3. Electronic Theses and Dissertations (ETDs) - All submissions
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Item Defining the burden of pulmonary tuberculosis and probing the prevalence of pneumococcal bacterial co-infections among children hospitalised with pulmonary tuberculosis that were enrolled in a pneumococcal vaccine trial(2010-01-29T10:32:57Z) Moore, David PaulBackground In settings with a high burden of tuberculosis, children with unrecognised culture-confirmed pulmonary tuberculosis (PTB) may be discharged from hospital before mycobacterial culture results are available; in these cases clinical improvement may have been due to successful treatment of an intercurrent viral or bacterial co-infection. Aim To estimate the burden of tuberculosis in children who were enrolled in a double-blind, placebo-controlled pneumococcal conjugate vaccine (PCV) trial, and to probe for the presence of pneumococcal co-infection in trial participants who had a hospital-based diagnosis of PTB. Methods A retrospective case-finding strategy was adopted in order to define the tuberculosis case load amongst 39 836 children that had been enrolled in a PCV efficacy trial in Soweto, Gauteng Province. The trial follow-up period was 5.3 years. Children with a hospital-based diagnosis of tuberculosis were categorised by strength of evidence for the disease, HIV status and PCV vaccination status. Incidence rates and risk ratio assessments were conducted using standard statistical methods. Results Four-hundred and ninety-two episodes of tuberculosis arose amongst 425 of the 39 836 PCV Study participants. Tuberculosis incidence was 1067 per 100 000 children (95% Confidence Interval [CI], 968 – 1173), with the greatest burden observed amongst HIV-infected children (10 633 per 100 000 children [95% CI, 9411 – 11 969]; Risk Ratio [RR] 27.5 [95% CI, 22.6 – 33.5], P<0.001). The burden of PTB in the cohort was 982 cases per 100 000 children (95% CI, 887 – 1084): 9895 per 100 000 (95% CI, 8718 – 11 187) in the HIV-infected children and 352 per 100 000 (95% CI 294 – 417) in the HIV-uninfected children (RR 28.1; 95% CI, 22.9 – 34.6), P<0.001. PCV recipients exhibited a 44 percent (95% CI, 11 – 65), P=0.010, reduction in incident culture-confirmed PTB compared to placebo recipients; this apparent reduction was demonstrated chiefly in PCV-vaccinated HIV-infected children (RR 0.53; 95% CI, 0.31 – 0.90) compared to HIV-infected placebo recipients, P=0.017. Conclusions A high burden of tuberculosis is carried by children under 5.3 years in the study setting, with HIV-infected children bearing the brunt of the morbidity. Pneumococcal co-infections are common in the context of hospitalised PTB in the study setting.Item Chemokine production in HIV-1 infection and pulmonary tuberculosis(2009-04-29T07:56:51Z) Donninger, Samantha LouiseABSTRACT Introduction Circulating levels, and the ex vivo production, of the chemokines CCL3, CCL4, CCL5, CXCL8 and CXCL12 (known to play an important role in the pathogenesis of either human immunodeficiency virus type 1 (HIV-1) or tuberculosis (TB)) were examined in the context of both single infections with HIV-1 or Mycobacterium tuberculosis (Mtb) and coinfection with both organisms. We hypothesised that CCL3L1 gene copy number (known to affect CCL3 production, associated with susceptibility to and disease progression of HIV-1) would be associated with mother-to-child transmission (MTCT) of HIV-1, and that the IL8-251T→A single nucleotide polymorphism (SNP) (associated with enhanced CXCL8 production and susceptibility to TB in African Americans) would be highly represented in the South African Black population. Methods Samples used included (i) plasma, DNA samples and cell culture supernatants from control, HIV-1, TB and HIV-1/TB groups, (ii) DNA samples from mothers and their infants (grouped as HIV-1 exposed-uninfected, infected in utero, or infected intrapartum), and (iii) DNA samples from a populationbased study cohort. Chemokines were quantified by enzyme-linked immunosorbent assay (ELISA), CCL3L1 gene copy numbers were determined by real-time polymerase chain reaction (PCR), and a real-time PCR method was developed for identification of