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Background: Thrombocytopenia was common in the coronavirus disease 2019 (COVID-19) patients during the infection, while the role of thrombocytopenia in COVID-19 pathogenesis and its relationship with systemic host response remained obscure. The study aimed to systematically evaluate the relationship between thrombocytopenia in COVID-19 patients and clinical, haematological and biochemical markers of the disease as well as adverse outcomes., Methods: To assess the relationship between abnormal platelet levels and disease progression, a multi-center retrospective cohort study was conducted. COVID-19 patients with thrombocytopenia and a sub-cohort of matched patients without thrombocytopenia were compared for their clinical manifestations, haematological disorders, biochemical parameters, inflammatory markers and clinical outcome., Results: Thrombocytopenia was present in 127 of 2,209 analyzed patients on admission. Compared with the control group, thrombocytopenia patients developed significantly higher frequency of respiratory failure (41.9% vs. 22.6%, P  = 0.020), intensive care unit entrance (25.6% vs. 11.5%, P  = 0.012), disseminated intravascular coagulation (45.2% vs. 10.6%, P  < 0.001), more altered platelet morphology indexes and coagulation perturbation, higher levels of inflammatory markers. In addition, a significantly increased all-cause mortality (hazard ratio 3.08, 95% confidence interval 2.26-4.18, P  < 0.001) was also observed in the patients with thrombocytopenia. Late development of thrombocytopenia beyond 14 days post-symptom was observed in 61 patients, from whom a comparable mortality rate yet longer duration to death was observed compared to those with early thrombocytopenia., Conclusions: Our finding from this study adds to previous evidence that thrombocytopenia is associated with adverse outcome of the disease and recommend that platelet count and indices be included alongside other haematological, biochemical and inflammatory markers in COVID-19 patients' assessment during the hospital stay., Competing Interests: The authors declare there are no competing interests., (©2022 Yuan et al.)

Severe Fever with Thrombocytopenia Syndrome (SFTS) is an emerging infectious disease caused by a novel bunyavirus, SFTS virus (SFTSV), with fatal outcome developed in approximately 17% of the cases. Thrombocytopenia is a hallmark feature of SFTS, and associated with a higher risk of fatal outcome, however, the pathophysiological involvement of platelet in the clinical outcome of SFTS remained under-investigated. In the current study, by retrospectively analyzing 1538 confirmed SFTS patients, we observed that thrombocytopenia was associated with enhanced activation of the cytokine network and the vascular endothelium, also with a disturbed coagulation response. The platelet phenotypes were also extensively altered in the process of thrombocytopenia development of SFTS patients. More importantly, all these disturbed host responses were related to the severity of thrombocytopenia, thus were considered to play in a synergistic way to influence the disease outcome. Moreover, the clinical effect of platelet transfusion was assessed by comparing two groups of patients with or without receiving this therapy. As a result, we observed no therapy effect in altering frequencies of fatal outcome, clinical bleeding development, or dynamic change of platelet count during the hospitalization. It's suggested that platelet supplementation alone acted a minor role in improving disease outcome, therefore new therapeutic intervention to regulate host response should be proposed. The current results revealed some evidence of interrelationship between platelet count and clinical outcome of SFTS disease from the perspective of activation of the cytokine network, the vascular endothelium, and the coagulation/fibrinolysis system. These evaluations might help to attain a better understanding of the pathogenesis and therapy choice in SFTS., Competing Interests: The authors have declared that no competing interests exist.

