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Clinical laboratory parameters and fatality of Severe fever with thrombocytopenia syndrome patients: A systematic review and meta-analysis [1]
['Yao Wang', 'Department Of Microbiological Laboratory Technology', 'School Of Public Health', 'Cheeloo College Of Medicine', 'Shandong University', 'Jinan', 'Zexuan Song', 'National Tuberculosis Reference Laboratory', 'Chinese Center For Disease Control', 'Prevention']
Date: 2022-07
We identified 34 relevant studies, with over 3300 participants across three countries. The following factors were strongly (SMD>1 or SMD<-0.5) and significantly (P<0.05) associated mortality: thrombin time (TT) (SMD = 1.53), viral load (SMD = 1.47), activated partial-thromboplastin time (APTT) (SMD = 1.37), aspartate aminotransferase (AST) (SMD = 1.19), lactate dehydrogenase (LDH) (SMD = 1.13), platelet count (PLT) (SMD = -0.47), monocyte percentage (MON%) (SMD = -0.47), lymphocyte percentage (LYM%) (SMD = -0.46) and albumin (ALB) (SMD = -0.43). Alanine aminotransferase, AST, creatin phosphokinase, LDH, PLT, partial-thromboplastin time and viral load contributed to the risk of dying of SFTS patients in each subgroup analyses. Sensitivity analysis demonstrated that the results above were robust.
The systematic review was conducted in accordance with The Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. We searched (from inception to 24th February 2022) Web of Science, PubMed, National Knowledge Infrastructure databases and Wan Fang Data for relevant researchers on SFTS. Studies were eligible if they reported on laboratory parameters of SFTS patients and were stratified by clinical outcomes. A modified version of Newcastle-Ottawa scale was used to evaluate the quality of included studies. Standardized mean difference (SMD) was used to evaluate the association between laboratory parameters and outcomes. The between-study heterogeneity was evaluated quantitatively by standard Chi-square and the index of heterogeneity (I 2 ). Heterogeneity was explored by subgroup and sensitivity analyses, and univariable meta-regression. Publication bias was determined using funnel plots and Egger’s test.
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with high case-fatality rate and lack of vaccines, calling for an urgent need to identify the risk factors of mortality. Compared to the previous studies concentrating on clinical manifestations diagnosed partly relying on empirical subjective assessment, our study aimed to systematically analyzed the association between SFTS patients’ outcomes and clinical laboratory parameters. What’s more, no consistent conclusion derived because of sample sizes with enormous differences. In this systematic review, we searched the medical literature and found 34 studies evaluating associations between laboratory factors and risk of dying among SFTS patients. These studies described 3388 SFTS patients of whom 739 (21.81%) died. SFTS patients were at increased risk of dying if they had abnormal strongly levels of viral load, PLT, coagulation function and liver function. Therefore, the patients with above-mentioned situations should be monitored and cured carefully.
We therefore set out to conduct a systematic review to identify key clinical laboratory parameters associated with mortality among SFTS patients and used several methods to justify the robustness of results. To our knowledge, this is the first meta-analysis exclusively concerning the laboratory indexes to clarify the association between clinical laboratory tests and SFTS patients’ outcomes.
Some published meta-analysis studies had described the potential risk factors contributing to fatality of SFTS disease. Liu MM et al. found that old age, central nervous system manifestations, bleeding tendency, elevated serum enzymes and high vial load were risk factors for fatality among SFTS patients [ 6 ]. Wang X et al. found that there were some significant differences between the nonfatal and fatal groups, such as headache, fatigue, diarrhea, vomiting and arrhythmia [ 7 ]. Dualis et al. emphasized the importance of delay in hospital admission, high viral load, older age and presence of comorbid or complications on risk of dying of SFTS cases [ 8 ]. Routine laboratory parameters mentioned in another meta-analysis paper were just used to evaluate the severity of SFTS patients [ 9 ]. In brief, the previous meta-analysis studies associating with risk factors related to mortality were concentrated on clinical manifestations diagnosed partly relying on empirical subjective assessment, and they lacked effective methods to deal with significant heterogeneity justifying the robustness of results [ 6 – 9 ]. Though some researches had demonstrated the clinical laboratory parameters contributing to fatality of SFTS disease, the results were inconsistent. In fact, clinical laboratory parameters, the relatively objective factors, are more suitable for future application of predictors for outcome of SFTS disease.
