key: cord-0769787-wokw6w62
authors: Bogojevic, Marija; Bansal, Vikas; Pattan, Vishwanath; Singh, Romil; Tekin, Aysun; Sharma, Mayank; La Nou, Abigail T.; LeMahieu, Allison M.; Hanson, Andrew C.; Schulte, Phillip J.; Deo, Neha; Qamar, Shahraz; Zec, Simon; Valencia Morales, Diana J.; Perkins, Nicholas; Kaufman, Margit; Denson, Joshua L.; Melamed, Roman; Banner‐Goodspeed, Valerie M.; Christie, Amy B.; Tarabichi, Yasir; Heavner, Smith; Kumar, Vishakha K.; Walkey, Allan J.; Gajic, Ognjen; Bhagra, Sumit; Kashyap, Rahul; Lal, Amos; Domecq, Juan Pablo
title: Association of hypothyroidism with outcomes in hospitalized adults with COVID‐19: Results from the International SCCM Discovery Viral Infection and Respiratory Illness Universal Study (VIRUS): COVID‐19 Registry
date: 2022-03-02
journal: Clin Endocrinol (Oxf)
DOI: 10.1111/cen.14699
sha: a16420e936b5f180d113cf128a27951838dcc9e6
doc_id: 769787
cord_uid: wokw6w62

INTRODUCTION: Coronavirus disease 2019 (COVID‐19) is associated with high rates of morbidity and mortality. Primary hypothyroidism is a common comorbid condition, but little is known about its association with COVID‐19 severity and outcomes. This study aims to identify the frequency of hypothyroidism in hospitalized patients with COVID‐19 as well as describe the differences in outcomes between patients with and without pre‐existing hypothyroidism using an observational, multinational registry. METHODS: In an observational cohort study we enrolled patients 18 years or older, with laboratory‐confirmed severe acute respiratory syndrome coronavirus‐2 infection between March 2020 and February 2021. The primary outcomes were (1) the disease severity defined as per the World Health Organization Scale for Clinical Improvement, which is an ordinal outcome corresponding with the highest severity level recorded during a patient's index COVID‐19 hospitalization, (2) in‐hospital mortality and (3) hospital‐free days. Secondary outcomes were the rate of intensive care unit (ICU) admission and ICU mortality. RESULTS: Among the 20,366 adult patients included in the study, pre‐existing hypothyroidism was identified in 1616 (7.9%). The median age for the Hypothyroidism group was 70 (interquartile range: 59–80) years, and 65% were female and 67% were White. The most common comorbidities were hypertension (68%), diabetes (42%), dyslipidemia (37%) and obesity (28%). After adjusting for age, body mass index, sex, admission date in the quarter year since March 2020, race, smoking history and other comorbid conditions (coronary artery disease, hypertension, diabetes and dyslipidemia), pre‐existing hypothyroidism was not associated with higher odds of severe disease using the World Health Organization disease severity index (odds ratio [OR]: 1.02; 95% confidence interval [CI]: 0.92, 1.13; p = .69), in‐hospital mortality (OR: 1.03; 95% CI: 0.92, 1.15; p = .58) or differences in hospital‐free days (estimated difference 0.01 days; 95% CI: −0.45, 0.47; p = .97). Pre‐existing hypothyroidism was not associated with ICU admission or ICU mortality in unadjusted as well as in adjusted analysis. CONCLUSIONS: In an international registry, hypothyroidism was identified in around 1 of every 12 adult hospitalized patients with COVID‐19. Pre‐existing hypothyroidism in hospitalized patients with COVID‐19 was not associated with higher disease severity or increased risk of mortality or ICU admissions. However, more research on the possible effects of COVID‐19 on the thyroid gland and its function is needed in the future.

is associated with high rates of morbidity and mortality. Primary hypothyroidism is a common comorbid condition, but little is known about its association with COVID-19 severity and outcomes. This study aims to identify the frequency of hypothyroidism in hospitalized patients with COVID-19 as well as describe the differences in outcomes between patients with and without pre-existing hypothyroidism using an observational, multinational registry.

