Severe Fever With Thrombocytopenia Syndrome Research Articles

Immunogenicity and protective efficacy of an inactivated SFTS vaccine candidate in mice

Severe fever with thrombocytopenia syndrome (SFTS), caused by a novel identified bunyavirus SFTS virus (SFTSV), was an emerging viral infectious disease that was firstly reported in China. There are no licensed vaccines and therapeutics against SFTSV currently. B-Propiolactone (BPL) inactivated whole virions of SFTSV strain AH12 were prepared as experimental vaccine in different antigen dose with or without Al(OH)3 adjuvant. The experimental SFTS vaccine was a satisfying immunogen, which could efficiently trigger the development of high levels of SFTSV NP-specific IgG antibodies and neutralizing antibodies against SFTSV Strain HB29 in BALB/c and C57/BL6 mice, and could induce SFTS virus-specific cellular immune responses to a certain extent. A single dose of vaccine was immunogenically insufficient in BALB/c mice; the second and third dose resulted in significant boost in antibody response. The use of Al(OH)3 adjuvant resulted in higher antibody titers. The mediate-dose of vaccine could induce as high and equivalent level of antibody titer as that of high-dose. The experimental SFTS vaccine in mediate- and high antigen dose with adjuvant resulted in solid protection of C57/BL6 mice against wild-type SFTSV challenge with markedly accelerated virus clearance from blood and spleen compared with controls. The experimental SFTS vaccine prepared in this study could efficiently elicit virus specific humoral and cellular immune responses in both BALB/c and C57/BL6 mice, and could protect C57/BL6 mice against SFTS virus challenge. These results supplied evidence that inactivated vaccine was a promising vaccine candidate for the prevention of SFTSV infection.

The Evaluation of Surrogate Laboratory Parameters for Predicting the Trend of Viral Loads in Patients with Severe Fever with Thrombocytopenia Syndrome: Cross-Correlation Analysis of Time Series

BackgroundThere is a correlation between the severe fever with thrombocytopenia syndrome (SFTS) viral load and disease severity; however, measurement of viral load is difficult in general laboratory and it takes time to obtain a viral load value. Here, the laboratory parameters for predicting the dynamic changes in SFTS viral load were identified. In addition, we tried to evaluate a specific time point for the early determination of clinical deterioration using dynamic change of laboratory parameters.Materials and MethodsThis observational study included SFTS patients in Korea (2013 - 2020). Cross-correlation analysis at lagged values was used to determine the temporal correlation between the SFTS viral loads and time-series variables. Fifty-eight SFTS patients were included in the non-severe group (NSG) and 11 in the severe group (SG).ResultsIn the cross-sectional analyses, 10 parameters -white blood cell, absolute neutrophil cell, lymphocyte, platelet, activated partial thromboplastin time (aPTT), C-reactive protein, aspartate aminotransferase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK)- were assessed within 30 days from the onset of symptoms; they exhibited three different correlation patterns: (1) positive, (2) positive with a time lag, and (3) negative. A prediction score system was developed for predicting SFTS fatality based on age and six laboratory variables -platelet, aPTT, AST, ALT, LDH, and CPK- in 5 days after the onset of symptoms; this scoring system had 87.5% sensitivity and 86.0% specificity (95% confidence interval: 0.831 - 1.00, P <0.001).ConclusionThree types of correlation patterns between the dynamic changes in SFTS viral load and laboratory parameters were identified. The dynamic changes in the viral load could be predicted using the dynamic changes in these variables, which can be particularly helpful in clinical settings where viral load tests cannot be performed. Also, the proposed scoring system could provide timely treatment to critical patients by rapidly assessing their clinical course.

Serological and molecular survey of tick-borne zoonotic pathogens including severe fever with thrombocytopenia syndrome virus in wild boars in Miyazaki Prefecture, Japan.

