Biomedical subjects
Publications and source records attributed to William J Moss.
Age-related changes in lymphocyte subsets in HIV-uninfected Zambian children are described. The total lymphocyte count and numbers of CD4+ and CD8+ T-lymphocytes declined with increasing age, while the percentage of CD4+ and CD8+ T-lymphocytes changed little during childhood. Girls between the ages of 12 and 71 months had a higher percentage of CD4+ T-lymphocytes and a higher CD4:CD8 ratio than did boys of a similar age.
Measles is associated with a million deaths a year in developing countries because of secondary infections. Morbidity is particularly severe in young infants. Both measles-induced immune suppression and atypical measles have been associated with a type 2 cytokine bias of the immune response. The role of individual virus proteins in the induction of these cytokine responses is unknown and could be important for the development of new vaccines. We have used a rhesus macaque model and DNA vaccines to investigate cytokine responses to the individual measles virus (MV) protective antigens, hemagglutinin and fusion. The hemagglutinin protein primed for a type 2 cytokine response, with suppression of interleukin (IL)-12 and preferential production of IL-4 after MV challenge. The fusion protein primed for a type 1 response with preferential production of interferon-gamma. Responses were modulated when both proteins were used for priming. Therefore, the specific proteins included in a new measles vaccine will affect the type of cytokine response elicited.
This paper reviews the English language literature on the safety, immunogenicity and effectiveness in children infected with the human immunodeficiency virus (HIV) of vaccines currently recommended by WHO for use in national immunization programmes. Immunization is generally safe and beneficial for children infected with HIV, although HIV-induced immune suppression reduces the benefit compared with that obtained in HIV-uninfected children. However, serious complications can occur following immunization of severely immunocompromised children with bacillus Calmette-Gu rin (BCG) vaccine. The risk of serious complications attributable to yellow fever vaccine in HIV-infected persons has not been determined. WHO guidelines for immunizing children with HIV infection and infants born to HIV-infected women differ only slightly from the general guidelines. BCG and yellow fever vaccines should be withheld from symptomatic HIV-infected children. Only one serious complication (fatal pneumonia) has been attributed to measles vaccine administered to a severely immunocompromised adult. Although two HIV-infected infants have developed vaccine-associated paralytic poliomyelitis, several million infected children have been vaccinated and the evidence does not suggest that there is an increased risk. The benefits of measles and poliovirus vaccines far outweigh the potential risks in HIV-infected children. The policy of administering routine vaccines to all children, regardless of possible HIV exposure, has been very effective in obtaining high immunization coverage and control of preventable diseases. Any changes in this policy would have to be carefully examined for a potential negative impact on disease control programmes in many countries.
A 5-year-old child with simultaneous early Lyme disease and human granulocytic ehrlichiosis (HGE) is described. Because of the shared vector, HGE and Lyme disease are increasingly identified as coinfections in tick-exposed patients. Early recognition of concurrent Lyme disease and HGE is important because amoxicillin, an antibiotic of choice for young children with early Lyme disease, is ineffective for HGE.
Measles virus infects thymic epithelia, induces a transient lymphopenia, and impairs cell-mediated immunity, but thymic function during measles has not been well characterized. Thirty Zambian children hospitalized with measles were studied at entry, hospital discharge, and at 1-month follow-up and compared to 17 healthy children. During hospitalization, percentages of naïve (CD62L+, CD45RA+) CD4+ and CD8+ T lymphocytes decreased (P = 0.01 for both), and activated (HLA-DR+, CD25+, or CD69+) CD4+ and CD8+ T lymphocytes increased (P = 0.02 and 0.03, respectively). T-cell receptor rearrangement excision circles (TRECs) in measles patients were increased in CD8+ T cells at entry compared to levels at hospital discharge (P = 0.02) and follow-up (P = 0.04). In CD4+ T cells, the increase in TRECS occurred later but was more sustained. At discharge, TRECs in CD4+ T cells (P = 0.05) and circulating levels of interleukin-7 (P = 0.007) were increased compared to control values and remained elevated for 1 month, similar to observations in two measles virus-infected rhesus monkeys. These findings suggest that a decrease in thymic output is not the cause of the lymphopenia and depressed cellular immunity associated with measles.
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To determine the effect of measles virus infection on cytokine production in children from sub-Saharan Africa, temporal changes in cytokine production in vivo were analyzed and the T cell sources of type 1 and type 2 cytokines were identified in Zambian children with measles. The immune response during measles involved early type 1 responses, with production of interferon-gamma by CD8(+) T cells and of interleukin (IL)-2 by CD4(+) T cells. Subsequently, more-prolonged increases were observed in the type 2 cytokines IL-4 and IL-13, both produced by CD4(+) T cells. IL-5 was regulated differently from IL-4 and IL-13: levels were low compared with levels in control children and were reflected in lower eosinophil counts during measles. Immunoglobulin E was lower in children with measles, despite high levels of IL-4 and IL-13. Plasma levels of IL-10 were elevated for weeks, potentially contributing to impaired cellular immunity and depressed hypersensitivity responses following measles.
