Vertical Infection Research Articles

Cyclic cidofovir (cHPMPC) prevents congenital cytomegalovirus infection in a guinea pig model

BackgroundCongenital cytomegalovirus (CMV) infection is a major public health problem. Antiviral therapies administered during pregnancy might prevent vertical CMV transmission and disease in newborns, but these agents have not been evaluated in clinical trials. The guinea pig model of congenital CMV infection was therefore used to test the hypothesis that antiviral therapy, using the agent agent cyclic cidofovir (cHPMPC), could prevent congenital CMV infection.ResultsPregnant outbred Hartley guinea pigs were challenged in the early-third trimester with guinea pig CMV (GPCMV) and treated with placebo, or the antiviral agent, cyclic cidofovir. To optimize detection of vertical infection, an enhanced green fluorescent protein (eGFP)-tagged virus was employed. Compared to placebo, cyclic cidofovir-treated dams and pups had reduced mortality following GPCMV challenge. The magnitude of GPCMV-induced maternal and fetal mortality in this study was reduced from 5/25 animals in the placebo group to 0/21 animals in the treatment group (p = 0.05, Fisher's exact test). By viral culture assay, antiviral therapy was found to completely prevent GPCMV transmission to the fetus. In control pups, 5/19 (26%) were culture-positive for GPCMV, compared to 0/16 of pups in the cyclic cidofovir treatment group (p < 0.05, Fisher's exact test).ConclusionAntiviral therapy with cyclic cidofovir improves pregnancy outcomes in guinea pigs, and eliminates congenital CMV infection, following viral challenge in the third trimester. This study also demonstrated that an eGFP-tagged recombinant virus, with the reporter gene inserted into a dispensable region of the viral genome, retained virulence, including the potential for congenital transmission, facilitating tissue culture-based detection of congenital infection. These observations provide support for clinical trials of antivirals for reduction of congenital CMV infection.

TRANSMISSION OF HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 NEVIRAPINE RESISTANCE MUTATION K103N FROM A TREATMENT-NAIVE MOTHER TO HER CHILD

Vertical infection of drug-resistant human immunodeficiency virus type 1 (HIV-1) has occasionally been reported in children from pretreated mothers with HIV-1 infection. In this report, a treatment-naive mother transmitted HIV-1 resistance mutation K103N against nevirapine to her child.

Hematogenous vertical transmission of herpes simplex virus type 1 in mice.

Herpes simplex virus type 1 (HSV-1) is a neurotropic virus that causes severe disease and death in newborn humans but, to date, it remains unclear how neonatal infection occurs. We show here that the vertical transmission of HSV-1 in mice is mainly hematogenous and involves the colonization of the neonate central nervous system (CNS). HSV-1 DNA was mainly detected in the blood and CNS of the offspring born to latently infected mothers; no significant differences were seen between the viral DNA concentrations in the blood of these mothers and their female progeny (either neonate or adult). The administration of acyclovir during gestation reduced or eliminated both the maternal and the neonatal viral DNA in the blood. Embryo transfer was performed to ensure (as far as possible) that only vertical hematogenous infection took place. Immunohistochemical analysis detected viral proteins in the encephalon of the offspring. Immunofluorescence studies provided immunoreactive evidence of HSV-1 proteins in the neurons of the hippocampus and showed that these viruses can molecularly reactivate after hyperthermia. Neonatal HSV-1 infection therefore appears to be mainly caused by hematogenous vertical transmission, and the viruses that colonize the offspring CNS are capable of molecular reactivation after a period of latency.

Absence of vertical transmission ofHelicobacter pyloriin an experimental murine model

Helicobacter pylori (H. pylori) infection is acquired mainly in early childhood but the precise transmission routes are unclear. This study examined the maternal H. pylori infection status in order to determine the potential of perinatal transmission. These issues were investigated using an experimental murine model, the Mongolian gerbil, which has been reported to be the most suitable laboratory animal model for studying H. pylori. Pregnant Mongolian gerbils, infected experimentally with H. pylori, were divided into two groups. The stomachs of the mother and litters were isolated and assessed for the transmission of H. pylori at the prenatal period (2 weeks after pregnancy) and at the parturition day. The bacterial culture, polymerase chain reaction (PCR) and rapid urease test were used to examine the presence of the transmitted H. pylori. There was no H. pylori observed in any of the fetuses during pregnancy and in the litters at parturition. This suggests that vertical infection during the prenatal period or delivery procedure is unlikely to be route of mother-to-child transmission of a H. pylori infection.

