Charles D. Mitchell

Survival in children with perinatally acquired Human Immunodeficiency Virus type 1 infection

Abstract We describe our experience at Jackson Memorial Hospital in Miami, Florida, with 172 children who were given diagnoses of perinatally acquired infection with human immunodeficiency virus ty...

Renal Disease in Children with the Acquired Immunodeficiency Syndrome

Abstract Of 155 children with the acquired immunodeficiency syndrome (AIDS) whom we evaluated during a 6 1/2-year period, 12 were found to have proteinuria. Histologic studies of tissue from these 12 patients revealed a wide spectrum of renal disease: focal glomerulosclerosis in 5, mesangial hyperplasia in 5, segmental necrotizing glomerulonephritis in 1, and minimal change disease in 1. In addition, 6 had tubulointerstitial infiltrates, and 10 had glomerular dense deposits. All 10 renal specimens studied by electron microscopy contained endothelial tubuloreticular inclusions. The mean age (±SD) of the five patients with focal glomerulosclerosis when this condition was identified was 27±19 months. All five had severe renal failure within a year and died of other causes during the following year. The mean age of the five patients with mesangial hyperplasia was 38±31 months. Although none of them went on to have renal failure, four died within 8±7 months. Ten of the 12 patients with proteinuria died during ...

Evaluation of Tuberculosis Diagnostics in Children: 1. Proposed Clinical Case Definitions for Classification of Intrathoracic Tuberculosis Disease. Consensus From an Expert Panel

There is a critical need for improved diagnosis of tuberculosis in children, particularly in young children with intrathoracic disease as this represents the most common type of tuberculosis in children and the greatest diagnostic challenge. There is also a need for standardized clinical case definitions for the evaluation of diagnostics in prospective clinical research studies that include children in whom tuberculosis is suspected but not confirmed by culture of Mycobacterium tuberculosis. A panel representing a wide range of expertise and child tuberculosis research experience aimed to develop standardized clinical research case definitions for intrathoracic tuberculosis in children to enable harmonized evaluation of new tuberculosis diagnostic technologies in pediatric populations. Draft definitions and statements were proposed and circulated widely for feedback. An expert panel then considered each of the proposed definitions and statements relating to clinical definitions. Formal group consensus rules were established and consensus was reached for each statement. The definitions presented in this article are intended for use in clinical research to evaluate diagnostic assays and not for individual patient diagnosis or treatment decisions. A complementary article addresses methodological issues to consider for research of diagnostics in children with suspected tuberculosis.

Primary isoniazid prophylaxis against tuberculosis in HIV-exposed children

BACKGROUND The dual epidemic of human immunodeficiency virus (HIV) and tuberculosis is a major cause of sickness and death in sub-Saharan Africa. We conducted a double-blind, randomized, placebo-controlled trial of preexposure isoniazid prophylaxis against tuberculosis in HIV-infected children and uninfected children exposed to HIV during the perinatal period. METHODS We randomly assigned 548 HIV-infected and 804 HIV-uninfected infants (91 to 120 days of age) to isoniazid (10 to 20 mg per kilogram of body weight per day) or matching placebo for 96 weeks. All patients received bacille Calmette-Guérin (BCG) vaccination against tuberculosis within 30 days after birth. HIV-infected children had access to antiretroviral therapy. The primary outcome measures were tuberculosis disease and death in HIV-infected children and latent tuberculosis infection, tuberculosis disease, and death in HIV-uninfected children within 96 to 108 weeks after randomization. RESULTS Antiretroviral therapy was initiated in 98.9% of HIV-infected children during the study. Among HIV-infected children, protocol-defined tuberculosis or death occurred in 52 children (19.0%) in the isoniazid group and 53 (19.3%) in the placebo group (P=0.93). Among HIV-uninfected children, there was no significant difference in the combined incidence of tuberculosis infection, tuberculosis disease, or death between the isoniazid group (39 children, 10%) and the placebo group (45 children, 11%; P=0.44). The rate of tuberculosis was 121 cases per 1000 child-years (95% confidence interval [CI], 95 to 153) among HIV-infected children as compared with 41 per 1000 child-years (95% CI, 31 to 52) among HIV-uninfected children. There were no significant differences in clinical or severe laboratory toxic effects between treatment groups. CONCLUSIONS Primary isoniazid prophylaxis did not improve tuberculosis-disease-free survival among HIV-infected children or tuberculosis-infection-free survival among HIV-uninfected children immunized with BCG vaccine. Despite access to antiretroviral therapy, the burden of tuberculosis remained high among HIV-infected children. (Funded by the National Institutes of Health and Secure the Future; ClinicalTrials.gov number, NCT00080119.).