Background: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with an increasing case number and extensive geographical expansion, raising concerns locally and globally; however, the description of its clinical features needs to be addressed by large studies. We aimed to determine all the clinical features of SFTS in a large population of patients in an endemic area., Methods: In this prospective observational study, data were collected on patients admitted to the People's Liberation Army Hospital in Xinyang, Henan Province, China, with laboratory-diagnosed SFTS. Demographic, clinical, laboratory, and treatment data were collected for each patient, and patients were followed up within 2 weeks after discharge or discontinuation of treatment. The association between each demographic, clinical, and laboratory variable with a fatal outcome was assessed. A clinical scoring model was designed for the early prediction of a fatal outcome, and the effect of treatment on outcome was analysed., Findings: Between April 1, 2011, and Oct 31, 2017, 2096 patients with laboratory-confirmed SFTS were admitted. Mean age at admission was 61·4 years (SD 12·2) and 1239 (59%) patients were female. The case fatality rate (CFR) was 16·2% (95% CI 14·6-17·8). A higher risk was associated with being male (unadjusted odds ratio [OR] 1·45, 95% CI 1·15-1·83; p=0·002), older age (for a 10-year increase, unadjusted OR 1·82, 95% CI 1·62-2·04; p<0·0001), longer delay in admission (for every extra day taken before admission to hospital, unadjusted OR 1·18, 1·12-1·24; p<0·0001), presence of diarrhoea (adjusted OR 1·44, 1·12-1·87; p=0·005) or dyspnoea (adjusted OR 8·35, 5·97-11·69; p<0·0001), and development of haemorrhagic signs (adjusted OR 2·79, 95% CI 2·18-3·57; p<0·0001) or neurological symptoms (adjusted OR 30·26, 21·39-42·81; p<0·0001). Laboratory variables that were associated with death included abnormal concentrations of lactate dehydrogenase, aspartate aminotransferase, and blood urea nitrogen, and abnormal neutrophil percentage, which together with age and neurological symptoms were combined in the clinical scoring system. A total score of more than 8 was the optimal threshold to predict risk of death for patients who were evaluated within 6 days after symptom onset (area under the curve 0·879, 95% CI 0·855-0·902). For all participants, viraemia was a strong predictor of fatal outcome (all p<0·0001). Ribavirin therapy was effective in reducing CFR from 6·25% (15 of 240 participants) to 1·16% (two of 173 participants), but only in patients with a viral load below 1×10 6 copies per mL (hazard ratio 9·72, 95% CI 1·30-72·87; p=0·027)., Interpretation: The changing epidemiological features and high CFR of SFTS underscore the necessity of continued surveillance. Early prediction of fatal outcome can be attained by monitoring of clinical and laboratory data. Ribavirin should be applied early, with best results achieved before the viral load reaches 1 × 10 6 copies per mL., Funding: National Natural Science Foundation of China., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Severe fever with thrombocytopenia syndrome (SFTS) caused by a recently identified bunyavirus, SFTSV, is an emerging infectious disease with extensive geographical distribution and high mortality. Progressive viral replication and severe thrombocytopenia are key features of SFTSV infection and fatal outcome, whereas the underlying mechanisms are unknown. We revealed arginine deficiency in SFTS cases by performing metabolomics analysis on two independent patient cohorts, suggesting that arginine metabolism by nitric oxide synthase and arginase is a key pathway in SFTSV infection and consequential death. Arginine deficiency was associated with decreased intraplatelet nitric oxide (Plt-NO) concentration, platelet activation, and thrombocytopenia. An expansion of arginase-expressing granulocytic myeloid-derived suppressor cells was observed, which was related to T cell CD3-ζ chain down-regulation and virus clearance disturbance, implicating a role of arginase activity and arginine depletion in the impaired anti-SFTSV T cell function. Moreover, a comprehensive measurement of arginine bioavailability, global arginine bioavailability ratio, was shown to be a good prognostic marker for fatal prediction in early infection. A randomized controlled trial demonstrated that arginine administration was correlated with enhanced Plt-NO concentration, suppressed platelet activation, and elevated CD3-ζ chain expression and eventually associated with an accelerated virus clearance and thrombocytopenia recovery. Together, our findings revealed the arginine