儿童急性呼吸道感染病毒流行特征与基因特征研究
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摘要
背景
急性呼吸道感染(acute respiratory tract infection, ARTI)是在全球范围内人类最常见的传染性疾病之一,发病率居急性传染病的首位,平均每年下呼吸道感染导致大约4,000,000患者死亡。近些年来,非典、H5N1禽流感、猪流感、新型冠状病毒以及新出现的感染人的H7N9禽流感,让人类对呼吸道病毒性传染病的关注上升到一个前所未有的高度。ARTI也是威胁儿童健康的主要因素,造成每年大约2,000,000儿童死亡,已成为5岁以下儿童死亡的第二大病因,同时也是儿童主要的公共健康问题之一。面对当前呼吸道传染病防治的复杂形势,加强传染病疫情信息的监测报告和在人群中,尤其是儿童中,主动开展呼吸道病毒性病原体实验室监测,最大可能地对呼吸道传染病疫情进行预测预警,以期在疫情暴发流行早期及时发现并采取快速的应对措施,减少对社会和经济发展的影响。
目的
本研究在2009～2012年对ARTI儿童开展呼吸道病毒性病原体监测,主要包括呼吸道合胞病毒(respiratory syncytial virus, RSV)、鼻病毒(human rhinovirus,HRV)、流感病毒(influenza virus, IFV)、偏肺病毒(metapneumovirus, MPV),副流感病毒(parainfluenza virus, PIV)、人类博卡病毒(human bocavirus, HBoV),人冠状病毒(human coronavirus, HCoV)、人腺病毒(human adenovirus, HAdV),肠道病毒(human enterovirus, HEV),描绘在ARTI儿童中呼吸道病毒性病原体的病原谱和流行特征;分析呼吸道病毒在肺炎儿童和哮喘发作儿童中分布情况以及与重症的关系；分析呼吸道病毒在ARTI儿童中阳性检出率与气象因素的关系；了解呼吸道病毒之间以及呼吸道病毒与细菌之间的共生关系。
本研究分析HAdV、HRV、HEV以及HBoV全基因组或某些基因片段变异进化特征,尤其是新发或再发的病毒亚型,主要包括HAdV-7、HAdV-55、HRV-C、 HEV-68.HEV-118和HBoV-1。通过对病毒基因特征的分析,了解该病毒的起源、进化、流行株及耐药等信息,从而为病毒感染治疗、疫苗研究和疫情控制提供科学依据和参考意见,进而保障人民生命健康安全,促进社会安定和经济发展。
材料与方法
以重庆医科大学附属儿童医院作为监测哨点医院,从2009年6月到2012年5月在呼吸内科开展急性呼吸道感染病例标本收集和呼吸道传染病监测。研究人员在ARTI儿童入院当天采集鼻咽抽吸物标本并使用统一标准问卷,收集病例信息。
本研究共检测9种病毒性病原体,根据不同病原体采用相应的检测方法。IFV和HRV/HEV采用Real-Time PCR检测；RSV、PIV、HCoV、MPV(?)(?)HBoV采用巢式PCR检测；HAdV则使用单轮PCR检测。HAdV阳性标本扩增测定hexon基因和fiber基因序列,并测定了HAdV-55全基因组序列。HRV阳性标本扩增测定VP4/2基因序列,HEV扩增测定5'NTR序列和VP1基因序列。HBoV阳性标本扩增测定全基因组序列。
基因序列分析主要包括同源性分析、系统发育分析、重组分析、分子钟分析、选择压力分析和空间动力学分析。调查表数据使用EpiData3.0录入,建立数据库。所有数据统计分析均采用SAS9.3软件处理。
结果
1.呼吸道病毒概况
(1)本研究共纳入因ARTI(?)住院的儿童2451例,RSV阳性标本检出率最高,为36.7%,其余依次为PIV23.3%、IFV19.6%、HRV/HEV18.4%、HBoV14.1%、 HAdV7.9%、MPV3.4%和HCoV3.1%。至少一种呼吸道病毒阳性检出率为80.3%。单一呼吸道病毒感染率为45.2%。复合感染病毒阳性标本861例,复合感染率为352%。
(2} IFV在各年龄组均有较高的感染率,但与<6个月年龄组比,其他各年龄组感染率稍高,足其1.5-2倍。在≤5岁的儿童中,HAdV(?)誊染率随年龄增大而逐渐增大。男孩比女孩更容易感染IFV-B和1HRV/HEV, OR分别为2.19(95%CI：1.16-4.14)和1.28(95%CI:1.02-1.59)。 ARTI (?)儿童临床症状和体征主要包括发热、咳嗽、咳痰、腹泻,肺部湿罗音和呼吸增快。RSV-A容易导致呼吸困难(28.2%,P<0.001),而RSV-B容易导致较多的咳痰(88.1%,P<0.001)。IFV-A感染导致白细胞计数降低(P<0.05)；RSV和PIV-3感染导致嗜中性粒细胞百分比减少和淋巴细胞百分比和血小板计数增高(P<0.05)。
(3)在HAdV感染的儿童中,嗜中性粒细胞百分比升高,淋巴细胞百分比降低,血小板计数也降低(P<0.05)。
(4) Logistic回归模型结果表明,与无呼吸道病毒感染相比,呼吸道病毒感染未增高肺炎发生几率。RSV和HAdV感染较容易引起重症肺炎(OR=1.58,95%CI：1.08-2.30；OR=5.10,95%CI：3.17-8.21)。与无呼吸道病毒感染相比,RSV-B、IFV-A和HRV/HEV容易引发哮喘中重度发作,OR值分别为2.99(95%CI:1.28-6.97)、2.28(95%CI:1.01-5.15)和2.94(95%CI:1.35-6.41)。
(5)呼吸道病毒之间和呼吸道病毒与细菌感染之间的相关系数Rij均小于0.30,表明呼吸道病毒之间、病毒与细菌感染并不存有共生或抑制关系。RSV与月平均气温、大气压以及太阳光照时数相关度强,而其他呼吸道病毒与气象因素相关度均在中度以下,表明重庆地区气象因素对除RSV以外的呼吸道病毒流行影响较小