Seroprevalence of Human Herpesvirus 8 among Zambian Women of Childbearing Age without Kaposi's Sarcoma (KS) and Mother-Child Pairs with KS

The seroprevalence of human herpesvirus 8 (HHV-8) among a group of Zambian women of reproductive age and among mother-child pairs in which either one of them has Kaposis sarcoma (KS) was determined. A cross-sectional group of 378 pregnant women was randomly recruited into the study, and 183 (48.4%) had HHV-8 antibodies. Among the human immunodeficiency virus (HIV)-1-infected women, 51.1% were HHV-8-seropositive, whereas of HIV-1-negative women, 47.3% were HHV-8-seropositive. In addition, 21 women index patients with KS and 5 young children index patients with KS were studied. All children with KS had mothers who were HHV-8-seropositive, while not all children whose mothers had KS were infected with HHV-8. Our study suggests that there is a high HHV-8 seroprevalence among Zambian women, and the rate is almost the same in HIV-1-positive and -negative women. This high seroprevalence may be a contributing factor toward the increased frequency of KS in this population.

Distribution of Kaposi Sarcoma-Associated Herpesvirus/Human Herpesvirus 8 in Maternal Saliva and Breast Milk in Zambia: Implications for Transmission

BACKGROUND The seroprevalence of Kaposi sarcoma-associated herpesvirus (KSHV)/human herpesvirus 8 (HHV-8) in sub-Saharan Africa suggests that multiple routes of transmission exist. In the present study, we examined 2 possible routes of mother-to-child transmission, through breast milk and saliva, during the first 6 months after delivery. METHODS The prevalence of HHV-8 DNA in the breast-milk cells (n=75), milk supernatant (n=56), colostrum (n=2), and saliva cells (n=65) of HHV-8-seropositive mothers who recently gave birth was examined. Polymerase chain reaction analysis was performed for the detection of HHV-8 in cross-sectional samples isolated at 2, 4, and 6 months after delivery. RESULTS None of the 75 breast-milk samples but 2 of the colostrum samples that were analyzed contained HHV-8 DNA at a limit of detection of approximately 1 HHV-8 copy/10(4) cellular genomes, whereas Epstein-Barr virus DNA and HIV-1 DNA were detected in 16 and 22 samples, respectively. Analysis of 65 saliva cell samples, which were obtained from mothers who also provided milk samples, revealed that 19 of the samples had detectable HHV-8 DNA. Viral DNA was found at all time points, but the presence of viral DNA in saliva was independent of maternal HIV-1 serostatus (chi 2=0.33; P=.57). CONCLUSIONS Our findings demonstrate the lack of HHV-8 DNA in the breast milk of seropositive mothers, and they suggest that contact with breast milk is not a likely source of horizontal transmission of virus to infants in sub-Saharan Africa.

Vertical transmission of Kaposi's sarcoma-associated herpesvirus

Little is presently known about the specific routes of transmission of Kaposis sarcoma‐associated herpesvirus (KSHV) or human herpesvirus‐8 (HHV‐8). To investigate whether this agent might be transmitted vertically from mother to infant, we conducted a study on 89 KSHV seropositive mothers and their newborn infants. Thirteen mothers (14.6%) had KSHV DNA detected in their peripheral blood mononuclear cells (PBMC). Two of 89 samples drawn at birth from infants born to KSHV seropositive mothers had KSHV DNA detectable within their PBMC. These findings suggest that KSHV can be transmitted perinatally, but infrequently. Other routes of transmission such as horizontal transmission remain the most likely means of KSHV transmission.