BackgroundMiyazaki Prefecture is one of the hotspots of severe fever with thrombocytopenia syndrome (SFTS) cases and related deaths in Japan since 2013 and other pathogens of tick‐borne diseases (TBDs). Japanese spotted fever and scrub typhus are also endemic in this region.ObjectivesA total of 105 wild boars, hunted in 2009, were serologically examined as sentinels for TBDs to indirectly demonstrate the potential hazard of ticks transmitting pathogens to humans in the studied area.MethodsThe collected blood and spleens of the wild boars underwent serological and molecular tests for SFTSV, Rickettsia japonica (Rj) [antibody to spotted fever group rickettsiae (SFGR) were tested by using species‐common antigen], and Orientia tsutsugamushi (Ot).ResultsSeroprevalences of SFTSV, SFGR, and Ot were 41.9%, 29.5%, and 33.3%, respectively. SFTS viral RNA was identified in 7.6% of the sera, whereas DNA of Rj or Ot was not detected in any sample. In total, 43.8% of the boars possessed an infection history with SFTSV (viral gene and/or antibody). Of these, 23.8% had multiple‐infection history with SFGR and/or Ot.ConclusionsThe high prevalence of SFTSV in wild boars might reflect the high risk of exposure to the virus in the studied areas. In addition, SFTSV infection was significantly correlated with Ot infection, and so were SFGR infection and Ot infection, indicating that these pathogens have common factors for infection or transmission. These data caution of the higher risk of SFTSV infection in areas with reported cases of other TBDs.

A review on the epidemiology of severe fever with thrombocytopenia syndrome

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease discovered in the 21st century. This disease has been reported in several Asian countries, including China, Japan, South Korea, Vietnam, and Myanmar. Until 2019, SFTS cases have been reported in 25 provinces in China, and most of them were rural residents from mountains and hilly regions. Most SFTS cases were sporadic but geographically concentrated, mainly in Henan, Shandong, Anhui, Hubei, Liaoning, Zhejiang, and Jiangsu provinces. SFTSV infection was transmitted predominantly by a tick bite and potentially through close contact with the patient's blood or body fluids. Fever, gastrointestinal symptoms, thrombocytopenia, and leukopenia were common initial manifestations, and multiple organ failure or even death could occur in severe cases. The reported cases of SFTS have been gradually increasing, and the case fatality rate has remained at a high level, posing a severe threat to public health in China. This paper reviewed the epidemiological features, risk factors for disease transmission, and the clinical characteristics of SFTS to gain further knowledge of the disease, guide the prevention and management, and help reduce the case fatality rate.

Clinical features of severe fever with thrombocytopenia syndrome and analysis of risk factors for mortality

BackgroundTo understand the clinical characteristics of and explore the risk factors for mortality in patients with severe fever with thrombocytopenia syndrome (SFTS).MethodsData from SFTS patients diagnosed by laboratory examination at Chaohu Hospital affiliated with Anhui Medical University from June 2017 to January 2021 were retrospectively analysed. According to the clinical results, all confirmed patients were divided into the surviving group (80 patients) and non-surviving group (20 patients). The two groups were compared in terms of general characteristics, clinical symptoms and signs, laboratory indicators and other aspects. The independent risk factors for mortality in SFTS patients were analysed by multivariate binary logistic regression.ResultsUnivariate analysis showed a significant difference in age and the incidence of consciousness disturbance, respiratory failure, haemorrhagic manifestations, renal dysfunction, shock, aspartate aminotransferase (AST) ≥400 U/L, creatine kinase (CK)≥1000 U/L, creatine kinase isoenzymes (CK-MB) ≥100 U/L, lactate dehydrogenase (LDH) ≥1000 U/L, serum creatinine ≥100 mmol/L, blood urea nitrogen ≥7.5 mmol/L and C-reactive protein ≥8 mg/L between the two groups (P < 0.05).ConclusionsConsciousness disorder, haemorrhagic manifestations, renal dysfunction, AST ≥ 400 U/L, and LDH ≥ 1000 U/L are independent risk factors for mortality in SFTS patients and merit close attention in clinical treatment to avoid fatal consequences.