2.人腺病毒亚型分布及基因特征
(1)在重庆地区,HAdV亚型主要包括HAdV-7型48.7%、HAdV-3型37.3%和HAdV-55型3.1%；其次还有HAdV-5型2.6%、HAdV-1型2.1%和HAdV-2型0.5%。
(2)在2010年7月～2011年6月期间HAdV阳性检出率较高。在2010年8月之前,HAdV-3为优势亚型；而从2010年9月开始,HAdV-7演变为占主导地位的HAdV亚型。HAdV-7引起的临床症状比例高,尤其以呼吸困难与湿罗音为最高(P<0.05),并且住院时间较其他亚型长(P=0.002)。各亚型复合感染率从45.7%到100%不等,以HAdV-7为最低(P=0.044)。HAdV-7(?)(?)起重症疾病的几率是HAdV-3的3.52倍(45.7%vs.18.1%,95%CI:1.60-7.74,P=0.002)。
(3)重庆地区HAdV-7型主要以7d2为主。HAdV-7型hexon基因序列同源性均在99.8%-100%。系统发育分析显示重庆地区hexon基因序列主要分布在7d2和7d两个分支。7d分支更容易引起重症肺炎(OR=2.50,95%CI：1.05-5.94)。HAdV-7型fiber基因同源性在99.7%～100%,存在两个基因位点的改变：c111T和A253G。A253G位点仅出现在CQ1243和CQ1379,造成了氨基酸Thr85GLA改变。
(4) HAdV-3型hexon基因序列形成多个分支,呈现地域差异,但同时存在地域之间的传播。HAdV-3型fiber基因序列4个碱基变异位点：T520C(CQ5685)、A567C、C722A (CQ5)和G742A (CQ483)。其中,A567C位点变异在多株中出现,但未引起氨基酸位点变异；而C722A位点和G742A位点使氨基酸位点发生了改变：Pro261His和Glu278LyS。系统发育树形成三个分支,重庆地区序列均位于A支,遗传距离较近,序列较稳定。
(5)本研究成功扩增3株HAdV-55基因组全序,与其他HAdV-55之间同源性在99.8%-99.9%；与HAdV-B2同源性在96.1%-98.7%,以与HAdV-14同源性最高。系统发育分析表现为HAdV-55基因序列具有地域特征。我国地区流行的HAdV-55显示有HAdV-14特征。我国HAdV-55分歧时间大约在1992年,其中CQ814、CQ1657、CQ2903、Hebei/BD/2012随时间依次分化,而Shaanxi/QSDLL/2006分化与CQ1657同时出现。大陆和台湾地区hexon基因分歧时间大约在1997年,我国大陆内分歧时间则更近一些,大约在2005年。我国大陆与新加坡fiber序列分歧时间大约在2004年,与台湾地区分歧时间在2001年左右。
3.鼻病毒和肠道病毒
(1)在1564份标本中,共检出HRV阳性标本223(14.3%)例,包括HRV-A型120(53.8%)例,HRV-B型11(4.9%)例和HRV-C型92(41.3%)例;同时检出HEV41(2.6%)份,主要包括HEV-687(17.1%)例,HEV-71和CV-A6各5(12.2%)例。
(2)重庆地区HRV-C型以HRV-C2为主,其次依次为HRV-C43、HRV-C1和HRV-C17。此外,尚有5条VP4/2基因序列与已知的51个亚型基因序列同源性差异超过10%,本研究暂时命名为HRV-C52, HRV-C53和HRV-C54。分子钟分析发现HRV-C型VP4/2基因序列整体进化速率为6.9×10-3s/s/y (95%HPD:2.5×10-3～12.5×10-3s/s/y)。重庆地区所有HRV-C型基因序列在分子钟树中分为两支,两支的分化时间大约为113年前。从BSP可以看出大约在40年前,人群中有效感染人数出现了大幅度的上升。
(3)分子钟分析表明HEV-68VP1基因序列整体进化速率为9.6×1O-3s/s/y (95%HPD:6.9×10-3～12.5×10-3s/s/y)。系统发育树包括三个分支,Lineage3中国分支大约在1973年与其他分支分化,以较高的进化速率进化(3.2×10-2s/s/y,95%HPD:2.1×10-2～4.7×10-2s/s/y),直到2008年进化速率恢复到正常水平。选择压力分析发现VP1基因片段未发现正选择位点,HEV-68主要通过纯化选择方式进化。BSP表明HEV-68有效感染人数在2-4年前出现了短暂的上升,在1998年前保持平稳。空间动力学分析表明日本山形省和美国德克萨斯州是HEV-68迁移的地域源头。
(4)首次检测到HEV-118在中国ARTI儿童中存在,其基因序列与HEV-109和HEV-104高度同源。HEV-118中国株VP1基因序列与以色列ISR10株同源性为97%,与秘鲁PERI61株(JX393301)同源性为91%。HEV-118分支进化速率为3.6×10-3s/s/y (95%HPD:1.2×10-3～6.7×10-3s/s/y),与HEV-109分歧时间大约在168年前。
4.人博卡病毒
(1)重庆地区HBoV全基因组序列同源性为99.4%-100%。其中,HBoV-1各个基因片段序列同源性均高于97%。从同源性分析可以看出HBoV-1基因序列稳定保守。
(2) HBoV全基因组序列和各基因片段构建的树基本一致,在HBoV-1分支内并没有出现Bootstrap值>750的分支,推测HBoV-1基因序列不具有时空分布特征。
(3) HBoV-1进化速率为1.89×10-4s/s/y(95%HPD：0.01-4.54×10-4s/s/y),低于HBoV整体进化速率。选择压力分析发现VPl基因第40位点为正选择位点,而NP、NS和VP2未发现正选择位(?)
