Clinical Epidemiological Characteristics Analysis,Prognostic Risk Factors Assessment And Risk Model Construction For Hemorrhagic Fever With Renal Syndrome

【Background and objectives】With rodents as the main infectious agent,hemorrhagic fever with renal syndrome(HFRS)is a natural focus disease caused by Hantavirus infection,and its main clinical features are fever,hemorrhage,hypotensive shock,and kidney injury.The key link in the pathogenesis of HFRS is the vascular endothelial injury and the microvascular permeability increase caused by the strong and rapid immune response of the body after Hantavirus infection of endothelial cells.The clinical manifestations and prognostic outcomes of patients may vary greatly depending on the immune status of the body.Mild patients may only present with "transient" viral infection symptoms such as fever,fatigue,and mild kidney damage,with mild clinical symptoms and good prognosis.Severe patients usually present with an abrupt onset and obvious symptoms of congestion and hemorrhage,as well as exudation and edema,and the critical even accompanied with hypotension shock,acute kidney injury,pulmonary edema,acute respiratory distress syndrome,disseminated intravascular coagulation and multiple organ dysfunction syndrome,which resulting in a poor prognosis.Therefore,disease severity assessment and prognosis prediction at an early stage are of great significance to guide the clinical diagnosis and treatment of HFRS.However,there are relatively few clinical epidemiological studies focusing on the impact of individual factors such as population susceptibility,lifestyle habits and previous medical history on the severity and prognostic outcome of HFRS,and there is still a lack of precise and effective severity assessment criteria,prognostic prediction models or risk stratification tools for clinical usings.Based on the above research background,the aim of this study is to analyze the clinical epidemiological characteristics of HFRS patients,to screen and evaluate the risk factors and early warning indicators which affect the condition and prognosis of patients,and to construct a prognostic(death)risk model and scoring standard for HFRS,so as to provide a theoretical basis for helping clinicians to assess the disease severity early and quickly and accurately predict the patient’s prognosis,thereby guiding clinical diagnosis and treatment decisions and improving the prognosis of patients.【Methods】1.The medical records of 1873 HFRS patients who met the inclusion criteria and were admitted to Tangdu Hospital of Air Force Medical University from September 1,2008 to December 31,2018 were reviewed,and then established a clinical diagnosis and treatment database for HFRS.The gender and age distribution,case fatality rate,contact history,vaccination,duration from illness onset to admission and hospitalization days of HFRS patients in different years,seasons and regions were compared to describe the prevalence trends and clinical epidemiological characteristics of HFRS.2.Based on the established clinical diagnosis and treatment database of HFRS,the differences in baseline characteristics,epidemiological data,personal lifestyle habits,previous medical history and laboratory parameters between patients with different clinical subtypes and different prognosis were comparatively analyzed.The risk factors affecting the severity and prognosis of HFRS were screened by logistic regression analysis,and the predictive value of laboratory parameters on the condition(severe)and prognosis(death)of HFRS was evaluated by receiver operating characteristic curve(ROC curve)analysis.3.Taking the clinical diagnosis and treatment database of HFRS as the training set,the HFRS prognosis(death)risk model based on risk factors,clinical manifestations and laboratory parameters was constructed by multivariate logistic regression analysis,and the nomogram of the model was drawn to establish the HFRS prognosis(death)risk scoring standard.From January 1,2019 to December 31,2021,a total of 372 HFRS patients who met the inclusion criteria and admitted by Tangdu Hospital of Air Force Medical University were prospectively included as the external validation set.In the training set and validation set,Hosmer-Lemeshow test and Bootstrap resampling method were used to evaluate the goodness of fit and calibration of the model and scoring standard,and the ROC curves,net reclassification index(NRI),integrated discrimination improvement(IDI)and decision curve analysis(DCA)were used to comprehensively evaluate and prospectively validate the prognostic predictive efficacy and clinical utility value of the risk model and scoring standard.