肾综合征出血热发病机制的研究进展

肾综合征出血热(hemorrhagic fever with renal syndrome, HFRS)是由汉坦病毒感染引起的以发热、休克、出血和肾脏损害为主要特征的急性自然疫源性疾病。汉坦病毒主要感染人血管内皮细胞,引起小血管和毛细血管广泛损伤。血管通透性增加是HFRS临床表现的病理基础。国内外学者尽管在汉坦病毒致病机制方面开展了诸多研究,如病毒诱导的免疫病理反应、宿主遗传与细胞凋亡、血小板减少与功能障碍、血管内皮损伤等,但HFRS发病机制仍未完全阐明,也无特效治疗药物,深入探讨汉坦病毒致病的分子机制,寻找有效治疗药物仍是汉坦病毒/HFRS领域的研究热点。本文结合近年来国内外相关研究,阐述HFRS发病机制的研究进展。     

Severity Biomarkers in Puumala Hantavirus Infection

Annually, over 10,000 cases of hemorrhagic fever with renal syndrome (HFRS) are diagnosed in Europe. Puumala hantavirus (PUUV) causes most of the European HFRS cases. PUUV causes usually a relatively mild disease, which is rarely fatal. However, the severity of the infection varies greatly, and factors affecting the severity are mostly unrevealed. Host genes are known to have an effect. The typical clinical features in PUUV infection include acute kidney injury, thrombocytopenia, and increased vascular permeability. The primary target of hantavirus is the endothelium of the vessels of different organs. Although PUUV does not cause direct cytopathology of the endothelial cells, remarkable changes in both the barrier function of the endothelium and the function of the infected endothelial cells occur. Host immune or inflammatory mechanisms are probably important in the development of the capillary leakage. Several immunoinflammatory biomarkers have been studied in the context of assessing the severity of HFRS caused by PUUV. Most of them are not used in clinical practice, but the increasing knowledge about the biomarkers has elucidated the pathogenesis of PUUV infection.     

Central Nervous System and Ocular Manifestations in Puumala Hantavirus Infection

Puumala hantavirus (PUUV), carried and spread by the bank vole (Myodes glareolus), causes a mild form of hemorrhagic fever with renal syndrome (HFRS) called nephropathia epidemica (NE). Acute high fever, acute kidney injury (AKI), thrombocytopenia, and hematuria are typical features of this syndrome. In addition, headache, blurred vision, insomnia, vertigo, and nausea are commonly associated with the disease. This review explores the mechanisms and presentations of ocular and central nervous system involvement in acute NE.     

肾综合征出血热抗病毒治疗及疫苗研发进展

肾综合征出血热(hemorrhagic fever with renal syndrome, HFRS)是由汉坦病毒感染引起的一种自然疫源性疾病,在世界范围内广泛流行,我国一直是流行高发区,患者占所有HFRS患者一半以上,其主要临床特征为发热、出血、低血压休克和肾脏损害,严重危害人类健康。尽管抗病毒治疗和疫苗免疫接种可以防治汉坦病毒感染,但目前尚无特效抗病毒药物。近年来,随着医学科技进步,汉坦病毒的抗病毒治疗和疫苗研发有了新的进展。本文基于近年体内外研究及临床试验结果,对HFRS抗病毒治疗和疫苗研发进展作一综述。     

Hemorrhagic fever with renal syndrome: four decades of research

Hemorrhagic fever with renal syndrome is an acute infectious illness characterized by fever, hemorrhage, and renal failure. Research over the last 40 years has led to the discovery and characterization of the causative viruses, detailed knowledge of the epidemiology of the disease, development of sensitive diagnostic assays, and improvements in patient management, which in turn have led to significant reductions in mortality. Considerable progress has also been made in elucidating the pathophysiology of the disease, although much more needs to be learned. Recent data show that hemorrhagic fever with renal syndrome has a wider geographic occurrence than previously thought. This syndrome must be considered in the differential diagnosis of acute renal failure of unknown cause.     