SFTS was first described in China in 2009, and subsequently reported in South Korea, Japan and the United States. Moreover, an increasing number of novel SFTSV-like viruses continue to be isolated from wild animals and tick vectors around the world with spatial expansion of ticks due to environmental changes, indicating a broader global distribution and raising serious concerns about potentially growing epidemics of SFTSV across continents [ 1 – 2 ]. SFTS has been listed doubtlessly as one of 10 priority diseases by the World Health Organization since 2017 [ 5 ]. Unfortunately, no vaccine or antiviral specifically targeting SFTSV is available for the time being, suggesting that capturing the risk factors contributing to fatality is urgent.
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease characterized by fever, leukopenia, thrombocytopenia, central nervous system symptoms and even multiple organ dysfunctions, with high case fatality rate of 12–50% [ 1 – 3 ]. The pathogen responsible for SFTS was identified as SFTS virus (SFTSV) which is a tick-borne virus in the genus Bandavirus in the family Phenuiviridae, order Bunyavirales [ 4 ]. The genome of SFTSV is a single-stranded negative sense RNA virus and comprises three segments (S, M, L) [ 4 ].
In an attempt to account for high heterogeneity, we performed subgroup analyses for factors which were reported in at least five studies and meta-regression analyses for factors which were reported in at least ten studies [ 14 ]. We conducted subgroup and meta-regression analyses according to the study types (retrospective and prospective), mean age of the participants (<60, 60–65, >65), study sites (one, two or more) and sample sizes (<50, 50–100, >100). Because the numbers and characteristics of laboratory parameters were different, subgroup analyses and meta-regression of some parameters did not include the above variables simultaneously. Furthermore, the sensitivity analysis was performed by doing leave-one-out analysis to assess the influence of individual study.
The heterogeneity between studies was assessed using the standard Chi-square and index of heterogeneity squared (I 2 ) statistic with value of >50% denoting high level of heterogeneity. Fixed effect meta-analysis was used if no heterogeneity was found (I 2 <50%), otherwise, the random effect model was used. However, fixed effect model was considered irrespective of the degree of heterogeneity if the number of studies included in analysis was small (<five) [ 13 ].
Two authors (Y.W and X.Y.X) each separately evaluated the quality of each included study using a modified version of the Newcastle-Ottawa Quality Assessment Scale (NOS) [ 10 ], and A third investigator (H.L.W) was consulted when disagreements arose. The NOS tool has scores ranging from 0 to 9. In accordance with the protocol, the NOS scores were divided into low quality (scores 1–4), intermediate quality (scores 5–7), and high-quality (scores 8–9) ( S2 Table ).
The core information was the strength of association between laboratory parameters and mortality. We extracted the information of clinical laboratory parameters at baseline. The following information was extracted from every eligible article: first author, publication year, region, number of patients. Meanwhile clinical laboratory parameters were extracted, including viral load (log 10 ), platelet count (PLT), lymphocyte percentage (LYM%), monocyte (MON), monocyte percentage (MON%), hemoglobin (Hgb), neutrophil percentage (NEU%), white blood cell (WBC), lymphocyte (LYM), red blood cell (RBC), neutrophil (NEU), activated partial-thromboplastin time (APTT), partial-thromboplastin time (PT), thrombin time (TT), fibrinogen (FIB), gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), creatin phosphokinase (AST), alkaline phosphatase (ALP), total bilirubin (TB), albumin (ALB), blood urea nitrogen (BUN), serum creatinine (sCr), creatin phosphokinase (CK), creatinine kinase myocardial b fraction (CK-MB), lactate dehydrogenase (LDH), C-reactive protein (CRP), K (potassium), D-dimer (D-D) and Na (sodium). Two authors (H.W.Y and X.Y.X) independently extracted and recorded data from selected studies. Disagreements were resolved by a third author (W.Y.).