L-DOPA, a treatment for Parkinson's disease, and its enantiomer D-DOPA inhibit severe fever with thrombocytopenia syndrome virus infection in vitro

Severe fever with thrombocytopenia syndrome (SFTS) is a hemorrhagic fever. Patients mainly develop fever, thrombocytopenia, and leukopenia. A high case fatality rate of 16.2–47% has been reported. Vaccines and antivirals that are effective against SFTS virus (SFTSV) are not yet available in clinical practice. We previously showed that o-dihydroxybenzene is the important chemical core structure for anti-SFTSV activity. In this study, we evaluated the anti-SFTSV efficacy of 3-Hydroxy-L-tyrosine (L-DOPA), a treatment for Parkinson's disease and its enantiomer, 3-hydroxy-D-tyrosine (D-DOPA), both of which have an o-dihydroxybenzene backbone. SFTSV was preincubated with L- or D-DOPA and then inhibition of viral infection as well as viral attachment to host cells were evaluated by viral quantification. Both L- and D-DOPA inhibited SFTSV infection in a dose-dependent manner, mainly by blocking viral attachment to host cells. The half-maximal inhibitory concentration (IC50) of L-DOPA was 4.46–5.09 μM. IC50 of D-DOPA was 4.23–6.72 μM. IC50 of L-DOPA is very close to its maximum blood concentration after oral administration as a therapy for Parkinson's disease. D-DOPA, which IC50 was almost the same as that of L-DOPA, might not cause side effect. Thus, our present study demonstrated that L- and D-DOPA are potentially useful candidates for anti-SFTSV drugs.

Experimental infection of dogs with severe fever with thrombocytopenia syndrome virus: Pathogenicity and potential for intraspecies transmission.

Severe fever with thrombocytopenia syndrome (SFTS) is caused by infection with Dabie bandavirus [formerly SFTS virus (SFTSV)] and is an emerging zoonotic disease. Dogs can be infected with SFTSV, but its pathogenicity and transmissibility have not been fully elucidated. In experiment 1, immunocompetent dogs were intramuscularly inoculated with SFTSV. In experiment 2, immunosuppressed dogs (immunosuppressed group; oral azathioprine 5mg/kg/day for 30 days) were intramuscularly inoculated with SFTSV. Both immunosuppressed and immunocompetent contact dogs were co-housed with the SFTSV-inoculated dogs that had been immunosuppressed. Immunocompetent SFTSV-infected dogs did not show any clinical symptom. However, immunosuppressed SFTSV-infected dogs showed high fever and weight loss without lethality. In all SFTSV-infected dogs, viral RNA could be measured in the serum only after 3 days post infection (DPI) and neutralizing antibodies were detected in the serum beginning 9 DPI. SFTSV shedding in the urine and faeces of some infected dogs occurred between 4 and 6 DPI. The immunocompromised SFTSV-infected dogs showed thrombocytopenia beginning 3 DPI to the end of the experiment (24 DPI). We confirmed SFTSV transmission to one of three immunocompetent co-housed dogs. This dog showed a high fever, weight loss, and shed viral RNA by urine. Viral RNA and neutralizing antibodies were also detected in the serum. These results demonstrated that intramuscular inoculation with SFTSV induced minor clinical symptoms in dogs, and intraspecies SFTSV transmission in dogs can occur by contact.