catabolism pathway-associated regulation of platelet homeostasis and T cell dysregulation after SFTSV infection, which not only provided a functional mechanism underlying SFTS pathogenesis but also offered an alternative therapy choice for SFTS., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Severe fever with thrombocytopenia syndrome virus (SFTSV) infection typically causes acute fever, thrombocytopenia and leucopenia, presenting with a high case fatality rate. The pathogenesis of SFTSV infection, however, is not well described. It was hypothesized that endothelial dysfunction might play part in the disease process. In current study, we retrospectively analyzed the clinical manifestations among a large group of confirmed SFTS cases and found evidence of plasma leakage and vascular endothelial injury. Then we established a SFTSV infection cell model and determined the infectivity and stimulation of SFTSV on vascular endothelial cells in vitro. The hyperpermeability of endothelial cells directly induced by SFTSV was confirmed by electrical resistance and dextran diffusion assay. The virus induced alterations of cell junctions and cytoskeleton was also revealed. It's suggested that vascular endothelial cell injury and barrier function damage were induced after SFTSV infection, which is a vital but neglected pathogenesis of SFTS., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease that is caused by a novel bunyavirus, SFTSV. We assessed whether the single nucleotide polymorphisms (SNPs) in the tumor necrosis factor-alpha (TNF-α) were associated with risk to severity of SFTS. Five TNF-α SNPs (SNP1: T-1031C; SNP2: C-863A; SNP3: C-857T; SNP4: G-308A; SNP5: G-238A) were genotyped in 987 hospitalized SFTS patients and 633 asymptomatic/mild SFTSV-infected subjects of Chinese Han origin. Multivariate logistic regression analysis was used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs). The hospitalized SFTS patients had significantly lower frequency of G-238A A allele than those with mild/asymptomatic infection (P = 0.006). Furthermore, T-1031C C allele (P < 0.001) and G-238A A allele (P < 0.001) were significantly associated with decreased risk of death. Multiple haplotypes were significantly associated with decreased risk of SFTS hospital admission (SNP1-2, CC; SNP1-3, CCC; SNP1-4, CCCG; SNP1-5, CCCGA; SNP2-4, CCGA; SNP3-5, CGA; SNP4-5, GA) and death (SNP1-2, CA; SNP1-3, CAG; SNP1-4, CACG; SNP1-5, CACGG; SNP2-3, AC; SNP2-4, ACG; SNP2-5, ACGG) after correction for multiple comparisons. By using the ELISA assay, we observed that TNF-α concentration of hospitalized patients was significantly increased in acute phase than in convalescent phase (P < 0.001). Elevated TNF-α concentration was also revealed from fatal patients (P < 0.001). The -238A allele was associated with decreased serum TNF-α levels in SFTS patients in acute phase (P = 0.01). Our findings suggest that polymorphisms in TNF-α gene may play a role in mediating the risk to disease severity of SFTS in Chinese Han population., Competing Interests: The authors have declared that no competing interests exist.

Background: Pathogenesis of severe fever with thrombocytopenia syndrome (SFTS) has not been well described yet. Recent studies indicate that SFTSV could replicate in endothelial cells. Here we performed a case-control study to determine whether endothelial activation/dysfunction occurred in SFTSV infection and to identify the biomarkers reflecting endothelial dysfunction. Methodology/Principal findings: In a case-control study of 134 SFTS patients and 68 healthy controls, serum levels of plasminogen activator inhibitor 1, tissue plasminogen activator, P-selectin, platelet endothelial cell adhesion molecular, CD40 ligand, E-selectin, vascular endothelial growth factor A, serum amyloid antigen 1 (SAA-1) and vascular cell adhesion molecular 1 were significantly enhanced in the patients than the controls (all P<0.05), indicating the occurrence of endothelial activation/dysfunction in SFTS. The intercellular adhesion molecular 1 (ICAM-1) and SAA-1 at the convalescent phase were also significantly associated with severe patients, after adjusting for the potential confounders. The odds ratio was estimated to be 3.364 (95% CI 1.074–10.534) for ICAM-1, and 1.881 (95% CI 1.166–3.034) for SAA-1, respectively. Cutoff value of 1.1×107 pg/mL SAA-1 or 1.2×106 pg/mL ICAM-1 were found to have moderate power of predicting fatal cases. Conclusions: The endothelial dysfunction may be one of the pathogenic mechanism of SFTS. The serum levels of ICAM-1 and SAA-1 might be used to predict adverse outcome. [ABSTRACT FROM AUTHOR]