According to the PRISMA guidelines, we did a systematic literature review from four databases (PubMed, Web of Science, National Knowledge Infrastructure databases (CNKI), Wan Fang Data) covering literature until February 24, 2022. The search strategy combined terms indicating the disease (such as “severe fever with thrombocytopenia syndrome”, “SFTS”, “bunyavirus” and “Dabie bandavirus”) with terms indicating the outcomes of SFTS cases (such as “outcome”, “fatal”, “death” and “deceased”). Exact search terms are provided in S1 Table .
We aimed to include studies on SFTS patients from all over the world, with laboratory-confirmed diagnosis and treated in hospitals or other health care structures. We included all articles that fulfilled the following inclusion criteria: i) Patients included must meet one or more of the following criteria: (1) isolated the virus from serum samples, (2) a 4-fold or greater increase of antibody titers was detected between a paired serum samples of the patient collected from the acute and convalescent phases of infection, (3) SFTSV RNA was detected from the patient’s serum by reverse-transcriptase PCR (RT-PCR). ii) The clinical outcomes were categorized by “non-fatal” verse “fatal”, and the article must include the total fatal and non-fatal number, and the fatal and non-fatal number associated with various clinical laboratory parameters. iii) The study was published in English or Chinese.
Leave-one-out sensitivity analysis showed that there was no effect of removing any study on the summary estimates but MON and FIB ( S4 Text ). MON was associated with SFTS fatality after excluding Jia B et al. (SMD = -0.47, 95%CI: -0.67~-0.27) [ 20 ]. Further, the association between FIB and SFTS fatality became significant after excluding Zhang YZ et al. [ 46 ] (SMD = -0.91, 95%CI: -1.43~-0.39), respectively ( S4 Text ). Funnel plot asymmetry was done with the estimates of factors which was reported at least five studies ( S5 Text ). The Egger’s test suggested statistical evidence of publication bias of ALT (t = 2.47, P = 0.022), CK (t = 2.57, P = 0.018), AST (t = 2.26, P = 0.033), K (t = -3.51, P = 0.039) and BUN (t = -4.11, P = 0.001) ( S5 Text ).
The results of subgroup analyses indicated that number of study sites had effects on heterogeneity of ALT, and sample size had effects on heterogeneity of CK, LDH and PT ( S5 Table ). Overall, the heterogeneities of prospective and elder age groups were lower. However, subgroup analyses of most of factors had large heterogeneity and unevenly distributed subgroups. ALT, AST, CK, LDH, PLT, PT and viral load contributed to the risk of dying of SFTS patients in each subgroup analyses ( S5 Table ). Meta-regression in estimates of LDH showed that sample size was significantly associated with the fatality risk of SFTS patients ( S3 Text ).
Further, the concentration of CRP (SMD = 0.50, 95%CI: 0.30~0.71, P<0.001), D-D (SMD = 0.48, 95%CI: 0.16~0.81, P = 0.004) and K (SMD = 0.47, 95%CI: 0.31~0.63 P<0.001) were significantly higher in patients who died than in those who survived, but the level of Na (SMD = -0.06, 95%CI: -0.22~0.09, P = 0.44) was not significantly associated with the fatal outcome. No heterogeneity was observed from this group of meta-analysis ( S2 Text ).
Liver function indexes analysis showed that the concentration of GGT (SMD = 0.46, 95%CI: 0.26~0.65, P<0.001), ALT (SMD = 0.92, 95%CI: 0.61~1.24, P<0.001), AST (SMD = 1.19, 95%CI: 0.87~1.50, P<0.001), ALP (SMD = 0.52, 95%CI: 0.33~0.72, P<0.001) and TB (SMD = 0.52, 95%CI: 0.18~0.86, P = 0.003) were significantly higher in patients who died than in those who survived, excluding ALB (SMD = -0.43, 95%CI: -0.63~-0.22, P<0.001). Obvious heterogeneities were observed from this group of meta-analysis (ALT: I 2 = 85% and P<0.001; AST: I 2 = 89% and P<0.001; ALB: I 2 = 57% and P = 0.007; TB: I 2 = 73% and P = 0.005) except ALP (I 2 = 49% and P = 0.12) and GGT (I 2 = 39% and P = 0.18). ( S2 Text ).
