Tuberculosis In Africans Research Articles

Exploring the eligibility of all reported lipoarabinomannan-testing assays in different clinical situations: a systematic review and meta-analysis of 97 articles

ObjectivesHow to choose proper lipoarabinomannan-testing assays for diagnosing tuberculosis (TB) in different populations baffles clinicians. This work assessed all reported lipoarabinomannan assays’ performance and aimed to identify the eligibility of each assay and offer guidance for clinicians. MethodsWe searched PubMed, Embase, and Web of Science until August 23, 2020. The risk of bias was evaluated by QADAS-2. Heterogeneity was evaluated by the Cochran Q test and I2. Sensitivity and specificity were pooled by a bivariate mixed model (register number: CRD42021270506). ResultsA total of 97 articles, covering 144 trials, 16 assays, 45,679 participants, and eight sample types, were divided into five groups. Electrochemiluminescence (ECL) had a sensitivity of 65%, specificity of 92%, and an area under curve (AUC) of 0.85 in diagnosing pulmonary TB in adults. ECL showed a promising diagnostic ability (sensitivity: 78%; specificity: 88%; AUC: 0.88) in patients with HIV, especially for urine detection (sensitivity: 90%; specificity: 89%; AUC: 0.95). The enzyme-linked immune assay showed a preference for diagnosing TB in Asians and Africans, especially in Africans who were smear-positive (sensitivity: 80%; specificity: 88%; AUC: 0.91). ConclusionECL was recommended for diagnosing pulmonary TB in adults, especially for TB/HIV co-infection. Taking urine as a sample further enhanced ECL's diagnostic performance. Enzyme-linked immune assay was recommended as an additional TB-related detection for smear-positive Africans.

Low expression Macrophage Migration Inhibitory Factor (MIF) alleles and tuberculosis in HIV infected South Africans

Host immunity is crucial for controlling M. tuberculosis infection. Functional polymorphisms in the cytokine macrophage migration inhibitory factor (MIF) show global population stratification, with the highest prevalence of low expression MIF alleles found in sub-Saharan Africans, which is a population with the greatest confluence of both TB and HIV infection and disease. We investigated the association between MIF alleles and tuberculosis (TB) and HIV in South Africa. We acquired clinical information and determined the frequency of two MIF promoter variants: a functional −794 CATT5-8 microsatellite and an associated −173 G/C SNP in two HIV-positive cohorts of patients with active laboratory-confirmed TB and in controls without active TB who were all HIV positive. We found a greater frequency of low expression MIF promoter variants (-794 CATT5,6) among TB disease cases compared to controls (OR = 2.03, p = 0.023), supporting a contribution of genetic low MIF expression to the high prevalence of TB in South Africa. Among those with HIV, circulating MIF levels also were associated with lower CD4 cell counts irrespective of TB status (p = 0.016), suggesting an influence of HIV immunosuppression on MIF expression.

Injecting drug use predicts active tuberculosis in a national cohort of people living with HIV.

Tuberculosis (TB) is common in people living with HIV, leading to worse clinical outcomes including increased mortality. We investigated risk factors for developing TB following HIV diagnosis. Adults aged at least 15 years first presenting to health services for HIV care in England, Wales or Northern Ireland from 2000 to 2014 were identified from national HIV surveillance data and linked to TB surveillance data. We calculated incidence rates for TB occurring more than 91 days after HIV diagnosis and investigated risk factors using multivariable Poisson regression. A total of 95 003 adults diagnosed with HIV were followed for 635 591 person-years; overall incidence of TB was 344 per 100 000 person-years (95% confidence interval 330-359). TB incidence was high for people who acquired HIV through injecting drugs [PWID; men 876 (696-1104), women 605 (365-945)] and black Africans born in high TB incidence countries [644 (612-677)]. The adjusted incidence rate ratio for TB amongst PWID was 4.79 (3.35-6.85) for men and 6.18 (3.49-10.93) for women, compared with MSM. The adjusted incidence rate ratio for TB in black Africans from high-TB countries was 4.27 (3.42-5.33), compared with white UK-born individuals. Lower time-updated CD4 cell count was associated with increased rates of TB. PWID had the greatest risk of TB; incidence rates were comparable with those in black Africans from high TB incidence countries. Most TB cases in PWID were UK-born, and likely acquired TB through transmission within the United Kingdom. Earlier HIV diagnosis and quicker initiation of antiretroviral therapy should reduce TB incidence in these populations.