Methods: In an observational cohort study we enrolled patients 18 years or older, with laboratory-confirmed severe acute respiratory syndrome coronavirus-2 infection between March 2020 and February 2021. The primary outcomes were (1) the disease severity defined as per the World Health Organization Scale for Clinical Improvement, which is an ordinal outcome corresponding with the highest severity level recorded during a patient's index COVID-19 hospitalization, (2) in-hospital mortality and (3) hospital-free days. Secondary outcomes were the rate of intensive care unit (ICU) admission and ICU mortality.

Results: Among the 20,366 adult patients included in the study, pre-existing hypothyroidism was identified in 1616 (7.9%). The median age for the Hypothyroidism group was 70 (interquartile range: 59-80) years, and 65% were female and 67%

were White. The most common comorbidities were hypertension (68%), diabetes (42%), dyslipidemia (37%) and obesity (28%). After adjusting for age, body mass index, sex, admission date in the quarter year since March 2020, race, smoking history and other comorbid conditions (coronary artery disease, hypertension, diabetes and dyslipidemia), pre-existing hypothyroidism was not associated with higher odds of severe disease using the World Health Organization disease severity index Syndrome is the most common severe complication that can lead to a fatal outcome, other common risk factors in the infection's progression were considered to be the pre-existing comorbidities, such as diabetes, obesity, coronary artery disease, psychiatric and neurological complications. [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] Given these multitude of complications, scientists and healthcare workers around the world have not formed a consensus over a uniform therapy for treating [13] [14] [15] [16] Thyroid hormones are highly involved in regulating innate and adaptive immune responses. [17] [18] [19] Additionally, thyroid hormone dysregulation is commonly described in critically ill patients admitted to the intensive care unit (ICU). 20 While the severe respiratory syndrome coronavirus 2 (SARS-CoV-2) uses angiotensin-converting enzyme 2 (ACE2) receptors to enter human cells, 21 which are also expressed on the thyroid gland, 22 integrins facilitate internalization of the SARS-CoV-2 and may also serve as alternative receptors. 23 The receptor for levothyroxine in tissues is located in close vicinity to the viral binding region or domain of the integrin αvβ3. Levothyroxine is known to regulate the internalization of αvβ3, and proteins bound to it, and also influence cytokine expression. Therefore, levothyroxine is proposed to potentially enhance SARS-CoV-2 uptake and facilitate cytokine storm. 24 Zhang et al. 20 studied thyroid functions in 71 patients with COVID-19 infection. This retrospective study found that 64% of the patients had thyroid dysfunction, and 56% of the COVID-19 patients had lower thyroid-stimulating hormone (TSH) levels than the control. Similarly, Chen et al. 25 described low TSH and total triiodothyronine (TT3) in COVID-19 patients and a positive correlation between TSH and TT3 serum levels and COVID-19 infection severity after retrospectively studying 50 COVID-19 patients. Also, there is suspicion that the destruction of thyroid tissue may be a complication of COVID-19, even in patients without pre-existing endocrinological conditions. 26 Even when it is known that the thyroid gland expresses angiotensin-converting enzyme 2 (ACE2) receptors, 27 the association between hypothyroidism and outcomes in patients with COVID-19 has been explored mainly in small singlecentre retrospective studies. 28 It is therefore essential to understand the correlation between hypothyroidism and COVID-19.

In this observational study, we are describing the frequency of 

This study was performed as an ancillary project on data collected within the scope of the VIRUS: COVID-19 Global Registry. [29] [30] [31] The VIRUS: COVID-19 Registry is an international database of hospitalized patients with COVID-19. The study was approved by the Mayo Clinic International Review Board as exempt (IRB:20-002610). [29] [30] [31] The database collected hospitalization information of more than 20,000 patients with COVID-19 from March 2020 to February 2021.