S4 Table provides the overall quality score for each study included in the review. No study met the threshold for high quality. 33 studies were found to be of moderate quality, and the remaining 1 study had poor quality particularly because there was a poor description of the study population (how and why participants were sampled, adequacy of sample size) and impact of bias. Finally, the poor-quality study was excluded from meta-analysis.
The basic characteristics and data extraction from these included studies were shown in Table 1 . 23.53% (8/34) of them enrolled SFTS patients prospectively. All studies were conducted in Western Pacific Region, of which China, South Korea and Japan accounted for 85.29% (29/34), 8.82% (3/34) and 5.88% (2/34), respectively. 67.65% (23/34) of studies enrolled participants just from one hospital. Patient inclusion criteria varied across studies: most studies included all SFTS patients [ 16 , 18 – 23 , 25 , 28 – 30 , 32 – 35 , 37 , 40 – 48 ], whereas others had strict enrolment criteria. For example, SFTS cases were excluded if they had a history of serious chronic diseases or they were coinfected by other viruses in some studies [ 15 , 17 , 24 , 26 , 36 , 39 ]. Besides, some studies focused on specific SFTS patients, such as critical ill patients [ 27 , 38 ]. The included study sample size ranged from 23 [ 31 , 38 ] to 429 [ 36 ].
The flow chart of literature searching and selection was shown in Fig 1 . A total of 1834 studies were identified by database searches and 2 studies were identified from reference lists, of which 539 duplicates and 946 irrelevant studies (solitary fibrous tumors) were removed. Then 273 articles were excluded due to case reports / animal experiments / guides / no laboratory parameter / systematic reviews / genotypes analysis / no English titles and other outcomes after review of the titles and abstracts. After carefully reviewing the full text and data of the remaining 76 articles, 42 ineligible records were excluded due to overlapping data or failing to extract data. Finally, 34 studies containing 3,388 SFTS patients (2,649 survival cases and 739 fatality cases) were included in the final analysis.
Discussions
For an emerging infectious disease without effective therapy and vaccine, identification of risk factors associated with disease progression is essential to clinical monitoring and treatment, avoiding a fatal outcome to the greatest extent. Though laboratory indicators contributing to fatal clinical outcome of SFTS cases have been investigated in different countries and regions in recent years, unfortunately, no consistent conclusion derived because of sample sizes with enormous differences. Therefore, it is necessary to summarize previous studies for a robust and convincing consequence. We found that elevated level of viral load, PT, ALT, AST, LDH and CK significantly increased the risk of dying of SFTS patients, whereas reduced level of PLT was associated with the fatality of SFTS cases. These findings accord with findings of previous meta-analysis [6–9].
High viral load was found to be associated with mortality in several studies. We found that viral load contributes to the progression of SFTS and fatal outcome development, which has similar effects on different age groups. Preceding the clinical deterioration, significantly enhanced viral load was observed, while the laboratory parameters, especially LDH, AST, CK, PLT, began to deviate sharply from normal ranges [49]. A previous study [37] showed that higher numbers of the virus were capable of inducing higher levels of IFN-inducible protein-10 and macrophage inflammatory protein-1 while repressing the production of activation normal T cell expressed and secreted factor, which further cause the severity and even death [50]. The rapidly rising level of viral load activated the innate and acquired immune system, causing the released of proinflammatory cytokines in quantity, and further aggravating tissues and organs damage [51]. Even worse, the “cytokine storm” formed after the body oversecreted proinflammatory cytokines and anti-inflammatory cytokines would lead to serious immune imbalance and extensive tissues and organs damage, thus accelerating the progress of the disease [52]. Besides, previous study had confirmed the importance of viraemia evaluation and given treatment as early as possible due to the viral-load dependent therapeutic effect of ribavirin for SFTSV infection [1].