Variants in toll-like receptors 2 and 9 influence susceptibility to pulmonary tuberculosis in Caucasians, African-Americans, and West Africans

Tuberculosis (TB) is a global public health problem and a source of preventable deaths each year, with 8.8 million new cases of TB and 1.6 million deaths worldwide in 2005. Approximately, 10% of infected individuals develop pulmonary or extrapulmonary TB, suggesting that host defense factors influence development of active disease. Toll-like receptor' (TLR) polymorphisms have been associated with regulation of TLR expression and development of active TB. In the present study, 71 polymorphisms in TLR1, TLR2, TLR4, TLR6, and TLR9 were examined from 474 (295 cases and 179 controls) African-Americans, 381 (237 cases and 144 controls) Caucasians, and from 667 (321 cases and 346 controls) Africans from Guinea-Bissau for association with pulmonary TB using generalized estimating equations and logistic regression. Statistically significant associations were observed across populations at TLR9 and TLR2. The strongest evidence for association came at an insertion (I)/deletion (D) polymorphism (-196 to -174) in TLR2 that associated with TB in both Caucasians (II vs. ID&DD, OR = 0.41 [95% CI 0.24-0.68], p = 0.0007) and Africans (II vs. ID&DD, OR = 0.70 [95% CI 0.51-0.95], p = 0.023). Our findings in three independent population samples indicate that variations in TLR2 and TLR9 might play important roles in determining susceptibility to TB.

DC-SIGN (CD209), pentraxin 3 and vitamin D receptor gene variants associate with pulmonary tuberculosis risk in West Africans

We investigated the role of DC-SIGN (CD209), long pentraxin 3 (PTX3) and vitamin D receptor (VDR) gene single nucleotide polymorphisms (SNPs) in susceptibility to pulmonary tuberculosis (TB) in 321 TB cases and 347 healthy controls from Guinea-Bissau. Five additional, functionally relevant SNPs within toll-like receptors (TLRs) 2, 4 and 9 were typed but found, when polymorphic, not to affect host vulnerability to pulmonary TB. We did not replicate an association between SNPs in the DC-SIGN promoter and TB. However, we found that two polymorphisms, one in DC-SIGN and one in VDR, were associated in a nonadditive model with disease risk when analyzed in combination with ethnicity (P=0.03 for DC-SIGN and P=0.003 for VDR). In addition, PTX3 haplotype frequencies significantly differed in cases compared to controls and a protective effect was found in association with a specific haplotype (OR 0.78, 95% CI 0.63-0.98). Our findings support previous data showing that VDR SNPs modulate the risk for TB in West Africans and suggest that variation within DC-SIGN and PTX3 also affect the disease outcome.

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.

Identification of Susceptibility Genes for Tuberculosis in Southern and West Africans Using Family-Based Linkage Analysis and Linkage Disequilibrium Mapping

