戊型肝炎病原学诊断策略初探及江苏农村地区戊型肝炎流行病学特征研究
摘要
随着对戊型肝炎(简称戊肝)研究的深入和诊断方法的进步,为戊肝诊断提供了更多可靠的工具。目前临床上常用的戊肝病原学诊断指标主要包括抗-HEV IgM抗体、抗-HEV IgG抗体和HEV RNA。
分析戊肝病例的病原学指标发现,抗-HEV IgM抗体在4w左右达到峰值,发病2个月后开始下降直至阴转;抗-HEV IgG抗体在4w左右达到最高峰,在2个月开始下降,但抗体能在较长时间内一直保持阳性;PCR阳性率在急性早期较高,在4w时显著下降,3m以后基本检测不到HEV RNA。
由于抗-HEV IgG抗体能长期维持阳性,单次IgG检测值不宜做为诊断依据,而系列血清的抗体阳转或滴度4倍以上升高则可确诊;PCR阳性可以做为确诊依据,但检测时间若在急性晚期或恢复期,则会有较多漏诊;IgM做为诊断依据时,若早期就诊时阴性则必须进行随访检测以免漏诊。
根据采样时间的不同,设定IgM的不同临界值,可提高诊断准确性。在发病后1w、2w时IgM抗体的最佳临界值为sco=3,而4w-3m标本的最佳临界值为sco=2。戊肝病例就诊时极少会超过发病2m,在此期间内,抗-HEV IgM是一个较可靠的诊断指标,阳性预测值和阴性预测值在95%以上,诊断的准确率为96.3%(95%CI:93.3%～98.2%)。
现有关于较大人群中的戊型肝炎流行病学特征的资料大多来源于爆发调查,国内外对散发性戊型肝炎的流行病学特征的了解一般来源于城市中心医院的临床病例调查,由于各种选择性偏倚的存在,无法全面地反映戊肝的流行全貌。木研究选取了江苏东台市的十个乡镇建立了基于各级医疗点的疑似肝炎主动监测系统,进行了连续12个月的监测,以较全面地了解我国农村地区戊型肝炎的流行病学特征。
该地区自然人群中抗-HEV抗体情况显示当地HEV感染率为51.2%,随年龄累积明显,男性感染率高于女性;一年时间内有11.2%的抗体阴性者发生了抗体阳转,提示在此期间内发生了HEV新发感染。
当地戊肝病例多见于40岁以上中老年人群;男性多于女性,男女比例为3.4:1;各个监测乡镇均有病例,且自西向东可发现东部沿海三个乡镇发病率较高;全年均有散发,季节性差异不明显;病例中HEV基因4型为绝大多数,占94.7%,基因1型占5.3%。在监测期间未发现戊肝爆发。
分析疑似肝炎病因谱发现,急性肝炎构成比由高到低依次为:戊肝、急性乙肝和甲肝;戊肝表现的症状、体征以及肝功能损伤比其他肝炎明显。
With increasing understanding of hepatitis E and developing of its diagnoses, there are more reliable diagnostic tools. At present, ALT, anti-HEV IgM, anti-HEV IgG and HEV RNA are usually detected for clinical diagnosing of hepatitis E.
In this study, the dynamic analysis of those serological markers showes: the titer of anti-HEV IgM reaches peak about 4 weeks after illness onset, decreases about 2 months till seroreversion; the titer of anti-HEV IgG reaches peak about 4 weeks also, but it can persist for a long time at high titer; the positive rate of HEV RNA is higher at early acute stage, but decreases markedly, and no HEV RNA can be detected 3 months after onset.
As mentioned above, these different serological markers have different clinical signification in different illness stage. Regarding anti-HEV IgG, positive result of single sample has no clinical signification. But if there is seroconversion or 4 folds elevation of its titer, acute hepatitis E can be diagnosed. If there is detectalbe HEV RNA, acute hepatitis can be diagnosed also. But only depending on HEV RNA detection, there will be many false negative results in later acute phase or convalescence.
When anti-HEV IgM is used for diagnostic marker for acute hepatitis E, it will lift diagnostic accuracy that different threshold value is used in different illness stage. The best clinical threshold value of anti-HEV IgM is s/co=3 in the first 2 weeks of illness and s/co=2 from 15~(th) day to 3~(th) month after onset. The majority of haptitis E patients visit a doctor within 2 months after onset. In this clinical stage, anti-HEV IgM is a reliable clinical diagnostic marker with accuracy of 96.3% (95% CI: 93.3%-98.2%, both PPV and NPV are more than 95%).
At present, the epidemiology character of hepatitis E in large population is mostly based on outbreak investigations, and the epidemiology character of sporadic hepatitis E is drawed from case investigations in urban central hospitals. For investigating epidemiology of hepatitis E in Chanese rural district all sidely, an active survaillence system for suspected hepatitis patients based on medical aid posts at different levels was established in 10 selected towns in DongTai, Jiangsu, and a survaillence lasting one year was conducted.
According to sero-epidemiology study on normal population, the infection rate of hepatitis E virus is 51.2% in this region and becomes higher with age, and the infection rate in male is higher than in female. There are 11.2% of population with anti-HEV seroconversion in this year, which clues to new infection of HEV.
In this region, sporadic hepatitis E mainly attackes older people (with age≥40 years); the attack rate of male is higher than female with M/F ratio of 3.4:1. Hepatitis E cases were found in all 10 surveiled towns, but the attack rate in the 3 eastern towns at seaside was higher; the cases could be found in all year with unobvious seasonal distribution. In all HEV isolates, the overwhelming majority (94.7%) belong to genotype 4, only 5.3% belong to genotype 1. In this one year survaillence period there is no outbreak of hepatitis E.
