Study On Surveillance,Clinical Diagnosis And Preventive Strategies Of Severe Fever With Thrombocytopenia Syndrome In China

Objective Severe Fever with Thrombocytopenia Syndrome(SFTS),caused by SFTS virus of genus Phlebovirus of the family Bunyaviridae,was a newly discovered highly pathogenic infectious disease with high fatality and public health importance.This study aimed to understand SFTS epidemiological characteristics,to furher understand the host range of SFTS virus,to know the status of SFTS clinical diagnosis,and to analyze the applications of SFTS virus RNA and antibodies detections for the clinical diagnosis.Through the above aspects,this study analysed the problems existing in SFTS monitoring,diagnosis,and provide suggestions for better prevention and control.Methods1 SFTS cases data in China(not including Hong Kong,Macao and Taiwan)between 2010 and 2016 were obtained from the China disease prevention and control information system.SPSS 18.0 software was used to analyzed morbidity and mortality,epidemic trend and characteristics,and status of diagnosis.ArcGIS 9.3 software was used to display spatial distribution of SFTS cases.2 Real time RT-PCR method was used to detect SFTS virus and Hantavirus(SEO virus and HTN virus)RNA among small wild animals.SFTS virus RNAs amplified by Nested RT-PCR were sequenced and analyzed by using MEGA 5.1 software.Meanwhile,we tried to isolated SFTS virUs from SFTS virus RNA positive or suspected specimens.3 Retrospective investigation of SFTS virus infection was conducted in several hospitals of two SFTS high endemic provinces(Shandong and Anhui).During retrospective investigation,sera were collected;SFTS virus IgM and IgG antibodies were measured by enzyme-linked immunosorbent assay.In order to further understand SFTS virus infection,acute phase sera were detected;also,SFTS virus infection rate among healthy population in an area without SFTS cases reported was investigated to get basic level of SFTS infection.SPSS 18.0 was used to compare clinical manifestations and SFTS virus antibodies positive rates in different groups.Estimated miss diagnosis rate was also calculated.4 Acute sera and convalescent sera of SFTS motitoring cases used in this study were collected from Shandong province in 2014-2015.IgM and IgG antibodies against SFTS virus were detected by enzyme-linked immunosorbent assay.The detection rates and coincidence of SFTS RNA and antibodies against SFTS virus were compared and analyzed.Results1 Epidemiologic characteristics of Severe Fever with Thrombocytopenia Syndrome in ChinaTotal 10917 SFTS cases,including 484 deaths,were reported in mainland China from 2010 to 2016.The average fatality rate was 4.4%.SFTS cases increased from 107(in 2010)to 2949(in 2016),but fatality rate deceased from 14%(in 2010)to 2.5%(in 2016).According to the national data,the average fatality rate of SFTS laboratory confirmed cases was higher than that of clinical diagnosis cases and suspected cases.However,the fatality rate of suspected cases(16%)in Shandong was very high,which should be paid more attention to.Currently,SFTS cases distributed in 448 counties of 25 provinces.The epidemic areas expanded.But over 99%SFTS cases distributed in seven provinces(Henan,Shandong,Hubei,Anhui,Liaoning,Zhejiang,and Jiangsu).SFTS peaked between April and October.Older farmers represented the largest portion of SFTS cases.The classification of SFTS cases included suspected cases,laboratory confirmed cases and clinical diagnosis cases although the later one was not officially defined as one SFTS classification.The laboratory confirmed cases accounted for 50%of the total cases.From 2011 to 2016,the proportion of laboratory confirmed SFTS cases changed little,but that of clinical diagnosis cases increased annually(from 9.1%in 2011 to 42.3%in 2016).However,the proportion of suspected cases showed a downward trend from 42.1%to 11.8%.The proportions of different SFTS cases classification were different in different provinces.Between 2010 and 2016,a total of 186 SFTS cases(1.7%)were ever misdiagnosed,which were once diagnosed as human granulocytic anaplasmosis(48.9%),hemorrhagic fever with renal syndrome(17.7%),and other diseases.Fatality rate was much higher in these SFTS cases.2 Status of Severe Fever with Thrombocytopenia Syndrome virus infection in wild small animals in ChinaOut of 1368 small wild animals,SFTS RNA was only detected from 4(0.3%)animals’ lungs,including three Apodemus chevrieriwere trapped in Guizhou province and one Myodes rutilus in Heilongjiang province.No co-infection with Hantavirus(SEO virus and HTN virus)was found among SFTS RNA positive animals.3 Severe Fever with Thrombocytopenia Syndrome virus infection analysis in hospitalized patientsAmong 246 study patients,13 cases(5.3%)were SFTS virus IgM antibody seropositive;48 cases(19.5%)were IgG antibody positive;and 11 