结论
1.呼吸道病毒流行特征
(1)在ARTI儿童中,呼吸道病毒感染率为80.3%,是引起儿童ARTI最主要的病原体。RSV在ARTI儿童中阳性检出率最高,其余依次为PIV、IFV、HRV/HEV和HBoV。重庆地区在2010～2011年期间儿童中可能出现过HAdV暴发。
(2)RSV和HAdV感染易引发重症肺炎,而RSV-B、IFV-A和HRV/HEV与哮喘中重度发作有关。
2.人腺病毒
(1) HAdV在急性呼吸道感染的儿童中存在多个亚型流行,以HAdV-7、HAdV-3和HAdV-55为主;HAdV-7较HAdV-3以及其他亚型更容易引起重症肺炎。
(2) HAdV-7和HAdV-3hexon基因和fiber基因序列比较稳定和保守,具有地域特征；其中,HAdV-7hexon基因主要以7d和7d2存在,7d与重症疾病有关。HAdV-55全基因组序列变异较大,具有空间和时间的进化特性。
3.鼻病毒和肠道病毒
(1) HRV主要以A型和C型为主；而HRV-C又以C2型为主。此外发现并命名三个新亚型：C52～C54。
(2)首次在中国急性呼吸道感染儿童中检出HEV-68；系统发育分析发现中国存有多个分支,并且在38年前形成一个新的分支,具有较高的进化速率；HEV-68在世界范围内存在迁移现象。
(3)首次获得HEV-118全基因组序列,通过对VP1基因序列分析发现中国株不同于秘鲁株和以色列株。
4.人博卡病毒
(1) HBoV-1基因序列稳定保守,变异较小
(2)选择压力分析发现HBoV-1VP1基因存有正选择位点,表明HBoV-1基因突变不仅存在纯化作用选择,也有正向选择作用影响。
Background
Acute respiratory tract infection (ARTI) is one of the most common infectious diseases in the world with the first incidence rate in acute infectious diseases. About4millions patients diedfrom the lower ARTI every year. In recent years, SARS,avian influenza A (H5N1) viruses,influenza A (H1N1) pdm2009, the emergencing avian influenza A (H7N9) virus, cause humans to pay more attention to respiratory viruses. ARTI is the main factor for threatening children' health, leading to2million children death each year and has become the second etiology of death in the children under5years old. Facing the current complex situationsfor prevention and control of respiratory infectious diseases, we should strengthen the monitoring report about infectious disease information and active to surveillance the respiratory viral pathogens in the populations, especially in the children. And thentry the best to forecast and warnabout the outbreak of respiratory infectious diseasesin order to reduce the influence on social and economic development.
Objective
In the current study, we performed sentinel surveillance for respiratory viruses among pediatric patients with ARTI presenting at a large referral hospital during2009-2012in Chongqing. China. The respiratory viruses mainly included respiratory syncytial virus (RSV). human rhinovirus (HRV), influenza virus (IFV), metapneumovirus (MPV), parainfluenza virus(PIV), human bocavirus (HBoV), human coronavirus (HCoV), human adenovirus (HAdV), and human enterovirus (HEV). This study was aimed to describe the spectrum and epidemiological characteristics of respiratory viruses in the children with ARTI and explore the association of respiratory tract viruses in the children with pneumonia and with asthma attack. Moreover we want to analysis the relationship between the positive rate of respiratory viruses and meteorological factors and to understand the symbiotic relationship between respiratory viruses and bacteria.
This study demonstratedgenetic characteristics of complete genome or genes of HAdV、HRV、HEV and HBoV, especially emerging respiratory virusor subtypes, including HAdV-7, HAdV-55, HRV-C, HEV-68, HEV-118and HBoV-1. Analysis of genetic characteristics of respiratory viruses in order to explore the origin, evolution, epidemic strains and drug resistance type and other information of the viruses, and then provide a scientific basis and reference for treatment, vaccine research and epidemic control for virus infection.
Materials and Methods
In the current study, we performed sentinel surveillance for respiratory viruses among pediatric patients with ARTI presenting at Children'Hospital, Chongqing Medical University during2009-2012in Chongqing, China. Nasopharyngeal aspirates were collected at admission to hospital for the children. The clinical information were got form the medical records.
The study performed the detection for respiratory viruses with different methods.HAdV hexon and fiber genes were sequenced for HAdV positive samples, VP4/2for HRV,5'NTR and VP1for HEV and complete genome for HAdV-55and HBoV.
Genetic sequences analysis includedidentities, phylogenetic tree, recombination, molecular clock, selective pressure and spatial dynamical analysis. The dataset were built by Epidata3.0. Statistical analyses were conducted by SAS9.3software.
Results
1. Epidemiological characteristics of respiratory viruses
(1) A total of2451children with ARTI were recruited in the study. The positive rate for RSV were36.7%, the highest among the nine respiratory viruses and then PIV23.3%、IFV19.6%、HRV/HEV18.4%、HBoV14.1%、HAdV7.9%、MPV3.4%as well as HCoV3.1%. The detection rate for at least one respiratory virus was80.3%and45.2%for single infection.
(2) Compared to the group aged<6months, the positive rate for IFV were1.5～2folders in the other groups. The positive rate for HAdV increased with children's age under5years old. Boys were easier to infect IFV-B and HRV/HEV than girls, ORs were2.19(95%CI:1.16-4.14) and1.28(95%CI:1.02-1.59), respectively. The clinical manifestation of the children with ARTI were fever, cough, expectoration, diarrhea, tachypnea and moist rales. RSV-A caused more dyspnea (28.2%, P<0.001) and RSV-B caused more expectoration (88.1%, P<0.001).The white blood cell count decreased in the children infected IFV-A. Neutrophil percentage decreased and lymphocyte percentage and platelet count increased in the childreninfected with RSV or PIV-3. While opposite for the children infected with HAdV.
(3) Logistic regression model results showed respiratory viruses infection did not increase the risk for pneumonia compared to non-respiratory viruses infection. RSV and HAdV were related withsevere pneumonia (OR=1.58,95%CI:1.08-2.30; OR=5.10,95%CI:3.17-8.21). RSV-B, IFV-A and HRV/HEV were associated with moderate/severe asthma attacks, ORs were2.99(95%CI:1.28-6.97),2.28(95%CI:1.01-5.15) and2.94(95%CI:1.35-6.41).