Estimating severe fever with thrombocytopenia syndrome transmission using machine learning methods in South Korea

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease in China, Japan, and Korea. This study aimed to estimate the monthly SFTS occurrence and the monthly number of SFTS cases in the geographical area in Korea using epidemiological data including demographic, geographic, and meteorological factors. Important features were chosen through univariate feature selection. Two models using machine learning methods were analyzed: the classification model in machine learning (CMML) and regression model in machine learning (RMML). We developed a novel model incorporating the CMML results into RMML, defined as modified-RMML. Feature importance was computed to assess the contribution of estimating the number of SFTS cases using modified-RMML. Aspect to the accuracy of the novel model, the performance of modified-RMML was improved by reducing the MSE for the test data as 12.6–52.2%, compared to the RMML using five machine learning methods. During the period of increasing the SFTS cases from May to October, the modified-RMML could give more accurate estimation. Computing the feature importance, it is clearly observed that climate factors such as average maximum temperature, precipitation as well as mountain visitors, and the estimation of SFTS occurrence obtained from CMML had high Gini importance. The novel model incorporating CMML and RMML models improves the accuracy of the estimation of SFTS cases. Using the model, climate factors, including temperature, relative humidity, and mountain visitors play important roles in transmitting SFTS in Korea. Our findings highlighted that the guidelines for mountain visitors to prevent SFTS transmissions should be addressed. Moreover, it provides important insights for establishing control interventions that predict early identification of SFTS cases.

Evaluating the spatial and temporal patterns of the severe fever thrombocytopenia syndrome in Republic of Korea.

Severe fever with thrombocytopenia syndrome (SFTS) is a new infectious disease with a high mortality rate and increased incidence in Republic of Korea since the first case was reported in 2013. The average mortality rate varies by region and year but remains high in Asia. This study aimed to evaluate the spatial and temporal patterns of SFTS cases reported to the national Disease Control and Prevention Agency (KDCA). We analysed the spatial and temporal distribution of SFTS and observed changes in areas vulnerable to the disease. We analysed data concerning 1086 confirmed SFTS patients from 2013 to 2019 categorized according to the 247 district level administrative units. To better understand the epidemiology of SFTS, we carried out spatiotemporal analyses on a yearly basis and also calculated and mapped spatial clusters of domestic SFTS by global (regional) and local Moran's indices. To observe the annual changes in SFTS incidence rate, scan statistics for each city and district were calculated. The incidence rate showed significant clustering in specific regions, which reoccurred annually in some regions. In Republic of Korea, SFTS clusters have been expanding into the southern regions, with annual clusters concentrated between May and October. This pattern allows prediction of SFTS occurrences through spatiotemporal analysis, which makes it possible to guide measures of disease prevention.

Vectors, Hosts, and the Possible Risk Factors Associated with Severe Fever with Thrombocytopenia Syndrome.

Severe fever with thrombocytopenia syndrome (SFTS) is a disease caused by infection with the SFTS virus (SFTSV). SFTS has become a crucial public health concern because of the heavy burden, lack of vaccines, effective therapies, and high-fatality rate. Evidence suggests that SFTSV circulates between ticks and animals in nature and is transmitted to humans by tick bites. In particular, ticks have been implicated as vectors of SFTSV, where domestic or wild animals may play as the amplifying hosts. Many studies have identified antigens and antibodies against SFTSV in various animals such as sheep, goats, cattle, and rodents. Besides, person-to-person transmission through contact with blood or mucous of an infected person has also been reported. In this study, we reviewed the literature and summarized the vectors and hosts associated with SFTS and the possible risk factors.

Single-cell landscape of peripheral immune responses to fatal SFTS

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with high fatality. Poor prognosis of SFTS has been associated with dysregulated host immunity; however, the immune patterns associated with pathophysiology involving SFTS exacerbation remain unclear. Here, we show that the single-cell landscape of peripheral immune responses is reprogrammed in SFTS and characterized by monocyte shift to an intermediate type along with complement activation, perturbation of plasmablast composition, and highly exhausted Tcells, all correlated with lethal consequences. We identify the overexpression of interferon (IFN)-stimulated genes across most immune cell types after SFTSV infection, which are simultaneously related to older age, high viremia, and a hyperinflammatory response. A retrospective clinical study reveals no efficiency of IFN-α in treating SFTS. These data collectively support the intermediate monocytes and IFN-I-inducible plasmablasts to be major targets for SFTS virus infection, and they indicate the pivotal role of the IFN-I response in exacerbating hyperinflammation and lethal SFTS.