Bacterially derived heat shock proteins have been shown to be powerful adjuvants of the immune response. Due to their ability to bind protein ligands, it has been shown that they can chaperone peptide epitopes for cross-presentation of antigen by dendritic cells (DC) to CD8+ lymphocytes. We have been able to elicit very powerful cyto-toxic T cell (CTL) responses by pulsing human monocyte derived DC with HSMO-peptide complexes. Free peptide alone or use of another adjuvant such as LPS with free peptide did not elicit such powerful responses. We have shown that peptidebinding fragments of HSP70, without a nuclcotide-binding domain, are as effective in eliciting this response. To quantify the efficiency of peptide delivered on HSP70 we determined the affinity of HSP70 for peptide by suface plasmon resonance and fluorescence anisotropy. Furthermore, the role of peptide binding to HSMO was investigated by site-directed mutagenesis of the substrate-binding pocket of HSP70. The V410F mutant, which cannot bind peptide, is unable to generate CTL even in the presence of excess free peptide, but is as good an adjuvant as wild-type HSP70. These data demonstrate a poweful method of eliciting human CTL responses by DC using HSP70 to deliver antigen and stimulate DC simultaneously. To our knowledge, this is the first instance that HSPchaperone antigens have been used to elicit a human CTL response. M153

Genetic susceptibility to tuberculosis in Africans: a genome-wide scan.

Human genetic variation is an important determinant of the outcome of infection with Mycobacterium tuberculosis. We have conducted a two-stage genome-wide linkage study to search for regions of the human genome containing tuberculosis-susceptibility genes. This approach uses sibpair families that contain two full siblings who have both been affected by clinical tuberculosis. For any chromosomal region containing a major tuberculosis-susceptibility gene, affected sibpairs inherit the same parental alleles more often than expected by chance. In the first round of the screen, 299 highly informative genetic markers, spanning the entire human genome, were typed in 92 sibpairs from The Gambia and South Africa. Seven chromosomal regions that showed provisional evidence of coinheritance with clinical tuberculosis were identified. To identify whether any of these regions contained a potential tuberculosis-susceptibility gene, 22 markers from these regions were genotyped in a second set of 81 sibpairs from the same countries. Markers on chromosomes 15q and Xq showed suggestive evidence of linkage (lod = 2.00 and 1.77, respectively) to tuberculosis. The potential identification of susceptibility loci on both chromosomes 15q and Xq was supported by an independent analysis designated common ancestry using microsatellite mapping. These results indicate that genome-wide linkage analysis can contribute to the mapping and identification of major genes for multifactorial infectious diseases of humans. An X chromosome susceptibility gene may contribute to the excess of males with tuberculosis observed in many different populations.

Identifying genetic susceptibility factors for tuberculosis in Africans: a combined approach using a candidate gene study and a genome-wide screen

Identifying genetic susceptibility factors for tuberculosis in Africans: a combined approach using a candidate gene study and a genome-wide screen

Identifying genetic susceptibility factors for tuberculosis in Africans: a combined approach using a candidate gene study and a genome-wide screen

There is convincing evidence that host genes affect the outcome of infection in human tuberculosis. Two complementary strategies were used to identify the genes involved. A linkage-based genome-wide screen was carried out to locate the positions of genes exerting a major population-wide effect on tuberculosis susceptibility. A candidate-gene-based case-control study was used to examine the effects of genes that may exert a more moderate effect on risk of clinical tuberculosis. The genome screen was conducted in two stages. In the first stage 299 microsatellite markers, spanning all 23 chromosomes, were typed in 92 independent sib-pairs, and seven regions showed some evidence of co-segregation with the disease. These seven regions were examined in a second set of 81 sib-pairs, and markers on chromosomes 15q and Xq showed evidence of linkage to tuberculosis. An X chromosome susceptibility gene may contribute to the excess of males with tuberculosis observed in many populations. The candidate gene approach compared the frequency of polymorphisms in several genes in over 400 subjects with smear-positive pulmonary tuberculosis and 400 ethnically matched healthy controls. Polymorphisms in genes encoding natural-resistance-associated macrophage protein, vitamin D receptor and mannose-binding lectin were associated with tuberculosis. These results suggest that many genes may be involved in determining host susceptibility to tuberculosis, and highlight the importance of using several different study methods to locate them.

Sustained plasma TNF-alpha and HIV-1 load despite resolution of other parameters of immune activation during treatment of tuberculosis in Africans.

