Efficacy Evaluation Of Treatment Regimen Of Severe Fever With Thrombocytopenia Syndrome

BackgroundSevere fever with thrombocytopenia syndrome（SFTS）was firstly discovered in2009,and its pathogen was SFTSV,which was a tick-borne phlebovirus of the family Phenuiviridae in the order Bunyavirales.SFTSV is mainly transmitted to human by tick bites in natural foci,with a possible human-to-human transmission through contacts with infected blood or body fluid.SFTS cases mainly distributed in individuals among25⁸0-years old,with the mean age of 61.4（SD 12.2）years.Most of the patients had symptom onset between March to November.According to the latest study,the mortality was as high as 16.2%（95%CI:14.6%-17.8%）.The symptoms of SFTS patients are fever,thrombocytopenia and leukopenia,accompanying with or without digestive and respiratory symptoms.Liver dysfunction may occur as the disease progresses.Severe cases often had bleeding symptoms and neurological symptoms,and some cases even developed to fatal outcome due to multiple organ failure.As a new infectious disease,there are no specific and effective treatments for SFTS.Ribavirin,as an antiviral drug that can inhibit the activity of DNA and RNA viruses,had been confirmed to have effect of inhibiting SFTSV replication in vitro.Accordingly,the guidelines published in China recommends using ribavirin for the treatment of SFTS,but the efficacy was controversial.Other supportive treatments for SFTS were as follows:infusion of plasma and platelets in patients with significant bleeding or thrombocytopenia;granulocyte colony-stimulating factor（GSF）in patients with severely low neutrophils;sensitive antibiotics in patients with bacterial and fungal infections.As the effect of corticosteroid is not clear,we should be careful when use it.However,there is currently still lack of unified strategies and effective treatment for SFTS.ObjectiveThe main purpose of the study is to evaluate the efficacy of treatment regimen and find out the risk factors of SFTS,so that we can take some effective measures to reduce the mortality.MethodThe study was performed on a prospectively observed cohort of SFTSV infected patients who were recruited in People’s Liberation Army（PLA）154 hospital.The medical records of all the hospitalized patients were maintained in an electronic system with logic error correction function,ensuring the credibility of the data.For the current research,a medical record review was performed to collect the information on demographic characteristics,preexisting comorbidities,clinical information,laboratory test results and treatment regimens during the entire hospitalization.Analysis was performed using Stata14.0 statistical analysis software,Excel 2013 and GraphPad Prism7.0.Propensity matching（PSM）was used to adjust the influencing factors.Generalized estimating equation（GEE）was constructed to compare the laboratory parameters that were evaluated over time.Results2096 SFTS patients with the mean age of 61.4（SD 12.2）were enrolled during2011-2017.Among them 1239（59.1%）were women and 340 developed fatal outcome with the mortality 16.2%（95%CI:14.6%-17.8%）.Efficacy evaluation of ribavirin264 cases of ribavirin group and the same number of non-ribavirin group were screened by using PSM.When the patients were grouped according to the usage of ribavirin,the mortality rate（OR=0.826;95%CI:0.480-1.422;P=0.490）and the SFTSV viral load（?=0.177;95%CI:-0.121 to 0.475;P=0.245）were comparable between ribavirin group and non-ribavirin group.When kicked out the patients without viral loads or receiving treatment less than 2 days in 2096 SFTS patients,the remaining 1403patients were divided into four groups according to the viral load at admission（<10⁶,10⁶-10⁷,10⁷-10⁸,>10⁸ copies/ml）.Cox regression analysis showed that the mortality of the patients treated with ribavirin with viral load less than 1×10⁶ copies/ml was 1.16%（2/173）,which was significantly lower than that of the control group 6.25%（15/240）.The patients who did not received ribavirin had 9.72 times higher risk of death than that of the ribavirin group（95%CI:1.30-72.87;P=0.027）.For other groups,effect of ribavirin on reducing mortality was not observed.180 cases of ribavirin and interferon co-treated group and 180 cases of untreated group were included in our analysis after performing PSM.GEE analysis showed that lower aspartate aminotransferase（AST）（?=-62.341;95%CI:-109.395至-21.287;P=0.004）,blood urea nitrogen（BUN）（?