(4) The correlation coefficients were lower than0.30among respiratory viruses or between respiratory viruses and bacteria.The degrees of correlation were moderate between RSV and atmosphere, average month temperature and average sunshine duration, while were low between positive rates of other respiratory viruses and meteorologicalfactors, demonstrating meteorologicalfactors were less affected the epidemiology of respiratory viruses except for RSV.
2. HAdV subtypes and genetic characteristics
(1) Among all the tested children, HAdV subtypes included HAdV-7(48.7%), HAdV-3(37.3%), HAdV-55(3.1%), HAdV-5(2.62%), HAdV-1(2.1%), and HAdV-2(0.5%).
(2) HAdV had a higher positively rate during July2010to June2011. HAdV-7became the predominant subtype from September2010, and caused more dyspnea, moist rales and a longer hospitalization. Compared to HAdV-3, HAdV-7was associated with severe diseases (45.7%vs.18.1%, OR=3.52,95%CI:1.60-7.74, P=0.002).
(3)7d2was the main subtype of HAdV-7. Identities of hexon gene of HAdV-7were99.8%～100%. Phylogenetic tress showed the strains in the study distributed in the7d2and7d lineages with geographical characteristic. The strains from7d lineage were easier to cause severe pneumonia (OR=2.50,95%CI:1.05-5.94). Identities for fiber gene of HAdV-7were99.7%～100%and two mutations were found: C111T and A253G. The latter changed amino acid Thr85GLA.
(4) The sequences of hexon gene of HAdV3formed multiple lineages with geographical differenece and migration events. Four mutations in the fiber gene of HAdV-3were found:T520C (CQ5685)、A567C、C722A (CQ5) and G742A (CQ483). C722A and G742A changed the amino acid:Pro261His and Glu278Lys. Phylogenetic tree demonstrated three lineages and the strains located in A lineage.
(5) Identities of HAdV-55in the study were99.8%～99.9%with other strains from other regions,96.1%-98.7%with HAdV-B2and highest with HAdV-14.
(6) CQ-814(China/2010) was most closely related to HAdV-11a (P14) from Beijing, followed by CQ-1657(China/2011) and CQ-2903(China/2012)(Figure1A). Surprisingly, the closest genetic relationship existed between the2012Chongqing strain (CQ-2903) and the2006Shaanxi strain (QS-DLL). The HAdV-11a strains from mainland China seems to have diverged from their TMRCA with other strains from Taiwan Province/Singapore/South Dakota around15years ago considering the hexon gene,10years ago considering the fiber gene and35years ago considering the whole genome, respectively.
3. HRV and HEV subtype and genetic characteristics
(1) Among1564samples,223(14.3%) were positive for HRV. which included HRV-A120(53.8%), HRV-B11(4.9%) and HRV-C92(41.3%);41(2.6%) were positive for HEV, mainly including HEV-687(17.1%), HEV-71and CV-A65(12.2%), respectively.
(2) C2were the predominant subtype of HRV-C in Chongqing region, and the following were C43, C1and C17. In addition, another5sequences of VP4/2were different from the51known subtypes (more than10%differences). We named them C52, C53and C54.The overall evolutionary rate of VP4/2for HRV-C was6.9×10-3s/s/y (95%HPD:2.5×10-3～12.5×10-3s/s/y). The number of effective infection increased sharply before40years observed from Bayesian skyline plot.
(3) Molecular clock analysis revealed the overall evolutionary rate of VP1for HEV-68was9.6×1O-3s/s/y (95%HPD:6.9×10-3～12.5×10-3s/s/y). On the phylogenetic tree based on VP1gene nucleotide sequences, all modern HEV-68strains were grouped into three separate lineages (Figure2). Six Chinese strains from the study fit into Lineage3, being divided into two branches with a high bootstrap value with divergence in1973. The lineage evolved with a high speed (3.2×10-2s/s/y,95%HPD:2.1×10-2～4.7×10-2s/s/y) before recovered to normal in2008. Positive selectively position was not found on VP1gene. The number of effective infection kept steady, with fluctuating in2～4years before. The migration events inferred across the parsimony genetic phylogenies for the160VP1sequences of HEV-68from19locations among five continents, and their concatenation showed the Japanese province of Yamagata and the American state of Texas acted as the geographic source.
4. HBoV genetic characteristics
(1) Identities forHBoV complete genome were99.4%～100%, and more than97%in the four genes. The sequences of HBoV were conserved.
(2) The phylogenetic trees based on the four genes and complete genome were similar and formed branches with a bootstrap>750support. HBoV-1sequences did not reveal temporal and geographic distribution.
(3) The evolutionary rate of HBoV-1was1.89×1O-4s/s/y (95%HPD:0.01～4.54×1O-4s/s/y), lower than that of HBoV. Selective pressure analyzed that Position40of VPl was the positive selection site, while none were found in NP, NS, and VP2gene.
Conclusions
1. Epidemiological characteristic of respiratory viruses
(1) The positive rate of respiratory viruses was80.3%, demonstrating respiratory viruses was the predominant pathogen in the children with ARTI.
(2) RSV and HAdV were associated with severe pneumonia, while RSV-B,IFV-A and HRV/HEV were related with moderate/severe asthma attack.
2. HAdV
(1) Multiple HAdV subtype circulated in Chongqing region, mainly including HAdV-7, HAdV-3and HAdV-55. HAdV-7caused more severe pneumonia than HAdV-3and others.
(2) The sequences of hexon and fiber genes of HAdV-7and HAdV-3were steady and conserved and geographical distribution. HAdV-7existed with7d and7d2, and7d2may be related with severe diseases. HAdV-55complete genome sequences revealed temporal and geographical distribution.
3. HRV and HEV
(1) HRV-A and HRV-C were the main subtypes of HRV in the children with ARTI and C2was the predominant subtype of HRV-C.Three new subtype of HRV-C were found and named.
(2) This is the first report to detect HEV-68in the children with ARTI in China. The strains in the study formed a branch. HEV-68revealed migration events in the world.
(3) This is the first time to get the complete genome of HEV-118. Phylogenetic tree demonstrated the strain in China differed from that in Peru and Israel.
4. HBoV
(1) The sequences of HBoV-1were conserved and less variant.
(2) The positive selectively site on VP1gene revealed co-existence of purifying and positive selection during the evolution of HBoV-1.