Natural maternal transmission of H. pylori in Mongolian gerbils.

To investigate maternal H. pylori infection status to determine the potential of maternal transmission. In the present study, we examined these issues in an experimental murine model, which is a Mongolian gerbil model that has been reported as an optimal laboratory animal model to study H. pylori. Pregnant Mongolian gerbils, infected experimentally with H. pylori, were divided into as four groups. Following the experimental design, the stomachs of the mother and litters were isolated and assessed for transmission of H. pylori at the prenatal period, parturition day, 1-wk old and 3-wk old respectively. Bacterial culture and polymerase chain reaction (PCR) were used to examine the presence of transmitted H. pylori. All litters showed no transmission of H. pylori during pregnancy and at parturition day. However, they revealed 33.3% and 69.6% at 1-wk and 3-wk of age respectively by PCR. These results suggested that vertical infection during the prenatal period or delivery procedure is unlikely as a route of mother-to-child H pylori infection. It may be that H. pylori is acquired through breast-feeding, contaminated saliva and fecal-oral transmission during co-habitation.

Growth in the First 5 Years of Life is Unaffected in Children with Perinatally-acquired Hepatitis C Infection

To identify the effect of vertical hepatitis C virus (HCV) infection or exposure on growth in childhood. Children (n=1203) born to HCV-infected mothers were followed up from birth prospectively in centers of the European Paediatric Hepatitis C virus Network. Z-scores compared height- and weight-for-age in HCV-infected and -uninfected children, adjusting for other factors using linear regression. We also quantified the effect of maternal chronic infection with HCV on childhood growth. There was no significant effect of vertical HCV infection on growth (height P=.223, weight P=.095) nor a significant effect of maternal chronic infection with HCV (height P=.733, weight P=.274). Prematurity and maternal injecting drug use were associated with a significant reduction in height (P < .001) and weight (P < .001) in all HCV-exposed children. This population of HCV exposed infants has higher rates of maternal injecting drug use and prematurity than standard populations and so there are implications for growth of these children, but this is not a direct result of HCV infection or exposure to chronic maternal HCV infection.

Three Broad Modalities in the Natural History of Vertically Acquired Hepatitis C Virus Infection

Little is known about the natural history of vertically acquired hepatitis C virus (HCV) infection. We performed a large, multicenter, prospective study of children born to HCV-infected women in Europe. Children were considered to be infected on the basis of > or = 2 polymerase chain reaction (PCR) test results positive for HCV RNA and/or test results positive for anti-HCV antibody > 18 months after birth. Two hundred sixty-six children with vertical HCV infection were followed up until a median of 4.2 years of age (range, 3.2 months to 15.9 years of age). Twenty-six children were coinfected with human immunodeficiency virus. Hepatomegaly, the only clinical sign reported, was found in 10% of children and was significantly associated with a high proportion of abnormal alanine transaminase (ALT) levels (adjusted odds ratio [OR], 4.17; 95% confidence interval [CI], 1.67-10.42; P = .002). An estimated 21%-25% of children may have cleared the virus (i.e., had 2 consecutive PCR test results negative for HCV RNA, normal ALT levels, and no clinical signs) at a median age of 14.9 months. A high proportion of positive PCR test results obtained in the first year of life was associated with a lower likelihood of clearance (OR, 9.77; 95% CI, 2.92-32.67; P < .0001) and persistent viremia in children > 1 year old (adjusted OR, 2.92; 95% CI, 1.09-7.80; P = .03). We confirm the low prevalence of HCV-related clinical signs and symptoms among vertically infected children in the first 10-15 years of life. Approximately 20% of children appear to clear the infection, 50% have evidence of chronic asymptomatic infection, and 30% have evidence of chronic active infection. Although viremia and abnormal ALT levels were associated with hepatomegaly, further investigation is necessary before these markers can be used in the clinical management of HCV infection in children.

