Risk factors for defaulting from tuberculosis treatment: a prospective cohort study of 301 cases in the Gambia.

SETTING: An urban tuberculosis (TB) clinic, The Gambia. OBJECTIVE: To identify patient characteristics associated with increased rates of defaulting from treatment, specifically knowledge and cost factors amenable to intervention. DESIGN: Prospective cohort study of TB cases at least 15 years of age commencing treatment, interviewed by semi-structured questionnaire and followed for attendance at thrice-weekly directly observed treatment (DOT). RESULTS: Of 301 patients, 76 (25.2%) defaulted from treatment and 25 did not return for treatment. The defaulting rate was higher among those who said they were uncertain that their treatment would work (HR 3.64; 95%CI 1.42-9.31, P = 0.007) and among those who incurred significant time or money costs travelling to receive treatment (HR 2.67; 95%CI 1.05-6.81; P = 0.04). These factors had differing effects with respect to time: uncertainty over treatment success was important in the first 90 days of treatment, while increased cost of travelling to the clinic was important after 90 days. CONCLUSION: In The Gambia, risk groups for defaulting can be recognised at the start of treatment and are at highest risk at different times. Home-based self-administration of medications after 3 months of DOT should be considered as confidence in treatment success rises, and the costs of travelling to receive treatment start to take their toll.     

耐多药结核病治疗的有关不良反应

背景:土耳其Istanbul市Süreyyapa?a胸部疾病及胸外科中心。目的:报告耐多药结核病(MDR-TB)治疗中不良反应的发生率。设计:根据病历记载,回顾性总结1992年4月至2004年6月期间接受耐多药结核病个体化治疗的263例患者的情况。结果:共有182例(69.2%)发生1或1项以上的不良反应,其中146例(55.5%)需在治疗方案中撤去1或1种以上的药物。最常见的不良反应有:耳毒性反应(41.8%)、精神心理障碍(21.3%)、胃肠道不适(14.0%)、关节痛(11.4%)、癫痫发作(9.9%)、肝炎(4.5%)、皮肤反应(4.5%)。治疗结果显示,治疗成功者204例(77.6%)、疗效不佳者59例(22.4%)。结论:耐多药结核病治疗的不良反应发生率高,但及时的积极处理可不影响MDR-TB的治疗成功率。     

Long-term follow-up of autologous bone marrow transplantation in patients with relapsed follicular lymphoma.

We report the results of high-dose chemoradiotherapy and anti-B-cell monoclonal antibody-purged autologous bone marrow transplantation (ABMT) in patients with relapsed indolent follicular lymphoma. Between March 1985 and May 1995, 153 patients underwent ABMT using a uniform ablative regimen with cyclophosphamide and total body irradiation and bone marrow (BM) purging. All patients received multiple chemotherapy regimens before ABMT. At BM harvest, only 30% of patients were in complete remission, and overt BM infiltration was present in 47%. The disease-free survival (DFS) and overall survival (OS) are estimated to be 42% and 66% at 8 years, respectively. Patients whose BM was negative by polymerase chain reaction (PCR) for bcl2/IgH rearrangement after purging experienced longer freedom from recurrence than those whose BM remained PCR positive (P <.0001). Continued PCR negativity in follow-up BM samples was also strongly predictive of continued complete remission (CR). The 12-year survival from diagnosis for these 153 patients is 69%. Considering that the median survival from diagnosis and first recurrence of patients with advanced follicular lymphoma are 8 and 5 years, respectively, our results provide evidence that myeloablative therapy and ABMT may prolong overall survival.     

Investigation of malaria susceptibility determinants in the IFNG/IL26/IL22 genomic region

Interferon-gamma, encoded by IFNG, is a key immunological mediator that is believed to play both a protective and a pathological role in malaria. Here, we investigate the relationship between IFNG variation and susceptibility to malaria. We began by analysing West African and European haplotype structure and patterns of linkage disequilibrium across a 100 kb genomic region encompassing IFNG and its immediate neighbours IL22 and IL26. A large case-control study of severe malaria in a West Africa population identified several weak associations with individual single-nucleotide polymorphisms in the IFNG and IL22 genes, and defined two IL22 haplotypes that are, respectively, associated with resistance and susceptibility. These data provide a starting point for functional and genetic analysis of the IFNG genomic region in malaria and other infectious and inflammatory conditions affecting African populations.     

Complex haplotypic structure of the central MHC region flanking TNF in a West African population

TNF polymorphisms have been associated with susceptibility to malaria and other infectious and inflammatory conditions. We investigated a sample of 150 West African chromosomes to determine linkage disequilibrium (LD) between 25 SNP markers located in an 80 kb segment of the MHC Class III region encompassing TNF and eight neighbouring genes. We observed 45 haplotypes, and 22 of them comprise 80% of the sample. The pattern of LD is remarkably patchy, such that many markers show no LD with adjacent markers but high LD with markers that are much further away. We introduce a method of examining the implications of LD data for disease association studies based on sample size considerations: this shows that certain TNF polymorphisms would be likely to yield positive associations if the true disease allele resided in LTA or BAT1. We conclude that detailed marker maps are needed to resolve the causal origin of disease associations observed at the TNF locus.     