急性呼吸道感染(acute respiratory tract infection, ARTI)是在全球范围内人类最常见的传染性疾病之一,发病率居急性传染病的首位,平均每年下呼吸道感染导致大约4,000,000患者死亡。近些年来,非典、H5N1禽流感、猪流感、新型冠状病毒以及新出现的感染人的H7N9禽流感,让人类对呼吸道病毒性传染病的关注上升到一个前所未有的高度。ARTI也是威胁儿童健康的主要因素,造成每年大约2,000,000儿童死亡,已成为5岁以下儿童死亡的第二大病因,同时也是儿童主要的公共健康问题之一。面对当前呼吸道传染病防治的复杂形势,加强传染病疫情信息的监测报告和在人群中,尤其是儿童中,主动开展呼吸道病毒性病原体实验室监测,最大可能地对呼吸道传染病疫情进行预测预警,以期在疫情暴发流行早期及时发现并采取快速的应对措施,减少对社会和经济发展的影响。
目的
本研究在2009～2012年对ARTI儿童开展呼吸道病毒性病原体监测,主要包括呼吸道合胞病毒(respiratory syncytial virus, RSV)、鼻病毒(human rhinovirus,HRV)、流感病毒(influenza virus, IFV)、偏肺病毒(metapneumovirus, MPV),副流感病毒(parainfluenza virus, PIV)、人类博卡病毒(human bocavirus, HBoV),人冠状病毒(human coronavirus, HCoV)、人腺病毒(human adenovirus, HAdV),肠道病毒(human enterovirus, HEV),描绘在ARTI儿童中呼吸道病毒性病原体的病原谱和流行特征;分析呼吸道病毒在肺炎儿童和哮喘发作儿童中分布情况以及与重症的关系；分析呼吸道病毒在ARTI儿童中阳性检出率与气象因素的关系；了解呼吸道病毒之间以及呼吸道病毒与细菌之间的共生关系。
本研究分析HAdV、HRV、HEV以及HBoV全基因组或某些基因片段变异进化特征,尤其是新发或再发的病毒亚型,主要包括HAdV-7、HAdV-55、HRV-C、 HEV-68.HEV-118和HBoV-1。通过对病毒基因特征的分析,了解该病毒的起源、进化、流行株及耐药等信息,从而为病毒感染治疗、疫苗研究和疫情控制提供科学依据和参考意见,进而保障人民生命健康安全,促进社会安定和经济发展。
材料与方法
以重庆医科大学附属儿童医院作为监测哨点医院,从2009年6月到2012年5月在呼吸内科开展急性呼吸道感染病例标本收集和呼吸道传染病监测。研究人员在ARTI儿童入院当天采集鼻咽抽吸物标本并使用统一标准问卷,收集病例信息。
本研究共检测9种病毒性病原体,根据不同病原体采用相应的检测方法。IFV和HRV/HEV采用Real-Time PCR检测；RSV、PIV、HCoV、MPV(?)(?)HBoV采用巢式PCR检测；HAdV则使用单轮PCR检测。HAdV阳性标本扩增测定hexon基因和fiber基因序列,并测定了HAdV-55全基因组序列。HRV阳性标本扩增测定VP4/2基因序列,HEV扩增测定5'NTR序列和VP1基因序列。HBoV阳性标本扩增测定全基因组序列。
基因序列分析主要包括同源性分析、系统发育分析、重组分析、分子钟分析、选择压力分析和空间动力学分析。调查表数据使用EpiData3.0录入,建立数据库。所有数据统计分析均采用SAS9.3软件处理。
结果
1.呼吸道病毒概况
(1)本研究共纳入因ARTI(?)住院的儿童2451例,RSV阳性标本检出率最高,为36.7%,其余依次为PIV23.3%、IFV19.6%、HRV/HEV18.4%、HBoV14.1%、 HAdV7.9%、MPV3.4%和HCoV3.1%。至少一种呼吸道病毒阳性检出率为80.3%。单一呼吸道病毒感染率为45.2%。复合感染病毒阳性标本861例,复合感染率为352%。
(2} IFV在各年龄组均有较高的感染率,但与<6个月年龄组比,其他各年龄组感染率稍高,足其1.5-2倍。在≤5岁的儿童中,HAdV(?)誊染率随年龄增大而逐渐增大。男孩比女孩更容易感染IFV-B和1HRV/HEV, OR分别为2.19(95%CI：1.16-4.14)和1.28(95%CI:1.02-1.59)。 ARTI (?)儿童临床症状和体征主要包括发热、咳嗽、咳痰、腹泻,肺部湿罗音和呼吸增快。RSV-A容易导致呼吸困难(28.2%,P<0.001),而RSV-B容易导致较多的咳痰(88.1%,P<0.001)。IFV-A感染导致白细胞计数降低(P<0.05)；RSV和PIV-3感染导致嗜中性粒细胞百分比减少和淋巴细胞百分比和血小板计数增高(P<0.05)。
(3)在HAdV感染的儿童中,嗜中性粒细胞百分比升高,淋巴细胞百分比降低,血小板计数也降低(P<0.05)。
(4) Logistic回归模型结果表明,与无呼吸道病毒感染相比,呼吸道病毒感染未增高肺炎发生几率。RSV和HAdV感染较容易引起重症肺炎(OR=1.58,95%CI：1.08-2.30；OR=5.10,95%CI：3.17-8.21)。与无呼吸道病毒感染相比,RSV-B、IFV-A和HRV/HEV容易引发哮喘中重度发作,OR值分别为2.99(95%CI:1.28-6.97)、2.28(95%CI:1.01-5.15)和2.94(95%CI:1.35-6.41)。
(5)呼吸道病毒之间和呼吸道病毒与细菌感染之间的相关系数Rij均小于0.30,表明呼吸道病毒之间、病毒与细菌感染并不存有共生或抑制关系。RSV与月平均气温、大气压以及太阳光照时数相关度强,而其他呼吸道病毒与气象因素相关度均在中度以下,表明重庆地区气象因素对除RSV以外的呼吸道病毒流行影响较小