=-1.504;95%CI:-2.282 to-0.726;P<0.001）and higher albumin（ALB）（?=1.607;95%CI:0.986-2.228;P<0.001）were observed in co-treated group.The extreme values of laboratory parameters during hospitalization showed that the highest viral load in the co-treated group was lower than that of untreated group（P=0.005）,and the lowest platelet count（PLT）was higher than that of the untreated group（41×10⁹/L vs.36×10⁹/L;P=0.005）.GEE analysis showed that the SFTSV viral loads were comparable between group.The patients whose SFTSV viral loads<1×10⁷copies/ml had lower risk of death in the ribavirin and interferon co-treated group than the untreated group.However,the risk of death（OR=0.590;95%CI:0.319-1.093;P=0.093）and SFTSV viral load（?=1.053;95%CI:0.990-1.221;P=0.102）had no statistical differences between the two groups.Efficacy evaluation of supportive treatmentEfficacy evaluation of platelet transfusion:a total of 56 cases with platelets below30×10⁹/L who didn’t receive platelet transfusion were defined as the control group.56cases with platelets below 30×10⁹/L who were given platelet transfusion were defined as the platelet transfusion group.The baseline of the two groups at admission were comparable.Logistic regression analysis showed that there was no statistical differences of mortality between the two groups（28.6%vs.35.7%;P=0.226）.Moreover,statistical differences in the frequency of bleeding symptoms were also not observed between the two groups（30.3%vs.15.6%;P=0.330）.The percent of patients in the platelet transfusion group with platelets counts increased more than 10×10⁹/L within 24 hours after transfusion of platelets was significantly higher than that of the untreated group（35.7%vs.16.1%;P=0.019）.The days of platelets return to 50×10⁹/L（4 days vs.4.5days;P=0.797）were comparable between the two groups,indicating that platelet transfusion were not helpful to accelerate platelets recovery and reduce the risk of bleeding in SFTS patients.Efficacy evaluation of steroid therapy:corticosteroid-treated 173 cases were defined as the corticosteroid group and the same number of patients who didn’t receive corticosteroid selected using PSM were defined as the control group.There were no statistical differences of mortality between the two groups（10.4%vs.9.3%;P=0.718）.GEE analysis found that the viral load of the corticosteroid group was higher than that of the control group（?=1.876;95%CI:1.275-2.761;P=0.001）.On the second day（6.0%vs.15.3%;P=0.044）and the third day（20.2%vs.34.7%,P=0.030）after admission,the negative rate of SFTSV in the corticosteroid group was lower than that of the control group,suggesting that corticosteroid may have the effect of inhibiting viral clearance and prolonging the duration of viremia.In addition,we found that WBC in the corticosteroid group was higher than that of the control group（?=2.175;95%CI:1.525-3.101;P<0.001）,which may due to the effect of hormone-stimulated bone marrow granulocyte proliferation.In addition,the differences of the frequency of neurological symptoms,bleeding symptoms,and other laboratory parameters between the two groups were not observed.Efficacy evaluation of doxycycline:In laboratory-confirmed SFTS patients,doxycycline-treated 145 cases were defined as the doxycycline group and the same number of patients selected using PSM were defined as the control group.In clinical diagnosis of SFTS patients,181 cases who received doxycycline were defined as the doxycycline group and the same number of patients selected using PSM were defined as the control group.After adjusted by age,sex,delay time from disease onset to admission,the mortality of patients who received doxycycline was comparable with the control group either in laboratory-confirmed SFTSV patients（HR=1.254;95%CI:0.587-2.679;P=0.559）or in clinical diagnosis of SFTSV patients（HR=2.001;95%CI:0.501-8.002;P=0.326）.Efficacy evaluation of treatment against underlying diseases of SFTSUnderlying diseases were risk factors for developing severe and fatal outcomes after SFTSV infection.By analyzing the underlying diseases of SFTS,we found that there were mainly 9 kinds of diseases in the SFTS patients.The top four were hyperlipidemia（256,12.2%）,hypertension（HT）（230,11.0%）,chronic viral hepatitis（CVH）（195,9.3%）and diabetes（DM）（142,6.8%）.Stepwise logistic analysis showed that the underlying diseases related to the fatal outcome of SFTS were