Biomedical subjects

Sian Floyd

Publications and source records attributed to Sian Floyd.

17 recordsLinked to original sources

PubMed2006

Immunogenicity of Danish-SSI 1331 BCG vaccine in the UK: comparison with Glaxo-Evans 1077 BCG vaccine.

The immunogenicity and reactogenicity, in British schoolchildren, of the newly introduced Danish-SSI 1331 BCG vaccine was compared with that of the previously used Glaxo-Evans 1077 BCG vaccine. Interferon-gamma (IFN-gamma) response to M. tuberculosis purified protein derivative (M.tb PPD) in a 6-day whole blood assay and delayed type hypersensitivity (DTH) to tuberculin PPD were determined before and 1 year after receiving BCG or no vaccination. Scar size was measured 1 year after vaccination. There was no evidence of a difference in immunogenicity (IFN-gamma and DTH conversion rates) but evidence of lower reactogenicity (scar size) with Danish-SSI 1331 compared to Glaxo-Evans 1077 vaccines.

BCG Vaccine↗

PubMed2006

Distribution of environmental mycobacteria in Karonga District, northern Malawi.

The genus Mycobacterium includes many species that are commonly found in the environment (in soil and water or associated with plants and animals), as well as species that are responsible for two major human diseases, tuberculosis (Mycobacterium tuberculosis) and leprosy (Mycobacterium leprae). The distribution of environmental mycobacteria was investigated in the context of a long-term study of leprosy, tuberculosis, Mycobacterium bovis BCG vaccination, and the responses of individuals to various mycobacterial antigens in Karonga District, northern Malawi, where epidemiological studies had indicated previously that people may be exposed to different mycobacterial species in the northern and southern parts of the district. A total of 148 soil samples and 24 water samples were collected from various locations and examined to determine the presence of mycobacteria. The detection method involved semiselective culturing and acid-fast staining, following decontamination of samples to enrich mycobacteria and reduce the numbers of other microorganisms, or PCR with primers specific for the mycobacterial 16S rRNA gene, using DNA extracted directly from soil and water samples. Mycobacteria were detected in the majority of the samples, and subsequent sequence analysis of PCR products amplified directly from soil DNA indicated that most of the products were related to known environmental mycobacteria. For both methods the rates of recovery were consistently higher for dry season samples than for wet season samples. All isolates cultured from soil appeared to be strains of Mycobacterium fortuitum. This study revealed a complex pattern for the environmental mycobacterial flora but identified no clear differences between the northern and southern parts of Karonga District.

Bacteriological Techniques↗

PubMed2006

Tuberculosis transmission attributable to close contacts and HIV status, Malawi.

We conducted the first molecular study of tuberculosis (TB) to estimate the role of household contact and transmission from HIV-positive putative source contacts (PSCs) in a high HIV-prevalence area. TB patients in a long-term population-based study in Malawi were asked about past contact with TB. DNA fingerprinting was used to define clusters of cases with identical strains. Among 143 epidemiologically defined PSC-case pairs, fingerprinting confirmed transmission for 44% of household and family contacts and 18% of other contacts. Transmission was less likely to be confirmed if the PSC were HIV positive than if he or she was HIV negative (odds ratio 0.32, 95% confidence interval [CI] 0.14-0.74). Overall, epidemiologic links were found for 11% of 754 fingerprint-clustered cases. We estimate that 9%-13% of TB cases were attributable to recent transmission from identifiable close contacts and that nearly half of the TB cases arising from recent infection had acquired the infection from HIV-positive patients.

AIDS-Related Opportunistic Infections↗

PubMed2005

The PPD-specific T-cell clonal response in UK and Malawian subjects following BCG vaccination: a new repertoire evolves over 12 months.

Mycobacterium bovis bacille Calmette Guerin vaccination protects against pulmonary tuberculosis in the United Kingdom but not in Malawi. We investigated whether a difference in the clonal T-cell response to BCG vaccination might account for this. The results of clonal analysis were compared to those obtained by skin testing and in a whole blood interferon gamma assay. Pre-vaccination antigen specific T-cell clones were detected, but the majority of clones present 12 months after vaccination were not present earlier. The magnitude of the clonal response did not correlate well with results of the other assays. These data indicate that single assays may not be reliable and that a stable memory T-cell repertoire is slow to develop.

Antibody Formation↗

PubMed2005

HIV and mortality of mothers and children: evidence from cohort studies in Uganda, Tanzania, and Malawi.