Increased Heparanase Levels in Urine during Acute Puumala Orthohantavirus Infection Are Associated with Disease Severity

Old–world orthohantaviruses cause hemorrhagic fever with renal syndrome (HFRS), characterized by acute kidney injury (AKI) with transient proteinuria. It seems plausible that proteinuria during acute HFRS is mediated by the disruption of the glomerular filtration barrier (GFB) due to vascular leakage, a hallmark of orthohantavirus–caused diseases. However, direct infection of endothelial cells by orthohantaviruses does not result in increased endothelial permeability, and alternative explanations for vascular leakage and diminished GFB function are necessary. Vascular integrity is partly dependent on an intact endothelial glycocalyx, which is susceptible to cleavage by heparanase (HPSE). To understand the role of glycocalyx degradation in HFRS–associated proteinuria, we investigated the levels of HPSE in urine and plasma during acute, convalescent and recovery stages of HFRS caused by Puumala orthohantavirus. HPSE levels in urine during acute HFRS were significantly increased and strongly associated with the severity of AKI and other markers of disease severity. Furthermore, increased expression of HPSE was detected in vitro in orthohantavirus–infected podocytes, which line the outer surfaces of glomerular capillaries. Taken together, these findings suggest the local activation of HPSE in the kidneys of orthohantavirus–infected patients with the potential to disrupt the endothelial glycocalyx, leading to increased protein leakage through the GFB, resulting in high amounts of proteinuria.     

Leptospirosis misdiagnosed as pulmonary-renal syndrome

A case of leptospirosis complicated by diffuse alveolar hemorrhage, acute renal failure, and apparent hemoglobinuria was initially diagnosed and managed as a pulmonary-renal syndrome. However, renal biopsy findings were normal. Leptospirosis may manifest with severe lung injury characterized by diffuse alveolar hemorrhage, acute respiratory distress syndrome, and acute renal failure and be accompanied by high mortality rates. Leptospirosis should be considered in patients with features of pulmonary-renal syndrome, particularly in regions known to be endemic for leptospirosis. A history of potential exposure to Leptospira is an important diagnostic clue, and empiric antimicrobial therapy should be considered.     

肾综合征出血热流行过程及其影响因素研究进展

肾综合征出血热（hemorrhagic fever with renal syndrome, HFRS）是由汉坦病毒（hantavirus）感染引起的一种乙类传染病,可引发急性肾损伤,病死率较高。汉坦病毒型别与选择性宿主转换和地区适应密切相关,并由此不断以基因重组等方式进化,不同型别汉坦病毒所致疾病严重程度不同。全球环境变化及宿主动物习性改变加速了汉坦病毒基因组变异;同时,我国大规模土地改造、基础设施建设也使人群与病毒宿主和疾病传播媒介的接触机会增加,一定程度上增大了人群患病风险。本文综述了肾综合征出血热流行过程的主要特征及其相关影响因素,为有效防控该疾病的发生和流行提供参考依据。     

汉坦病毒激发人胃上皮细胞病变和凋亡

目的证实人胃粘膜上皮细胞是否为汉坦病毒属(HV)汉滩病毒型(HTN)和汉城病毒型(SEO)病毒的靶细胞,病毒对其是否有致细胞病变效应(CPE)和促凋亡作用。方法建立人胃上皮细胞(HGEC)离体培养;用HVN8、76118、Z37、Seoul8039株感染HGEC,观察细胞CPE,用直接免疫荧光法(IFA)检测病毒感染细胞和感染灶;用AnnexinV FITCkit观察HV的致HGEC凋亡和坏死作用。结果HTNV和SEOV可以感染离体培养的HGEC,形成感染灶并出现CPE;与模拟感染细胞相比,N8、76118、Z37、Seoul8039株感染的HGEC凋亡和坏死细胞比例明显增高,HTNV较SEOV促凋亡和坏死作用更强。结论HGEC可作为HTNV和SEOV感染的靶细胞,致CPE并促进细胞凋亡和坏死,在急性肾综合征出血热病人胃粘膜损害机制中起重要作用。     

Severe pulmonary involvement in a case attributed to domestically acquired Seoul hantavirus in the United States

Hantavirus is known to cause 2 distinct clinical syndromes: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome. Seoul virus is an Old World hantavirus known to cause HFRS. We report a case attributed to domestically acquired Seoul hantavirus with prominent pulmonary involvement and a fatal outcome.     

