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ABSTRACT PreS/S gene mutations could impact virus secretion, infection and immune evasion. However, the relationship between PreS/S mutations and intrauterine transmission has not yet been clarified. Thus, we aimed to explore the associations between PreS/S gene mutations of HBV isolated from mothers and intrauterine transmission. We analyzed the mutations of PreS/S regions of the HBV genome in mothers with HBV DNA levels ≥ 106 IU/mL whose neonates experienced HBV intrauterine transmission (transmission group, GT) and those whose neonates did not experience intrauterine transmission (control group, GC) analyzed using clone-based sequencing. In total, 206 sequences were successfully amplified, including 98 sequences (from 21 mothers) from GT and 108 sequences (from 20 mothers) from GC of genotype C for mutational analysis. Among the 1203 nucleotides of PreS/S regions, there were 219 (18.20%) base substitutions, of which 103 (47.03%) base mutations caused amino acid changes. F80S, A90V and I68T were mutation hotspots. Mothers in GT had a higher mutation rate of A90V in the PreS1 gene than mothers in GC. The A90V mutation increased the risk of HBV intrauterine transmission after adjusting the maternal age and the mode of delivery (OR = 6.23, 95% CI: 1.18-32.97). Moreover, the area under the ROC curve (AUC) for intrauterine transmission due to A90V and a combination of A90V with the mode of delivery were 0.723 (95% CI: 0.575 to 0.891, P = 0.011) and 0.848 (95% CI: 0.723 to 0.972, P < 0.001), respectively. Mothers with the A90V mutation in the PreS1 gene may be a potential risk factor for HBV intrauterine transmission.
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OBJECTIVE@#To investigate the relationship between maternal peripheral blood mononuclear cells (PBMC) hepatitis B virus (HBV) covalenty closed circular deoxyribonucleic acid (cccDNA) and other HBV serological markers and its effects on HBV intrauterine transmission.@*METHODS@#We enrolled 290 newborns and their hepatitis B surface antigen (HBsAg) positive mothers. HBV cccDNA in PBMC and HBV DNA in serum were detected by a real-time PCR-TaqMan probe while HBV serological markers were detected with an electrochemiluminescence immunoassay.@*RESULTS@#There was a positive correlation between the levels of PBMC HBV cccDNA and serum HBV DNA and HBeAg (r = 0.436 and 0.403, P < 0.001). The detection rate of pattern A ['HBsAg (+), HBeAg (+), and anti-HBc (+)'] was significantly higher in the PBMC HBV cccDNA positive group than in the control group (χ2 = 48.48, P < 0.001). There was a significant association between HBV intrauterine transmission and PBMC HBV cccDNA (χ2 = 9.28, P = 0.002). In the presence of serum HBV DNA, HBeAg, and PBMC HBV cccDNA, the risk of HBV intrauterine transmission was three times higher (OR = 3.69, 95% CI: 1.30-10.42) than that observed in their absence. The risk of HBV intrauterine transmission was the greatest (OR = 5.89, 95% CI: 2.35-14.72) when both PBMC HBV cccDNA and pattern A were present. A Bayesian network model showed that maternal PBMC HBV cccDNA was directly related to HBV intrauterine transmission.@*CONCLUSION@#PBMC HBV cccDNA may be a direct risk factor for HBV intrauterine transmission. Our study suggests that serological markers could be combined with PBMC-related markers in prenatal testing.