cases(4.5%)were positive with these IgG and IgM at the same time.Out of 48 IgG antibody positive cases,27 cases(56.3%)had IgG antibody titers equal to or higher than 1:400.Out of 13 IgM antibody positive cases,11 cases(84.6%)were IgG antibody positive,including 9 cases with IgG antibody titers equal to or higher than 1:400.IgM antibody against SFTS virus was not detected among healthy people and only 2 persons(1.3%)were IgG antibody positive(titers equal to 1:100).Seropositive rates were high(8.4%for IgM and 30.1%for IgG)in patients with fever,thrombocytopenia and leucopenia and in patients with fever,thrombocytopenia and without leucopenia(10.5%for IgM and 18.4%for IgG).Also,the IgG titers were higher in these patients.Of these subjects,28 were initially diagnosed as SFTS suspected cases and then were excluded.Of 28 patients,25%cases were IgM positive,67.9%were IgG positive,and the titers of 84.2%IgG positive cases were>1:400.Of 14 sera of hospitalized patients collected during hospitalization,9 cases(64.3%)and 3 cases(21.4%)were IgM or IgG positive respectively.Elevation of SFTSV IgG titers by four-fold or seroconversion was observed in 9 IgM positive patients;and of those 8 sera(88.9%)collected during retrospective investigation were IgG positive with titers equal to or higher than 1:400.The above results inferred that miss diagnosis existed in these study subjects.We speculated that 27 patients with IgG antibody titers equal to or more than 1:400 in the retrospective study were most likely miss diagnosed.So,we estimated that the miss diagnosis rate was about 8.3%in SFTS high endemic areas.Based on this,the actual SFTS incidence in high endemic areas was much higher than current reporting number.4 Comparison of Real time RT-PCR method and ELISA method in SBFTS routine surveillanceAmong 243 SFTS monitoring cases,the detection rates of SFTS virus RNA,IgM and IgG antibody were 49.0%,44.9%and 12.8%,respectively.The detection rate of SFTS RNA showed a decreasing trend with specimen collection time.To specimens within one week after disease onset,the detection rate of SFTS RNA was higher than that of IgM antibody.SFTS virus RNA and antibodies of paried sera from 57 monitoring cases were also detected.The results showed that viral RNA detection and IgM antibody detection used together were better than single assay in SFTS routine surveillance.Conclusions1 SFTS cases increased annually in mainland China,which mainly distributed in seven provinces including Henan,Shandong,Hubei,Anhui,Liaoning,Zhejiang,and Jiangsu,especially in Dabie mountain areas of the border of Henan,Hubei and Anhui provinces.Recent years,SFTS epidemic areas expanded.Targeted training and surveillance should be strengthened in non-endemic areas and low endemic areas.Temporal and population distribution of SFTS changed little.We suggested that targeted health education should be carried out in SFTS high endemic areas before the epidemic to raise awareness of the prevention and treatment of people.The classification of reported SFTS cases changed.Clinical diagnosis cases were reported(although it was not officially defined as one SFTS classification)and increased annually.So SFTS clinical diagnosis criterion should be considered to set and adding a new SFTS case category-"SFTS clinical diagnosis cases".Furthermore,the fatality rate of suspected cases in Shandong province was very high.Targeted study should be focused on this phenomenon.2 SFTS virus RNA detection results showed that the SFTS virus infection rate of little wild animals was low.Apodemus chevrieriwere and Myodes rutilus may be the potential host anminals of SFTS virus,but further study should be conducted.No co-infection with Hantavirus(SEO virus and HTN virus)was found among SFTS RNA positive animals.3 The positive rate of IgM and IgG antibodies against SFTS virus,and titers of IgG antibody were high in hospitalized patients in this study,which inferred that miss diagnosis cases existed among these patients.The reason of miss diagnosis may be excessively dependent on laboratory test results.So we suggested that the category of"SFTS clinical diagnosis cases" should be added or SFTS virus antibody detection should be conducted for highly suspected clinical cases with negative SFTS RNA detection results.4 SFTS virus RNA detection was a prior method for early pathogen detection of SFTS cases.We noticed that SFTS RNA was not detectable in about half SFTS monitoring cases.However,nearly 1/4 SFTS RNA negative cases were SFTS virus IgM positive.So,IgM antibody detection can be considered as a supplementary method used in SFTS early diagnosis,especially for cases that were highly suspected as SFTS but with SFTS viral RNA negative.Furthermore,cases with IgM antibody negative should be comprehensively diagnosed combiding clinical manifestations(e.g.cases can be considered to be clinical diagnosis cases).