Cardio-renal syndrome: an entity cardiologists and nephrologists should be dealing with collegially

Heart failure may lead to acute kidney injury and viceversa. Chronic kidney disease may affect the clinical outcome in terms of cardiovascular morbidity and mortality while chronic heart failure may cause CKD. All these disorders contribute to the composite definition of cardio-renal syndromes. Renal impairment in HF patients has been increasingly recognized as an independent risk factor for morbidity and mortality; however, the most important clinical trials in HF tend to exclude patients with significant renal dysfunction. The mechanisms whereby renal insufficiency worsens the outcome in HF are not known, and several pathways could contribute to the “vicious heart/kidney circle.” Traditionally, renal impairment has been attributed to the renal hypoperfusion due to reduced cardiac output and decreased systemic pressure. The hypovolemia leads to sympathetic activity, increased renin-angiotensin-aldosterone pathways and arginine-vasopressin release. All these mechanisms cause fluid and sodium retention, peripheral vasoconstriction and an increased congestion as well as cardiac workload. Therapy addressed to improve renal dysfunction, reduce neurohormonal activation and ameliorate renal blood flow could lead to a reduction in mortality and hospitalization in patients with cardio-renal syndrome.     

肾综合征出血热并发急性造血功能停滞的临床观察

目的 观察肾综合征出血热(HFRS)并发急性造血功能停滞(AAH)的临床特点,疗效和预后.方法 对18例HFRS并发AAH患者的临床特点进行回顾性分析.结果 18例HFRS患者,男10例.女8例,年龄14～55岁,发病第9～25天出现不规则发热、突发性贫血和多部位出血,外周血WBC降至(2.3～3.2)×109/L,PLT降至(23～31)×109/L,RBC降至(2.23～2.79)×1012/L,Hb降至52～67 g/L,网织红细胞0～0.002.骨髓穿刺(56次)示红细胞系增生降低,粒、红细胞比例明显升高,粒细胞系和巨核细胞系增生降低.采用糖皮质激素和输血为主的综合性治疗措施,26～60 d治愈.结论汉坦病毒感染可并发AAH,其预后良好.     

Experience with extrarenal manifestations of hemorrhagic fever with renal syndrome in a tertiary care hospital in South Korea

Reports on the clinical entity of hemorrhagic fever with renal syndrome (HFRS) have focused on acute renal failure. Data on the extrarenal manifestations are limited primarily to case reports. In this study, protean extrarenal manifestations involving the major organs occurred in one-third of patients with HFRS during various stages (i.e., febrile phase through diuretic phase). Pancreatobiliary manifestations and major bleeding occurred in 11% and 10% of patients, respectively. Cardiovascular and central nervous system manifestations developed during the febrile or oliguric phase, whereas pancreatobiliary manifestations and major bleeding were detected even in the diuretic phase. Thus, close monitoring of and additional knowledge about various extrarenal manifestations are needed.     