Development research that contributes to saving lives of patients with severe fever with thrombocytopenia syndrome (SFTS)

Severe fever with thrombocytopaenia syndrome (SFTS) is a tick-borne viral haemorrhagic fever with a high case fatality rate. Clinicians, veterinarians and scientists are working together to elucidate its pathophysiology and develop effective vaccines and treatments. The work is led by Dr Masayuki Saijo from the National Institute of Infectious Diseases (NIID) and also involves researchers from Yamaguchi University, Ehime University and Yamaguchi Grand Medical Center. The team is investigating the maintenance of the SFTS virus in nature by exploring the relationship of the virus between animals and ticks and the researchers are also working to clarify the pathophysiology of the disease, which will lead to the development of diagnostics, specific treatments and additional treatments and contribute to the further development of a vaccine. The researchers believe that a 'one health' approach to tackling SFTS is crucial, which is why they are tackling human and animal treatment and prevention in parallel. Favipiravir is an antiviral agent developed by Dr Yosuke Furuta from Toyama Chemicals and is the primary candidate for treatment. The team believes that if favipiravir can be administered to patients in the early stages of SFTS, this will reduce the case fatality rate of the disease. So far, the team has developed two recombinant vaccine candidates for SFTS that have so far demonstrated no major adverse effects. The researchers plan to develop other types of vaccines that will be safe for humans and animals.

Potential efficacy of existing drug molecules against severe fever with thrombocytopenia syndrome virus: an in silico study

Severe fever with thrombocytopenia syndrome (SFTS) is a zoonotic disease caused by the SFTS virus (SFTSV). SFTS can be considered a life-threatening notifiable infectious disease. The unavailability of specific therapeutics encourages the investigation of potential efficacy of existing drugs against this infection. Drug repurposing was done by performing virtual screening of already established drug molecules followed by 100 ns molecular dynamics simulations and molecular mechanics Poisson–Boltzmann surface area–based binding-energy calculation by targeting the SFTS L protein. On the basis of binding energy and protein–ligand interactions, top 10 promising hits were identified, showing stable binding with SFTS L protein. Further 100 ns atomistic MD simulation refined the hits from top 10 to top 4 with docking-based binding energy lesser than −8.0 kcal/mol toward the SFTS L protein and engaged in π–π interactions with pivotal amino acid residues. Various parameters and binding affinity of top 4 ligands towards L protein was computed. Ligand zaltoprofen exhibited best binding energy −220.095 kJ/mol. The present work is the first in silico study to assess bromfenac, cinchophen, elliptinium, and zaltoprofen; four promising hits against SFTS. Nonetheless, further proper biological evaluation is necessary to determine their efficacy against SFTS.

Sex Differences in Case Fatality Rate of Patients With Severe Fever With Thrombocytopenia Syndrome.