Children with HIV: improved mortality and morbidity with combination antiretroviral therapy

Advances in the management of children with vertical HIV-1 infection in the developing and developed worlds are discussed in reference to literature published in 2003/4. Studies in mother-to-child transmission are beyond the scope of this review. Improvements in mortality and morbidity from HIV-1 infection following combination antiretroviral therapy are extremely encouraging. There is an increase in the understanding of the immune response to HIV-1 in infants and children and a possible future role for immunomodulatory therapies. Preliminary data are available on the timing of initiation of antiretroviral therapy, the optimization of drug combinations and the clinical interpretation of genotypic resistance testing and therapeutic drug monitoring. Evidence is emerging that early antiretroviral therapy can protect the central nervous system in infants. In resource-limited settings, mortality and morbidity remain extremely high but low-cost health interventions such as prophylactic co-trimoxazole can reduce mortality prior to the expansion of antiretroviral therapy programmes. Further randomized controlled trials assessing antiretroviral therapy combinations with a sustained virological/immunological response with minimal toxicities are required. The roles of therapeutic drug monitoring and resistance testing require further elucidation. The expansion of antiretroviral therapy programmes is essential for children with HIV living in resource-limited settings.

Short antibiotic prophylaxis for bacterial infections in a neonatal intensive care unit: a randomized controlled trial

We compared the effectiveness of a single dose and a three-day course of antibiotic prophylaxis in preventing bacterial infections in high-risk neonates. The study was a prospective, randomized controlled trial conducted in a 20-bed tertiary referral neonatal intensive care unit (NICU). A series of 130 neonates admitted consecutively to the NICU, fulfilling risk factors for infection, were assigned at random to receive intravenous antibiotic prophylaxis with ampicillin and netilmicin either in two daily doses for 72 h (three-day-administration group, 67 infants) or in a single bolus injection on admission (bolus group, 63 infants). Hospital-acquired infection, the main outcome measure, was defined as infection that developed at least 48 h after admission, and vertical infection (maternally transmitted) was considered to be present when clinical symptoms and abnormal laboratory findings became evident within 48 h of birth. Infections were considered as suspected when clinical and laboratory findings of infection were present, without positive cultures, and as confirmed when positive cultures were also present. No significant differences were found between the two groups of neonates studied in mean birth weight, gestational age or postnatal age on admission. The incidence of vertical infection was similar in the two groups (16/67, 23.9% vs. 14/63, 22.2%). Of the 130 newborns studied, 29 (22.3%) acquired at least one nosocomial infection during their NICU stay; total hospital-acquired infections, calculated as the incidence density of infection (the number of infective episodes divided by the number of days in the NICU), were less frequent among newborns who received the three-day course than the bolus (relative risk 0.69). This difference, although not statistically significant, depended on the different incidence density of confirmed nosocomial infections rather than on suspected infections (relative risk 0.59; 95% confidence interval 0.32-1.09; P=0.1). There were no significant differences between the two groups in overall mortality. A single bolus administration on admission is therefore likely to be as effective as a three-day course of antibiotic prophylaxis in preventing bacterial infection in high-risk infants admitted to an NICU.

Immunosuppression in progeny of chinook salmon infected with Renibacterium salmoninarum: re-analysis of a brood stock segregation experiment

Female spawner infection level and temperature variation through rearing are sufficient to explain in-hatchery mortality rates and infection levels and smolt to adult return ratios (SARs) of progeny of Renibacterium salmoninarum infected spring chinook salmon. Data from published reports and manuscripts regarding a 1988 brood stock segregation experiment that held progeny of highly infected female spring chinook salmon spawners separate from progeny of other spawners during 16 mo of hatchery rearing are analyzed to test the hypothesis that immunosuppression could account for differences in survival and infection levels between the 2 segregates. Immunosuppression, caused by the presence of the p57 antigen of R. salmoninarum in sufficient concentration within the salmon egg before spawning, can account for differences in infection levels, mortality rates, and SARs for each hatchery raceway in that study. This immunosuppression may be characterized by immunotolerance, or might only affect cell mediated immunity, which appears the most effective defense mechanism against R. salmoninarum infection, as antibody production can result in tissue damaging antibody-antigen complexes. Low-temperature mediated immunosuppression can account for the nearly identical trajectories of infection and mortality between the 2 segregates during the first 8 mo of hatchery rearing. There is no evidence of widespread vertical infection from spawner to progeny, nor is there evidence that brood stock segregation reduces overall mortality. Rather, the suppression of cell-mediated immune mechanisms may condemn progeny of highly infected female spawners to an almost certain eventual premature demise.

