【作者】 倪进东；

【导师】 叶冬青；

【作者基本信息】 安徽医科大学 ， 流行病与卫生统计学， 2008， 博士

【摘要】 流行性脑脊髓膜炎(简称流脑)是由脑膜炎双球菌引起的一种急性呼吸道传染病,是我国法定乙类传染病。安徽省历来是流脑高发地区之一,上世纪80年代后随疫苗的推广使用,流脑的发病得到有效的控制,但近年来,如一些曾经很好控制传染病死灰复燃一样,流脑发病出现迅速上升态势,伴随发病率上升,流脑的流行特征也出现明显变化。安徽省地处我国中部地区,特定的地理环境使得对安徽省相关疾病的流行特征的研究具有较普遍的外推价值,同时,作为C群流脑疫情首先发生省份之一,也为我们开展相关研究工作提供了可能。为此,我们结合对安徽省既往流脑疫情资料的回顾,开展了本课题研究工作,希望为流脑以及部分疫苗可预防疾病的预防策略及控制措施的制定、改进提供参考依据。目的了解安徽省流脑流行特征以及近年来出现的变化情况,为预防控制策略及措施的制定提供理论依据材料方法1、依托疫情报告系统收集安徽省历年流脑疫情资料。以10年为一时间段将整个研究时间分成6个年代,以淮河、长江为主要参照标记,将安徽省分成江淮、淮北和江南三个地区,比较分析了不同年代、不同地区流脑发病变化情况。对研究期间安徽省流脑发病的人群、地区、时间分布情况进行描述性分析。2、对2003年7月到2007年6月之间合肥地区所有报告疑似流脑病例进行流脑流行病学个案调查和临床病历资料回顾性调查;2005年11月份和2006年4月份,采集不同年龄段健康人群咽拭子。根据我国在校学生年龄分布情况将所调查病例分成6个年龄组,统计时间周期以上年7月1日到第二年6月31日为一个统计年份。分年龄组、城乡地区的不同分别统计发病率和病死率,不同年龄组病例构成情况也进行描述。不同性别病例年龄中位数及死亡病例年龄中位数分别进行计算。对分类资料进行卡方检验,应用非参检验对不同性别间、死亡病例与成活病例年龄进行比较分析。应用单因素logistic将年龄、发病与就诊时间间隔及临床表现等逐个纳入分析其与病死结局关联,对其中有意义的因素,再共同纳入多因素logistic回归分析,以了解影响流脑病例死亡结局的危险因素。结果1951-2007年安徽省共发生流脑病例799387例,年平均发病率为28.90/10万,死亡41337例,死亡率为1.49/10万,病死率为5.17%。在此期间安徽省范围出现3次大的流行疫情:最大的一次出现在1975-1979年间,并于1977年达到此次流行年发病高峰729.25/10万;疫苗前时期,安徽省流脑疫情有8-10年流行(峰高不同)的规律,每次大流行持续时间大约为6-7年左右。上世纪80年代后随A群流脑多糖疫苗的推广使用,流脑发病率出现持续下降趋势,流脑的流行周期也越来越不明显,但仍在间隔10年左右出现发病率小幅度异常波动。2003年我省出现C群流脑局部地区爆发疫情后,全省流脑疫情呈现小幅反弹现象。安徽省流脑发病一般是从每年的10-11月份开始出现疫情上升迹象,至第二年的4-5月份达到发病高峰,与流行年份相比,散发年份发病率的季节高峰持续时间要长一个月左右时间。10或11月份发病率较前5年同月发病平均水平明显升高往往预示下年度发病上升。1994-1999年间,15岁以下占中病例的78.94%;2000-2007年间,15岁以下占中病例的17.20%,10-25岁年龄组病例占到63.03%。总的男女病例比为1.46:1,但25岁后,男女比为0.70:1。在发生全省范围的流脑流行情况下,淮北地区早于其他两地区1-2年出现疫情上升及出现发病率高峰,但2002年后的C群流脑流行先发生于江南地区。江淮、江南、淮北地区流脑发病率分别为33.20/10万、29.03/10万和30.44/10万(P = 0.000),三地区病死率分别为4.37%、4.92%和6.00%(P = 0.000)。2003年至2007年合肥市累计发现报告流脑病例386例,年平均发病率为2.09/10万,2006/2007年度发病率达到2.86/10万。经实验室确诊病例135例,都为C群流脑。城市地区病例235例(60.88%)、农村地区病例151例(39.12%)。病例年龄中位数为15岁(最小为2个月,最大为78岁),发病率最高年龄组为12-17岁组(6.57/10万),男性病例219例,占总病例的56.7%。在小于22岁病例中,男女病例比例为1.5:1,在大于22岁病例中,男女性别比例为1:1.8。98.2%的病例发生11月份到第二年的5月份之间。临床表现:急性起病的有334例(96.53%),371例病例有发热(96.11%),其它主要症状有:有呕吐的322例(83.42%),恶心311例(80.57%),颈项强直的285例(77.9%),头痛278例(72.02)。临床分型:普通型225例(58.29%),暴发型54例(13.9%),轻型2例(0.52%)。共发生死亡病例28例,平均病死率为7.25%,死亡病例年龄中位数为10岁(2个月龄到27岁),比成活病例年龄低,成活病例年龄中位数为15岁(6个月龄到78岁),通过非参检验,两者分布差异有统计学意义(Z=2.54,P=0.01)。分析影响病例死亡的主要因素,单因素logistic回归分析结果显示:头痛、神志不清、恶心、出血点或瘀斑、瘀点数目超过3个、颈项强直、抽搐、中性粒细胞>80%、克氏征阳性、布氏征阳性以及年龄小于12岁与病例死亡相关(P < 0.05);将这些因素纳入logistic回归模型进行多因素分析,瘀点数目超过3个、中性粒细胞>80%、布氏征阳性为病例死亡危险因素(P < 0.05)。聚集性病例21起,病例年龄中位数为16岁(1岁到69岁),其中年龄在12-21岁的病例占59.31%;健康人群流脑带菌率流行期为5.99%,高于流行前期的3.05%, ,流行期B群和C群带菌率上升明显;健康人群带菌率有随年龄增加而升高的趋势。结论安徽省是流脑易发生地区,历史上A群流脑是本地区占绝对优势的流行菌株,A群多糖疫苗的推广使用,有效控制了安徽省流脑的发病;疫苗后时期流脑的流行周期性不再明显,但每隔10年左右仍能观察到发病率小幅度异常上升的现象;C群流脑代替了A群成为安徽省近几年的流行优势菌株,并引起流脑疫情的反弹上升,病例年龄分布出现上移趋势,但目前尚处于菌群转换的不稳定的过渡时期,需要进一步的监测研究;流脑流行优势菌群的转换反映了疫苗接种远期副(附)效应的影响,提示免疫策略及时修订变化的必要性;从病例性别构成来看,男性病例明显高于女性,该现象值得进一步关注。合肥地区针对C群流脑疫情开展的A+C群流脑群体接种效果并不明显;流脑发生季节性明显,10及11月份发病情况对下年度疫情变化有一定预示作用; C流脑病死率高于A群;瘀点数目超过3个、中性粒细胞>80%、布氏征阳性等影响C群流脑病例死亡结局。更多还原

