroid testing were compared to 12-month surveillance. More abnormal tests requiring dose changes were found in people who were in 12-month surveillance compared to those who were on 18-month surveillance. Lesser frequency of testing sufficed for people who are <60 years of age and on a daily dose of 100–150 μg/day. More frequent monitoring has to be done in children with congenital hypothyroidism, in childhood and adolescence, in symptomatic patients, when thyroxin doses are changed, in people with cardiovascular diseases, older people and for those in pregnancy [Table 1]. With limited access to testing during pandemics, consideration should be given to reduce the frequency of testing in people on stable dose of thyroxine and use of home blood sampling services for the same. Physicians should encourage people with hypothyroidism to be compliant with medicines, to ensure the potency by storing it at optimum temperatures, and to consume it 30–60 min before the first meal of the day. In pregnant women who are unable to access thyroid testing, consideration should be given to increase the thyroxine doses by 30%.
|Table 1: Suggested clinical guidance for common clinical scenarios with reference to thyroid disorders|
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Access to specific brands of thyroxine may be limited in pandemics due to production and supply chain logistics. Physicians should consider substituting generics in this scenario knowing well that they may not be bioequivalent. Consideration for testing should be done as soon as access is improved. Increased requirement of thyroxine may be considered in people taking ritonavir in the management protocols of COVID-19.
In people who are admitted with COVID and are able to tolerate orally, thyroxine should be continued orally with doses decided on the basis of testing. Various factors such as enteral feeding, use of proton pump inhibitors, bowel edema, and motility may result in changes in thyroxine dosing during intensive care admission. COVID-19 is associated with increased mortality and hospital admissions in the elderly. A possibility of myxedema coma should be considered in the differential diagnosis of any person with preexisting hypothyroidism presenting with the suspect symptoms, especially in the elderly. Management of these individuals will include the use of parenteral thyroxine and steroids in addition to other supportive measures.
| Hyperthyroidism|| |
People with hyperthyroidism are likely to face various challenges during the time of the pandemic. People with suppressed TSH and elevated thyroid hormones traditionally undergo TSH receptor antibody testing or nuclear imaging to make a differential diagnosis. With limited access to testing, clinical evaluation of signs and symptoms assumes more importance. In a series of people with hyperthyroidism, clinical diagnosis had a sensitivity, specificity, positive predictive value, and negative predictive value of 88%, 66%, 72%, and 84%, respectively, in differentiating Graves' from non-Graves' hyperthyroidism. Presence of soft diffuse vascular goiter, orbitopathy, dermopathy, and longer duration of symptoms favors the diagnosis of GD.
Treatment options for most people diagnosed with Graves' toxicosis are RAI ablation therapy or antithyroid drugs (ATD). Because there may be significant disruptions of supply chains for the availability of iodine-based isotopes, delays in RAI iodine ablation are expected. It is preferable that physicians opt for anti-thyroid drugs for patients with GD. It is recommended to do baseline complete blood counts and liver function tests before starting people with GD on anti-thyroid drugs. Physicians should give education on possible adverse effects related to ATDs including the risks of agranulocytosis and liver dysfunction. Patients should be educated to identify the symptoms of agranulocytosis such as sore throat, mouth ulcerations, high fever, and flu-like symptoms. In a study, it was found that 61% of the people taking ATDs were unaware of the symptoms of agranulocytosis. It is preferable that this information be conveyed to patients in writing and reinforced during all visits. The symptoms of agranulocytosis can overlap with that of COVID-19 infections and hence a history of ATD use should not be overlooked by the physicians who take care of these patients. However, neutropenia is uncommon in COVID-19 infection. ATDs can be continued in people with COVID-19 unless neutropenia (antineutrophil count <1000/mm3) is documented.
In some countries, both methimazole and carbimazole are available, and the use of these drugs depends on physician preference and availability. Carbimazole is a prodrug and gets metabolized to methimazole. Physicians should consider changing patients to carbimazole if the availability of methimazole is a constraint. The drugs can be considered equipotent on a molar basis and should be converted in a 1:1 proportion. On a similar note, people using propylthiouracil (PTU) should consider changing to carbimazole or methimazole in case of nonavailability unless there is a compelling indication for the former. A conversion of 30 mg of methimazole for 300 mg of PTU should be considered although the response to drugs may vary between individuals.
