Evaluation Of Early Prediction Factors And Construction Of Risk Models For The Severity And Prognosis In Patients With Hemorrhagic Fever With Renal Syndrome

Hemorrhagic fever with renal syndrome (HFRS) is a rodent-borne disease caused byHantavirus with major manifestation of fever, hemorrhage and kidney injury. In the lastthree years, there has been a higher and increasing incidence of HFRS in China, especiallyin Guanzhong region, the Shaanxi province, with the higher incidence of critical-typeHFRS infected by hantaan virus (HTNV) and higher mortality rate.Hantaan virus is a major serotype of Hantavirus which is also the major serotype ofHFRS in Shaanxi province. Until now, it has been reported there are only cases infectedby HTNV in Xi’an district. It has been accepted that HFRS has general pathophysiologiccharacteristics of systemic inflammatory response syndrome (SIRS) with typicalpathological manifestation of vascular leak syndrome resulting in body edema, shock,hemorrhage and acute tubulointerstitial nephritis. Generally, typical cases of HFRS progress through five successive phases: febrile, hypotensive, oliguric, diuretic andconvalescent. In some grave cases, the febrile, hypotensive and oliguric phases canoverlap, resulting in refractory shock, acute kidney injury (AKI) or acute renal failure,respiratory failure, severe blood clotting dysfunction and multiple organ dysfunctionsyndrome (MODS).Although ribavirin and interferon-α has been proved to be effective on theanti-hantanvirus, they are seldom used in the clinical practice because the optimal timingof using the drugs on patients are often missed. The patients with HFRS are usuallydiagnosed and treated in hospital during the interval between the forth and the sixth dayfrom the onset of the disease when the duration are usually late and are difficult to observethe therapeutic effect of the antiviral drugs. The early discovery, early diagnosis, earlymonitoring and early supportive management are still the major treatment principle untilnow. Although the standard of HFRS clinical classification has been created since the endstage of the twentieth century, and the standard plays an important role on the treatmentand prevention of HFRS, its prediction ability and evaluation the severity of HFRS andprognosis is still poor and can not guide clinician to inatiate effective treatment andintervention to patients because lots of the parameters from the standand of the clinicalclassification are based on the evaluation of the physician’s subjective judgement andphysical examination and some of them are still not quantized. Accompanied with thedevelopment of the medical ecsomatics, imageology and intensive care technology, therehave been a large number of laboratory parameters which can be considered as thereference by clinician, while, just as other severe illness, there are still less studies on theselection, integration and analysis of the detective data or parameters of the grave HFRSpatients which could guide clinical practice more effectively. So, exploring early and newbiomarkers and combining clinical and laboratory parameters to detect the severity andoutcome in advance are still very important and necessary to guide clinicians takeeffective treatment and improve the remedy achievement ratio in the near future.Based upon the direction of the study mentioned above, in this subject, we evaluated thevalue of early warning of severity and prognosis on routinely clinical and laboratory parameters in clinical practice, analyzed the clinical characteristics and outcome ofcritical-type patient with HFRS, tried to construct risk models for prognosis based uponthe clinical and laboratory parameters and identified the value of high mobility group boxprotein-1(HMGB-1), adiponectin (APN), ferritin (FRT) and pentraxin3(PTX-3) onevaluation of the severity and prognosis in patients with HFRS.1. Early indicators of severity and construction of a risk model for prognosis basedupon laboratory parameters in patients with HFRSIn this part, we constructed the platform of HFRS database and chose356typicalHFRS patients treated between January2008and August2012from the databaserandomly. We further reviewed the general medical records of the patients who weredivided into four groups including mild-type, moderate-type, severe-type and critical-typeaccording to the standard of HFRS clinical classification. Twelve routinely testedlaboratory parameters were analyzed including WBC, HGB, PLT, ALT, AST, ALB, BUN,SCr, UA, PT, APTT and Fib. The dynamic changes of the levels of the