【Abstract】 BackgroundMeningococcal disease is a contagious disease caused by the bacterium N.meningitidis. It is still an important public heath issue because of theunexpected onset and rapid progress of the disease combined with a highcase-fatality rate (CFR). Meningococcal disease is mandatory notifiablein China. Among the 13 meningococcal serogroups defined by serologicreactivity of the meningococcal capsular polysaccharide, serogroups A, B,and C are the most commonly associated with the disease. In China, theleading causative agent of epidemics was serogroups A, and serogroup Acapsular polysaccharide vaccines have been used in infants and school-agedchildren since the beginning of the 1980s. Since then, the intervals betweenepidemics have become more irregular, and the number of cases ofmeningococcal meningitis has declined to a few per year. However, in recentyears, the number of meningococcal meningitis cases attributed to serogroupC has increased substantially in China. Anhui Province—a region situatedin middle China—is one of the areas where the first outbreak ofmeningococcal disease caused by serogroup C was found in China. Since thespring in 2003, the incidence of meningococcal disease due to serogroupC increased rapidly. Significant changes might have occurred inepidemiology features accompanying this incidence shift. There was few published report about the epidemiological characteristics of meningococcal disease caused by serogroup C in China. In order to propose appropriate preventive and control measures, the present study first focused on the epidemiological characteristics of meningococcal diseases caused by serogroup C in China. We evaluated epidemiological trends of meningococcal disease in Anhui province and examined demographic and clinical characteristics of the meningococcal cases caused by serogroup C in Hefei area to assess the impact of the disease.ObjectivesTo determine the shift of the epidemiologic characteristics of meningococcal disease in Anhui province and to provide valuable information for developing timely and appropriate public health interventions.MethodsData about the patients with meningococcal disease were collected according to the National Disease Surveillance System.The territories of Anhui province was divided by the Huaihe river and the Yangzi river into three areas: the middle part, southern part and northern area.During July. 2003 and June. 2007, information about the patients with meningococcal disease in Hefei city would collected with a uniform questionnaire including demographic characteristics, clinical presentations, and medications, etc. A total of 6 age groups, and the first 4 age groups in which coincide with the main levels of education in China, were selected. The statistical period was defined to follow the possible seasonal pattern, from July 1 to the next June 30. (e.g., 1 July 2003 to 30 June 2004 was regarded as the year, 2003–2004).The incidence rate and case fatality rate (CFR) were calculated according to year, age groups, and different areas. The proportion of the cases was calculated by age groups. Categorical variables were compared using chi-squared or a two-tailed Fisher’s exact test. Median age of cases and death rates were calculated according to sex and the seasonality by monthly average incidence. Because data of age were not normally distributed, the difference of age between the sexes, death cases