Thillagavathie Pillay

CD8 Epitope Escape and Reversion in Acute HCV Infection

In the setting of acute hepatitis C virus (HCV) infection, robust HCV-specific CD8+ cytotoxic T lymphocyte (CTL) responses are associated with initial control of viremia. Despite these responses, 70–80% of individuals develop persistent infection. Although viral escape from CD8 responses has been illustrated in the chimpanzee model of HCV infection, the effect of CD8 selection pressure on viral evolution and containment in acute HCV infection in humans remains unclear. Here, we examined viral evolution in an immunodominant human histocompatibility leukocyte antigen (HLA)-B8–restricted NS3 epitope in subjects with acute HCV infection. Development of mutations within the epitope coincided with loss of strong ex vivo tetramer and interferon γ enzyme-linked immunospot responses, and endogenous expression of variant NS3 sequences suggested that the selected mutations altered processing and presentation of the variant epitope. Analysis of NS3 sequences from 30 additional chronic HCV-infected subjects revealed a strong association between sequence variation within this region and expression of HLA-B8, supporting reproducible allele-specific selection pressures at the population level. Interestingly, transmission of an HLA-B8–associated escape mutation to an HLA-B8 negative subject resulted in rapid reversion of the mutation. Together, these data indicate that viral escape from CD8+ T cell responses occurs during human HCV infection and that acute immune selection pressure is of sufficient magnitude to influence HCV evolution.

Maternal mortality associated with tuberculosis-HIV-1 co-infection in Durban, South Africa.

ObjectivesTo document the impact of tuberculosis and HIV-1 on maternal mortality. DesignProspective study, 1997 and 1998; retrospective analysis, 1996. ParticipantsKnown maternal deaths, defined as the death of a mother within a year post-delivery, were studied in Durban, KwaZulu Natal. The HIV-1 status, presence of tuberculosis, maternal clinical features and perinatal outcomes were documented. The overall as well as HIV-1 and tuberculosis-specific maternal mortality rates for the hospital were calculated. The attributable fraction of deaths as a result of HIV-1 was calculated in the overall group and in those with tuberculosis co-infection. ResultsA total of 50 518 deliveries and 101 maternal deaths were recorded. Of the deaths, 29.7% (30/101) were HIV-1 infected. The overall mortality rate was 200/100 000; for HIV-1-infected women this was 323.3/100 000, HIV-1-negative mothers, 148.6/100 000 live births. The attributable fraction of overall deaths as a result of HIV-1 was 15.9% Fourteen of the 15 mothers with tuberculosis were HIV-1 co-infected. The mortality rate for tuberculosis and HIV-1 co-infection was 121.7/1000; for tuberculosis without HIV-1 co-infection, 38.5/1000. Fifty-four per cent of maternal deaths caused by tuberculosis were attributable to HIV-1 infection. Thirty-five per cent of maternal deaths were associated with stillbirths; perinatal outcomes were no different between groups of mothers with tuberculosis, HIV-1 or neither infection. ConclusionTuberculosis and HIV-1 are emerging as significant contributors to maternal mortality in KwaZulu Natal. Any attempt to improve maternal health must also include careful screening and investigation for tuberculosis in high-risk pregnant women.

Tuberculosis in the newborn: an emerging disease

BACKGROUND In spite of the global increase in tuberculosis, which is in part fueled by the HIV pandemic, tuberculosis in the perinatal period is rare, and to date it has not been directly associated with maternal or neonatal HIV infection. OBJECTIVES To detect tuberculosis in newborns from a province with epidemics of both tuberculosis and HIV infection and to analyze the profile of tuberculosis in their mothers. METHODS At King Edward VIII Hospital, in KwaZulu Natal, South Africa, during a 1-year period all neonates at the neonatal unit in whom a differential diagnosis of tuberculosis was considered were investigated. The clinical profiles, short term outcome and relationship to maternal tuberculosis and HIV infection were determined for those neonates in whom the diagnosis of tuberculosis was confirmed. RESULTS From the investigation of 77 neonates 11 with culture confirmed perinatal tuberculosis were identified. Six of these infants were born to mothers who had HIV and tuberculosis coinfection. Six of the 11 neonates could be classified as congenital tuberculosis. The predominant clinical findings were progressive pneumonia (9 of 11), pyrexia (9 of 11), growth retardation (7 of 11), hepatomegaly (6 of 11), splenomegaly (4 of 11) and meningitis (2 of 11). Seven of their mothers had evidence of current or past tuberculosis or had close contact with a tuberculosis case. One neonate and two mothers died within the first 3 months. CONCLUSIONS This is the first report of perinatal tuberculosis in association with maternal HIV and tuberculosis coinfection.

Unique acquisition of cytotoxic T-lymphocyte escape mutants in infant human immunodeficiency virus type 1 infection.