the IL8-251T→A SNP. DNA sequencing was used for confirmation. Results We found reduced ex vivo chemokine production in response to phytohaemagglutinin (PHA) together with increased plasma levels of chemokines in HIV-1 and TB patients. In contrast to that seen in Caucasians (median CCL3L1 copy number of 2), in Black individuals (median CCL3L1 copy number of 5) circulating levels of CCL3 did not correlate with CCL3L1 gene copy number; in addition, a high proportion of Black individuals were found to have CCL3L1 copy numbers below their population-specific median. Using MTCT as a model for studying HIV-1 transmission, infants who became infected with HIV-1 had significantly reduced CCL3L1 gene copy numbers. IL8-251A allele frequencies were found to be 0.41 for Caucasian groups, and 0.85 for Black groups; due to study limitations, the possible association of IL8-251T→A with TB susceptibility could not be addressed. Discussion The increased plasma levels of chemokines seen in HIV-1 and TB, likely due to chronic immune activation in vivo, may result in T cell anergy which in turn might be the cause of reduced PHA-stimulated ex vivo chemokine production. Our results suggest that Black South Africans may be at particularly high risk for acquiring HIV-1 (at least with respect to CCL3L1 gene copy number), and further imply the presence of other genetic polymorphisms which may influence plasma CCL3 levels. In addition, the high IL8-251A allele frequency (if indeed associated with TB in South African populations) in Black individuals suggests a greater risk for infection with Mtb. It will be important, in larger studies, to gain a more in-depth understanding of the relationships between host genotype and chemokine production phenotype, and to relate these measures to infection outcomes. Conclusions Together, these results highlight the importance of gaining an understanding of the effects of host genotype on the development of innate and acquired immunity to HIV-1 and TB, which will be key in the design of efficient therapies and prevention strategies.Item Pulmonary tuberculosis treatment outcome in a rural setting in Northern Ghana(2007-02-23T12:22:43Z) Baiden, RitaTuberculosis ranks among the top ten causes of global mortality. Globally it kills nearly 2 million people each year and is the second leading cause of death after Human Immune Deficiency Virus/Acquired Immune Deficiency Syndrome (HIV/AIDS).Tuberculosis (TB) is primarily an illness of the respiratory system, and is spread by coughing and sneezing from an infectious person. Nearly a third of the world’s population is infected with the bacilli that causes TB and are at risk of developing tuberculosis (TB).1, 2 Left untreated, each person with active TB disease will infect on average between 10 and 15 people every year. In 2004, estimated per capita TB incidence was stable or falling in five out of six World Health Organization (WHO regions, but growing at 0.6% per year globally. The exception is the African region, where TB incidence was still rising.3, 4 HIV increases the risk of developing TB and accounts for much of the increase in countries where prevalence is high. 4 Co-infection is common and could be as high as 70% in high-burdened countries. Gains made in global TB control in the 1970 and 80s are being dramatically reversed by the effect of HIV/AIDS. HIV is the main reason for failure to meet Tuberculosis (TB) control targets in high HIV settings.3 Drug-resistant TB is a major problem. Resistance to single anti-tuberculosis drugs have been reported in almost every country surveyed. To make the situation worse, drugs resistant to all the major anti-TB drugs have emerged. 4 Drug-resistant TB is caused by inconsistent or partial treatment, when patients do not take all their medicines regularly for the required period because they start to feel better, because doctors and health workers prescribe the wrong treatment regimens, or because the drug supply is unreliable. A particularly dangerous form of drug-resistant TB is multidrug-resistant TB (MDR-TB), which is defined as the disease caused by TB bacilli resistant to at least isoniazid and rifampicin, the two most powerful anti-TB drugs.4, 5