DM（OR=2.518;95%CI:1.691-3.751;P<0.001）,CVH（OR=1.675;95%CI:1.149-2.442;P=0.007）and chronic obstructive pulmonary disease（COPD）（OR=2.562;95%CI:1.468-4.472;P=0.001）.Logistic analysis showed that the glucose level was related to the severity of the disease and the poor prognosis.Compared with the patients whose random glucose lower than 7.0 mmol/L,the patients whose glucose between 7.0-11.1 mmol/L and greater than 11.1 mmol/L had significantly higher possibility to develop fatal outcome with OR 1.630（95%CI:1.212-2.192;P=0.001）and 4.130（95%CI:2.952-5.779;P<0.001）.When DM-SFTS patients were grouped according to the times of using insulin,we found that the risk of death was significantly lower in DM-SFTS patients using insulin over four times compared with the control OR=0.187（95%CI:0.082-0.430;P<0.001）.CVH-SFTS patients had significantly higher frequency of neurological symptoms and hemorrhagic symptoms than those SFTS patients without CVH（33.3%vs.25.6%,P=0.006;45.1%vs.34.0%,P=0.002）.There were no significant differences of mortality between the HT-SFTS patients and SFTS patients after adjusted by sex,age and delay time from disease onset to admission.However,when taking the medicine for treating HT into consideration,we found that the medicine for treating HT（OR=0.191;95%CI:0.075-0.490;P=0.001）were associated with fatal outcome of SFTS.It has been confirmed that the use of calcium channel blockers can inhibit Ca²⁺influx and virus replication.So we further analyzed the effect of nifedipine,a calcium channel blocker.When nifedipine was used in patients with viral load≥10⁶ copies/ml at admission,the mortality was significantly lower than that of the SFTS group（2.4%vs.29.0%;P<0.001）.Kaplan-Meier survival analysis showed that the risk of death was 0.148（95%CI:0.046-0.477;P=0.001）times lower in the nifedipine group than the SFTS group.The viral load in patients treated with nifedipine was significantly lower than that of the SFTS group（β=-0.548;95%CI:-0.842 to-0.254;P<0.001）.The virus negative rate in the nifedipine treatment group was 29.5%,47.6%,56.5%,and 80.9%on the 2nd to 5th day after treatment,and the four nodes were higher than the SFTS group（14.5%,28.9%,35.6%and 64.2%;P<0.05）.Furthermore,the platelets counts in the nifedipine group were higher than the SFTS group（P=0.020）.All of the results suggested that nifedipine may have the effect of anti-SFTSV virus.Univariate logistic regression analysis found that the level of Ca²⁺concentration at admission was associated with fatal outcome（OR=4.331;95%CI:2.242-8.369;P<0.001）.What’s more,the concentration of Ca²⁺in the nifedipine group during hospitalization was significant higher than that of the SFTS group（P=0.001）,suggesting that the antiviral effect of nifedipine may be related to Ca²⁺concentration.ConclusionRibavirin had the effect of reducing the mortality when the patients’SFTSV viral load was under 10⁶ copies/ml.Treatment with ribavirin in combination with interferon may have the effects of improving the severity of the disease and lower the risk of developing fatal outcome in the patients whose viral loads under 10⁷ copies/ml.Infusion of platelets had no significant effect on reducing the probability of bleeding and accelerating recovery of platelets when the patients’plaletes counts under30×10⁹/L.Steroid therapy may prolong the viremia and should be used carefully.Doxycycline for SFTS patients with co-infection with spotted fever group rickettsiae had no significant effect on improving SFTS prognosis.CVH,DM,and HT could augment the severity of SFTSV infection.Controlling glucose of DM-SFTS patients by using insulin can significantly reduce the mortality.Nifedipine,a kind of calcium channel blocker that was commonly used to treat hypertension,had the effect of inhibiting virus replication and reducing SFTS mortality.The conclusions were all obtained through retrospective analysis.Although we used PSM to correct the problem of comparability,there were still some other potential biases we didn’t take into consideration.The conclusions need further randomized controlled trial（RCT）to confirm.Significance and innovationThis study is the first to analyze the efficacy of treatment regimen of SFTS.Some of the conclusions probably are inconsistent with the vitro experiments.Our conclusion can provide a reference for clinicians to treat SFTS so that they can improve the efficience in the treatment of SFTS and reduce the mortality of patients.