Background: Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne disease with high mortality. However, detailed analysis is lacking to explore the complex effect of sex with age or comorbidities.Methods: A retrospective cohort study was performed among 2,938 SFTS patients entered during 2011–2020 in Xinyang, China. The case fatality rate (CFR) was estimated for their association with sex, age, and comorbidities by an interactive way. The difference of immune response between sex was explored in an age dependent way.Results: An overall CFR of 15.3% (450/2,938) was obtained, which appeared to be higher in males than in females [17.7% vs. 13.6%, adjusted odds ratio (aOR) = 1.24; 95% CI, 1.00–1.53; P = 0.048] and increased dramatically with age (P < 0.001). The associations between sex and SFTS fatal outcome were age-dependent and varied according to the status of comorbidities. The mortality-related risk conferred by older age was more pronounced in males, with aOR (95% CI) to be 5.76 (3.75–8.84) vs. 5.30 (3.54–7.95) in female. Sex-stratified analysis disclosed significant associations between death and comorbidities among female patients (aOR = 1.87, 95% CI: 1.40–2.49; P < 0.001), while none among males. Among females, the significant associations between presence of comorbidity and fatal outcome differed among age groups, with aOR (95% CI) decreased from 2.28 (1.16–4.46) in ≤60 years, to 2.06 (1.34–3.18) in 60–70 years and further to 1.55 (0.97–2.47) in >70 years. Altogether 194 SFTS patients were randomly selected for the test of B cells, natural killer (NK) cells, CD4 cells percentages, and anti-SFTSV IgM antibody level, the results revealed that males >60 years had significantly decreased percentages of B cells, CD4 cells, lower anti-SFTSV IgM antibody titer, and increased level of NK cells than male aged ≤60 years, while none of these age specific differences was observed in the females. This finding underlies the more pronounced age specific difference in CFR among male than female.Conclusions: Males had a significantly higher mortality of SFTS than did females, and more likely to be affected by aging for SFTS mortality. This difference can be explained by the effect from comorbidities and the host immunity. It is essential to take a sex- and age-based approach to SFTS treatment and management.

Time Course of Severe Fever With Thrombocytopenia Syndrome Virus and Antibodies in Patients by Long-Term Follow-Up Study, China.

Objectives: The objective was to describe the changes of severe fever with thrombocytopenia syndrome virus (SFTSV) and antibody in the disease course and explore the relationship between antibody titers and patients’ prognosis.Methods: The levels of SFTSV, virus-specific immunoglobulin M (IgM), immunoglobulin G (IgG) titers, and cytokines in 37 patients with severe fever with thrombocytopenia syndrome (SFTS) were measured dynamically by real-time PCR and ELISA during the disease course; IgG titers were followed up in 53 cases. The correlation analysis of antibody titers with individual serum cytokines was calculated using the Spearman test.Results: The average time of SFTSV duration in individual serum was 22.45 ± 7.6 days from onset. We found SFTSV turned negative within the 10th day from the onset in two patients. SFTSV-specific IgM seroconversion occurred as early as within 3 days from the onset, increased gradually within the first 2 months, decreased gradually 3 months later, and disappeared after 6 months in all the patients. The average time of SFTSV-specific IgG antibody seroconversion was at 17 days from onset in the patients; the time was later in severe cases than in mild cases (23 ± 1.4 vs. 14.3 ± 1.0 days, p < 0.0001). IgG titers were maintained at the peak levels during the periods from 6 months to 1 year and decreased from the second year gradually. Severe cases had higher IgG levels than mild cases and also had a slower decreasing trend. During follow-up, only one lost IgG antibody 7 years later; no chronic infection and sequela were found among the 53 patients. None of the patients had SFTSV reinfection even if they were bitten by ticks again. The correlation analysis showed a positive relationship between inflammatory factors and IgG antibody levels.Conclusion: IgM antibody has important value in early diagnosis of SFTS. A moderate inflammatory response is beneficial for production and duration of IgG antibodies.

Clinical Usefulness of Nested Reverse-Transcription Polymerase Chain Reaction for the Diagnosis of Severe Fever with Thrombocytopenia Syndrome.

Severe fever with thrombocytopenia syndrome (SFTS), caused by SFTS virus (SFTSV) is an emerging tick-borne infectious disease. Few studies have assessed the clinical usefulness of nested reverse-transcription polymerase chain reaction (RT-PCR) for diagnosing SFTS. We performed conventional RT-PCR targeting the M segment, nested RT-PCR targeting M and S segments, and real-time RT-PCR targeting the S segment of SFTSV for four patients with suspected SFTS. Although conventional RT-PCR results for the first two patients were negative at admission, nested RT-PCR using the S or M targets was positive for the same samples. Likewise, in the other two patients, initial samples were confirmed positive in all three tests, but follow-up testing demonstrated negative conventional RT-PCR and positive nested RT-PCR results. Thus, delayed testing using conventional RT-PCR or real-time RT-PCR in symptomatic patients with SFTS may result in missed diagnoses, and compared with these methods, nested RT-PCR may increase the window for obtaining positive SFTSV PCR results. Meanwhile, the indirect immunofluorescence assay showed seroconversion to SFTSV antibodies in all four patients. Nested RT-PCR for SFTSV M and S segments could help diagnose SFTS in patients testing negative by conventional RT-PCR.