Sperm washing, use of HAART and role of elective Caesarean section

Today, 50% of people living with HIV are women and most have been sexually infected. Highly active antiretroviral therapy (HAART) reduces the rates of both sexual and vertical infection, but maximum protection is achieved with sperm washing and elective Caesarean section. Men taking HAART have lower seminal concentration of HIV, and sexual transmission may be reduced. However, a certain percentage of aviraemic men retain viral presence in semen, and unprotected intercourse to achieve fertilization must be discouraged as it carries the risk of sexual transmission of the virus. HIV-discordant couples should be informed that sperm washing can remove HIV from semen, allowing conception without the risk of infection for the seronegative female and eventually the child. In HIV-positive women, perinatal transmission of HIV can be curtailed to less than 2% by using HAART to decrease maternal viral load and offering prenatal preexposure prophylaxis of the fetus, and elective Caesarean section. Each intervention carries specific risks and benefits. The contribution of each preventive arm in achieving fetal protection can only be crudely measured and optimal obstetric management must involve discussion with the pregnant woman of the pros and cons of each strategy. In HIV-positive men taking HAART, seminal viral load is decreased but not eliminated and fertilization should be achieved through sperm washing to offer maximum protection for the uninfected female. Pregnant HIV-positive women on antiretroviral medication have a reduced risk of transmitting the virus, but should still be counselled about the possibility to further limit the chances of infecting their infant through elective Caesarean section.

Vertical Dengue Infection

Two vertical dengue infection cases are presented, and 15 others are reviewed. Twelve mothers had fever 0-9 (median, 2) days antepartum. The fevers of 17 neonates occurred at 1-11 (median, 4) days of life and lasted for 1-5 (median, 3) days. Neonatal thrombocytopenia was detected at 1-11 (median, 6) days of life and lasted for 3-18 (median, 6) days; the lowest platelet counts were 5-75 x 10(3) (median, 19 x 10 (3))/mm3. One neonate died.

P0530 DIFFERENT CLINICAL PATTERNS OF GASTROINTESTINAL CYTOMEGALOVIRUS INFECTION IN IMMUNOCOMPETENT CHILDREN: REPORT OF FOUR CASES

Introduction: Gastrointestinal manifestations of Cytomegalovirus (CMV) infection have been frequently observed in mmunocompromised subjects, while are rare in immunocompetent individuals and particularly in children. Methods: We report four cases of immunocompetent paediatric patients affected by different gastrointestinal diseases caused by CMV infection observed during the last two years and whose medical records were reviewed with regard to clinical and laboratory data and outcome. Results: We observed 4 patients: 2 with severe protracted diarrhoea, 1 with severe hemorrhagic colitis and 1 with gastro-esophageal reflux. They shared uneventfully birth, unrelative parents, beginning of symptoms in the first months of life, no underlying disease, no bacterial pathogens nor Giardia antigen isolation, histologic evaluation of duodenal mucosa with no macroscopic lesions, positive CMV-polimerase chain reaction (PCR) in urine, stool, gastric aspirate and intestinal mucosa. Specific inclusions were seen only in duodenal mucosa of patient 2. All patients needed for prolonged artificial nutrition and showed food allergy and a recurrence of infections during their hospital stay. Case 1. S.A. Male, born in March 2002 presenting a protracted diarrhea. The diagnosis was made only after 3 months of PN and because of his improved condition and parents refusal he was not treated with antiviral agent. Case 2. V.P. Male, born in December 2002, presenting with a protein-loosing protracted diarrhea. In this case too we failed to demonstrate the presence of CMV-IgM but he had high CMV-IgG and received an intravenous therapy with ganciclovir. Now he is still on HPN after nine months, now associated with a partial oral alimentation, and he is still treated with ganciclovir by mouth. Case 3. F.E. Female, born in June 2002, showing a severe hemorrhagic colitis and needed total PN for 13 months and ganciclovir several treatments first given intravenously and then by mouth. Case 4. F.A. Male, born in April 2003, at two months of age he began to present vomiting, food refusal and recurrent upper respiratory tract infections. He was started on enteral nutrition. He had a positive CMV-PCR in gastric aspirate, urine, and gastric mucosa. He was treated with ganciclovir by month. Conclusion: Our experience seems to demonstrate that CMV gastrointestinal infection with severe symptoms is less rare than we are used to think also in children. It could be more frequent as vertical infection in gastroesophageal reflux and as primary infection in enterocolitis and that pharmacological treatment may not be indispensable.