BACKGROUND: The steady decline in child mortality observed in most African countries through the 1960s, 1970s, and 1980s has stalled in many countries in the 1990s because of the AIDS epidemic. However, the census and household survey data that generally are used to produce estimates of child mortality do not permit precise measures of the adverse effect of HIV on child mortality. METHODS: To calculate excess risks of child mortality as the result of maternal HIV status, we used pooled data from 3 longitudinal community-based studies that classified births by the mother's HIV status. We also estimated excess risks of child death caused by increased mortality among mothers. The joint effects of maternal HIV status and maternal survival were quantified using multivariate techniques in a survival analysis. RESULTS: Our analysis shows that the excess risk of death associated with having an HIV-positive mother is 2.9 (95% confidence interval = 2.3-3.6), and this effect lasts throughout childhood. The excess risk associated with a maternal death is 3.9 (2.8-5.5) in the 2-year period centered on the mother's death, with children of both infected and uninfected mothers experiencing higher mortality risks at this time. CONCLUSION: HIV impacts on child mortality directly through transmission of the virus to newborns by infected mothers and indirectly through higher child mortality rates associated with a maternal death.

Adult↗

PubMed2005

Mycobacterium tuberculosis Beijing genotype, northern Malawi.

In a 7-year population-based study in Malawi, we showed that Beijing genotype tuberculosis (TB) increased as a proportion of TB cases. All the Beijing genotype strains were fully drug sensitive. Contact histories, TB type, and case-fatality rates were similar for Beijing and non-Beijing genotype TB.

Adolescent↗

PubMed2004

DNA fingerprint changes in tuberculosis: reinfection, evolution, or laboratory error?

BACKGROUND: DNA fingerprint patterns of Mycobacterium tuberculosis strains vary within individuals and between epidemiologically linked individuals because of pattern evolution, new infections, and laboratory error. We explored the importance of these factors. METHODS: Cultures from individuals in northern Malawi who had been diagnosed with tuberculosis (TB) during 1996-2001 were fingerprinted with restriction fragment-length polymorphism (RFLP). Probable laboratory error was inferred by use of dates or isolated positive cultures. Pattern evolution was explored within and between individuals, and the relative importance of relapse and reinfection was estimated in individuals with recurrent TB. RESULTS: RFLP results were available for 930 isolates from 806 individuals. The maximum laboratory-error rate was 3.9%. Pattern evolution was more common in linked individuals (17%) than on relapse (11%) or during treatment (3%). Twenty individuals had recurrent TB after completing treatment: in human immunodeficiency virus (HIV)-positive individuals, 7 of 12 recurrences were due to reinfection, compared with 0 of 8 in HIV-negative individuals (P=.01). CONCLUSIONS: The rate of DNA fingerprint-pattern evolution is not linear, and rates of change calculated from repeat cultures within individuals may not be applicable to transmission between individuals. The high proportion of recurrence due to reinfection found in HIV-positive individuals suggests that secondary prophylaxis and/or antiretroviral treatments are needed for such individuals.

Adolescent↗

PubMed2004

Trends in tuberculosis and the influence of HIV infection in northern Malawi, 1988-2001.

OBJECTIVE: To document the changing incidence and patterns of tuberculosis (TB) in rural Africa and the extent to which they are influenced by HIV. METHODS: As part of longstanding epidemiological studies in Karonga District, Malawi, a series of case control studies of TB and HIV were conducted from 1988 onwards. Data from these studies, from a total population survey, and from the Malawi national census have been used to reconstruct the changes in the TB epidemic in the area from 1988 to 2001, examining the role of HIV. RESULTS: The incidence of all confirmed TB, and of new smear-positive TB, in adults increased to peak in the late 1990s but appears to have decreased since. Two-thirds of cases are now HIV positive. The rise in incidence was greatest in the 30-44-year-old age group and was particularly marked for women, leading to a decrease in the male : female ratio for TB incidence from 1.3 to 0.8. The proportion of new smear-positive TB cases attributable to HIV increased from 17% in 1988-1990 to 57% in 2000-2001, but the estimated rate of smear-positive TB in the absence of HIV decreased from 0.78/1000 to 0.45/1000. CONCLUSIONS: Without HIV the incidence of smear-positive TB would have fallen in this population. Instead it has risen and is predominantly affecting young adults and women. There is some evidence that the HIV-associated TB epidemic may have passed its peak.

AIDS-Related Opportunistic Infections↗

PubMed2004

Mycobacterial purified protein derivatives stimulate innate immunity: Malawians show enhanced tumor necrosis factor alpha, interleukin-1beta (IL-1beta), and IL-10 responses compared to those of adolescents in the United Kingdom.