To determine the impact of treatment of tuberculosis on plasma HIV-1 load in African subjects and to correlate viral load with response to treatment and changes in immune activation. Clinical and microbiological responses, immune activation parameters and plasma HIV-1 load were determined in 20 patients with pulmonary tuberculosis and HIV-1 coinfection in Ghana, West Africa during the first 3 months of anti-tuberculosis treatment. Plasma HIV-1 load and markers of immune activation were determined by commercially available assays. Human leukocyte antigen (HLA)-DR incorporation into the HIV-1 envelope was measured by using an immunomagnetic capture technique. Treatment of tuberculosis resulted in significant improvements in weight and haemoglobin, a high sputum smear conversion rate and marked reductions in mean plasma tumour necrosis factor (TNF) receptor-1, interleukin-6 and C-reactive protein. Furthermore, incorporation of host HLA-DR into the HIV-1 envelope decreased; this also suggested a reduction in immune activation of the cells supporting viral replication. However, of importance with regard to AIDS pathogenesis, neither mean plasma TNF-alpha nor HIV-1 load decreased significantly. The failure of HIV-1 plasma load to decline significantly during the initial months of anti-tuberculosis treatment is associated with high, sustained systemic levels of TNF-alpha. The dissociation between the sustained levels of plasma TNF-alpha and the major reductions in other, diverse immune activation parameters may represent dysregulation of cytokine production in these African patients.

The immunogenetics of human infectious diseases.

Twin and adoptee studies have indicated that host genetic factors are major determinants of susceptibility to infectious disease in humans. Twin studies have also found high heritabilities for many humoral and cellular immune responses to pathogen antigens, with most of the genetic component mapping outside of the major histocompatibility complex. Candidate gene studies have implicated several immunogenetic polymorphisms in human infectious diseases. HLA variation has been associated with susceptibility or resistance to malaria, tuberculosis, leprosy, AIDS, and hepatitis virus persistence. Variation in the tumor necrosis factor gene promoter has also been associated with several infectious diseases. Chemokine receptor polymorphism affects both susceptibility ot HIV-1 infection and the rate of progression to AIDS. Inactivating mutations of the gamma-interferon receptor lead to increased susceptibility to typical mycobacteria and disseminated BCG infection in homozygous children. The active form of vitamin D has immunomodulatory effects, and allelic variants of the vitamin D receptor appear to be associated with differential susceptibility to several infectious diseases. NRAMP1, a macrophage gene identified by positional cloning of its murine homologue, has been implicated in susceptibility to tuberculosis in Africans. Whole genome linkage analysis of multi-case families is now being used to map and identify new loci affecting susceptibility to infectious diseases. It is likely that susceptibility to most microorganisms is determined by a large number of polymorphic genes, and identification of these should provide insights into protective and pathogenic mechanisms in infectious diseases.

Variations in the NRAMP1 gene and susceptibility to tuberculosis in West Africans.

Genetic factors may affect the susceptibility to tuberculosis, but no specific genes governing susceptibility have been identified. In mice, natural resistance to infection with some mycobacteria is influenced by the gene for natural-resistance-associated macrophage protein 1 (Nramp1), but the role of the human homologue of this gene, NRAMP1, in tuberculosis is unknown. We typed polymorphisms in NRAMP1 in a case-control study of tuberculosis in the Gambia, West Africa. Sequence-specific oligonucleotide hybridization and microsatellite analysis were used to type NRAMP1 polymorphisms in 410 adults (mean age, 34.7 years) with smear-positive pulmonary tuberculosis and 417 ethnically matched, healthy controls. Patients with human immunodeficiency virus infection were excluded. Four NRAMP1 polymorphisms were each significantly associated with tuberculosis. Subjects who were heterozygous for two NRAMP1 polymorphisms in intron 4 and the 3' untranslated region of the gene were particularly overrepresented among those with tuberculosis, as compared with those with the most common NRAMP1 genotype (odds ratio, 4.07; 95 percent confidence interval, 1.86 to 9.12; chi-square= 14.58; P<0.001). Genetic variation in NRAMP1 affects susceptibility to tuberculosis in West Africans.