Which patients with chronic hepatitis B are more likely to relapse after interferon alpha-induced hepatitis B e antigen loss in Korea?

Although hepatitis B e antigen (HBeAg) loss after interferon-alpha (IFN-alpha) therapy in patients with chronic hepatitis B is durable in whites, frequent relapse of hepatitis B virus (HBV) has been reported in endemic areas. This study was to evaluate the durability of interferon-induced HBeAg loss and find the risk factors for relapse. We retrospectively analyzed 32 patients with IFN-alpha-induced HBeAg loss. They were followed up to 50 months. Age, sex, presumed route of infection, pretreatment levels of serum alanine aminotransferase and HBV DNA, and histologic findings were evaluated as potential risk factors for relapse. The cumulative relapse rates at 1-, 2- and 3-year were 25.5%, 35.7%, and 43.5%, respectively. They were higher in the older patients (>37 years) than in the younger ones (43.5% vs. 6.7% at 1-year, 50.6% vs. 20% at 2-year, and 64.7% vs. 20% at 3-year; P = 0.017). Patients with presumed vertical HBV infection tended to have a higher relapse rate (P = 0.11). Old age and presumed vertical infection were 2 independent risk factors for relapse. Relapse after IFN-alpha-induced HBeAg loss was common in this endemic area, especially in old patients and in those with presumed vertical HBV infection. Intensive surveillance and other therapeutic modalities would be necessary for these patients.

Hypermutation of HIV type 1 genomes isolated from infants soon after vertical infection.

Hypermutation involving excessive G-to-A substitutions in the dinucleotide context GA or GG is common among the lentiviruses and results in multiple stop codons across the genome. Hypermutated viruses have been associated with slower disease progression and might reflect an antiviral cell-defense mechanism. However, it is unclear how soon G-to-A substitutions are generated after infection and whether they occur randomly along the genome. In this report we describe for the first time hypermutated sequences detected at delivery and in the first weeks of life, which suggests that they could be either generated in utero and soon after birth and/or vertically transmitted. Hypermutated C2-C5 env clones were harbored in 13.2% of 243 infants and 18.6% of 199 mothers. A lower extent of hypermutation was found in infants than in mothers (Fisher's exact p = 0.034), but there was no relationship between the percent hypermutated Gs and viral subtype or transmission status of the mother. Analyses of six hypermutated full-length HIV-1 clones showed that although all genes could be affected by G-to-A substitutions, there was a significant drop in the extent of hypermutation between the central polypurine tract and the beginning of env, indicating that hypermutation across the HIV-1 genome might occur in a specific pattern. The genomic regions most affected by hypermutation were pol and env while both polypurine tracts remained unaffected. A better understanding of the mechanism of hypermutation may reveal novel virus-host interactions that could be targeted in drug development.

CD8+CD28- T cells in vertically HIV-infected children.

