【作者】 高海女；

【导师】 李兰娟；

【作者基本信息】 浙江大学 ， 内科学（专业学位）， 2013， 博士

【摘要】 2013年春季,一种新的禽源性甲型流感(H7N9)病毒在中国出现。基因分析显示病人中分离出来的H7N9禽流感病毒显示出对哺乳动物的部分适应性,增加了与人类呼吸道上皮细胞唾液酸a-2,6型受体的亲和力,对小鼠的毒力增加,对金刚烷胺耐药,而对奥司他韦敏感。我们尚没有这种病毒所致感染的临床特点的资料。以及与其他流感病毒比如H5N1、pHlNl在发病危险因素、临床表现以及住院后疾病进展方面的比较。方法：我们设计病例报告表格,收集了截至2013年10月25日,中国大陆报道的137例经实验室检查确诊的禽源性甲型流感病毒(H7N9)感染病人的数据,以及119例H5N1和3486例pH1N1病人的临床数据。评估校正了年龄和性别特异性的危险因素流行率以后的因流感住院的危险因素,比较了不同亚型之间的临床、实验室以及临床预后的差别。对其中的40例H7N9病人进行了细胞因子和病毒载量的检测,与疾病的严重性进行了相关性分析；并分析了李氏人工肝治疗疾病快速进展,并检测到细胞因子风暴的重症H7N9禽流感病毒病人的疗效。结果：在我们所研究的137例患者中,77.4%入住了重症监护病房(ICU)33.6%死亡。患者年龄的中位数为61岁,42.3%的患者年龄≥65岁,其中31.4%为女性。共有61.9%的患者至少存在一种基础疾病。发热和咳嗽是最为常见的起病症状。入院时,133例患者(98.5%)有肺炎的表现。双肺毛玻璃样阴影和实变是典型的x线表现。88.3%的患者中观察到了淋巴细胞减少,73%的患者中观察到了血小板减少。133例患者(97.1%)在发病后7天(中位时间)时开始了抗病毒药物治疗。发病及开始抗病毒治疗至实时逆转录聚合酶链反应检测病毒结果为阴性的中位时间间隔分别为11天(四分位间距为9～16天)和6天(四分位间距为4～7天)。多变量分析结果显示,存在基础疾病是H7N9病人发生急性呼吸窘迫综合征(ARDS)唯一的独立危险因素(比值比为3.44,95%可信区间为1.25-9.78,P=0.02)。对其中40名H7N9病人进行了细胞因子动态检测,发现与健康对照组比较,H7N9病人细胞因子水平高,通过Spearsman等级相关性分析发现,患者外周血病毒载量与IP-10(p=-0.692)、HGF(p=-0.509)、MIG(p=-0.500)的水平密切相关,患者APACHEII评分与IP-10(p=0.690), IL-18(p=0.658), HGF(p=0.642)水平密切相关。研究结果表明患者感染H7N9病毒细胞因子趋化因子水平显著升高,起病第二周最为显著,且与患者的疾病严重程度密切相关。对16名疾病快速进展,检测到细胞因子风暴的病人进行了李氏人工肝治疗,发现李氏人工肝可以快速下降血浆中细胞因子水平,对于IP-10水平的下降尤为显著。将其中的111例病人与其他流感病毒的比较发现,H7N9组年龄的中位时间要大于其他组(61岁,P<0.01),男性居多(68.6%,P<0.02),校正年龄和性别以后,慢性心脏疾病与H7N9的住院风险增加有关(RR9.68;95%CI5.24-17.90). H7N9病人与H5N1比较,更易于出现咳痰和咳血,H7N9与H5N1相似,均有白细胞减少、血小板减少、转氨酶、CK、CRP、LDH的升高,与pH1N1相比有显著性差异P<0.005,与H5N1、pH1N1比较,H7N9组有更长的住院时间。H5N1死亡风险最高,(55%,95%CI47-64%),发生更早,疾病出现到死亡的中位时间为11天,H7N9为18天(P=0.002), pHlN1与15天(P=0.154)。结论：在研究期间,这种新的H7N9病毒引起了严重的疾病(包括肺炎和ARDS),患者的ICU入住率和死亡率均高。研究发现HGF, SCF,IL-18,IP-10,MIF以及SCGF-beta可以做为H7N9禽流感病毒感染严重性的生物标志物,起病第二周是检测这些生物标志物的最佳时间,针对这些生物标志物的治疗可能成为潜在的治疗靶点。李氏人工肝可以降低细胞因子,从而可能针对发病机制治疗重症H7N9病人。慢性心脏疾病是H7N9住院的危险因素。H7N9住院病人的临床特点与H5N1住院病人相似,但是与H5N1或pH1N1比较,H7N9的临床过程更长。更多还原