CD40L association with protection from severe malaria

CD40 ligand (CD40L), a glycoprotein involved in B cell proliferation, antigen presenting cell activation, and Ig class switching, is important in the immune response to infection. Rare coding mutations in CD40L can lead to life-threatening immunodeficiency but the potential for common variants to alter disease susceptibility remains to be explored. To identify polymorphisms in CD40L, we sequenced 2.3 kb of the 5' flanking region and the first exon of the gene in DNA samples from 36 Gambian females and one chimpanzee. Diversity was lower than the average reported for other areas of the X chromosome, and only two polymorphisms were identified. The polymorphisms were genotyped in DNA samples from 957 Gambian individuals, cases and controls from a study of severe malaria. A significant reduction in risk for severe malaria (OR = 0.52, P = 0.002) was associated with males hemizygous for the CD40L-726C. Analysis by transmission disequilibrium test of 371 cases, for whom DNA from both parents was also available, confirmed the result was not due to stratification (P = 0.04). A similar but non-significant trend was found in females. This preliminary association of a common variant in CD40L with a malaria resistance phenotype encourages further genetic characterization of the role of CD40L in infectious disease.     

Genetic variation at the TNF locus and the risk of severe sequelae of ocular Chlamydia trachomatis infection in Gambians

Tumor necrosis factor (TNF) is thought to be a key mediator of the inflammatory and fibrotic response to Chlamydia trachomatis (Ct) infection. A large matched-pair case-control study investigated putative functional single nucleotide polymorphisms (SNPs) across the major histocompatibility complex (MHC) class III region, including TNF and its immediate neighbors nuclear factor of kappa light polypeptide gene enhancer in B cells (IkappaBL), inhibitor like 1 and lymphotoxin alpha (LTA) in relation to the risk of scarring sequelae of ocular Ct infection. Haplotype and linkage disequilibrium analysis demonstrated two haplotypes, differing at position TNF-308, conferring an increased risk of trichiasis. The TNF-308A allele, and its bearing haplotype, correlated with increased TNF production in lymphocyte cultures stimulated with chlamydial elementary body antigen. Thus TNF-308A may determine directly, or be a marker of a high TNF producer phenotype associated with increased risk of sequelae of chlamydial infection. Multivariate analysis provided evidence for the presence of additional risk-associated variants near the TNF locus.     

Killer-cell immunoglobulin-like receptors and malaria caused by Plasmodium falciparum in The Gambia

The relevance of innate immune responses to Plasmodium falciparum infection, in particular the central role of natural killer (NK) cell-derived interferon gamma (IFN-γ), is becoming increasingly recognised. Recently, it has been shown that IFN-γ production in response to P. falciparum antigens is in part regulated by killer-cell immunoglobulin-like receptor (KIR) genes, and a study from malaria-exposed Melanesians suggested an association between KIR genotypes and susceptibility to infection. This prompted us to determine and compare the frequencies of 15 KIR genes in Gambian children presenting with either severe malaria (n = 133) or uncomplicated malaria (n = 188) and in cord-blood population control samples (n = 314) collected from the same area. While no significant differences were observed between severe and uncomplicated cases, proportions of individuals with KIR2DS2+C1 and KIR2DL2+C1 were significantly higher among malaria cases overall than in population control samples. In an exploratory analysis, activating KIR genes KIR2DS2, KIR3DS1 and KIR2DS5 were slightly higher in children in disease subgroups associated with the highest mortality. In addition, our data suggest that homozygosity for KIR genotype A might be associated with different malaria outcomes including protection from infection and higher blood parasitaemia levels in those that do get infected. These findings are consistent with a probable role of KIR genes in determining susceptibility to malaria, and further studies are warranted in different populations.     

A hallmark of balancing selection is present at the promoter region of interleukin 10

As an anti-inflammatory mediator IL10 is beneficial in certain contexts and deleterious in others. As increased production of IL10 favours protection against inflammatory disease, whereas low production promotes elimination of foreign pathogens by the host, we investigated the possible influence of balancing selection at this locus. We began by resequencing 48 European and 48 African chromosomes across 2.2 kb of the IL10 promoter region, and compared this with four neighbouring gene regions: MK2, IL19, IL20 and IL24. Analysis of nucleotide diversity showed a positive Tajima's D-test for IL10 in Europeans, of borderline statistical significance (1.89, P=0.05). Analysis of F(st) values showed significant population divergence at MK2, IL19, IL20 and IL24 (P<0.01) but not at IL10. Taken together, these findings are consistent with the hypothesis that balancing selection has played a role in the evolution of polymorphisms in the IL10 promoter region.