and survival cases was tested by nonparametric Mann-Whitney U Test. The association between clinical signs, symptoms, laboratory findings, sex, age and mortality was first examined by univariate logistic analysis. And then, these factors associated with death significantly would be further test by multivariate logistic analysis. The level of significance was fixed atα=0.05.ResultsFrom 1951 to 2007, a total of 799,387 cases with meningococcal disease was reported in Anhui province, the annual incidence rate was 28.90 per 100,000 population, 41,337 death cases, the mortality rate was 1.49 per 100,000 population and the average CFR was 5.17%. Three epidemic outbreaks of meningococcal meningitis occurred in the period, and the largest one was occurred during 1975 to 1979 with the peak incidence in 1977(729.35/100,000). In the pre-vaccine era, periodic epidemics occurred every 7–10 years. Serogroup A capsular polysaccharide vaccines have been used in infants and school-aged children since the beginning of the 1980s. Since then, these (serogroup A) epidemic cycles have become more irregular, the number of cases of meningococcal meningitis has declined to a few per year. But the incidence increased slightly every 10 years. Since spring in 2003, there were outbreaks of meningococcal disease caused by serogroup C in some local areas, the incidence of meningococcal disease in Anhui province increased. Meningococcal disease cases increased in winter (starting in October or December) with the incidence peak in April to May. The male-to-female ratio was 1.46:1, but the ratio was 0.70:1 in the patients age older than 25 years. When epidemics occurred throughout Anhui province, it often observed that the incidence increased early in the northern part than the other two areas, but in 2002, the outbreak caused by serogroup C was first found in the southern part of Anhui province.During the study period, the average incidence of meningococcal disease was 30.82/100,000,25.15/100,000 and 29.88/100,000 in the middle, southern and northern parts of Anhui province respectively, and the CFR was 4.37%,4.92% and 6.00% respectively.From July 2003 to June 2007, meningococcal disease was confirmed in 386 cases among the total population in Hefei area, the average annual incidence rate was 2.09 per 100,000 population. The N. meningitidis serogroup was identified in 135 cases (34.97%) of the Meningococcal disease cases—all in serogroup C. The median age of these patients was 15 years (age ranged from 2 months to 78 years). By age group, the highest incidence rate (6.6 per 100,000 population) and the highest proportion (31.35%) of cases occurring in aged 12–17 years old. 219 cases were male(56.74%) . Patients 6–21 years old were more likely to be male, with a male-to-female ratio of 1.6:1; the male-to-female ratio of the age group older than 21 years was 1:1.8. The average CFR was 7.3% with a peak of 16.90%—in children younger than 6 years old. Since winter 2003, a vaccination campaign was recommended and partially implemented, but the effectiveness of the vaccine was limited. 334(86.53%) with a sudden onset. 