To evaluate whether vertical HIV infection interferes with the expression of CD28 on T lymphocytes, 25 HIV-infected children and 29 seroreverted children born to HIV+ mothers were studied. The percentage of CD28- cells among CD8+ T lymphocytes was higher in HIV-infected children than in controls (P < 0.001). In fact, in HIV-infected children, this percentage was elevated from the first year of life, while in healthy seroreverted children, the proportion of CD28- cells among CD8+ cells rose progressively with age (r = 0.49; P = 0.008). In HIV+ children, the CD8+ CD28-, but not CD8+ CD28+ cell proportion was significantly correlated with immunological markers of disease progression, such as CD4+ cell loss (r = -0.65; P < 0.001) and the level of in vitro spontaneous lymphocyte apoptosis (r = 0.53; P = 0.03).

Neuroprotective effects of early antiretrovirals in vertical HIV infection

We performed a retrospective study of a series of 58 of 189 vertically HIV-1 infected children who went on to develop progressive HIV-1-associated encephalopathy to assess real-life effects of early antiretroviral therapy on neurologic outcome. Our findings clearly indicate that antiretroviral therapy before the onset of neurologic symptoms delayed presentation of progressive HIV-1-associated encephalopathy, with an additional beneficial effect on survival.

Abortion epidemic in a dairy herd associated with horizontally transmitted Neospora caninum infection

A dairy herd experienced an abortion epidemic during which 43 per cent of the cows at risk aborted. Neospora caninum infection was demonstrated in four of six fetuses suitable for...

Consumo de drogas durante el embarazo y morbilidad neonatal: cambios epidemiológicos en los últimos 10 años

In the last few years, patterns of drug abuse have varied. This may have changed the problems presented by the infants of drug-abusing mothers. To determine the incidence of prenatal drug-exposure in neonates in our health area in the last decade, to analyze possible changes in the drugs consumed, routes of administration and the infectious diseases affecting drug-abusing mothers, and to study possible changes in the clinical features presented by their offspring. An observational, descriptive, retrospective study of all the infants born to drug-abusing mothers from January 1, 1992 to December 31, 2001 was performed. The series was analyzed and the periods 1992-1996 and 1997-2001 were compared. The mean incidence was 7.5 cases per 1000 live-born infants (8.7 in 1992-1996 and 6.3 in 1997-2001). Mothers in the second half of the study were less likely to use heroin and the intravenous route and were more likely to use methadone and cocaine than mothers in the 1997-2001 period. Hepatitis C virus infection and instrumental delivery were more frequent in the 1997-2001 period. No differences were found in neonates born in either period. Birthweight was less than 2500 g in 40 % and was low for gestational age in 20 %. Preterm deliveries were performed in 24 %. Congenital malformations were found in 6 %, neonatal withdrawal syndrome in 79 %, human immunodeficiency virus infection in 2 %, and hepatitic C virus infection in 3 %. Four percent were given in adoption. Maternal drug abuse patterns changed in the ten years under study, but outcome in their offspring showed no differences. Drug abuse by pregnant women is linked to a high rate of low birthweight, prematurity, neonatal withdrawal syndrome, vertical infection by human immunodeficiency virus and hepatitis C virus, as well as to social and family problems.

Hepatitis C virus in human immunodeficiency virus-infected individuals: an emerging comorbidity with significant implications.

As antiretroviral (ARV) therapy has become more effective, hepatitis C virus (HCV) infection has emerged as an important cause of morbidity and mortality in human immunodeficiency virus (HIV)-infected individuals. HIV alters HCV clinical presentation, epidemiology, virology, and pathogenesis compared with HCV monoinfected individuals. The incidence of chronic and vertical HCV infection is increased, the rate of hepatic fibrosis progression is accelerated, peripheral and intrahepatic HCV RNA levels are increased, and end-stage liver disease (ESLD) and cirrhosis develop more rapidly in coinfected individuals. Based on these observations, combined with the increased efficacy of ARV therapy, several societies have recommended the diagnosis and treatment of HCV in coinfected individuals. HCV treatment with nonspecific antivirals, pegylated interferon alpha (PEG-IFN) and ribavirin (RBV), is more complex in coinfected individuals compared with monoinfected individuals because these regimens appear to have decreased efficacy and the incidence of complications is increased. Although new HCV-specific regimens show early promise in HCV monoinfected individuals, it is likely that these agents will be used in combination with nonspecific therapies and additional studies will be required to evaluate their efficacy in coinfected individuals.