Study data were recorded and managed using the Research Electronic Data Capture System. 32 The study is registered on Clinicaltrials. gov: NCT04323787. We included patients where we have responses (yes or no) for hypothyroidism as documented comorbidities in the VIRUS Registry case report form. We mainly focus on primary hypothyroidism as comorbidities, which accounts for over 95% of cases of hypothyroidism. 33, 34 The clinical definition of primary hypothyroidism and associated International Classification of Diseases 9 and 10 (ICD 9 and ICD 10) codes were provided in VIRUS standard operating procedure to all participating sites and data abstractor before filling data in redcap for VIRUS Registry to identify a preadmission diagnosis of hypothyroidism in the electronic medical record. Comorbidities were a "check all that apply" response, and a "none" option was only recently added. As such, (i) for specific comorbidities, we were unable to separate a "no" and "unknown/missing" response, and (ii) at the patient level, we were unable to separate "none" from "did not complete" the section. Because comorbidities should frequently be present in adult patients hospitalized with COVID-19, as identified previously in our registry, 9 where 87% of included patients had at least one comorbid condition, we excluded hospitals with more than 70% of patients having "none" comorbidities were excluded. Hospitals below the threshold were considered noncompliant or not fully contributing. We took into consideration that the range of comorbidities in hospitalized patients is indeed around 90%, but also there are data showing that the percentage of the US adult population known to have two or more underlying medical conditions ranges is highly variable (38%-64% by state); therefore, we choose a value in between these two statistics. 35 Additionally, we used histograms to select natural cutoff values for comorbidities and oxygen support ( Figures S1 and S2 ). The histograms reflected the distribution of the percentage of comorbidity data and percentage of oxygen support data that were captured at each site. The oxygenation method, which corresponds to the disease severity outcome, was similarly recorded. Because some level of supplemental support was common amongst hospitalized COVID-19 patients, we excluded hospitals with more than 50% of patients having "none" oxygenation support documented. The large majority of excluded patients were from sites in the United States. The average number of patients BOGOJEVIC ET AL. | 3 excluded from sites in the United States was 923, and the median number excluded was 17.5.

The primary outcome of interest was disease severity, which is an ordinal outcome based on the Ordinal Scale for Clinical Improvement developed by WHO 36 that uses the highest severity level recorded during a patient's index COVID hospitalization. The severity levels pertinent to our population are (i) hospitalized but did not receive any oxygen support, (ii) oxygen by mask or nasal prongs, (iii) noninvasive ventilation or high-flow oxygen, (iv) intubation and mechanical ventilation, (v) ventilation and additional organ support (pressors, renal replacement therapy and/or extracorporeal membrane oxygenation) and (vi) death.

Other predefined outcomes of interest were in-hospital mortality and hospital-free days, ICU admission rate and ICU mortality. We calculated the hospital-free days subtracting hospital length of stay from 28. If patients died in the hospital, hospital-free days were 0. If hospital length of stay was longer than 28, then hospital-free days were 0.

Patient demographics were summarized using median and interquartile range (IQR, i.e., 25th, 75th percentile) for continuous variables and frequency counts and percentages for categorical variables.

These characteristics were presented separately for patients with hypothyroidism and those without. We evaluated the frequency of hypothyroidism and the association of outcomes with hypothyroidism. Unadjusted and multivariable mixed-effects proportional odds regression models assessed the association between hypothyroidism and ordinal disease severity during hospitalization. Models were fitted using a random intercept at the hospital level to account for the clustering of patients within locations. A proportional odds regression model analyses the relationship between pre-existing hypothyroidism and odds of the worse (higher level) outcome, that is, an odds ratio (OR) > 1 would suggest that pre-existing hypothyroidism is associated with worse outcomes than no pre-existing hypothyroidism. Unadjusted and multivariable-adjusted logistic regression models assessed the association between hypothyroidism and binary outcomes of interest. Models were fitted with generalized estimating equations (GEEs) 37 and an exchangeable working correlation to account for the clustering of patients within locations. Similarly, unadjusted and multivariable-adjusted linear regression models with GEE assessed the association between hypothyroidism and continuous outcomes.