Survey of ticks and severe fever with thrombocytopenia syndrome in Zhoushan, Zhejiang, 2018–2020

Objective To investigate the density and seasonal fluctuation of ticks and its association with the incidence of severe fever with thrombocytopenia syndrome (SFTS) in Zhoushan of Zhejiang province. Methods From 2018 to 2020, the surveillance data of free ticks were collected from Dinghai, Putuo, Daishan and Shengsi districts of Zhoushan and the information about laboratory confirmed cases of fever with thrombocytopenia syndrome were collected. The surveillance data of parasitic ticks and free ticks were collected from the areas where SFTS cases occurred. RT-PCR was used to detect SFTSV in ticks. Results A total of 612 free ticks were captured from 2018 to 2020. Haemaphysalis longhorni accounted for 83.82%, Rhipicephalus falciparum accounted for 14.05%. There were 20 cases of new fever with thrombocytopenia syndrome reported from 2018 to 2020, and the cases mainly occurred in Daishan county. A total of 51 free ticks and 86 parasitic ticks were captured near the area where the confirmed case occurred, all of which were Haemaphysalis longhorni. All the ticks tested by RT-PCR were negative for SFTSV. Conclusion The predominant species of ticks in Zhoushan was Haemaphysalis longicorni. The rural environment was the main habitat of ticks. The activity peak of ticks was during May - September. The incidence of fever with thrombocytopenia syndrome was related to the activity peak of ticks.

A longitudinal sampling study of transcriptomic and epigenetic profiles in patients with thrombocytopenia syndrome

Severe fever with thrombocytopenia syndrome (SFTS) is a novel tick-borne infectious disease caused by a new type of SFTS virus (SFTSV). Here, a longitudinal sampling study is conducted to explore the differences in transcript levels after SFTSV infection, and to characterize the transcriptomic and epigenetic profiles of hospitalized patients. The results reveal significant changes in the mRNA expression of certain genes from onset to recovery. Moreover, m6A-seq reveals that certain genes related with immune regulation may be regulated by m6A. Besides the routine tests such as platelet counts, serum ALT and AST levels testing, distinct changes in myocardial enzymes, coagulation function, and inflammation are well correlated with the clinical data and sequencing data, suggesting that clinical practitioners should monitor the above indicators to track disease progression and guide personalized treatment. In this study, the transcript changes and RNA modification may lend a fresh perspective to our understanding of the SFTSV and play a significant role in the discovery of drugs for effective treatment of this disease.

Clinical efficacy and safety evaluation of favipiravir in treating patients with severe fever with thrombocytopenia syndrome.