Practice of Feeding Premasticated Food to Infants: A Potential Risk Factor for HIV Transmission

OBJECTIVES: Although some caregivers are known to premasticate food for infants, usually during the weaning period, HIV transmission has not been linked to this practice. We describe 3 cases of HIV transmission in the United States possibly related to this practice. PATIENTS AND METHODS: Three cases of HIV infection were diagnosed in children at ages 9, 15, and 39 months; clinical symptomatology prompted the testing. A thorough investigation to rule out alternative modes of transmission was conducted. In addition, phylogenetic comparisons of virus from cases and suspected sources were performed by using the C2V3C3 or gp41 region of env and the p17 coding region of gag. RESULTS: In 2 cases, the mothers were known to be infected with HIV, had not breastfed their children, and perinatal transmission of HIV had previously been ruled out following US HIV testing guidelines. In the third case, a great aunt who helped care for the child was infected with HIV, but the childs mother was not. All 3 children were fed food on multiple occasions that had been premasticated by a care provider infected with HIV; in 2 cases concurrent oral bleeding in the premasticating adult was described. Phylogenetic analyses supported the epidemiologic conclusion that the children were infected through exposure to premasticated food from a caregiver infected with HIV in 2 of the 3 cases. CONCLUSIONS: The reported cases provide compelling evidence linking premastication to HIV infection, a route of transmission not previously reported that has important global implications including being a possible explanation for some of the reported cases of “late” HIV transmission in infants, so far attributed to breastfeeding. Until the risk of premastication and modifying factors (eg, periodontal disease) are better understood, we recommend that health care providers routinely query childrens caregivers and expecting parents who are infected with HIV or at risk of HIV infection about this feeding practice and direct them to safer, locally available, feeding options.

Postnatal Human Herpesvirus 8 and Human Immunodeficiency Virus Type 1 Infection in Mothers and Infants from Zambia

The specific route and timing of human herpesvirus (HHV) 8 infection in regions where Kaposi sarcoma is endemic are not known. HHV-8 infection and any risk factors that may be associated with HHV-8, including human immunodeficiency virus (HIV) type 1 infection, were monitored during the 12-month postdelivery period for 416 mothers and 485 infants from Lusaka, Zambia. HHV-8 incident infection rates during this period were 3.2 and 5.3 infections/100 person-years for infants and mothers, respectively. HHV-8 infection among infants was not associated with HHV-8 or HIV-1 infection in the mother. Among the HHV-8-positive infants, 2 of 12 tested were found to have HHV-8 DNA in their peripheral blood mononuclear cells at birth, which suggests that in utero infection is possible. However, most HHV-8-positive infants appeared to have acquired infection either intrapartum or postpartum. The present study indicates that transmission of HHV-8 to infants can occur early and is likely via multiple routes.

Characterization of HIV-1 Subtype C Envelope Glycoproteins From Perinatally Infected Children With Different Courses of Disease

BackgroundThe causal mechanisms of differential disease progression in HIV-1 infected children remain poorly defined, and much of the accumulated knowledge comes from studies of subtype B infected individuals. The applicability of such findings to other subtypes, such as subtype C, remains to be substantiated. In this study, we longitudinally characterized the evolution of the Env V1–V5 region from seven subtype C HIV-1 perinatally infected children with different clinical outcomes. We investigated the possible influence of viral genotype and humoral immune response on disease progression in infants.ResultsGenetic analyses revealed that rapid progressors (infants that died in the first year of life) received and maintained a genetically homogeneous viral population throughout the disease course. In contrast, slow progressors (infants that remained clinically asymptomatic for up to four years) also exhibited low levels variation initially, but attained higher levels of diversity over time. Genetic assessment of variation, as indicated by dN/dS, showed that particular regions of Env undergo selective changes. Nevertheless, the magnitude and distribution of these changes did not segregate slow and rapid progressors. Longitudinal trends in Env V1–V5 length and the number of potential N-glycosylation sites varied among patients but also failed to discriminate between fast and slow progressors. Viral isolates from rapid progressors and slow progressors displayed no significant growth properties differences in vitro. The neutralizing activity in maternal and infant baseline plasma also varied in its effectiveness against the initial virus from the infants but did not differentiate rapid from slow progressors. Quantification of the neutralization susceptibility of the initial infant viral isolates to maternal baseline plasma indicated that both sensitive and resistant viruses were transmitted, irrespective of disease course. We showed that humoral immunity, whether passively acquired or developed de novo in the infected children, varied but was not predictive of disease progression.ConclusionOur data suggest that neither genetic variation in env, or initial maternal neutralizing activity, or the level of passively acquired neutralizing antibody, or the level of the de novo neutralization response appear to be linked to differences in disease progression in subtype C HIV-1 infected children.