Adjustment variables included age, 38 body mass index (BMI), 38 gender, 38 race, 39 smoking history, 40 Despite hospital-level exclusions, there remained missing data.

Data were missing for at least 10% of patients for disease severity (14%), ICU admission (11%), hospital mortality (10%), ICU mortality (15%), ICU-free days (15%), BMI (28%), admission date (36%) and smoking history (30%). Multiple imputation was used assuming data were missing at random, possibly related to other observed variables.

Twenty imputed data sets were created, analyses run on each and results pooled across imputations to account for uncertainty in missingness. A sensitivity analysis was conducted for primary outcomes using only patients with complete data. Models for the sensitivity analysis were the same as the models used for the main analysis. In all analyses, two-tailed p values of .05 or less were considered statistically significant. Data management and statistical analysis were performed in SAS Studio 3.8 (SAS Institute Inc.).

After following the eligibility criteria, we included 20,366 adult patients with laboratory SARS CoV2 |infection (Figure 1, flowchart Pre-existing hypothyroidism was not associated with ICU admission or ICU mortality in unadjusted as well as in adjusted analysis (Table 3 ). The sensitivity analysis using complete case data yielded similar estimates and conclusions to the main analysis results (Table S1 ). Our study has several strengths. First, we included 20,366 adult patients from 28 countries and 306 different sites, including academic, community and private hospitals, which, to our knowledge, is one of the largest international studies evaluating the presence of hypothyroidism in COVID-19; thus, increasing the external validation of our findings. Second, we were able to perform multivariable analyses adjusting for several known confounders and effect modifiers.

Third, we were able to explore patient-important outcomes such as mortality, hospital-free days and ICU admission. Reporting on these outcomes will help clinicians to provide accurate and meaningful information to patients with hypothyroidism if they get infected with SARS CoV-2. Fourth, due to the large number of patients enrolled in F I G U R E 1 Study flowchart BOGOJEVIC ET AL. | 5 the registry, we were able to protect our findings against nonrandom missingness by excluding "noncompliant" sites but still having a significant amount of patients for analyses.

The study's results should be considered in the context of its limitations. First, the retrospective, observational study design leaves the possibility of unmeasured confounders that could impact our results. Second, we are aware that missing may not be missing at random; however, we are reporting how missingness was strictly handled following the recommendations from the Strengthening the Reporting of Observational Studies in Epidemiology guidelines for observational studies. 49 Third, we did not have baseline data for thyroid lab panel and preadmission use of thyroid medication, especially levothyroxine for correlation with outcomes; therefore, we could not differentiate between patients with restored euthyroid state, patients still having a hormonal deficit and patients with over-replacement. However, interpretation of thyroid function tests with outcomes could be complex as both critical illness 50 and many medications are known to affect thyroid function tests. [51] [52] [53] Fourth, we did not include various prognostic markers in the final analysis such as C-reactive protein, estimated glomerular filtration rate and so forth for adjustment due to lack of data.

To our knowledge, this is the first multinational study exploring COVID-19 outcomes with pre-existing hypothyroidism. 

Our results showed that hypothyroidism is commonly identified in No oxygen therapy 300 (20) 3941 (25) Oxygen by mask or nasal prongs 438 (30) 4413 (27) Oxygen by noninvasive ventilation or high-flow oxygen 207 (14) 2177 (14) Hospitalized, and require intubation and oxygen by mechanical ventilation 81 (6) 1228 (8) Mechanical ventilation and required additional organ support (pressors, RRT and/or ECMO) 97 (7) 1132 (7) Death 

WHO Director-General's opening remarks at the media briefing on COVID-19-11. World Health Organization

A review of neurological complications of COVID-19

Association of gastrointestinal system with severity and mortality of COVID-19: a systematic review and meta-analysis

The association of acute kidney injury with disease severity and mortality in COVID-19: a systematic review and meta-analysis

The role of psychological first aid to support public mental health in the COVID-19 pandemic

