Severe fever with thrombocytopenia syndrome (SFTS), an emerging infectious disease, is caused by a novel member of phlebovirus called SFTS virus (SFTSV) which is classified into the Bunyaviridae family (1). The SFTS was first reported in China in 2009 and subsequently reported in Vietnam, Japan, South Korea and other Asian countries (1–4). This disease is mainly transmitted by tick bite from Haemaphysalis longicornis. The SFTS antibody seroprevalence presented in mammal including wild boars, sheep, cattle, cats, and dogs (5–8). A few studies had provided evidence for the direct cat-to-human transmission of the virus (9, 10). In addition, transmission through close contact with blood or body fluid from infected patients is also reported (11–13). The SFTSV infection is characterized by abrupt onset of fever, thrombocytopenia, leukopenia and other non-specific clinical manifestations with a reported case fatality ratio ranging from 2.5 to 47% in different areas (1, 14–16). The mortality rate is showing a decreased trend due to more cases identified by the viral RNA or SFTSV specific antibodies (17).

Pathogenesis of SFTS is not well described. A common pathogenic feature of bunyaviruses is their ability to inhibit the host immune response. Currently, the main therapeutic plan is symptomatic and supportive therapy. Ribavirin as an antiviral therapy have been applied to SFTS patients but the efficacy remains limited (18). Favipiravir is a new anti-influenza drug approved for human use in Japan (19) and has showed efficacy for the prevention and treatment of SFTSV infection in animal models (20, 21). Favipiravir treatment lowered the case fatality rate of patients with SFTS by around 10% compared with those received supportive therapy in a few clinical trials (22–24). However, the sample size is limited and the side effect is still unclear. The disease is still an important public health problem. The present studies mainly focused on describing the clinical features and laboratory results. Therefore, it is necessary to discover prognostic biomarkers that can contribute to clinical decision-making and help to individualize treatments for SFTS patients.

Regular laboratory tests for the assessment of inflammatory status and organ function are very useful in the early phase diagnosis of many diseases. The complete blood count could provide information including different cell types and morphological parameters. In addition, it is very easy and inexpensive to perform. The ratios derived from the complete blood count such as neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) have been used as inflammation indexes to evaluate the progression, risk and prognosis of inflammatory diseases (25–28). Other indexes including three or more blood count values, systemic immune-inflammation index (SII), systemic inflammation response index (SIRI) and aggregate index of systemic inflammation (AISI) are considered to reflect the immune and inflammatory state, and have been observed related to risk and mortality of various cancers (29, 30), autoimmune diseases (31) and infectious diseases (32). The C-reactive protein (CRP) is an acute phase protein produced in the liver and is utilized as a marker of infection and inflammatory processes. Albumin (ALB) is synthesized by the liver. Hypoalbuminemia is an indicator of liver dysfunction, malnutrition, systemic inflammation and some other diseases (33). The combined indexes CAR (CRP/ALB) and prognostic nutritional index (PNI) based on the CRP, ALB and peripheral blood lymphocyte count have been used to predict the poor outcome in malignant and non-malignant diseases (34–38). The inflammation and malnutrition are ubiquity in SFTS patients, but few studies have investigated their prognostic value.

In our study, we aimed to investigate the association of these indexes including NLR, PLR, MLR, AISI, SII, SIRI, PNI, and CAR with the SFTS, hoping to find a valuable marker for predicting the prognosis of SFTS.

The SFTS is becoming a public health threat in China, South Korea, Japan and some other east Asian countries since 2010. SFTS mostly arises as sporadic cases in the spring and summer with a high fatality rate. The disease is characterized by abrupt onset of fever, respiratory tract or gastrointestinal symptoms, followed by a progressive decline in platelets and white blood cells (39). And the SFTSV infection is characterized by four typical periods: incubation, fever, multiple organ failure, and convalescence (39). The SFTS patients could rapidly progress to critical illness, and the average period from onset of illness to death is 9 days (40). Since there is no specific treatment and available vaccine, the symptomatic and supportive therapy are the major therapeutic methods. There is an urgent need of the early biomarkers to identify SFTS patients at higher risk of death, and these patients need more attention of early diagnosis and aggressive treatment.