There are suggestions on the use of block and replace regimens to defer thyroid testing and provide stable thyroid levels in people with thyrotoxicosis in resource-constrained circumstances. In general, block and replace regimens use higher doses of ATDs and are associated with more adverse effects. The adverse effects of methimazole are dose related but not that of PTU. Clinical monitoring of antithyroid therapy based on toxic symptoms, pulse rate, and weight gain should be done in the absence of biochemical monitoring [Table 1]. Various symptom scores including Wayne's score may be considered in these circumstances for monitoring.
Most people with GD on ATDs are treated for 12–18 months, following which the drugs are stopped and TFT are assessed. There is a 20%–70% chance of relapse following stopping of ATDs. Due to lack of access to thyroid testing, it is preferable to continue ATDs after clinical assessment instead of stopping and reassessing. Definitive treatments such as RAI therapy and thyroidectomy may be deferred. Long-term antithyroid drug therapy has been found to be safe and effective in adults with hyperthyroidism.
Thyroid storm is a potential complication of thyrotoxicosis especially in the presence of infections. Thyroid storm precipitated by infection due to H1N1 infections has been described. As many of the symptoms of thyroid storm may overlap with that of severe COVID infection, clinical suspicion should be high to make a definitive diagnosis.
| Graves' Orbitopathy|| |
Graves' orbitopathy (GO) is an immunologically mediated disease which can have serious consequences such as visual loss. Delaying therapy in patients with severe active GO can have serious consequences such as worsening of diplopia, corneal ulceration, and sight loss. During the current scenario, people with GO may have constraints to accessing recommended specialist care [Table 1].
Immunomodulatory therapy is the mainstay of treatment in patients with moderate-to-severe symptoms. It includes GCs, (oral/intravenous [IV]), rituximab, teprotumumab, tocilizumab, and mycophenolate mofetil. GCs is the initial preferred treatment for most people with GO. Observational studies have consistently shown an increase in the risk of opportunistic infections with long-term use of GCs. However, in trials of IV methylprednisolone therapy, the risk of serious viral infection is limited. In a trial, activation of herpes simplex (1/39) and herpes zoster (1/39) occurred in a group of patients who were on mycophenolate and methylprednisolone., IV methyl prednisolone pulse therapy may be more effective compared to oral GCs in GO. However, restrictions to travel and risk of infections due to hospitalization may restrict people from receiving injections. The option of oral GCs may be considered along with strict home isolation followed by clinical assessment. If there is no significant clinical improvement after 2–3 weeks, switching to IV steroid be considered.
Rituximab, an anti-CD20 antibody which depletes B cells, is used as a second-line therapy in people with GO. Although the risk of opportunistic infections is increased in the long-term follow-up trials of rituximab in rheumatoid arthritis, the risk is likely to be minimal in those with GO receiving low doses. Teprotumumab (an insulin-like growth factor1 [IGF1] receptor inhibitor) has been recently approved for the treatment of moderate-to-severe GO. Preliminary data have shown no significant increase in the rate of infections in patients on teprotumumab. It may be a suitable alternative to GCs during the COVID-19 pandemic, but the cost and availability will limit the number of people who may benefit.
| Thyroid Nodules and Thyroid Cancers|| |
It is likely that there is an increased detection of thyroid nodules in chest imaging for people suspected with COVID-19 infection. In unselected thyroid nodules, there is a 7%–15% risk of malignancy, most of which are differentiated thyroid cancers (DTCs). Conventionally, all thyroid nodules are investigated with TFTs and ultrasonography followed by fine-needle aspiration cytology (FNAC) based on ultrasound characteristics. FNAC may be deferred for most people detected to have thyroid nodules [Table 1]. When there is a strong suspicion of medullary carcinoma thyroid (MTC), calcitonin may be done to establish a diagnosis. It is recommended that people with suspected MTC and calcitonin >100 pg/ml be considered for total thyroidectomy without FNAC. When calcitonin levels are equivocal, FNAC should be done for definitive diagnosis. Operators should follow all precautions including testing for possible COVID-19 infection and personal protective equipment during procedures. In anaplastic cancer which is potentially fatal in the absence of treatment, consideration should be given for core biopsy or direct surgical management without a FNAC.