Mannose binding protein deficiency is not associated with malaria, hepatitis B carriage nor tuberculosis in Africans.

We retrospectively studied MBP genotypes in patients with malaria, tuberculosis (TB), and persistent hepatitis B virus (HBV) carriage, in clinics and hospitals in The Gambia. Children under 10 years with cerebral malaria and/or severe malarial anaemia, were compared with children with symptomatic, mild malaria, and controls of the same age and ethnicity. Adult TB cases with smear-positive pulmonary TB were compared with healthy blood donors from the same ethnic groups. Malaria cases and controls were tested for hepatitis B core antibody (anti-HBc) and surface antigen (HBsAg). TB patients were tested for HIV antibodies. Genotyping used sequence-specific oligonucleotide analysis to identify MBP variant alleles. Overall, 46% (944/2041) of patients and controls were homozygous for the wild-type MBP allele, 45% (922/2041) were carriers of a single variant allele and 8.6% (175/2041) had two variant alleles. Neither homozygotes nor heterozygotes for MBP variants were at increased risk of clinical malaria, persistent HBV carriage or TB. The most common mutation in Africans, the codon 57 variant allele, was weakly associated with resistance to TB (221/794 in TB cases and 276/844 in controls, p = 0.037). MBP deficiency is not a significant risk factor for persistent HBV, severe malaria nor pulmonary TB in West Africa.

Spectrum of disease in Africans with AIDS in London.

To compare the spectrum of disease, severity of immune deficiency and chemoprophylaxis prescribed in HIV-infected African and non-African patients in London. Retrospective review of case notes of all HIV-infected Africans and a comparison group of non-Africans attending 11 specialist HIV/AIDS Units in London. Comparison of demographic information, first and subsequent AIDS-defining conditions, levels of immune deficiency, and chemoprophylactic practices between the African and non-African groups. A total of 1056 Africans (313 developing AIDS) and 992 non-Africans (314 developing AIDS) were studied. Africans presented later than non-Africans (median CD4+ lymphocyte counts at diagnosis 238 and 371 x 10(6)/l, respectively). Tuberculosis accounted for 27% of initial episodes of AIDS in Africans and 5% in non-Africans; Pneumocystis carinii pneumonia (PCP) was the initial AIDS-defining condition in 34% of non-Africans and 17% of Africans. The incidence of tuberculosis in Africans with another AIDS-indicator disease was 16 per 100 person-years. PCP prophylaxis was prescribed for 40% Africans and 32% non-Africans; only 8% of Africans received tuberculosis preventive therapy. HIV-infected African patients presented at lower levels of CD4+ lymphocyte count, at a more advanced clinical stage, and with different AIDS-indicator diseases as compared with non-Africans. Prophylaxis against tuberculosis should be considered for all HIV-infected African patients in industrialized countries. The high incidence of diseases that are indicative of advanced immunodeficiency (e.g., cytomegalovirus disease) in African patients contrasts with data from Africa, suggesting better survival chances in the UK.