Measles in persons coinfected with human immunodeficiency virus (HIV) has been reported to be unusual in its presentation and frequently fatal. To determine the effect of HIV coinfection on the clinical features and outcome of measles, a prospective study of hospitalized children with measles was conducted between January 1998 and October 2000 in Lusaka, Zambia. One-sixth (17%) of 546 children hospitalized with laboratory-confirmed measles were coinfected with HIV. One-third of the HIV-infected children hospitalized with confirmed measles were <9 months old, compared with 23% of HIV-uninfected children (P=.03). Few differences in clinical manifestations, complications, or mortality were found between HIV-infected and HIV-uninfected children with measles. HIV-infected children constitute a significant proportion of children hospitalized with measles in countries with high HIV prevalence and are more likely to be younger than the age for routine measles immunization.
To determine the effect of measles virus coinfection on plasma human immunodeficiency virus (HIV) RNA levels, a prospective study of hospitalized children with measles was conducted between January 1998 and October 2000 in Lusaka, Zambia. Plasma HIV RNA levels were measured during acute measles and 1 month after hospital discharge. The median plasma HIV RNA level in 33 children with measles who were followed longitudinally was 5339 copies/mL at study entry, 60,121 copies/mL at hospital discharge, and 387,148 copies/mL at 1-month follow-up. The median plasma HIV RNA level in children without acute illness was 228,454 copies/mL. Plasma levels of immune activation markers were elevated during the period of reduced plasma HIV RNA. Plasma levels of several potential HIV suppressive factors also were elevated during acute measles. HIV replication is transiently suppressed during acute measles at a time of intense immune activation.
OBJECTIVE: This pilot study was performed to determine the safety and size of effect of antibiotic cycling to reduce colonization and infection with antibiotic-resistant bacteria. DESIGN: Open, observational study. SETTING: The study was performed in a 16-bed pediatric medical-surgical intensive care unit. PATIENTS: Critically ill children requiring antibiotic therapy. INTERVENTIONS: Three antibiotic classes were systematically cycled for 3-month intervals over 18 months. Antibiotic regimens were used for all empirical therapy and continued if the bacterial isolate was susceptible. MEASUREMENTS: The primary outcome was colonization with antibiotic-resistant bacteria, determined by surveillance cultures obtained twice monthly from all patients in the unit. Rates of antibiotic-resistant, nosocomial blood stream infections, and risks of colonization over calendar time in the intensive care unit were also evaluated. MAIN RESULTS: The cycling of broad-spectrum, empirical antibiotics was safe and did not generate increased antibiotic resistance nor select for new organisms. Over the study period, the trend in prevalence of children colonized with antibiotic-resistant bacteria was from 29% to 24% (p =.41). The effect on prevalence of resistant blood stream infections was similar (p =.29). Changes in individual risks of colonization with resistant bacteria over calendar time were consistent with the ecologic effect in size and direction. CONCLUSIONS: Results of this pilot intervention suggest that cycling antibiotics may be a safe and viable strategy to minimize the emergence of antibiotic resistance in intensive care units. A definitive study will require a randomized and controlled trial of only four pediatric intensive care units over an 18-month period.
Measles is associated with immunosuppression and increased susceptibility to secondary infections and is a particular problem in developing countries. Lymphocyte changes accompanying immune activation and regulation of the immune response may contribute to immunosuppression. To evaluate lymphocyte changes during measles, children (n = 274) hospitalized with measles in Lusaka, Zambia, were evaluated at entry, discharge, and 1-month follow-up and compared to healthy Zambian children (n = 98). Lymphopenia was present on hospital admission and reflected decreased CD4 and CD8 T cells but resolved quickly. Lymphopenia was most marked in girls, in those with temperatures of >38.5 degrees C, and in malnourished children. CD4/CD8 ratios were decreased at all time points and were lower in boys than in girls at discharge and follow-up. Spontaneous death occurred in cultured lymphocytes, and the proportions of freshly isolated cells undergoing apoptosis, based on annexin V and propidium iodide staining, were increased. Surface Fas was increased on both CD4 and CD8 T cells compared to controls, and expression was greater on CD4 T cells and was inversely correlated with lymphocyte viability in culture at study entry. Mitogen stimulation of lymphocytes improved viability, but inhibitors of Fas, tumor necrosis factor (TNF)-related apoptosis-inducing ligand, and TNF did not. Plasma levels of beta(2) microglobulin and soluble Fas, Fas ligand, CD8, CD4, and TNF receptor were increased, and soluble CD8 was higher in boys than in girls. The multiple effects of measles on lymphocytes from Zambian children include decreased numbers in circulation, increased activation, and increased susceptibility to cell death, with substantive differences in the magnitude of these changes between boys and girls.
Immunosuppression during and after measles results in increased susceptibility to other infections and 1 million deaths annually. The mechanism by which measles virus (MV) induces immune suppression is incompletely understood, but a type 2 skewing of the cytokine response after infection has been documented. In vitro studies suggest that lack of interleukin (IL)-12 production by monocytes and dendritic cells plays an early role in the skewed response. In addition, immunization with an inactivated measles vaccine before measles develops appears to lead to an even stronger type 2 skewing of the cytokine response and atypical measles. In this study, the cytokine responses in rhesus macaques were compared after vaccination with live and formalin-inactivated vaccines and after challenge with MV. In vivo production of IL-12 was decreased during the viremic phase of the illness, and production of IL-4 was increased during and after atypical measles, compared with measles.