哈尔滨地区肾综合征出血热患者临床特征及感染的汉坦病毒血清型分析

目的研究哈尔滨地区肾综合征出血热患者的流行病学、临床特征及感染的汉坦病毒的血清型。方法对哈尔滨地区87例肾综合征出血热患者的流行病学资料、临床表现、实验室检查、转归等进行回顾性分析,并对发病5 d内患者感染的汉坦病毒血清型进行分析。结果87例患者中74.7%为农民.14.9%为林业工人.6.9%为学生、干部职员,3.4%为居民;农村56例,林区13例,郊区9例,城市9例。临床表现发热87例(100%),头痛44例(50.6%),腰痛35例(40.2%),眼眶痛17例(19.5%),恶心呕吐79例(90.8%),皮下出血点、淤斑29例(33.3%),少尿52例(59.8%),黑便35例(40.2%),腹痛26例(29.9%),腹胀61例(70.1%),抽搐2例(2.3%),呼吸困难4例(4.6%),三红征40例(46.0%),肾区叩痛52例(59.7%),球结膜水肿47例(54.0%)。实验室检查肝功能异常70例(80.5%);心肌酶学升高80例(92.0%);血糖异常53例(60.7%)。患者感染的汉坦病毒血清型,汉滩病毒占34.8%,汉城病毒占65.2%。结论哈尔滨地区肾综合征出血热的流行病学和临床特征的改变可能与汉坦病毒血清型的变化有关。     

重症肾综合征出血热患者心脏损害的多普勒超声心动图的研究

目的研究重症肾综合征出血热（ＨＦＲＳ）患者的心脏损害。方法应用多普勒超声（ＵＣＧ）随访观测５０例急性期、恢复期ＨＦＲＳ患者及３０例正常对照组的心脏解剖结构及心脏功能。结果急性期患者室壁及心包较正常对照组轻度增厚、动度减弱，不同程度的回声改变。１８例有心包积液，３８例瓣膜返流，心脏舒缩功能减退。结论重症ＨＦＲＳ患者心脏损害是心肌、心内膜及心包广泛受累的全心炎症，与预后密切相关。     

Hemorrhagic fever with renal syndrome in the Dolenjska region of Slovenia--a 10-year survey.

This report describes the first investigation of clinical findings for a larger series of patients with hemorrhagic fever with renal syndrome (HFRS) who were infected with Dobrava virus. From 1985 to 1995, 38 patients with serologically confirmed HFRS were hospitalized at the regional hospital in Novo mesto in the Dolenjska region of Slovenia. On the basis of results of serological examination, 24 patients had Dobrava virus infection, and 14 patients had Puumala virus infection. Complete clinical data were available for 31 patients. Eleven patients underwent hemodialysis for treatment of acute oliguric or anuric renal failure. Four patients, all infected by Dobrava virus, had signs of shock and severe bleeding. Three severely ill Dobrava virus-infected patients died of hemorrhagic complications. We have demonstrated that Dobrava and Puumala viruses coexist in a single region of endemicity and are capable of causing HFRS with significant differences in severity.     

肝功指标判断汉坦病毒所致肝损害的临床价值

目的探讨常用肝功能指标判断汉坦病毒所致肝损害的临床价值。方法回顾性分析367例肾综合征出血热(HFRS)患者肝功能指标、病情及治疗结局的关系。结果HFRS患者ALT、AST、TBIL及白蛋白异常分别占73.84%(271/367)、79.84%(293/367)、13.35%(49/367)和44.41%(163/367)。HFRS不同临床型间ALT、AST和TBIL差异有统计学意义(P<0.001),而白蛋白各型间差异无统计学意义(P>0.05)。结论汉坦病毒易于引起肝脏损害,肝损害程度与病情、预后有关;ALT、AST及TBIL是反映肝脏损害程度的重要指标;而白蛋白不能作为汉坦病毒肝损害程度的判断指标。     

The protean manifestations of hemorrhagic fever with renal syndrome. A retrospective review of 26 cases from Korea

