Background
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging virus infectious disease caused by SFTS virus (SFTSV), a novel tick-borne bunyavirus of the genus Phlebovirus and family Phenuiviridae. SFTS has been reported endemic in some of Eastern Asia and Southeast Asia countries, including China, Korea, and Japan, which has a high mortality rate in humans [
1]. Clinical symptoms of SFTS involve multi-organ dysfunction manifestations. Central nervous system (CNS) injury presented as acute encephalopathy/encephalitis symptoms are a severe and common complication of SFTS, mainly including headache, confusion and seizure [
2]. It has been reported that approximately 19% of SFTS patients developed encephalitis and fatal outcome occurred in 44.7% of these patients [
3].
The exact mechanisms of SFTS-associated encephalopathy/encephalitis (SFTSAE) were unclear. Several factors have been suggested to be associated with pathogenesis of SFTSAE, including direct invasion of SFTSV in the CNS [
4] and proinflammatory cytokine storm induced inflammatory response in the CNS [
5]. While other manifestations, such as apathy, slurred speech, and limb tremors can not be fully explained by SFTSAE. It has been proposed that SFTSV infection triggered cytokine storm highly resembles the immune activation seen in sepsis [
6], and sepsis is often accompanied by thyroid dysfunction called "low triiodothyronine (T3) syndrome" which greatly affects the prognosis of patients [
7]. Furthermore, development of peripheral and central neuropathy was observed at the early stage of disease in patients with hypothyroidism [
8]. Decreased conduction velocity and sensory function of the tibial and peroneal nerves observed in hypothyroid patients were also present in SFTS patients which might account for neuro-muscular symptoms [
9].
Whereas the prevalence of thyroid dysfunction and low T3 syndrome in SFTS has not yet been evaluated. In this study, we intended to assess the incidence of low T3 syndrome in SFTS and its association with neuropsychiatric manifestations, severity of the disease and mortality.
Patients and methods
Patients diagnosis and symptom evaluation
Two hundred and seven SFTS patients admitted to our hospital from January 2016 to December 2020 who have thyroid function test results were included. Diagnosis of SFTS was confirmed by detected positive SFTSV from peripheral blood samples using reverse transcription–polymerase chain reaction (RT–PCR). Demographic and physiological parameter including age, gender, body temperature, pulse, respiratory rate and blood pressure were collected at admission. Serum free T3 (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH) were detected using an automatic chemiluminescence immunoanalyzer (Mindray CL-6000i). Timing points of estimation of FT3, FT4 and TSH were selected on admission and remission for survivors and only on admission for nosurvivors due to their short hospital stays. Serum biochemical parameters were assayed by Beckman AU5800 automatic biochemical analyzer.
Central neuropsychiatric symptoms and peripheral motor nerve symptoms were evaluated by careful physical examinations. Patients were divided into different groups according to survival state, or whether with or without central neuropsychiatric symptoms and peripheral motor nerve symptoms. Thirty old individuals with no significant cardiovascular disease, endocrine diseases and SFTSV infection who underwent health physical examination were included as controls.
This study was performed according to the Helsinki II Declaration and was approved by the ethics committee of Qishan (Infectious Disease) hospital of Yantai, Shandong, China (Ethics number 202201).
Statistical analysis
Data are presented as mean ± SD or median (Q25–Q75). The student t test or paired t test, Mann–Whitney U test or paired nonparametric test and one-way ANOVA were used for the comparison of variables between or among groups. Proportions of variables between groups were compared using χ 2 tests. Correlation analysis was done using Spearman's correlation analysis. Multivariate and univariate logistic regression analysis were used to obtain independent risk factors associated with mortality. A risk model based on these independent risk factors was established. Area under the receiver operating characteristic curve (ROC) (AUC) with the highest Youden index was used to evaluate the prognostic values of these factors and the model. The KaplanMeier survival analysis was utilized to compare the cumulative risk for mortality using the log-rank test. SPSS software (version 23.0, IBM, Armonk, NY, USA) and MedCalc software were used for statistical analysis and p values < 0.05 were considered significant.