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Adolescent , Adult , Female , Humans , Infant, Newborn , Male , Middle Aged , Young Adult , DNA, Viral , Blood , Disease Transmission, Infectious , Hepatitis B , Hepatitis B e Antigens , Blood , Leukocytes, Mononuclear , VirologyABSTRACT
Objective@#To investigate the expression of IL-18 in peripheral blood of HBsAg positive parturients in intrauterine transmission of HBV.@*Methods@#A case-control study was conducted in 282 HBsAg positive parturients and 43 health parturients (control group) in Northwest Women and Children Hospital of Shaanxi Province. Enzyme-linked immunosorbent assay (ELISA) was used to detect five serological makers of hepatitis B, real time PCR was used to detect HBV DNA, and flow liquid chip method was used to detect IL-18 levels in peripheral blood of parturients and newborns.@*Results@#The incidence of dominant HBV infection (DBI), occult HBV infection (OBI) and intrauterine transmission of HBV were 8.42% (24/285), 40.00% (114/285) and 48.42% (138/285), respectively. The level of IL-18 in peripheral blood of HBsAg-negative parturients were significantly lower than those of HBsAg-positive parturients (P=0.001), non-HBV intrauterine transmission (NBIT) group (P=0.001) and OBI group (P<0.001). The level of IL-18 in HBeAg negative group was significantly lower than that in HBeAg positive group (P=0.023). When HBV DNA load was ≥103 copies/ml, the level of IL-18 was significantly higher than that in HBsAg-negative group (P<0.01). With the increase of HBV DNA load in maternal blood, the level of IL-18 increased (P=0.024). When HBV DNA load was 103-106 copies/ml, the level of IL-18 in DBI group was significantly lower than that in NBIT group (P=0.022), and increased with the increase of HBV DNA load in maternal blood (P=0.016). With the increased severity of intrauterine transmission of HBV, the level of IL-18 in non-hepatitis B vaccine group decreased significantly (P=0.044). The level of IL-18 in non-hepatitis B vaccine group and immunoglobulin injection group was significantly higher than that in NBIT group (P<0.05). Multivariate analysis showed that the linear relationship between maternal HBeAg status and maternal IL-18 levels had statistical significance (P=0.01).@*Conclusions@#IL-18 is a higher level balance regulator of Th1/Th2 immune network. Monitoring the level of IL-18 in HBsAg-positive parturients can be used not only for predicting the probability of DBI and OBI, but also as an intervention mean, especially for those who are HBeAg-positive and had HBV DNA load ≥103 copies/ml, to improve maternal cellular immune function, which is conducive to interrupting intrauterine transmission and providing a theoretical basis for the prevention and control of HBV intrauterine transmission.
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Objective@#To explore the role of TLR 9 in intrauterine transmission of hepatitis B virus (HBV) through blood pathway and placenta.@*Methods@#Epidemiological investigation was carried out in 290 HBsAg positive parturients and 45 normal parturients (control group) in Northwest Women and Children Hospital of Shaanxi Province. Enzyme-linked immunosorbent assay (ELISA) was used to detect five serological makers of hepatitis B and TLR 9 levels in peripheral blood of pregnant women and newborns. HBV DNA was detected by real-time fluorescence quantitative PCR. Detection of TLR 9 expression in placenta by immunohistochemical method. A case-control study was conducted to analyze the difference of TLR 9 levels in placenta and peripheral blood of HBsAg- positive pregnant women with intrauterine transmission of HBV.@*Results@#The incidence of dominant HBV infection (DBI), occult HBV infection (OBI) and intrauterine transmission of HBV were 9.28% (27/291), 40.21% (117/291) and 49.48% (144/291) respectively. (1) The level of TLR 9 in peripheral blood of HBsAg-positive parturients, non-HBV intrauterine transmission (NBIT) group and OBI group were significantly lower than that of control group (P<0.001). The level of TLR 9 in DBI group was significantly higher than those in NBIT group and OBI group (P=0.000). (2) The TLR 9 level in HBeAg-negative group was significantly lower than that in HBeAg-positive parturients in OBI group (P=0.01). (3) With the increased severity of intrauterine transmission of HBV in each HBV DNA load group, the TLR 9 level in maternal peripheral blood increased significantly (P<0.05). (4) With the increased severity of intrauterine transmission of HBV, the levels of TLR 9 increased significantly in antiviral therapy, immunoglobulin injection and non-hepatitis B vaccine groups (P<0.05). (5) The expression of TLR 9 in placenta tissues with DBI group was significantly higher than that in OBI group and NBIT group (P<0.05).@*Conclusions@#HBV can inhibit the secretion of TLR 9 in parturient to some extent, but HBeAg can stimulate the secretion of TLR 9. However, with the increased severity of intrauterine transmission of HBV, the level of TLR 9 in parturients is increased by intra-group cross-differentiation. Therefore, TLR 9 is not an independent marker for screening and grouping, but it can be used as an reference indicator for the monitoring and management of HBsAg-positive parturients.