Twenty-six cases of hemorrhagic fever with renal syndrome from 1981 to 1986 were retrospectively reviewed to determine the scope of clinical presentation and the unique complications of the illness. The diagnosis was confirmed by detection of Hantaan virus antibody in 25 cases and by characteristic autopsy findings in 1 case. The illness could be classified into three distinct clinical subgroups. Fever was universally present. Two patients presented with intractable shock and diffuse hemorrhage and died within 6 days from multi-organ system failure, mimicking the clinical picture of overwhelming sepsis. Eighteen patients presented with acute renal failure with an illness lasting a mean of 21 days (range, 10 to 36 days). Resolution of thrombocytopenia heralded recovery of renal function. At discharge, the serum creatinine level was normal in 13 patients; 5 patients had evidence of minimal renal dysfunction. Acute pulmonary edema requiring hemodialysis and retroperitoneal hemorrhage were the major complications in this subgroup. Six patients had an undifferentiated febrile illness with normal renal function. Fever, thrombocytopenia, abnormal urinalysis, hypertransaminasemia, and a benign clinical course characterized the third clinical pattern. The recent availability of serodiagnostic methods to detect Hantavirus group antibody facilitates the diagnosis of hemorrhagic fever with renal syndrome. Application of this test in the described clinical settings will identify unsuspected cases, broaden the knowledge of the geographic distribution of Hantavirus infection, and increase physician awareness of its protean manifestations.     

High risk of hypopituitarism in patients who recovered from hemorrhagic fever with renal syndrome

CONTEXT: Hemorrhagic fever with renal syndrome (HFRS) caused by hantaviruses, is a severe systemic infection, with acute shock, vascular leakage, hypotension, and acute renal failure. Pituitary ischemia/infarction and necrosis are known causes of hypopituitarism, often remaining unrecognized due to subtle clinical manifestations. Cases of hypopituitarism after HFRS were previously only sporadically reported. OBJECTIVE: The aim of this study was to determine, for the first time, the prevalence of hypopituitarism among HFRS survivors. SUBJECTS AND METHODS: In 60 adults (aged 35.8+/-1.3 yr) who recovered from HFRS 3.7 +/- 0.5 yr ago (median 2 yr), assessment of serum T(4), free T(4), TSH, IGF-I, prolactin, cortisol, and testosterone (in males) was followed by insulin tolerance test and/or GHRH+GH-releasing peptide-6 stimulation tests. RESULTS: Severe GH deficiency was confirmed in eight of 60 patients (13.3%): in five with multiple pituitary hormone deficiencies (MPHDs) and isolated in three. Thyroid axis deficiency was confirmed in five of 60 patients (8.3%), all with MPHD. Hypothalamus-pituitary-adrenal axis deficiency was observed in six of 60 (10.0%); in five with MPHD and isolated in one. Gonadal axis deficiency was confirmed in seven of 56 male subjects (12.5%): five with MPHD and isolated in two. Overall six patients (10.0%) had a single pituitary deficit (three GH, two gonadal, and one adrenal), and five (8.3%) had MPHD. The prevalence of patients having any endocrine deficiency was 18% (11 of 60). CONCLUSION: A high prevalence of hypopituitarism after recovery from HFRS is identified, with magnetic resonance imaging revealing atrophic pituitary and empty sella. Awareness is raised to neuroendocrine consequences of HFRS because unrecognized hypopituitarism significantly affects the physical and psychological well-being.     

Prompt plasmapheresis successfully rescue pulmonary-renal syndrome caused by ANCA-negative microscopic polyangiitis

Pulmonary-renal syndrome (PRS) associated with antineutrophil cytoplasmic antibodies (ANCA)-negative microscopic polyangiitis (MPA) is relatively rare, and the effects of plasmapheresis on these patients remain unclear. Here, we report the case of a 66-year-old man who presented with fever, acute renal failure, thrombocytopenia, and sudden onset of diffuse pulmonary hemorrhage. Prompt plasmapheresis and concurrent pulse therapy with methylprednisolone effectively rescued his pulmonary-renal syndrome. The patient was then diagnosed with MPA on the basis of typical histological findings and the absence of surrogate markers of Wegener's granulomatosis and Churg–Strauss syndrome. This case demonstrates the therapeutic effects of plasmapheresis on ANCA-negative MPA and highlights the necessity of prompt plasmapheresis for not only resolving pulmonary hemorrhage but also increasing the likelihood of renal function restoration in patients with PRS.