To investigate the role of innate immunity in variable efficacy of Mycobacterium bovis BCG vaccination in Malawi and the United Kingdom, we examined 24-h tumor necrosis factor alpha, interleukin-1beta (IL-1beta), and IL-10 responses to mycobacterial purified protein derivatives (PPDs). The rank order in stimulatory potency for different PPDs was the same for all three cytokines. Before vaccination Malawians made higher pro- and anti-inflammatory responses than did United Kingdom subjects. Fewer than 5% of United Kingdom subjects made IL-10 in response to any PPD, compared to 19 to 57% responders among Malawians. Priming for regulatory IL-10 may contribute to the smaller increase in gamma interferon responses in Malawians compared to United Kingdom subjects following BCG vaccination.

Adaptation, Physiological↗

PubMed2004

Cotrimoxazole prophylaxis reduces mortality in human immunodeficiency virus-positive tuberculosis patients in Karonga District, Malawi.

OBJECTIVE: To estimate the impact of cotrimoxazole prophylaxis on the survival of human immunodeficiency virus (HIV)-positive tuberculosis (TB) patients. METHODS: A cohort study with a historical comparison group was conducted. End-of-treatment outcomes and 18-month survival were compared between TB patients registered in 1999 and patients registered in 2000 in Karonga District, Malawi. Case ascertainment, treatment and outpatient follow-up were identical in the two years except that in 2000 cotrimoxazole prophylaxis was offered to HIV-positive patients in addition to routine care. The prophylaxis was provided from the time a patient was identified as HIV-positive until 12 months after registration. Analyses were carried out on an intention-to-treat basis for all TB patients, and also separately by HIV status, TB type and certainty of diagnosis. FINDINGS: 355 and 362 TB patients were registered in 1999 and 2000, respectively; 70% were HIV-positive. The overall case fatality rate fell from 37% to 29%, i.e. for every 12.5 TB patients treated, one death was averted. Case fatality rates were unchanged between the two years in HIV-negative patients, but fell in HIV-positive patients from 43% to 24%. The improved survival became apparent after the first 2 months and was maintained beyond the end of treatment. The improvement was most marked in patients with smear-positive TB and others with confirmed TB diagnoses. CONCLUSION: Survival of HIV-positive TB patients improved dramatically with the addition of cotrimoxazole prophylaxis to the treatment regimen. The improvement can be attributed to cotrimoxazole because other factors were unchanged and the survival of HIV-negative patients was not improved. Cotrimoxazole prophylaxis should therefore be added to the routine care of HIV-positive TB patients.

AIDS-Related Opportunistic Infections↗

PubMed2004

Large-scale candidate gene study of leprosy susceptibility in the Karonga district of northern Malawi.

We present a large case-control candidate gene study of leprosy susceptibility. Thirty-eight polymorphic sites from 13 genes were investigated for their role in susceptibility to leprosy by comparing 270 cases with 452 controls in Karonga district, northern Malawi. Homozygotes for a silent T-->C change in codon 352 of the vitamin D receptor gene appeared to be at high risk (odds ratio [OR] = 4.3, 95% confidence interval [CI] = 1.6-11.4, P = 0.004), while homozygotes for the McCoy b blood group defining variant K1590E in exon 29 of the complement receptor 1 (formerly CD35) gene appeared to be protected (OR = 0.3, 95% CI = 0.1-0.8, P = 0.02). Borderline evidence for association with leprosy susceptibility was found for seven polymorphic sites in an additional six genes. Some of these apparent associations may be false-positive results from multiple comparisons, and several associations suggested by studies in other populations were not replicated here. These data provide evidence of inter-population heterogeneity in leprosy susceptibility.

Adolescent↗

PubMed2004

Large-scale candidate gene study of tuberculosis susceptibility in the Karonga district of northern Malawi.