【Results】1.A total of 1873 HFRS patients with an average age of 42 years were enrolled in this study,male patients accounted for 80.09%,and the overall case fatality rate was6.35%.The case fatality rate increased with the age of patients and was significantly higher in patients over 60 years old(10.42%)than that of other age groups(6.73% for30~60 years old,and 3.15% for those under 30 years old).The prevalence of HFRS has obvious seasonal characteristics,while after 2013,the proportion of large peak cases(55.67%)decreased compared with that before 2012(74.91%),and the proportion of small peaks and sporadic cases(44.33%)increased significantly compared with that before 2012(25.09%).In recent years,the numbers of HFRS cases and the fatality rate have shown a fluctuating downward trend.After 2013,the number of HFRS patients(785 cases)was significantly lower than that before 2012(1088 cases),and the case fatality rate(5.22%)also decreased significantly than that before(7.17%).The included HFRS patients were mainly from Xi’an(1308 cases,72.31%),and the fatality rate of non-Xi’an patients(8.50%)was significantly higher than that of Xi’an patients(5.43%).2.The age,the proportion of non-Xi’an patients,the smoking rate,the proportion of concomitant hypertension,and the incidence of hypotensive shock and hypoxemia in critical patients and the dead were significantly higher than those of other clinical types and survival patients.The results of univariate logistic regression analysis showed that the above parameters were significantly correlated with both the condition(severe)and prognosis(death)of HFRS,and the results of multivariate logistic regression analysis indicated that hypertension(OR=3.12),hypotensive shock(OR=8.94),and hypoxemia(OR=69.66)were the independent risk factors affecting the prognosis(death)of HFRS patients.3.The results of intergroup comparison analysis showed that the initial levels on admission of WBC,lymphocytes,monocytes,neutrophils,AST,ALT,BUN,PT,APTT,FDP,D-D,PCT,CK,LDH and MYO were gradually increased with the exacerbation of HFRS,and were significantly higher in the dead than in those who survived;while PLT,ALB,Ca2+ and Fib gradually decreased with the aggravation of the disease,which showed significant lower in the dead than in those who survived.The results of ROC curve analysis showed that the area under the ROC curve(AUC)of WBC,neutrophils,PLT,AST,Ca2+,APTT,LDH and MYO for predicting the condition(severe)and prognosis(death)of HFRS were all above 0.7.4.The HFRS prognosis(death)risk model based upon hypertension,hypotensive shock,hypoxemia,neutrophils,AST and APTT was constructed by multivariate logistic regression analysis,and the nomogram of the model was uesd to establish a prognosis(death)risk scoring standard for HFRS.The results of Hosmer-Lemeshow test and calibration curve showed that both the risk model and the scoring standard had a good goodness of fitting and calibration.The results of ROC curve analysis showed that the AUCs of both the risk model and the scoring standard for predicting the prognosis(death)of HFRS were all higher than 0.9,and the sensitivity and specificity of both were higher than 90% in the training set and also above 84% in the validation set.Compared with the risk model,the NRI and IDI of the scoring standard were 0.0217 and 0.0073 in the training set and 0.1260 and 0.0221 in the validation set,respectively.The DCA results showed that the clinical net benefit of using the risk model and the scoring standard to predict the prognosis(death)of HFRS was 0.067 and 0.066 in the training set and 0.028 and 0.030 in the validation set,respectively.【Conclusions】1.In recent years,HFRS has shown new epidemiological characteristics(the proportion of large peak cases has decreased,and the proportion of small peak and sporadic cases has increased).After 2013,the numbers of HFRS patients and fatality rates have decreased significantly compared with the previous years,and remarkable results have been achieved in HFRS epidemic prevention and control,as well as clinical diagnosis and treatment.2.Hypertension,hypotensive shock,and hypoxemia were the independent risk factors affecting the prognosis(death)of HFRS patients.WBC,neutrophils,PLT,AST,Ca2+,APTT,LDH and MYO have high clinical predictive values,which can be used as early warning indicators to evaluate the severity of HFRS and predict the prognosis of patients,and we need to focus on the changes of the above indicators at the early stage of clinical course in HFRS.3.Constructed based on hypertension,hypotensive shock,hypoxemia,neutrophils,AST and APTT,both the HFRS prognostic(death)risk model and the scoring standard have high predictive value and clinical utility.The scoring standard is more simple and convenient to use,which could help clinicians to stratify the mortality risk of HFRS patients early and quickly and accurately predict the prognosis of patients,thereby guiding clinical diagnosis and treatment decisions,and it is worthy of popularization and application.