mentionedparameters during the acute stage in patients were analyzed retrospectively, and theirvalues of early warning of severity were evaluated. The correlation index, predictive valueand influential value for prognosis were analyzed between the parameters and outcome,and a risk model for prognosis based upon the parameters was constructed. This studyrevealed that WBC, PLT, AST, ALB, BUN, SCr, PT and APTT demonstrated obviouslydynamic changes during the acute stage in the patients; WBC, AST, PT and Fib can beconsidered as independent influential factors for prognosis; combining detection of WBC,AST, PT and Fib was superior on predicting prognosis compared with the singleparameter.2. Clinical characteristics and construction of a risk model for prognosis based uponclinical parameters in critical-type patients with HFRSSeventy-five critical-type cases of the356HFRS patients from the part one of thesubject were enrolled in this study. According to the outcome, the patients were dividedinto a survivor group and non-survivor group. The general clinical characteristics, demographic and epidemiologic features, symptoms, signs, imaging, humor examination,invasive treatment measures and complications were compared between the two groups.The accumulative survival rate and28-day fatality rate were analyzed; the correlationindex, predictive value and influential value for prognosis were analyzed between theclinical parameters and outcome, and a risk model for prognosis based upon theparameters was constructed. This study revealed that the accumulative survival rate on thesecond week during the clinical course was70.7%, and with28-day fatality rate of36.3%.Agitation, conjunctival hemorrhage, coma, heart failure, ARDS, encephalopathy and acuterenal failure (ARF) were correlated with the outcome. ARDS, conjunctival hemorrhageand coma can be considered as independent risk factors for prognosis.3．Evaluation of the predictive value of HMGB-1、APN、FRT and PTX-3on severityand prognosis in patients with HFRSOne hundred and five patients with HFRS treated in our hospital between October2011and December2012were enrolled randomly. Ninety-three venous blood samplesduring the acute stage,78samples during the convalescent stage and28samples of thehealth volunteers were collected respectively. The plasma of the samples was separated,and HMGB-1、APN、FRT and PTX-3concentrations were detected by enzyme linkedimmunosorbent assay (ELISA). In this study, the levels of the HMGB-1、APN、FRT andPTX-3were observed prospectively on the patients during the acute and convalescentstage, and also the differences between the patients and health controls on the fourbiomarkers were compared in order to evaluate the value of the early warning of theclinical severity. The correlation index, predictive value and influential value for prognosiswere analyzed between the four biomarkers and outcome. This study revealed that therewere obviously changes on HMGB-1, APN, FRT and PTX-3during the acute andconvalescent stage among the different clinical type patients. HMGB-1, APN, FRT andPTX-3were also close correlated with the WBC, PLT and ALB. Except for APN, the areaunder the ROC curve (AUC) for predicting prognosis on HMGB-1, FRT and PTX-3wereall above0.800, and the predictive value of FRT and PTX-3was superior to WBC, PLTand ALB. Conclusions:Routine detection of WBC, PLT, AST, ALB, BUN, SCr, PT and APTT would bebeneficial to the early warning of clinical severity of HFRS. WBC, AST, PT and Fib canbe considered as independent influential factors for prognosis. Combining detection ofWBC, AST, PT and Fib are superior to single laboratory parameter. ARDS, conjunctivalhemorrhage and coma can be considered as independent influential factors for prognosis,which could alert clinician to pay attention to the fatal clinical complications and initiatesystematical and supportive therapy actively and effectively. HMGB-1, APN, FRT andPTX-3can be considered as new biomarkers on detection of clinical severity of HFRS.Except for APN, detection of HMGB-1, FRT and PTX-3would be beneficial to predictprognosis. In summary, the study revealed that combining detection of clinical andlaboratory parameters routinely tested, exploring and putting the application of theHMGB-1, APN, FRT and PTX3into clinical practice would be beneficial to the evaluationand prediction of the severity and prognosis which could provide more theoretical andexperimental evidence on the supplement of the HFRS clinical classification standard andconstruction of a new criterion of clinical scale of HFRS in the near future.