The results of routine blood tests failed in consistency intensively according to previous published papers [6,7,9]. This discrepancy can be primarily attributed to the differences of sample sizes and study regions. Our study using large amounts of published literature offered a new and credible perspective on the association between routine blood tests and SFTS patients’ outcome. We found that the reduced levels of PLT, LYM% and MON% were significantly associated with increased risk of mortality, as well as elevated Hgb and NEU%. Especially the PLT, though heterogeneity was detected, all subgroup analyses and sensitivity analysis demonstrated the pooled result was credible and steady. The decrease of PLT is the earliest indicator of laboratory abnormality with almost 100% probability, which can be used as indicator for early diagnosis of the disease [34]. However, considering that the decrease of PLT is also associated with many other diseases, we need other specific methods to identify SFTS patients. In addition, the reason why PLT was significantly correlated with the SFTS patients’ fatality was unclear. A previous study suggested that it might be related to the transient suppression of marrow hemopoietic function caused by viral infection [53]. Furthermore, it has been shown that in a mouse infection model, platelets were adhered to SFTSV, which further promoted the clearance of splenic macrophages [54]. Interestingly, this study did not find the association between WBC and SFTS outcomes even though leukopenia is the typical feature of SFTS patients.
Coagulation dysfunction was common in SFTS patients [27,29,55]. Our study showed that APTT, PT and TT were significantly prolonged in fatal patients compared to the non-fatal, which agreed with previous researches [6–9,53]. Similar to other viral hemorrhagic fevers such as Crimean-Conga hemorrhagic fever, SFTSV infection leads to significant damage of vascular endothelial cells and exposure of subcutaneous collagen fibers, promoting PLT aggregation and cytokines activation, which initiates endogenous coagulation system, and further leads to APTT, TT and PT significantly prolonged [56,57]. At the same time, coagulation disorder can cause secondary damage to endothelial cells, causing disseminated intravascular coagulation (DIC), and aggravating coagulation disorder [15]. Due to the above reasons, haemorrhagic signs were observed commonly in SFTS patients. In an observational study of the largest cohort of patients with SFTS to date, over a third of SFTS cases were signed haemorrhagic signs [1]. What’s more, almost all presentations of bleeding were significantly associated with death, indicating haemorrhagic symptoms should be closely monitored across the disease course. Sensitive analysis and subgroup analysis also showed great robustness, even if heterogeneity existed.
Besides PLT, WBC and APTT, the common laboratory indicators including CK, CK-MB, ALT, AST, LDH and BUN, were identified as abnormal in a high proportion at acute infections. Our study suggested that the elevated levels of indexes above significantly increased mortality risk of SFTS patients. Previous studies [41,58] demonstrated that the measurement indicative of pathological lesions mainly involved the hematological system, liver, kidney, muscle and lymphoid system in different stage, indicating acute inflammation and impairment of liver and renal function is present at an early phase of the illness, corroborating the notion that SFTS is a complicated multisystem disease. Liver and renal function parameters were identified as the critical predictors of fatal outcome because they were confirmed to be the major target organ in SFTSV infected animal model [54]. These factors could have crucial applications if confirmed in other cohorts [58]. Furthermore, in some score models for predicting the mortality of SFTS, LDH and BUN were used widely and were shown to achieve high sensitivity and specificity, suggesting that combined multi-markers representing different damage sources of SFTSV infection played an important role for predicting the disease progression [1,59]. Myocardial damage is another common symptom after SFTSV infection and makes SFTS patients more likely to develop critical cases [60]. One study [60] monitoring and analyzing electrocardiograph (ECG), myocardial enzyme and biochemical indexes of SFTS cases found that more than half of patients had ECG abnormalities with the characteristics of ST-T change, sinus bradycardia and atrial fibrillation. Though the ECG change of SFTS patients was reversible with the improvement of condition, the incidence of abnormal ECG in death patients was still at a high level, suggesting the ECG in critical patients was more difficult to recover. Our study showed that the pooled effect of K was labile, implying further researches were necessary and valuable.
This meta-analysis had some limitations. First, significant heterogeneity brought into question the suitability of performing this meta-analysis. Fortunately, the sensitivity analysis showed that the pooled rates were stable, and subgroup analyses also identified several value factors. Secondly, the published studies only contained hospitalized SFTS patients, which might lead to a likely biased toward severe cases. Third, the sample sizes of most studies were small.
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