BackgroundSevere fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with high mortality, however with no effective therapy available.MethodsThe effect of favipiravir (FPV) in treating SFTS was evaluated by an integrated analysis on data collected from a single-arm study (n=428), a surveillance study (n=2350) and published data from a randomized controlled trial study (n=145). A 1:1 propensity score matching was performed to include 780 patients: 390 received FPV and 390 received supportive therapy only. Case fatality rates (CFRs), clinical progress, and adverse effects were compared.FindingsFPV treatment had significantly reduced CFR from 20.0% to 9.0% (odds ratio 0.38, 95% confidence interval 0.23-0.65), however showing heterogeneity when patients were grouped by age, onset-to-admission interval, initial viral load and therapy duration. The effect of FPV was significant only among patients aged ≤70 years, with onset-to-admission interval ≤5 days, therapy duration ≥5 days or baseline viral load ≤1 × 106 copies/mL. Age-stratified analysis revealed no benefit in the aging group >70 years, regardless of their sex, onset-to-admission interval, therapy duration or baseline viral load. However, for both ≤60 and 60-70 years groups, therapy duration and baseline viral load differentially affected FPV therapy efficiency. Hyperuricemia and thrombocytopenia, as the major adverse response of FPV usage, were observed in >70 years patients.InterpretationFPV was safe in treating SFTS patients but showed no benefit for those aged >70 years. Instant FPV therapy could highly benefit SFTS patients aged 60-70 years.FundingChina Natural Science Foundation (No. 81825019, 82073617 and 81722041) and China Mega-project for Infectious Diseases (2018ZX10713002 and 2015ZX09102022).

Impact of interventions on the incidence of natural focal diseases during the outbreak of COVID-19 in Jiangsu Province, China

BackgroundDuring the period of the coronavirus disease 2019 (COVID-19) outbreak, strong intervention measures, such as lockdown, travel restriction, and suspension of work and production, may have curbed the spread of other infectious diseases, including natural focal diseases. In this study, we aimed to study the impact of COVID-19 prevention and control measures on the reported incidence of natural focal diseases (brucellosis, malaria, hemorrhagic fever with renal syndrome [HFRS], dengue, severe fever with thrombocytopenia syndrome [SFTS], rabies, tsutsugamushi and Japanese encephalitis [JE]).MethodsThe data on daily COVID-19 confirmed cases and natural focal disease cases were collected from Jiangsu Provincial Center for Disease Control and Prevention (Jiangsu Provincial CDC). We described and compared the difference between the incidence in 2020 and the incidence in 2015–2019 in four aspects: trend in reported incidence, age, sex, and urban and rural distribution. An autoregressive integrated moving average (ARIMA) (p, d, q) × (P, D, Q)s model was adopted for natural focal diseases, malaria and severe fever with thrombocytopenia syndrome (SFTS), and an ARIMA (p, d, q) model was adopted for dengue. Nonparametric tests were used to compare the reported and the predicted incidence in 2020, the incidence in 2020 and the previous 4 years, and the difference between the duration from illness onset date to diagnosed date (DID) in 2020 and in the previous 4 years. The determination coefficient (R2) was used to evaluate the goodness of fit of the model simulation.ResultsNatural focal diseases in Jiangsu Province showed a long-term seasonal trend. The reported incidence of natural focal diseases, malaria and dengue in 2020 was lower than the predicted incidence, and the difference was statistically significant (P < 0.05). The reported incidence of brucellosis in July, August, October and November 2020, and SFTS in May to November 2020 was higher than that in the same period in the previous 4 years (P < 0.05). The reported incidence of malaria in April to December 2020, HFRS in March, May and December 2020, and dengue in July to November 2020 was lower than that in the same period in the previous 4 years (P < 0.05). In males, the reported incidence of malaria in 2020 was lower than that in the previous 4 years, and the reported incidence of dengue in 2020 was lower than that in 2017–2019. The reported incidence of malaria in the 20–60-year age group was lower than that in the previous 4 years; the reported incidence of dengue in the 40–60-year age group was lower than that in 2016–2018. The reported cases of malaria in both urban and rural areas were lower than in the previous 4 years. The DID of brucellosis and SFTS in 2020 was shorter than that in 2015–2018; the DID of tsutsugamushi in 2020 was shorter than that in the previous 4 years.ConclusionsInterventions for COVID-19 may help control the epidemics of natural focal diseases in Jiangsu Province. The reported incidence of natural focal diseases, especially malaria and dengue, decreased during the outbreak of COVID-19 in 2020. COVID-19 prevention and control measures had the greatest impact on the reported incidence of natural focal diseases in males and people in the 20–60-year age group.Graphical