Twenty-seven polymorphisms from 12 genes have been investigated for association with tuberculosis (TB) in up to 514 cases and 913 controls from Karonga district, northern Malawi. Homozygosity for the complement receptor 1 (CR1) Q1022H polymorphism was associated with susceptibility to TB in this population (odds ratio [OR] = 3.12, 95% Confidence interval [CI] = 1.13-8.60, P = 0.028). This association was not observed among human immunodeficiency virus (HIV)-positive TB cases, suggesting either chance association or that HIV status may influence genetic associations with TB susceptibility. Heterozygosity for a newly studied CAAA insertion/deletion polymorphism in the 3'-untranslated region of solute carrier family 11, member 1 (SLC11A1, formerly NRAMP1) was associated with protection against TB in both HIV-positive (OR = 0.70, 95% CI = 0.49-0.99, P = 0.046) and HIV-negative (OR = 0.65, 95% CI = 0.46-0.92, P = 0.014) TB cases, suggesting that the SLC11A1 protein may have a role in innate TB immune responses that influence susceptibility even in immunocompromised individuals. However, associations of other variants of SCLA11A with TB reported from other populations were not replicated in Malawi. Furthermore, associations with vitamin D receptor, interferon-gamma, and mannose-binding lectin observed elsewhere were not observed in this Karonga study. Genetic susceptibility to TB in Africans appears polygenic. The relevant genes and variants may vary significantly between populations, and may be affected by HIV infection status.

Gene Frequency↗

PubMed2003

The long-term impact of HIV and orphanhood on the mortality and physical well-being of children in rural Malawi.

OBJECTIVE: To assess the influence of maternal HIV status and orphanhood on child mortality and physical well-being. DESIGN: Retrospective cohort study with > 10 years of follow-up. METHODS: From population-based surveys in Karonga District, Malawi in the 1980s, 197 individuals were identified as HIV-positive. These individuals and 396 HIV-negative individuals matched for age and sex, and their spouses and offspring, were sought in 1998-2000. RESULTS: All but 11 of the index individuals were traced, identifying 2520 offspring; of these, 1106 offspring were included in analyses. Among those with HIV-positive mothers, mortality was 27% [95% confidence interval (CI), 17-38] in infants (1-30 days), 46% (95% CI, 34-58) in those under 5 years and 49% (95% CI, 38-61) in those under 10 years. The corresponding figures for those with HIV-negative mothers were 11% (95% CI, 8-13), 16% (95% CI, 13-19) and 17% (95% CI, 14-20). Death of HIV-positive mothers, but not of HIV-negative mothers or of fathers, was associated with increased child mortality. Among survivors who were still resident in the district, neither maternal HIV status nor orphanhood was associated with stunting, being wasted, or reported ill-health. CONCLUSIONS: Mortality in children under 5 years is much higher in children born to HIV-positive mothers than in those born to HIV-negative mothers. With 10% of pregnant women HIV-positive, we estimate that approximately 18% of under-5 deaths in this population are attributable to HIV. Most of the excess is attributable to vertical transmission of HIV. Our findings suggest that, in terms of physical well-being, the extended family in this society has not discriminated against surviving children whose parents have been ill or have died as a result of HIV/AIDS.

Adult↗

PubMed2003

Gamma interferon responses induced by a panel of recombinant and purified mycobacterial antigens in healthy, non-mycobacterium bovis BCG-vaccinated Malawian young adults.

We have previously shown that young adults living in a rural area of northern Malawi showed greater gamma interferon (IFN-gamma) responses to purified protein derivatives (PPD) prepared from environmental mycobacteria than to PPD from Mycobacterium tuberculosis. In order to define the mycobacterial species to which individuals living in a rural African population have been exposed and sensitized, we tested T-cell recognition of recombinant and purified antigens from M. tuberculosis (38 kDa, MPT64, and ESAT-6), M. bovis (MPB70), M. bovis BCG (Ag85), and M. leprae (65 kDa, 35 kDa, and 18 kDa) in >600 non-M. bovis BCG-vaccinated young adults in the Karonga District of northern Malawi. IFN-gamma was measured by enzyme-linked immunosorbent assay (ELISA) in day 6 supernatants of diluted whole-blood cultures. The recombinant M. leprae 35-kDa and 18-kDa and purified native M. bovis BCG Ag85 antigens induced the highest percentages of responders, though both leprosy and bovine tuberculosis are now rare in this population. The M. tuberculosis antigens ESAT-6 and MPT64 and the M. bovis antigen MPB70 induced the lowest percentages of responders. One of the subjects subsequently developed extrapulmonary tuberculosis; this individual had a 15-mm-diameter reaction to the Mantoux test and responded to M. tuberculosis PPD, Ag85, MPT64, and ESAT-6 but not to any of the leprosy antigens. We conclude that in this rural African population, exposure to M. tuberculosis or M. bovis is much less frequent than exposure to environmental mycobacteria such as M. avium, which have antigens homologous to the M. leprae 35-kDa and 18-kDa antigens. M. tuberculosis ESAT-6 showed the strongest association with the size of the Mantoux skin test induration, suggesting that among the three M. tuberculosis antigens tested it provided the best indication of exposure to, or infection with, M. tuberculosis.

