key: cord-0879934-kvsmzco1
authors: Zhang, Yan; Lin, Fengyu; Tu, Wei; Zhang, Jianchu; Choudhry, Abira Afzal; Ahmed, Omair; Cheng, Jun; Cui, Yanhui; Liu, Ben; Dai, Minhui; Chen, Lingli; Han, Duoduo; Fan, Yifei; Zeng, Yanjun; Li, Wen; Li, Sha; Chen, Xiang; Shen, Minxue; Pan, Pinhua
title: Thyroid dysfunction may be associated with poor outcomes in patients with COVID-19
date: 2020-12-02
journal: Mol Cell Endocrinol
DOI: 10.1016/j.mce.2020.111097
sha: 71f75bae9079608b0fa3853dc0f1e8800076c9d7
doc_id: 879934
cord_uid: kvsmzco1

BACKGROUND: Coronavirus disease (COVID-19) has resulted in considerable morbidity and mortality worldwide. Thyroid hormones play a key role in modulating metabolism and the immune system. However, the prevalence of thyroid dysfunction (TD) and its association with the prognosis of COVID-19 have not yet been elucidated. In this study, we seek to address this gap and understand the link between TD and COVID-19. METHODS: Herein, we enrolled patients who were hospitalised with COVID-19 and had normal or abnormal thyroid function test results at the West Court of Union Hospital in Wuhan, China, between 29 January and 26 February 2020. We carried out follow up examinations until 26 April 2020. Data on clinical features, treatment strategies, and prognosis were collected and analysed. TD was defined as an abnormal thyroid function test result, including overt thyrotoxicosis, overt hypothyroidism, subclinical hypothyroidism, subclinical hyperthyroidism, and euthyroid sick syndrome. RESULTS: A total of 25 and 46 COVID-19 patients with and without TD, respectively, were included in the study. COVID-19 patients with TD had significantly higher neutrophil counts and higher levels of C-reactive protein, procalcitonin, lactate dehydrogenase, serum creatine kinase, aspartate transaminase, and high-sensitive troponin I and a longer activated partial thromboplastin time but lower lymphocyte, platelet, and eosinophil counts. A longitudinal analysis of serum biomarkers showed that patients with TD presented persistently high levels of biomarkers for inflammatory response and cardiac injury. COVID-19 patients with TD were more likely to develop a critical subtype of the disease. Patients with TD had a significantly higher fatality rate than did those without TD during hospitalisation (20% vs 0%, P<0.0001). Patients with TD were more likely to stay in the hospital for more than 28 days than were those without TD (80% vs 56.52%, P=0.048). CONCLUSIONS: Our preliminary findings suggest that TD is associated with poor outcomes in patients with COVID-19.

criteria included: (1) a medical history of an endocrine disorder or thyroid surgery; (2) 114 concurrent treatment with drugs that could affect hypothalamic-pituitary activity 115 within the past year; (3) pregnancy within the past six months, and (4) patients with 116 incomplete data for key parameters. 117 118

Demographic (age and sex) and clinical (symptoms, comorbidities, laboratory and 120 radiological findings, disease severity, detrimental complications, treatment strategies, 121

and prognosis) data of the included patients were collected from the electronic 122 medical records. All patients with COVID-19 were diagnosed according to the 123 positive detection of viral nucleic acids of SARS-CoV-2 from respiratory tract 124 specimens using real-time polymerase chain reaction assay, as previously described 125 thromboplastin time (APTT), international normalized ratio (INR), were obtained 135 from each patient. 136

All data including demographic features, symptoms, pre-existing chronic 137 comorbidities, and laboratory and radiologic results, were analysed and summarised 138 as well. Data on treatment strategies, such as oxygen support, antiviral and antibiotic 139 therapy, and corticosteroid use, and patient outcomes were also collected during Patients were identified as critical if they met the criteria above and also met one of 151 the following criteria: (1) needs mechanical ventilation due to respiratory failure, (2 

The laboratory and radiological results of the included COVID-19 patients with or 213 without TD on admission are presented in Table 2 . The results showed that those with 214 TD had lower lymphocyte, platelet, and eosinophil counts but higher neutrophil 215 counts and inflammatory markers levels, including CRP, PCT, LDH, and higher 216 biomarkers expression for cardiac injury, including hsTNI and pro-BNP. Other 217 parameters, including CREA, AST, APTT, and plasma fibrinogen, differed between 218 COVID-19 patients with TD and those without TD. Radiological imaging showed 219 that most patients (97.2%) had abnormal findings with bilateral lesions. Additionally, 220

analysis of the longitudinal changes in serum biomarkers expression showed that 221 COVID-19 patients with TD had higher dynamic biomarker expression, including 222 inflammatory markers (CRP, PCT, and LDH); higher D-dimer levels; and higher 223 acute cardiac injury marker (hsTNI) expression than did patients without TD during 224 the period of hospitalization (Figure 1 ). This indicates that TD might be associated 225 with stronger inflammatory response, coagulation function, and cardiac injury, 226 resulting in poorer outcomes from COVID-19. 227 228

Next, the disease severity, treatment strategies, and prognosis of the COVID-19 230 patients with or without TD are compared in Table 3 . Compared to subjects without 231 TD, patients with TD were more commonly categorised as critically ill and were more 232 likely to receive antibiotic treatment, corticosteroids, high-flow oxygen, non-invasive 233 ventilation, and invasive mechanical ventilation. Logistic regression analysis showed 234 that TD was independently associated with the critical subtype of COVID-19, ARDS, 235 antibiotic treatment, corticosteroid treatment, high-flow oxygen, non-invasive 236 ventilation, and invasive ventilation after adjusting for age, sex, and hypertension 237 (Table 3) . No patients without TD received invasive mechanical ventilation or died; 238 therefore, the odd ratios could not be calculated. 