To analyse the constituent ration of suspected acute hepatitis, the largest propotion is hepatitis E, the next is acute hepatitis B, and the smallest is hepatitis A. The physical symptom and liver injury of hepatitis E patients are more serious than other hepatitis.
分析戊肝病例的病原学指标发现,抗-HEV IgM抗体在4w左右达到峰值,发病2个月后开始下降直至阴转;抗-HEV IgG抗体在4w左右达到最高峰,在2个月开始下降,但抗体能在较长时间内一直保持阳性;PCR阳性率在急性早期较高,在4w时显著下降,3m以后基本检测不到HEV RNA。
由于抗-HEV IgG抗体能长期维持阳性,单次IgG检测值不宜做为诊断依据,而系列血清的抗体阳转或滴度4倍以上升高则可确诊;PCR阳性可以做为确诊依据,但检测时间若在急性晚期或恢复期,则会有较多漏诊;IgM做为诊断依据时,若早期就诊时阴性则必须进行随访检测以免漏诊。
根据采样时间的不同,设定IgM的不同临界值,可提高诊断准确性。在发病后1w、2w时IgM抗体的最佳临界值为sco=3,而4w-3m标本的最佳临界值为sco=2。戊肝病例就诊时极少会超过发病2m,在此期间内,抗-HEV IgM是一个较可靠的诊断指标,阳性预测值和阴性预测值在95%以上,诊断的准确率为96.3%(95%CI:93.3%～98.2%)。
现有关于较大人群中的戊型肝炎流行病学特征的资料大多来源于爆发调查,国内外对散发性戊型肝炎的流行病学特征的了解一般来源于城市中心医院的临床病例调查,由于各种选择性偏倚的存在,无法全面地反映戊肝的流行全貌。木研究选取了江苏东台市的十个乡镇建立了基于各级医疗点的疑似肝炎主动监测系统,进行了连续12个月的监测,以较全面地了解我国农村地区戊型肝炎的流行病学特征。
该地区自然人群中抗-HEV抗体情况显示当地HEV感染率为51.2%,随年龄累积明显,男性感染率高于女性;一年时间内有11.2%的抗体阴性者发生了抗体阳转,提示在此期间内发生了HEV新发感染。
当地戊肝病例多见于40岁以上中老年人群;男性多于女性,男女比例为3.4:1;各个监测乡镇均有病例,且自西向东可发现东部沿海三个乡镇发病率较高;全年均有散发,季节性差异不明显;病例中HEV基因4型为绝大多数,占94.7%,基因1型占5.3%。在监测期间未发现戊肝爆发。
分析疑似肝炎病因谱发现,急性肝炎构成比由高到低依次为:戊肝、急性乙肝和甲肝;戊肝表现的症状、体征以及肝功能损伤比其他肝炎明显。
With increasing understanding of hepatitis E and developing of its diagnoses, there are more reliable diagnostic tools. At present, ALT, anti-HEV IgM, anti-HEV IgG and HEV RNA are usually detected for clinical diagnosing of hepatitis E.
In this study, the dynamic analysis of those serological markers showes: the titer of anti-HEV IgM reaches peak about 4 weeks after illness onset, decreases about 2 months till seroreversion; the titer of anti-HEV IgG reaches peak about 4 weeks also, but it can persist for a long time at high titer; the positive rate of HEV RNA is higher at early acute stage, but decreases markedly, and no HEV RNA can be detected 3 months after onset.
As mentioned above, these different serological markers have different clinical signification in different illness stage. Regarding anti-HEV IgG, positive result of single sample has no clinical signification. But if there is seroconversion or 4 folds elevation of its titer, acute hepatitis E can be diagnosed. If there is detectalbe HEV RNA, acute hepatitis can be diagnosed also. But only depending on HEV RNA detection, there will be many false negative results in later acute phase or convalescence.
When anti-HEV IgM is used for diagnostic marker for acute hepatitis E, it will lift diagnostic accuracy that different threshold value is used in different illness stage. The best clinical threshold value of anti-HEV IgM is s/co=3 in the first 2 weeks of illness and s/co=2 from 15~(th) day to 3~(th) month after onset. The majority of haptitis E patients visit a doctor within 2 months after onset. In this clinical stage, anti-HEV IgM is a reliable clinical diagnostic marker with accuracy of 96.3% (95% CI: 93.3%-98.2%, both PPV and NPV are more than 95%).
At present, the epidemiology character of hepatitis E in large population is mostly based on outbreak investigations, and the epidemiology character of sporadic hepatitis E is drawed from case investigations in urban central hospitals. For investigating epidemiology of hepatitis E in Chanese rural district all sidely, an active survaillence system for suspected hepatitis patients based on medical aid posts at different levels was established in 10 selected towns in DongTai, Jiangsu, and a survaillence lasting one year was conducted.
According to sero-epidemiology study on normal population, the infection rate of hepatitis E virus is 51.2% in this region and becomes higher with age, and the infection rate in male is higher than in female. There are 11.2% of population with anti-HEV seroconversion in this year, which clues to new infection of HEV.
In this region, sporadic hepatitis E mainly attackes older people (with age≥40 years); the attack rate of male is higher than female with M/F ratio of 3.4:1. Hepatitis E cases were found in all 10 surveiled towns, but the attack rate in the 3 eastern towns at seaside was higher; the cases could be found in all year with unobvious seasonal distribution. In all HEV isolates, the overwhelming majority (94.7%) belong to genotype 4, only 5.3% belong to genotype 1. In this one year survaillence period there is no outbreak of hepatitis E.
To analyse the constituent ration of suspected acute hepatitis, the largest propotion is hepatitis E, the next is acute hepatitis B, and the smallest is hepatitis A. The physical symptom and liver injury of hepatitis E patients are more serious than other hepatitis.
引文
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