2.人腺病毒亚型分布及基因特征
(1)在重庆地区,HAdV亚型主要包括HAdV-7型48.7%、HAdV-3型37.3%和HAdV-55型3.1%；其次还有HAdV-5型2.6%、HAdV-1型2.1%和HAdV-2型0.5%。
(2)在2010年7月～2011年6月期间HAdV阳性检出率较高。在2010年8月之前,HAdV-3为优势亚型；而从2010年9月开始,HAdV-7演变为占主导地位的HAdV亚型。HAdV-7引起的临床症状比例高,尤其以呼吸困难与湿罗音为最高(P<0.05),并且住院时间较其他亚型长(P=0.002)。各亚型复合感染率从45.7%到100%不等,以HAdV-7为最低(P=0.044)。HAdV-7(?)(?)起重症疾病的几率是HAdV-3的3.52倍(45.7%vs.18.1%,95%CI:1.60-7.74,P=0.002)。
(3)重庆地区HAdV-7型主要以7d2为主。HAdV-7型hexon基因序列同源性均在99.8%-100%。系统发育分析显示重庆地区hexon基因序列主要分布在7d2和7d两个分支。7d分支更容易引起重症肺炎(OR=2.50,95%CI：1.05-5.94)。HAdV-7型fiber基因同源性在99.7%～100%,存在两个基因位点的改变：c111T和A253G。A253G位点仅出现在CQ1243和CQ1379,造成了氨基酸Thr85GLA改变。
(4) HAdV-3型hexon基因序列形成多个分支,呈现地域差异,但同时存在地域之间的传播。HAdV-3型fiber基因序列4个碱基变异位点：T520C(CQ5685)、A567C、C722A (CQ5)和G742A (CQ483)。其中,A567C位点变异在多株中出现,但未引起氨基酸位点变异；而C722A位点和G742A位点使氨基酸位点发生了改变：Pro261His和Glu278LyS。系统发育树形成三个分支,重庆地区序列均位于A支,遗传距离较近,序列较稳定。
(5)本研究成功扩增3株HAdV-55基因组全序,与其他HAdV-55之间同源性在99.8%-99.9%；与HAdV-B2同源性在96.1%-98.7%,以与HAdV-14同源性最高。系统发育分析表现为HAdV-55基因序列具有地域特征。我国地区流行的HAdV-55显示有HAdV-14特征。我国HAdV-55分歧时间大约在1992年,其中CQ814、CQ1657、CQ2903、Hebei/BD/2012随时间依次分化,而Shaanxi/QSDLL/2006分化与CQ1657同时出现。大陆和台湾地区hexon基因分歧时间大约在1997年,我国大陆内分歧时间则更近一些,大约在2005年。我国大陆与新加坡fiber序列分歧时间大约在2004年,与台湾地区分歧时间在2001年左右。
3.鼻病毒和肠道病毒
(1)在1564份标本中,共检出HRV阳性标本223(14.3%)例,包括HRV-A型120(53.8%)例,HRV-B型11(4.9%)例和HRV-C型92(41.3%)例;同时检出HEV41(2.6%)份,主要包括HEV-687(17.1%)例,HEV-71和CV-A6各5(12.2%)例。
(2)重庆地区HRV-C型以HRV-C2为主,其次依次为HRV-C43、HRV-C1和HRV-C17。此外,尚有5条VP4/2基因序列与已知的51个亚型基因序列同源性差异超过10%,本研究暂时命名为HRV-C52, HRV-C53和HRV-C54。分子钟分析发现HRV-C型VP4/2基因序列整体进化速率为6.9×10-3s/s/y (95%HPD:2.5×10-3～12.5×10-3s/s/y)。重庆地区所有HRV-C型基因序列在分子钟树中分为两支,两支的分化时间大约为113年前。从BSP可以看出大约在40年前,人群中有效感染人数出现了大幅度的上升。
(3)分子钟分析表明HEV-68VP1基因序列整体进化速率为9.6×1O-3s/s/y (95%HPD:6.9×10-3～12.5×10-3s/s/y)。系统发育树包括三个分支,Lineage3中国分支大约在1973年与其他分支分化,以较高的进化速率进化(3.2×10-2s/s/y,95%HPD:2.1×10-2～4.7×10-2s/s/y),直到2008年进化速率恢复到正常水平。选择压力分析发现VP1基因片段未发现正选择位点,HEV-68主要通过纯化选择方式进化。BSP表明HEV-68有效感染人数在2-4年前出现了短暂的上升,在1998年前保持平稳。空间动力学分析表明日本山形省和美国德克萨斯州是HEV-68迁移的地域源头。
(4)首次检测到HEV-118在中国ARTI儿童中存在,其基因序列与HEV-109和HEV-104高度同源。HEV-118中国株VP1基因序列与以色列ISR10株同源性为97%,与秘鲁PERI61株(JX393301)同源性为91%。HEV-118分支进化速率为3.6×10-3s/s/y (95%HPD:1.2×10-3～6.7×10-3s/s/y),与HEV-109分歧时间大约在168年前。
4.人博卡病毒
(1)重庆地区HBoV全基因组序列同源性为99.4%-100%。其中,HBoV-1各个基因片段序列同源性均高于97%。从同源性分析可以看出HBoV-1基因序列稳定保守。
(2) HBoV全基因组序列和各基因片段构建的树基本一致,在HBoV-1分支内并没有出现Bootstrap值>750的分支,推测HBoV-1基因序列不具有时空分布特征。
(3) HBoV-1进化速率为1.89×10-4s/s/y(95%HPD：0.01-4.54×10-4s/s/y),低于HBoV整体进化速率。选择压力分析发现VPl基因第40位点为正选择位点,而NP、NS和VP2未发现正选择位(?)