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Objective@#To investigate the current status and influence factors of HBV intrauterine transmission (BIT) in HBsAg-positive parturients and understand the outcome of HBV transmission and response to hepatitis B vaccine immunization in children in Xi’an.@*Methods@#An epidemiological survey was conducted in 341 HBsAg-positive parturients who gave birth in Northwest Women and Children Hospital of Shaanxi Province from January 2015 to January 2018. Serological tests were performed by using venous blood from 344 newborns within 24 hours after birth and at the age of 1 year old. A nested case-control study was conducted to analyze the infection rates of intrauterine dominate HBV infection (DBI) and intrauterine occult HBV infection (OBI) in BIT and their influencing factors in newborns. The epidemiological survey was conducted to collect the information about the outcome of HBV transmission and the positive rate of HBsAb in children at high-risk from August 2016 to October 2018.@*Results@#The BIT rate was 46.51%(160/344) in HBsAg-positive parturients, the DBI rate was 8.14% (28/344), the OBI rate was 38.37% (132/344), and the odds ratio of DBI and BIT in neonates of HBeAg-positive parturients were respectively 2.60 (95%CI: 1.19-5.70) and 2.21 (95%CI: 1.36-3.61) times higher than that of HBeAg-negative parturients. The odds ratio of BIT in neonates with maternal peripheral blood HBV DNA load ≥200, ≥103 and>106 copies/ml were 1.99 (95%CI: 1.29-3.08), 1.73 (95%CI: 1.11-2.69) and 2.33 (95%CI: 1.33-4.10) times higher than those in neonates with maternal peripheral blood HBV DNA<200,<103, and ≤106 copies/ml respectively. The incidence of DBI in neonates of parturients with placenta previa was 14.07 times higher than that of parturients without placenta previa (95%CI: 1.23-160.76). The incidence of BIT in neonates of parturients who received no hepatitis B immunoglobulin during pregnancy was 1.60 times higher than that in neonates of those who received hepatitis B immunoglobulin (95%CI: 1.02-2.53). Follow-up results showed that HBsAg negative conversion was found in 9 of 14 children with DBI, and 24.17%(22/91) of children had OBI. The overall rate of immune response to hepatitis B vaccine was 69.23%(63/91). The immune response rate in children with OBI was only 59.09%(13/22).@*Conclusion@#Newborns of HBsAg-positive parturients had high rate of OBI and lower rate of immune response to hepatitis B vaccine detected in follow-up, indicating a gap in hepatitis B prevention and control. HBV monitoring and intervention in HBsAg-positive women of childbearing age and hepatitis B antibody monitoring in children at high-risk are important measures to control infection source and protect susceptible population.
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The new research of intrauterine transmission of HBV includes intrauterine dominant infection and occult infection. Intrauterine dominant infection of HBV is the traditional intrauterine infection. Although intrauterine infection of HBV has been studied for decades, the intervention effects on HBV infection are very limited. As a result, mother to child transmission has become the main route of the transmission of HBV. With the development of science and technology, people’s understand of intrauterine occult infection of HBV has been deepened, and the definition of intrauterine transmission of HBV has been further completed and expanded. The study of intrauterine occult infection of HBV will play an important role in prevention and control of hepatitis B in China through filling in a gap in the field of prevention and control of vertical transmission of HBV, exploring new research perspective and providing guideline for related decision-making.
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Objective To explore the relationship between HBeAg in HBsAg positive mothers and CD4 + CD25 + Foxp3 + regulatory T cells (Treg) in newborns,as well as how they would influence the increasing risk on HBV intrauterine transmission.Methods We collected information on general demographic characteristics and delivery on 270 HBsAg positive mothers and their newborns from the Third People's Hospital of Taiyuan.Fluorescence quantitative polymerase chain reaction (FQ-PCR) and chemiluminescence immunoassay (CLIA) were used to detect HBV DNA and HBV serological markers in peripheral blood from both mothers and neonates.The expression of Treg and other immune cells in peripheral blood of neonates were detected with flow cytometry (FCM).Results Maternal HBeAg positive rates were associated with an increased risk of intrauterine transmission (0R=4.08,95％ CI:1.89-8.82).Rates of T.reg in newborns born to HBsAg-positive mothers were higher than that of the negative group (Z=2.29,P=0.022).Each pair of the subjects was assigned to five different groups according to the HBeAg titers of mothers.Frequencies of both Treg and HBeAg in newboms and HBV DNA in mothers between the above said 5 groups showed similar trends of changing patterns and the differences between groups were statistically significant (x2=18.73,P＜0.001;x2=181.60,P＜0.001;x2=183.09,P＜0.001).Results from partial correlation analysis showed that after adjusting for neonatal HBeAg and maternal HBV DNA,mother's HBeAg titers were positively related to the percentage of Treg in their newboms (rs=0.19,P=0.039).In addition,the frequencies of Treg were negatively correlated with pDC and CD4 + T cell in their newborns (rs=-0.21,P=0.017;r,=-0.23,P=0.009).Conclusion HBeAg from HBsAg positive mothers might have inhibited the function of neonatal DC cells and T cells to reduce the immune response to HBV by up-regulating the proportion of Treg and finally increased the risk of HBV intrauterine transmission.