Tuberculosis and human immunodeficiency virus infection in developing countries

Estimates show that 5 million people worldwide are infected with human immunodeficiency virus (HIV). Recent estimates are that 8-10 million new tuberculosis (TB) cases occur each year in the world. 2-3 million die. In developing countries, TB is one of the most common opportunistic infections in people who are seropositive for HIV-1. About 90% of the TB is pulmonary. Of those without pulmonary tuberculosis, 85% had lymphadenopathy, bone and joint disease, or pleural effusion. In adults and children over 15 who had pulmonary TB, 78% had positive sputum smears for acid-fast bacilli. 66% had cavitation on chest radiography. Many people with TB and HIV infection have typical clinical and radiologic features. However, African clinicians have seen a change. This makes TB harder to diagnose. In Bangui, Central African Republic, 30% of pulmonary TB patients were HIV seropositive. Studies from Zaire and Zambia also had patients with suspected TB and extrapulmonary TB with higher HIV seropositivity rates than those with sputum-positive TB. Haitians show a similar disease pattern to that of Africa. 70% of people with tuberculosis and the acquired immunodeficiency syndrome (AIDS) had extrapulmonary disease compared with 20% of the HIV-negative people with TB. Chemotherapy of TB in Africans who also have HIV infection is not certain. Clinical impressions suggest that the disease responds well to the usual therapy. However, a Central African study found that mortality 12 months after the start of the usual drug therapy was 32.5% in HIV-seropositives compared with 1.5% in HIV-seronegatives. Several countries in Africa use short-course drug therapy for smear-positive pulmonary TB. They use the usual regime for smear-negative and extrapulmonary TB. Since AIDS, there are more skin allergic reactions to the usual drug therapy. There are more severe reactions now. Thiacetazone is the drug which probably causes this reaction. BCG immunization is used to control TB in Africa. World Health Organization guidelines are to withhold BCG from HIV- seropositive people with symptoms. What about infants born to HIV- seropositive mothers?

Tuberculosis in Africans. Prolonged observations on drug sensitivity of M. tuberculosis during chemotherapy.

(1) The dynamics of changes in drug resistance in tubercle bacilli were studied in 82 patients kept under observation over a lengthy period (up to 57 months). More than 30 cultures of tubercle bacilli were isolated from each of 18 patients during the trials and studied.

Prolonged out-patient chemotherapy of pulmonary tuberculosis in West Africans following short-term hospital treatment

Summary An investigation has been undertaken to determine the effectiveness of out-patient chemotherapy (using isoniazid and PAS) following a short period of hospital treatment (using streptomycin combined with isoniazid, or streptomycin combined with isoniazid and PAS). The combinations used were reasonably effective in improving clinical condition and radiographic appearances, and in clearing tubercle bacilli from the sputum. In respect of bacteriological state and the behaviour of cavities, those commencing treatment with a triple drug combination improved to a greater extent in the early months. Reasons are given for the belief that there are serious and possibly dangerous limitations to the usefulness of oral chemotherapy of out-patients, when applied over a prolonged period, under existing conditions in West Africa.

Comparative trial of isoniazid in combination with thiacetazone or a substituted diphenylthiourea (SU1906) or PAS in the treatment of acute pulmonary tuberculosis in east africans: A Co-operative Investigation in East African Hospitals and Laboratories with the Collaboration of the British Medical Research Council

Comparative trial of isoniazid in combination with thiacetazone or a substituted diphenylthiourea (SU1906) or PAS in the treatment of acute pulmonary tuberculosis in east africans: A Co-operative Investigation in East African Hospitals and Laboratories with the Collaboration of the British Medical Research Council

Prednisolone in the treatment of acute extensive pulmonary tuberculosis in West Africans

A controlled trial has been undertaken to determine whether prednisolone, added to standard chemotherapy, hastens clinical and radiographic improvement, and clears the sputum more rapidly of tubercle bacilli, in acute extensive pulmonary tuberculosis in West Africans, during a short period of hospital treatment. Forty nine cases were treated with prednisolone combined with chemotherapy, and fifty one with chemotherapy alone. Clinical improvement was more rapid in the prednisolone treated group, particularly in those severely ill or in poor condition, during the first month of treatment. There were no significant differences in respect of weight change, radiographic clearing or cavity closure. Clearance of bacilli from the sputum was not hastened, and an initial rise in the bacterial count was noted in the prednisolone treated cases. A well marked rise in the circulating white cells (including a rise in eosinophils) was observed in the prednisolone cases.