结论
1.呼吸道病毒流行特征
(1)在ARTI儿童中,呼吸道病毒感染率为80.3%,是引起儿童ARTI最主要的病原体。RSV在ARTI儿童中阳性检出率最高,其余依次为PIV、IFV、HRV/HEV和HBoV。重庆地区在2010～2011年期间儿童中可能出现过HAdV暴发。
(2)RSV和HAdV感染易引发重症肺炎,而RSV-B、IFV-A和HRV/HEV与哮喘中重度发作有关。
2.人腺病毒
(1) HAdV在急性呼吸道感染的儿童中存在多个亚型流行,以HAdV-7、HAdV-3和HAdV-55为主;HAdV-7较HAdV-3以及其他亚型更容易引起重症肺炎。
(2) HAdV-7和HAdV-3hexon基因和fiber基因序列比较稳定和保守,具有地域特征；其中,HAdV-7hexon基因主要以7d和7d2存在,7d与重症疾病有关。HAdV-55全基因组序列变异较大,具有空间和时间的进化特性。
3.鼻病毒和肠道病毒
(1) HRV主要以A型和C型为主；而HRV-C又以C2型为主。此外发现并命名三个新亚型：C52～C54。
(2)首次在中国急性呼吸道感染儿童中检出HEV-68；系统发育分析发现中国存有多个分支,并且在38年前形成一个新的分支,具有较高的进化速率；HEV-68在世界范围内存在迁移现象。
(3)首次获得HEV-118全基因组序列,通过对VP1基因序列分析发现中国株不同于秘鲁株和以色列株。
4.人博卡病毒
(1) HBoV-1基因序列稳定保守,变异较小
(2)选择压力分析发现HBoV-1VP1基因存有正选择位点,表明HBoV-1基因突变不仅存在纯化作用选择,也有正向选择作用影响。
Background
Acute respiratory tract infection (ARTI) is one of the most common infectious diseases in the world with the first incidence rate in acute infectious diseases. About4millions patients diedfrom the lower ARTI every year. In recent years, SARS,avian influenza A (H5N1) viruses,influenza A (H1N1) pdm2009, the emergencing avian influenza A (H7N9) virus, cause humans to pay more attention to respiratory viruses. ARTI is the main factor for threatening children' health, leading to2million children death each year and has become the second etiology of death in the children under5years old. Facing the current complex situationsfor prevention and control of respiratory infectious diseases, we should strengthen the monitoring report about infectious disease information and active to surveillance the respiratory viral pathogens in the populations, especially in the children. And thentry the best to forecast and warnabout the outbreak of respiratory infectious diseasesin order to reduce the influence on social and economic development.
Objective
In the current study, we performed sentinel surveillance for respiratory viruses among pediatric patients with ARTI presenting at a large referral hospital during2009-2012in Chongqing. China. The respiratory viruses mainly included respiratory syncytial virus (RSV). human rhinovirus (HRV), influenza virus (IFV), metapneumovirus (MPV), parainfluenza virus(PIV), human bocavirus (HBoV), human coronavirus (HCoV), human adenovirus (HAdV), and human enterovirus (HEV). This study was aimed to describe the spectrum and epidemiological characteristics of respiratory viruses in the children with ARTI and explore the association of respiratory tract viruses in the children with pneumonia and with asthma attack. Moreover we want to analysis the relationship between the positive rate of respiratory viruses and meteorological factors and to understand the symbiotic relationship between respiratory viruses and bacteria.
This study demonstratedgenetic characteristics of complete genome or genes of HAdV、HRV、HEV and HBoV, especially emerging respiratory virusor subtypes, including HAdV-7, HAdV-55, HRV-C, HEV-68, HEV-118and HBoV-1. Analysis of genetic characteristics of respiratory viruses in order to explore the origin, evolution, epidemic strains and drug resistance type and other information of the viruses, and then provide a scientific basis and reference for treatment, vaccine research and epidemic control for virus infection.
Materials and Methods
In the current study, we performed sentinel surveillance for respiratory viruses among pediatric patients with ARTI presenting at Children'Hospital, Chongqing Medical University during2009-2012in Chongqing, China. Nasopharyngeal aspirates were collected at admission to hospital for the children. The clinical information were got form the medical records.
The study performed the detection for respiratory viruses with different methods.HAdV hexon and fiber genes were sequenced for HAdV positive samples, VP4/2for HRV,5'NTR and VP1for HEV and complete genome for HAdV-55and HBoV.
Genetic sequences analysis includedidentities, phylogenetic tree, recombination, molecular clock, selective pressure and spatial dynamical analysis. The dataset were built by Epidata3.0. Statistical analyses were conducted by SAS9.3software.
Results
1. Epidemiological characteristics of respiratory viruses
(1) A total of2451children with ARTI were recruited in the study. The positive rate for RSV were36.7%, the highest among the nine respiratory viruses and then PIV23.3%、IFV19.6%、HRV/HEV18.4%、HBoV14.1%、HAdV7.9%、MPV3.4%as well as HCoV3.1%. The detection rate for at least one respiratory virus was80.3%and45.2%for single infection.
(2) Compared to the group aged<6months, the positive rate for IFV were1.5～2folders in the other groups. The positive rate for HAdV increased with children's age under5years old. Boys were easier to infect IFV-B and HRV/HEV than girls, ORs were2.19(95%CI:1.16-4.14) and1.28(95%CI:1.02-1.59), respectively. The clinical manifestation of the children with ARTI were fever, cough, expectoration, diarrhea, tachypnea and moist rales. RSV-A caused more dyspnea (28.2%, P<0.001) and RSV-B caused more expectoration (88.1%, P<0.001).The white blood cell count decreased in the children infected IFV-A. Neutrophil percentage decreased and lymphocyte percentage and platelet count increased in the childreninfected with RSV or PIV-3. While opposite for the children infected with HAdV.
(3) Logistic regression model results showed respiratory viruses infection did not increase the risk for pneumonia compared to non-respiratory viruses infection. RSV and HAdV were related withsevere pneumonia (OR=1.58,95%CI:1.08-2.30; OR=5.10,95%CI:3.17-8.21). RSV-B, IFV-A and HRV/HEV were associated with moderate/severe asthma attacks, ORs were2.99(95%CI:1.28-6.97),2.28(95%CI:1.01-5.15) and2.94(95%CI:1.35-6.41).
(4) The correlation coefficients were lower than0.30among respiratory viruses or between respiratory viruses and bacteria.The degrees of correlation were moderate between RSV and atmosphere, average month temperature and average sunshine duration, while were low between positive rates of other respiratory viruses and meteorologicalfactors, demonstrating meteorologicalfactors were less affected the epidemiology of respiratory viruses except for RSV.