371 cases present fever (96.10%), 322 (88.42%) had vomiting, 311 (80.57%) was present nausea, 285 (73.83 percent) had stiff neck .and 278(72.02%) had headach. A total 28 fatal cases were reported, the average case fatality rate was 7.25%, the median age of death cases was 10 years (range from 2 months to 27 years), which was significantly younger than the living cases (15 years, range from 6 months to 78 years; Z=2.54, P=0.011). By univariate logistic analysis, the following factors were associated with death: headache, nausea, altered mental status, purpura or petechia, number of petechia>3, stiff neck, Neutrophil>80%, positive Kerning’s sign, positive Brudzinski’s signs and age younger than 12 years old (p < 0.05). Using a multivariate regression analysis model, number of petechia>3, Neutrophil>80%, and positive Brudzinski’s signs were associated with increased risk of mortality. 21 clusters were identified. All the cluster cases were caused by serogroup C. The highest proportion of cases (19 cases, 35.19%) occurred in age group of 12 to 17 years. The carrier rate of Neisseria meningitides in heathy people is higher in midldle period (5.99%) than it in the early period (3.05%), and an increase in the carrier rate with the growth trends was observed.ConclusionsMeningococcal disease is always a public health problem in Anhui province. In the past, serogroups A was predominant in Anhui province. Since serogroup A capsular polysaccharide vaccines have been used in infants and school-aged children in the early 1980s, a significant decrease in incidence was observed. In the post-vaccine era, epidemic cycles have become more irregular, however, the incidence slightly increased approximately every 10 years was also observed. Recently, serogroup C replaced serogroup A as the most predominant serogroup and the incidence of meningococcal disease substantially increased in our area, changes in the age distribution of the cases that from younger to older-age categories was also observed. These phenomenons would be temporal in epidemics, further investigation and strengthening the capacities for epidemiologic and microbiologic surveillance of meningococcal disease is still necessary. Changs in the capsular polysaccharide of meningococci might be due to the additional effect of vaccine. To achieve full control of meningococcal disease, particularly since the epidemiology of disease is unpredictable and is continuously evolving, better the prevention measure and immunity policy is desirable. Men were more susceptible than women of the same age group. After the onset of the outbreak caused by serogroup C in Hefei area, a campaign to vaccinate people under 15 years of age with the meningococcal bivalent polysaccharide A/C vaccine was carried out, but our study showed that the effectiveness of the vaccine was limited. The incidence of October and/or November might be an alert sign for incidence in next year. The CFR of the patients caused by serogroup C is higher than it by serogroup A. Some clinical and laboratory features, such as number of petechia>3, Neutrophil>80%, and positive Brudzinski’s signs were associated with fatal outcome.更多还原