As of 26 April 2020, 93% of the patients were discharged from the hospital, and five 242 had died. Notably, all deceased patients had manifestations of TD. Patients with TD 243 had a significantly higher fatality rate than those without TD during hospitalization 244 (20% vs. 0%, P<0.0001). The Kaplan-Meier survival curves are shown in Figure 2 . 245

Additionally, patients with TD were more likely to stay in hospital for more than 28 246 days than those without TD (80% vs. 56.52%, P=0.048) ( Table 3) . 247

248

The present study is the first to demonstrate a correlation between TD and the 250 prognosis of COVID-19. TD was associated with an unexpectedly higher risk of 251 fatality and poorer clinical outcomes during the hospitalization. 252

As of 7 July 2020, there have been more than 11 million laboratory-confirmed cases 253 of COVID-19, resulting in more than 500,000 deaths globally. Severe respiratory 254 distress is usually considered the main cause of death in patients with . TD and its association with the prognosis of COVID-19 has not yet been reported, 260 even though TD has been commonly observed among patients with severe Our study is the first to suggest that TD is associated with a higher fatality rate and 262 longer hospitalisation in patients with COVID-19. Compared to those without TD, 263 patients with TD presented with a severe subtype of critical illness and more 264 complications such as ARDS, acute cardiac injury, and AKI, and as a result, received 265 more antibiotic treatment, corticosteroids, and mechanical ventilations. and other immune cells [37] . Additionally, we found that COVID-19 patients with TD 295 presented with persistently higher inflammatory biomarkers (CRP and PCT). This 296 further indicates that TD might be closely associated with a more severe 297 inflammatory response. Additionally, acute cardiac injury has been observed in 298 patients with COVID-19 and has been found to be correlated with the fatality [25] . 299

Appropriate thyroid hormone levels are essential for the maintenance of the normal 300 electrical activity of the heart muscle [38] . Therefore, TD may favor cardiac injury 301 and influence the prognosis of COVID-19. This was consistent with our finding that 302 COVID-19 patients with TD presented with a higher level of hsTNI during 303 hospitalisation and more detrimental complications of acute cardiac injury than did 304 those without TD. Thyroid hormones are also associated with respiratory system. 305

Increased serum T3 levels could enhance the synthesis of pulmonary surfactant, 306 thereby reducing alveolar surface tension, increasing lung compliance, and improving 307 lung function [39, 40] . As the main pathophysiology of death in patients with 308 COVID-19 involves multiple organ dysfunction, these close associations between TD 309 and multiple organ disorders support the possibility that TD is a novel prognostic 310 factor among patients with COVID-19. 311 312

This study had several limitations. Firstly, the current study was a retrospective study 314

with a relatively small sample size, and a large cohort study is needed to confirm our 315 findings. Second, thyroid hormones also presented dynamic changes, which were not 316 captured by our study. Third, thyroid autoantibodies were not detected in most 317 patients in the study. Thus, there is a lack of evidence on the dysregulated immune 318 status of the thyroid gland caused by COVID-19. Lastly, none of the patients included 319 in the current study received supplementary treatment for dysregulated thyroid 320 hormones, and the potential role of thyroid hormones in COVID-19 needs to be 321 investigated further. 322

In this study, we showed that TD is closely associated with greater disease severity 325 and poorer prognosis, including longer hospitalization and a higher mortality rate. 326

More intensive surveillance and treatment should be considered for COVID-19 327 patients with complications of TD. However, our results are preliminary, and the 328 mechanism for TD in COVID-19 should be investigated in the future with larger, 329 more robust studies. J o u r n a l P r e -p r o o f 

Thyrotropin concentration predicts 364 outcome in critical illness

The sick euthyroid syndrome: 367 changes in thyroid hormone serum parameters and hormone metabolism

Euthyroid sick syndrome: an overview

Dangerous dogmas in medicine: the nonthyroidal illness syndrome

Nonthyroidal illness syndrome or euthyroid sick syndrome? Endocr

Clinical features of 378 patients infected with 2019 novel coronavirus in Wuhan

Pathology of the thyroid in severe acute respiratory syndrome

A Pathological Report of Three COVID-19 Cases by Minimally Invasive 472

Thyroid 475 hormones as potential prognostic factors in sepsis

Predictive value of thyroid hormone 478 assessment in septic patients in comparison with C-reactive protein

Metabolism modulators in sepsis: the abnormal 481 pituitary response

Molecular aspects of thyroid hormone 484 actions

Without TD (n=46) P Leucocytes (×10 9 /L), median (IQR)

LDH (U/L), median (IQR)

MYO (ng/mL), median (IQR)

ALT (U/L), median (IQR)

AST (U/L), median (IQR)

Sodium (mmol/L), median (IQR)

PT (sec), median (IQR)

WBC, white blood cell

PCT, procalcitonin; BNP, N-terminal pro-B-type natriuretic peptide

FBG, fasting blood glucose

CREA, serum creatine; BUN, blood Urea nitrogen

High-sensitivity troponin; CK-MB, creatine kinase isoenzyme MB

Aspartate aminotransferase; FIB, Plasma fibrinogen

thrombin time; INR, international normalized ratio. Data were presented as mean±SD or IQR