Adolescent↗

PubMed2002

Kinetics of delayed-type hypersensitivity to tuberculin induced by bacille Calmette-Guérin vaccination in northern Malawi.

During 1986-1989, a bacille Calmette-Guérin (BCG) vaccine trial was carried out in northern Malawi. The effects of age, sex, and prevaccination delayed-type hypersensitivity (DTH) on the time course of the DTH response over 1-36 months after vaccination were studied in 2418 persons. DTH response increased rapidly, to peak at 31-90 days after vaccination, when most persons had a measurable response. This was followed by a marked decline by 181-365 days, particularly in those <15 years old at vaccination, followed by a more gradual decline. Prevaccination DTH was the single best predictor of postvaccination DTH. BCG-induced DTH responsiveness appears to decline more rapidly in tropical than in temperate environments. This may reflect high prevalence of exposure to other infections, which induce a Th2 bias or compete for "space" within the T lymphocyte compartment. The inability of some persons to mount a persistent DTH response probably reflects genetic background and/or environmental exposure history.

Adolescent↗

PubMed2002

Long-term follow-up of HIV-positive and HIV-negative individuals in rural Malawi.

OBJECTIVE: To measure the effect of HIV on survival in rural Africa. DESIGN: A retrospective cohort study with more than 10 years follow-up. METHODS: Individuals with known HIV status in the 1980s were identified from previous population surveys in Karonga District, northern Malawi. Follow-up studies were conducted in 1998-2000 to trace 197 HIV-positive and 396 age-sex-matched HIV-negative individuals and their spouses. RESULTS: Information was obtained on all but 11 index individuals. Half (302) were found and the others were reported to have died (161) or to be alive outside the district (119). Ten year survival was 36% in the HIV-positive cohort and 90% in the initially HIV-negative cohort. The death rate was 93.3 per 1000 person-years in the HIV-positive individuals, and 11.3 in the initially HIV-negative individuals. Survival time since the initial test in HIV-positive individuals decreased with age, but relative survival, compared with HIV-negative individuals, was similar across age groups. The effect of HIV on survival was similar in men and women. Spouses of HIV-positive individuals had four times the mortality rate, and among survivors, four times the HIV prevalence, of spouses of initially HIV-negative individuals. CONCLUSION: HIV-infected individuals had very high mortality rates, but one-third were still alive at 10 years. This is consistent with median survival from seroconversion being similar to that found in developed countries before antiretroviral therapy. Mortality rates in HIV-positive individuals increased with age, but relative mortality changed little with age.

Acquired Immunodeficiency Syndrome↗

PubMed2002

BCG-induced increase in interferon-gamma response to mycobacterial antigens and efficacy of BCG vaccination in Malawi and the UK: two randomised controlled studies.

BACKGROUND: The efficacy of BCG vaccines against pulmonary tuberculosis varies between populations, showing no protection in Malawi but 50-80% protection in the UK. To investigate the mechanism underlying these differences, randomised controlled studies were set up to measure vaccine-induced immune responsiveness to mycobacterial antigens in both populations. METHODS: 483 adolescents and young adults in Malawi and 180 adolescents in the UK were tested for interferon-gamma (IFN-gamma) response to M tuberculosis purified protein derivative (PPD) in a whole blood assay, and for delayed type hypersensitivity (DTH) skin test response to tuberculin PPD, before and 1 year after receiving BCG (Glaxo 1077) vaccination or placebo or no vaccine. FINDINGS: The percentages of the randomised individuals who showed IFN-gamma and DTH responses were higher in Malawi than in the UK pre-vaccination-ie, 61% (331/546) versus 22% (47/213) for IFN-gamma and 46% (236/517) versus 13% (27/211) for DTH. IFN-gamma responses increased more in the UK than in Malawi, with 83% (101/122) and 78% (251/321) respectively of the vaccinated groups responding, with similar distributions in the two populations 1 year post-vaccination. The DTH response increased following vaccination in both locations, but to a greater extent in the UK than Malawi. The IFN-gamma and DTH responses were strongly associated, except among vaccinees in Malawi. INTERPRETATION: The magnitude of the BCG-attributable increase in IFN-gamma responsiveness to M tuberculosis PPD, from before to 1 year post-vaccination, correlates better with the known levels of protection induced by immunisation with BCG than does the absolute value of the IFN-gamma or DTH response after vaccination. It is likely that differential sensitisation due to exposure to environmental mycobacteria is the most important determinant of the observed differences in protection by BCG between populations.

Adolescent↗