Impact of COVID-19 on the mental health of children and adolescents

Association of Guillain-Barre Syndrome With COVID-19: A Case Report and Literature Review

A Review of cardiac complications in coronavirus disease 2019

Outcomes of patients with coronavirus disease 2019 receiving organ support therapies: the International Viral Infection and Respiratory Illness Universal Study Registry

Myocarditis associated with Covid-19 disease: a systematic review of published case reports and case series

Mortality and severity in COVID-19 patients on ACEIs & ARBs-A systematic review, meta-analysis, and meta-regression analysis

Metabolic syndrome and COVID-19 mortality among adult black patients in New Orleans

Mortality benefit of remdesivir in COVID-19: a systematic review and meta-analysis

Mortality benefit of convalescent plasma in COVID-19: a systematic review and metaanalysis

146: Controversial role of corticosteroids on mortality in COVID-19: systematic review and meta-analysis

Novel and controversial therapies in COVID-19

Thyroid hormones as modulators of immune activities at the cellular level

Thyroid hormone action on innate immunity

Thyroid disorders and SARS-CoV-2 infection: from pathophysiological mechanism to patient management

Thyroid dysfunction may be associated with poor outcomes in patients with COVID-19

Interaction of SARS-CoV-2 and other coronavirus with ACE (angiotensin-converting enzyme)-2 as their main receptor: therapeutic implications

Detection of SARS-COV-2 receptor ACE-2 mRNA in thyroid cells: a clue for COVID-19-related subacute thyroiditis

A potential role for integrins in host cell entry by SARS-CoV-2

Coronaviruses and integrin αvβ3: Does thyroid hormone modify the relationship?

Thyroid function analysis in 50 patients with COVID-19: a retrospective study

Pathology of the thyroid in severe acute respiratory syndrome

Risk and course of SARS-CoV-2 infection in patients treated for hypothyroidism and hyperthyroidism

Outcomes of patients with hypothyroidism and covid-19: a retrospective cohort study

The Viral Infection and Respiratory Illness Universal Study (VIRUS): an International Registry of Coronavirus 2019-Related Critical Illness

Guiding principles for the conduct of observational critical care research for coronavirus disease 2019 pandemics and beyond: The Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study Registry

Rapid project management in a time of COVID-19 crisis: lessons learned from a Global VIRUS: COVID-19 Registry

Research electronic data capture (REDCap)-a metadata-driven methodology and workflow process for providing translational research informatics support

The Clinician's Handbook of Natural Medicine

Diagnosis of and Screening for Hypothyroidism in Nonpregnant Adults

Prevalence of multiple chronic conditions by U.S. state and territory

Novel Coronavirus: COVID-19 Therapeutic Trial Synopsis

Statistical analysis of correlated data using generalized estimating equations: an orientation

Prevalence and associated risk factors of mortality among COVID-19 patients: a meta-analysis

Outcomes of COVID-19: disparities in obesity and by ethnicity/race

Prognostic factors for severity and mortality in patients infected with COVID-19: A systematic review

Risk factors for the exacerbation of patients with 2019 novel coronavirus: a meta-analysis

Dyslipidemia increases the risk of severe COVID-19: a systematic review, meta-analysis, and meta-regression

Association of hypertension and antihypertensive agents and the severity of COVID-19 pneumonia: monocentric French prospective study

Possible role of hypothyroidism in the prognosis of COVID-19

Is there an association between hypothyroidism and COVID 19?: A preliminary report

Prognostic significance of low TSH concentration in patients with COVID-19 presenting with nonthyroidal illness syndrome

Low free-T3 serum levels and prognosis of COVID-19: systematic review and meta-analysis

Thyroid disease is associated with severe coronavirus disease 2019 (COVID-19) infection

Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: guidelines for reporting observational studies

Thyroid function during critical illness

Effect of acute high dose dobutamine administration on serum thyrotrophin (TSH)

Phenytoin-medication that warrants deviation from standard approach for thyroid lab interpretation

Bexarotene: a rare cause of misleading thyroid function tests