Discussion
In this research, we found that the prevalence of low serum FT3 level was higher in nonsurvivors (81.8%) than in survivors (41.3%) (Table
1) and low serum level of FT3 was the independent risk factor of mortality for SFTS patients (Table
5). Though the prevalence of low serum FT3 was comparable among patients with central neuropsychiatric, peripheral neurological symptoms and those with no neurological symptoms, serum FT3 level was markedly lower in patients with central neuropsychiatric symptom than those in the other two groups (Table
4) which indicated that degree of low FT3 level was associated with central neuropsychiatric symptom.
Consistent with our results, previous studied had demonstrated that development of encephalopathy/encephalitis was associated with worse outcome in SFTS patients [
3]. SFTSV genome detected in cerebrospinal fluid (CSF) in SFTS patients suggests that direct invasion of SFTSV in the CNS may play an important role in the pathogenesis of SFTSAE [
3]. Our results showed that both of serum FT3 level and TSH level were decreased dramatically in nonsurvivors, which suggested that hormone regulation in hypothalamus-pituitary-thyroid axis was seriously harmed. And SFTSAE may be one of the reasons leading to damage of hypothalamus and pituitary and therefor resulting in hypothyroidism and low serum FT3 level, especially in patients of mortality.
On the other hand, indirect effect of the inflammation and cytokine storm triggered by SFTSV infection also involved in the disturbance of consciousness [
3,
4]. Consistent with this, inhibition of systemic inflammation by short-term methylprednisolone pulse therapy resulted in a favorable outcome in some patients. And this remedy led to no long term damage to neurological system [
10]. Low FT3 syndrome may also occur in inflammatory response syndrome (SIRS) or sepsis [
8,
11]. In line with this, we found that baseline serum FT3, TSH levels and Hs-CRP level were negatively correlated in survivors and no noteworthy correlations were observed between these parameters in remission and in nonsurvivors. These results indicated that systemic inflammatory response might play a key role in hypothalamus-pituitary-thyroid axis dysregulation and low FT3 syndrome development in survivors. Furthermore, though FT3 and FT4 levels were elevated significantly in admission than at baseline, TSH levels were still comparable with those at baseline which suggested that it might need a long period for the normalization of the hypothalamus-pituitary-thyroid axis hormone regulation or it might never return to normal regulation.
Nevertheless, our results indicated that low FT3 syndrome was mainly attributed to CNS injury and central hypothyroidism in SFTS patients, it might also be resulted from thyroid injury itself. Previous studies demonstrated that SFTSV antigens and SFTSV-nucleocapsid protein (NP) were positive in multiple organs including the heart, lung, kidney, spleen and CNS detected by immunohistochemistry and immunoblasts [
12,
13] which indicated that SFTSV led to systemic infection. We speculate that thyroid can also be infected and results in hypothyroidism which needs further investigation.
It has been shown that hypothyroidism is more common among older people in comparison to the youngsters. Because the hypothalamic-pituitary-thyroid axis and its secreted hormones undergo significant changes with the physiological aging [
14]. Our results showed that age of nonsurvivors was greater than that of survivors, and age was an independent risk factor for mortality, which suggested that preexist hypothyroidism might lead to a worse outcome in old patients. A risk model based on the combination of age and serum FT3 had a high prognostic predictive for adverse outcome of SFTS patients.
Thyroid hormones (THs) play an essential role in both the innate and adaptive immune responses [
15]. SFTSV infection induced hypothyroidism can in turn result in defective immune responses and aggravate infection leading to a vicious cycle. Here, we propose a potential treatment strategy supplement with THs and other supportive measures for the protection and promotion of recovery of severe hypothyroidism in SFTS.
There are several limitations in our study. Firstly, few second THs testing data were available due to short hospital stays in nonsurvivors which might affect analysis results. Secondly, lack of tissue infection results including thyroid and brain in nonsurvivors. Thirdly, lack of follow-up data of thyroid functions after being discharged from hospital. Fourthly, no data were available on effects of inflammation inhibition on thyroid function due to insufficient patients received glucocorticoid treatment. Lastly, data of changes of hypothalamus and pituitary hormone levels during SFTS disease course were absent.
Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit
http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (
http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.