2. HAdV subtypes and genetic characteristics
(1) Among all the tested children, HAdV subtypes included HAdV-7(48.7%), HAdV-3(37.3%), HAdV-55(3.1%), HAdV-5(2.62%), HAdV-1(2.1%), and HAdV-2(0.5%).
(2) HAdV had a higher positively rate during July2010to June2011. HAdV-7became the predominant subtype from September2010, and caused more dyspnea, moist rales and a longer hospitalization. Compared to HAdV-3, HAdV-7was associated with severe diseases (45.7%vs.18.1%, OR=3.52,95%CI:1.60-7.74, P=0.002).
(3)7d2was the main subtype of HAdV-7. Identities of hexon gene of HAdV-7were99.8%～100%. Phylogenetic tress showed the strains in the study distributed in the7d2and7d lineages with geographical characteristic. The strains from7d lineage were easier to cause severe pneumonia (OR=2.50,95%CI:1.05-5.94). Identities for fiber gene of HAdV-7were99.7%～100%and two mutations were found: C111T and A253G. The latter changed amino acid Thr85GLA.
(4) The sequences of hexon gene of HAdV3formed multiple lineages with geographical differenece and migration events. Four mutations in the fiber gene of HAdV-3were found:T520C (CQ5685)、A567C、C722A (CQ5) and G742A (CQ483). C722A and G742A changed the amino acid:Pro261His and Glu278Lys. Phylogenetic tree demonstrated three lineages and the strains located in A lineage.
(5) Identities of HAdV-55in the study were99.8%～99.9%with other strains from other regions,96.1%-98.7%with HAdV-B2and highest with HAdV-14.
(6) CQ-814(China/2010) was most closely related to HAdV-11a (P14) from Beijing, followed by CQ-1657(China/2011) and CQ-2903(China/2012)(Figure1A). Surprisingly, the closest genetic relationship existed between the2012Chongqing strain (CQ-2903) and the2006Shaanxi strain (QS-DLL). The HAdV-11a strains from mainland China seems to have diverged from their TMRCA with other strains from Taiwan Province/Singapore/South Dakota around15years ago considering the hexon gene,10years ago considering the fiber gene and35years ago considering the whole genome, respectively.
3. HRV and HEV subtype and genetic characteristics
(1) Among1564samples,223(14.3%) were positive for HRV. which included HRV-A120(53.8%), HRV-B11(4.9%) and HRV-C92(41.3%);41(2.6%) were positive for HEV, mainly including HEV-687(17.1%), HEV-71and CV-A65(12.2%), respectively.
(2) C2were the predominant subtype of HRV-C in Chongqing region, and the following were C43, C1and C17. In addition, another5sequences of VP4/2were different from the51known subtypes (more than10%differences). We named them C52, C53and C54.The overall evolutionary rate of VP4/2for HRV-C was6.9×10-3s/s/y (95%HPD:2.5×10-3～12.5×10-3s/s/y). The number of effective infection increased sharply before40years observed from Bayesian skyline plot.
(3) Molecular clock analysis revealed the overall evolutionary rate of VP1for HEV-68was9.6×1O-3s/s/y (95%HPD:6.9×10-3～12.5×10-3s/s/y). On the phylogenetic tree based on VP1gene nucleotide sequences, all modern HEV-68strains were grouped into three separate lineages (Figure2). Six Chinese strains from the study fit into Lineage3, being divided into two branches with a high bootstrap value with divergence in1973. The lineage evolved with a high speed (3.2×10-2s/s/y,95%HPD:2.1×10-2～4.7×10-2s/s/y) before recovered to normal in2008. Positive selectively position was not found on VP1gene. The number of effective infection kept steady, with fluctuating in2～4years before. The migration events inferred across the parsimony genetic phylogenies for the160VP1sequences of HEV-68from19locations among five continents, and their concatenation showed the Japanese province of Yamagata and the American state of Texas acted as the geographic source.
4. HBoV genetic characteristics
(1) Identities forHBoV complete genome were99.4%～100%, and more than97%in the four genes. The sequences of HBoV were conserved.
(2) The phylogenetic trees based on the four genes and complete genome were similar and formed branches with a bootstrap>750support. HBoV-1sequences did not reveal temporal and geographic distribution.
(3) The evolutionary rate of HBoV-1was1.89×1O-4s/s/y (95%HPD:0.01～4.54×1O-4s/s/y), lower than that of HBoV. Selective pressure analyzed that Position40of VPl was the positive selection site, while none were found in NP, NS, and VP2gene.
Conclusions
1. Epidemiological characteristic of respiratory viruses
(1) The positive rate of respiratory viruses was80.3%, demonstrating respiratory viruses was the predominant pathogen in the children with ARTI.
(2) RSV and HAdV were associated with severe pneumonia, while RSV-B,IFV-A and HRV/HEV were related with moderate/severe asthma attack.
2. HAdV
(1) Multiple HAdV subtype circulated in Chongqing region, mainly including HAdV-7, HAdV-3and HAdV-55. HAdV-7caused more severe pneumonia than HAdV-3and others.
(2) The sequences of hexon and fiber genes of HAdV-7and HAdV-3were steady and conserved and geographical distribution. HAdV-7existed with7d and7d2, and7d2may be related with severe diseases. HAdV-55complete genome sequences revealed temporal and geographical distribution.
3. HRV and HEV
(1) HRV-A and HRV-C were the main subtypes of HRV in the children with ARTI and C2was the predominant subtype of HRV-C.Three new subtype of HRV-C were found and named.
(2) This is the first report to detect HEV-68in the children with ARTI in China. The strains in the study formed a branch. HEV-68revealed migration events in the world.
(3) This is the first time to get the complete genome of HEV-118. Phylogenetic tree demonstrated the strain in China differed from that in Peru and Israel.
4. HBoV
(1) The sequences of HBoV-1were conserved and less variant.
(2) The positive selectively site on VP1gene revealed co-existence of purifying and positive selection during the evolution of HBoV-1.
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