In those detected to have DTC, management is based on risk stratification. Except in people with papillary thyroid microcarcinoma (PTMC), surgery remains the cornerstone of management. Active surveillance is an option for low-risk PTMC even in the absence of pandemic. In a meta-analysis of studies involving active surveillance of low-risk PTMC, the pooled percentage of people experiencing size enlargement was 5.3% (95% confidence interval [CI], 4.4%–6.4%) and lymph node metastasis at 5 years was 1.6% (95% CI, 1.1%–2.4%). Albeit small numbers, similar data exist for low-risk PTC up to 1.5 cm. Even in PTMC cases which were subsequently operated, there were no significant differences in persistent/recurrent disease between people operated within 6 months and those operated >12 months.
Countries all over the world are at different stages of COVID-19 spread, in terms of the rapidity of spread, infection and fatality rates, and utilization of hospital resources including personnel and equipment. Decisions to electively operate thyroid cancer will depend on strong indications such as airway compromise, aggressiveness of the cancer, and need for open biopsy to confirm anaplastic cancer or lymphoma. Surgery may be deferred for patients who fell into the following categories considered to be susceptible to COVID-19: elderly patients, patients with uncontrolled diabetes and hypertension, and those with comorbidities anticipated to require prolonged ventilation or ICU stay. The role of shared decision-making to allay patient concerns regarding delayed surgery versus the risk of a fatal infection cannot be overemphasized. The recommendations for preoperative screening for COVID infection prior to surgery have to be practiced to reduce the risk of disease transmission.
The role of RAI ablation is well established in people with DTC at high risk of recurrence. There are likely to be people who have completed thyroidectomy and waiting for RAI whole-body scan and ablation or people on regular follow-up. RAI may be delayed due to logistic issues in transporting isotopes, workforce shortages, and restriction of hospitalization following the procedure. In people with high- and intermediate-risk categories of DTC, delayed RAI ablation can be considered without significant increase in risk.,
RAI therapy can increase the serum levels of interleukin (IL)-6, CXCL-10, and ICAM-1 in patients with GD. COVID-19 can increase the levels of IL-6 dramatically, especially in people with cytokine storm and ARDS, and has been used as a marker of severity. In people who have undergone RAI ablation, this immunological response can confound the markers. Progressive metastatic DTC patients may be on multitargeted kinase inhibitors (lenvatinib, sorafenib, pazopanib, sunitib, vandetanib, etc.) for control of disease progression. These drugs can have adverse effects such as hypertension, nephrotoxicity, myelosuppression, arterial thromboembolism, and cardiotoxicity including prolonged QT interval and risk of arrhythmia.,, In view of myelosuppression, people on ongoing therapy with these agents should observe the highest degree of precautions against COVID-19. Caution should be observed while using drugs like Chloroquine, Azithromycin or combination of these drugs with multitargeted kinase inhibitors in view of increased risk of inducing cardiac arrhythmias. People with toxic multinodular goiter or toxic adenoma can be managed by ATDs during the pandemic. Definitive therapy in the form of RAI therapy or surgery can be undertaken once the pandemic settles down.
| Telehealth in Thyroid Diseases|| |
With limitations in mobility, limited medical infrastructure catering to chronic disease, and prioritizing medical workforce for dealing with the pandemic, there has been rapid adoption of telemedicine for various chronic diseases. The chronic nature of the disease, infrequent follow-up visits for stable people, and reliance on biochemical tests for decision-making make hypothyroidism a candidate disease for telehealth-based management. Various diseases of thyroid like DTC after surgery, follow-up of hyperthyroidism following radioactive iodine ablation, and hypothyroidism are amenable for telemedicine based management., Patient and physician perceptions, payment and reimbursement pattern, infrastructure availability, and regulations applicable on a local basis will form barriers to adoption of this practice.
| Conclusion|| |
There are likely to be various disruptions in the medical and surgical treatment of thyroid diseases during the current pandemic of COVID-19. We have reviewed various diseases of the thyroid in the background of the pandemic, probable scenarios which may limit optimum guideline-based management strategies in people with thyroid diseases, and suggestions for improving care in these scenarios. We realize that the situations in COVID-19 are fluid, with some countries recovering and some passing through severe phases. The suggestions based on limited evidence that we have now can be modified to suite local needs and medical infrastructure and policies.
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Conflicts of interest
There are no conflicts of interest.
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