ABSTRACT The role of cytotoxic T-lymphocyte (CTL) escape in rapidly progressive infant human immunodeficiency virus type 1 (HIV-1) infection is undefined. The data presented here demonstrate that infant HIV-1-specific CTL can select for viral escape variants very early in life. These variants, furthermore, may be selected specifically in the infant, despite the same CTL specificity being present in the mother. Additionally, pediatric CTL activity may be compromised both by the transmission of maternal escape variants and by mother-to-child transmission of escape variants that originally arose in the father. The unique acquisition of these CTL escape forms may help to explain the severe nature of some pediatric HIV infections.

An outbreak of neonatal infection with Acinetobacter linked to contaminated suction catheters.

An outbreak of multi-drug resistant Acinetobacter spp. infection in the neonatal unit at King Edward VIII hospital in Durban, South Africa, is described. Nine out of a total of 218 neonates were infected during the study period. The outbreak was characterized by early onset infection [median postnatal age 3 days (range 1-23 days)] in pre-term babies [median gestational age 33 weeks (range 30-35 weeks)] with an attributable mortality of 22%. The source of the outbreak, determined by ribotyping, was presumed to be contaminated suction bottles and catheters in the neonatal admission room. Five neonates were successfully treated with ciprofloxacin and amikacin. Enforcement of strict infection control practices curtailed the outbreak.

Severe, rapidly progressive human immunodeficiency virus type 1 disease in newborns with coinfections.

Aim. To describe a severe form of rapidly progressive HIV-1 infection manifesting in the neonatal period. Method. Prospective cohort study, King Edward VIII Hospital, Durban, South Africa. HIV-1-exposed neonates with hepatosplenomegaly, lymphadenopathy or persistent pneumonia within the first 28 days of life were investigated for perinatal infections. Confirmation of neonatal HIV-1 infection, HIV-1 subtype and clinical outcomes were studied. Results. Twenty-three (72%) of 32 symptomatic HIV-1-exposed neonates recruited at a mean of 15.2 days were HIV-1-infected. HIV-1 infection was detected in 5 patients who were tested within 48 h of birth, confirming congenital infection. Congenital infection was not excluded in any case. Median neonatal viral load at recruitment was 471 932 copies/ml and median CD4 was 777 cells/mm3. The predominant clinical presentation was growth retardation and prematurity. Perinatal infections detected included: tuberculosis (8), syphilis (6) and cytomegalovirus (10). All of the neonates with perinatal tuberculosis were HIV-1-coinfected. Maternal and neonatal viral load and CD4 at recruitment were not statistically different between the groups with tuberculosis vs. other coinfections. Gag gene sequence analysis confirmed closely aligned HIV-1 subtype C in mothers and neonates. Nineteen (83%) died by 9 months, with a mean age at death of 3.5 months. Conclusions. A distinct group of HIV-1-infected babies may clinically manifest in the neonatal period with perinatal coinfections, subsequent rapidly progressive HIV-1 and early death.

In utero HIV infection in pregnancies complicated by tuberculosis in Durban, South Africa

At the core of the HIV-1 and tuberculosis (TB) epidemics, a defined effect of these combined pathogens on maternal and child health has been observed at King Edward VIII Hospital in Durban South Africa.1,2 Here we report on the adverse effect of maternal HIV-1 infection with TB disease on fetal acquisition of HIV-1. In a prospective cohort study conducted at the hospital between April 1997 and July 1999, 42 HIV-1 infected pregnant women with active TB disease were investigated for …

Childhood Lichen Scrofulosorum Revisited

Lichen scrofulosorum (LS), an uncommon cutaneous tuberculous reaction, has been described in children and young adults. In the last three decades, there has been a dearth of literature on the entity in children, despite a global increase in tuberculosis. It is usually associated with localized cervical, hilar, or mediastinal lymphadenopathy or with osseous tuberculosis. The occurrence of LS in association with pulmonary tuberculosis is rare and its occurrence with generalized lymphadenopathy is unrecognized. We report LS in two children and highlight its occurrence with pulmonary tuberculosis and generalized lymphadenopathy.

Utility of surveillance bacterial cultures in neonatal exchange blood transfusions

Invasive procedures, like exchange blood transfusions via the umbilical vein, potentially expose the neonate to nosocomial infection. Attempts to limit hospital-acquired infection following exchange transfusions (ETF) in our unit have included umbilical vein blood cultures and swabs from umbilical stumps. The value of this surveillance was examined. Forty-four neonates undergoing ETF were studied prospectively. Specimens for bacterial cultures were taken from the umbilical stump and umbilical vein immediately before and after ETF and results correlated with clinical outcome and antibiotic use. Except for staphylococci, bacteria cultured in the asymptomatic neonates were similar to those cultured from neonates who had signs of infection. Polymicrobial cultures were obtained from both umbilical vein blood and stump specimens suggesting contamination with colonizing organisms. Surveillance bacterial culture results did not influence antimicrobial therapy. Therefore, we advocate microbiological investigations only when clinical infection is suspected.