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Objective To explore the relationship between HBeAg in HBsAg positive mothers and CD4 + CD25 + Foxp3 + regulatory T cells (Treg) in newborns,as well as how they would influence the increasing risk on HBV intrauterine transmission.Methods We collected information on general demographic characteristics and delivery on 270 HBsAg positive mothers and their newborns from the Third People's Hospital of Taiyuan.Fluorescence quantitative polymerase chain reaction (FQ-PCR) and chemiluminescence immunoassay (CLIA) were used to detect HBV DNA and HBV serological markers in peripheral blood from both mothers and neonates.The expression of Treg and other immune cells in peripheral blood of neonates were detected with flow cytometry (FCM).Results Maternal HBeAg positive rates were associated with an increased risk of intrauterine transmission (0R=4.08,95％ CI:1.89-8.82).Rates of T.reg in newborns born to HBsAg-positive mothers were higher than that of the negative group (Z=2.29,P=0.022).Each pair of the subjects was assigned to five different groups according to the HBeAg titers of mothers.Frequencies of both Treg and HBeAg in newboms and HBV DNA in mothers between the above said 5 groups showed similar trends of changing patterns and the differences between groups were statistically significant (x2=18.73,P＜0.001;x2=181.60,P＜0.001;x2=183.09,P＜0.001).Results from partial correlation analysis showed that after adjusting for neonatal HBeAg and maternal HBV DNA,mother's HBeAg titers were positively related to the percentage of Treg in their newboms (rs=0.19,P=0.039).In addition,the frequencies of Treg were negatively correlated with pDC and CD4 + T cell in their newborns (rs=-0.21,P=0.017;r,=-0.23,P=0.009).Conclusion HBeAg from HBsAg positive mothers might have inhibited the function of neonatal DC cells and T cells to reduce the immune response to HBV by up-regulating the proportion of Treg and finally increased the risk of HBV intrauterine transmission.
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Objective To investigate the influence factors of non-responsiveness and lowresponsiveness to hepatitis B vaccine of infants born to hepatitis 1 surface antigen (HBsAg) positive mothers.Methods A total of 219 HBsAg positive mothers and their full-term neonates were selected from July 2011 to December 2012 in the Third People's Hospital of Taiyuan.Serologic hepatitis B virus (HBV) markers and HBV DNA load of mothers and their neonates were determined.Neonates were followed up for 12 months to observe the effect of HBV intrauterine infection,hepatitis B e antigen (HBeAg) status,sex,delivery mode,feeding option and suffering from infectious disease during followup period on the immune response to hepatitis B vaccine.Chi-square test was used in univariate analyses and unconditional Logistical regression was used in multivariate analyses.Results There were 16 cases of non-responsiveness and 33 cases of low-responsiveness in all 219 neonates.The rate of non-responsiveness and low-responsiveness was 22.37 ％.In univariate analyses,neonatal HBeAg positivity (x2 =4.895,P=0.027),natural birth (x2 =5.210,P=0.022),suffering from infectious diseases during follow-up period (x2 =4.329,P=0.037) were significantly associated with non-responsiveness and low-responsiveness.There was no relationship between mother HBeAg positivity and the level of response to hepatitis B vaccine.In multivariate analyses,natural birth (OR=2.022,95 ％CI:1.045-3.914) and suffering from infectious diseases (OR=2.324,95 ％ CI:1.058-5.103) were associated with non-responsiveness and low-responsiveness.Conclusion Infants born to HBsAg positive mothers with natural birth or suffering from infectious diseases during follow-up period are more likely to be non-responsiveness and lowresponsiveness to hepatitis B vaccine.