The combined indexes based on the complete blood count and inflammatory indicators have been widely used as inflammatory biomarkers. These parameters could be simply and inexpensively obtained. Therefore, the combined biomarkers are recommended to assist in testing inflammatory processes, predicting the disease prognosis and risk stratification. In our study, we evaluated the clinical and prognostic roles of various inflammatory and nutritional indexes for SFTS, including the NLR, PLR, MLR, AISI, SII, SIRI, PNI, and CAR. Of them, CAR is higher in patients with fatal disease than in those with survival outcome. While the value of AISI and MLR was higher in the survival group compared to the death group. The logistic regression analysis discovered that CAR was an independent prognostic biomarker for poor prognosis in patients with SFTS. The CAR also exhibited a more robust risk assessment value in the ROC curve analysis. And in the dynamic analysis, the CAR kept increasing in the death group while gradually decreased in the survival group after receiving treatments during hospitalization. Eventually, CAR was considered as a promising early predictive biomarker of evaluating the SFTS patients.

C-reactive protein to albumin ratio is integrated by the two indexes, CRP and ALB. ALB is mainly synthesized by liver and is the most abundant circulating protein in the blood. It is the main determinant of plasma oncotic pressure, and plays a pivotal role in modulating the distribution of fluids between body compartments (41). The plasma ALB level might fall during the periods of stress, trauma, injury and infection, due to the redistribution from the intravascular to extravascular space, decreased synthesis and increased catabolism. In addition, ALB could reflect the nutritional status of body and contribute to the transportation of multiple substances. In our study, lower ALB level was also observed in the SFTS patients with poor clinical outcome compared to the survivors. This is possibly affected by the severe infection and multiple organ dysfunction resulted from the SFTSV. CRP exhibits elevated expression during inflammatory conditions such as rheumatoid arthritis, some cardiovascular diseases, and infection (42). As an acute-phase protein, the plasma concentration of CRP deviates by at least 25% during inflammatory disorders (43). While in our study, the CRP level was significant higher in the death group compared to the survival group which is consistent with the previous studies (44).

The association between inflammation and malnutrition is very close and complicated. The inflammation could result in malnutrition, and the malnutrition in turn could impact the development of inflammation. As a combined index, the CAR is becoming a promising prognostic biomarker in patients with various diseases, including the tumors (45–47), infectious diseases (48, 49), autoimmune diseases (31, 50) and some other diseases (51). However, no research about whether CAR can evaluate the prognosis of patients with SFTS has been reported so far. Our study showed that the CAR is able to be used as an independent risk factor with good predictive potential for a poor prognosis of SFTS patients. It could provide the physicians the information for predicting the early risk stratification of disease progression of SFTS patients and guide them to monitor and treat higher-risk patients more aggressively, which may help to improve clinical prognosis.

However, there were also limitations in our study. Firstly, this was a retrospective, single-center study with a relatively small cohort size and the number of death cases was also small which might lead to a possible statistical bias. Secondly, the observational endpoint of our study was defined as the in-hospital death lacking of further follow-up. Hence, a multi-center study with a larger cohort size and clinical follow-up visits is urgent in the future.

In conclusion, our study first found the CAR was significantly associated with the mortality of SFTS patients. Higher CAR was demonstrated to be an independent risk factor for death in patients with SFTS and could be used to predict the poor prognosis of SFTS.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by the Research Ethics Committee of the Second Affiliated Hospital of Dalian Medical University. The Ethics Committee waived the requirement of written informed consent for participation.

YL and RL designed the study. HY and CX collected the data from the electronic record system. XY and RL performed the data analyses and interpreted the data. XY and YL contributed to the writing of the manuscript. All authors reviewed the manuscript and approved the final version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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