【Abstract】 Background:During the spring of2013, a novel avian-origin influenza A (H7N9) virus emergedand spread among humans in China. Data were lacking on the clinical characteristicsof the infections caused by this virus and the assessment of similarities between illness due to infection with H7N9virus and that caused by other avian or human influenza A viruses, we compared risk factors, clinical presentation, and progression of hospitalized patients with H7N9, H5N1and H1N1/2009(pH1N1) virus infections.Methods:We collected and analyzed individual-level data from patients hospitalized with infection by H7N9virus (n=137), H5N1virus (n=119), and pHlN1virus (n=3486). We assessed risk factors for hospitalization after adjustment for age and gender specific prevalence of risk factors in the general population. Clinical, laboratory and outcome measures were compared between subtypes.Results:Of the137patients we studied,77.4%were admitted to an intensive care unit (ICU), and33.6%died. The median age was61years, and42.3%were65years of age or older;31.4%were female. A total of61.9%of the patients had at least one underlying medical condition. Fever and cough were the most common presenting symptoms. On admission,133patients (98.5%) had findings consistent with pneumonia. Bilateral ground-glass opacities and consolidation were the typical radiologic findings. Lymphocytopenia was observed in88.3%of patients, and thrombocytopenia in73.0%. Treatment with antiviral drugs was initiated in133patients (97.1%) at a median of7days after the onset of illness. The median times from the onset of illness and from the initiation of antiviral therapy to a negative viral test result on real-time reverse-transcriptase-polymerase-chain-reaction assay were1ldays(interquartile range,9to16) and6days (interquartile range,4to7), respectively. Multivariate analysis revealed that the presence of a coexisting medical condition was the onlyindependent risk factor for the acute respiratory distress syndrome (ARDS)(odds ratio,3.42;95%confidence interval,1.21to9.70; P=0.02).We have gained access to samples from a large cohort of H7N9-infected patients and we performed virological and serial immunological studies using40H7N9patient specimens. The plasma hypercytokinemia dynamics were observed concurrently with high pharyngeal viral load in these H7N9patients compared to healthy controls. Furthermore, we show that the plasma levels of HGF, SCF, IL-18, IP-10, MIF and SCGF-beta are highly positively associated with the APACHE II disease severity score in H7N9-infected patients, especially during the second week of disease onset, and they are also positively associated with mortality.Li’s ALS therapy was used in16patients with severe H7N9virus infection when the condition deteriorated rapidly and a cytokine storm was detected. We find Li’s ALS therapy could decrease the elevated levels of ctyokines of patients, especially IP-10, which was correlated with mortality.The median age of patients hospitalized with H7N9virus infection was older than the other patient groups (61years; P<0.001) and a higher proportion was male (P <0.02). After adjustment for age and gender, chronic heart disease (CHD) was associated with an increased risk of hospitalization with H7N9(relative risk9.68;95%CI5.24-17.90). H7N9patients were more likely to report a productive cough and hemoptysis at hospital admission than patients with H5N1infection. H7N9patients had similar patterns of leukopenia, thrombocytopenia, and elevated alanine aminotransferase creatinine kinase, C-reactive protein, and lactate dehydrogenase as H5N1patients, which were all significantly different from pH1N1patients (P<0.005). H7N9patients had a longer duration of hospitalization than either H5N1or pH1N1patients. The hospitalized case fatality risk was highest for H5N1(55%;95%CI47-64%) and death occurred earlier, with a median time from onset to death of11days for H5N1, versus18days for H7N9(P=0.002) and15days for pH1N1(P=0.154).Conclusions:During the evaluation period, the novel H7N9virus caused severe illness, including pneumonia and ARDS, with high rates of ICU admission and death. Our findings identify a group of hypercytokinemia dynamics signature proteins HGF, SCF, IL-18, IP-10, MIF, and SCGF-beta as biomarkers for severe and lethal flu infections, and we suggest the best time to detect these biomarkers is during the second week of disease onset. These results indicate that remedies targeting these proteins might constitute a future viable strategy to treat H7N9infections. Severe H7N9virus infection patients could benefit from Li’s ALS therapy that could decrease the elevated level of cytokines. CHD is a risk factor for H7N9hospitalization. The clinical profile of patients hospitalized with H7N9was similar to patients hospitalized with H5N1, but with a more protracted clinical course than either H5N1or pH1N1patients.更多还原