Allan Chiunda

Whole Blood Bactericidal Activity during Treatment of Pulmonary Tuberculosis

The timely evaluation of new drugs that can be used to shorten tuberculosis (TB) treatment will require surrogate markers for relapse. This study examined bactericidal activity against intracellular Mycobacterium tuberculosis in whole blood culture (whole blood bactericidal activity; WBA) during TB treatment. In the absence of chemotherapy, immune mechanisms in patient blood resulted in bacteriostasis, whereas administration of oral chemotherapy resulted in bacillary killing. Total WBA per dose was greater during the intensive phase of treatment than during the continuation phase (mean, -2.32 vs. -1.67 log(10) cfu-days, respectively; P<.001). Cumulative WBA throughout treatment was greater in subjects whose sputum cultures converted to negative by the eighth week of treatment than in those for whom conversion was delayed (mean, -365 vs. -250 log(10) cfu-days; P=.04) and correlated with the rate of decrease of sputum colony-forming unit counts during the first 4 weeks of treatment (P=.018), both of which are indicative of prognosis. These findings indicate that measurement of WBA may have a role in assessing the sterilizing activity of new anti-TB drugs.

Linkage and association analysis of candidate genes for TB and TNFα cytokine expression: evidence for association with IFNGR1, IL-10, and TNF receptor 1 genes

Tuberculosis (TB) is a growing public health threat globally and several studies suggest a role of host genetic susceptibility in increased TB risk. As part of a household contact study in Kampala, Uganda, we have taken a unique approach to the study of genetic susceptibility to TB by developing an intermediate phenotype model for TB susceptibility, analyzing levels of tumor necrosis factor-α (TNFα) in response to culture filtrate as the phenotype. In the present study, we analyzed candidate genes related to TNFα regulation and found that interleukin (IL)-10, interferon-gamma receptor 1 (IFNGR1), and TNFα receptor 1 (TNFR1) genes were linked and associated to both TB and TNFα. We also show that these associations are with progression to active disease and not susceptibility to latent infection. This is the first report of an association between TB and TNFR1 in a human population and our findings for IL-10 and IFNGR1 replicate previous findings. By observing pleiotropic effects on both phenotypes, we show construct validity of our intermediate phenotype model, which enables the characterization of the role of these genetic polymorphisms on TB pathogenesis. This study further illustrates the utility of such a model for disentangling complex traits.

Secondary attack rate of tuberculosis in urban households in Kampala, Uganda.

Background Tuberculosis is an ancient disease that continues to threaten individual and public health today, especially in sub-Saharan Africa. Current surveillance systems describe general risk of tuberculosis in a population but do not characterize the risk to an individual following exposure to an infectious case. Methods In a study of household contacts of infectious tuberculosis cases (n = 1918) and a community survey of tuberculosis infection (N = 1179) in Kampala, Uganda, we estimated the secondary attack rate for tuberculosis disease and tuberculosis infection. The ratio of these rates is the likelihood of progressive primary disease after recent household infection. Results The secondary attack rate for tuberculosis disease was 3.0% (95% confidence interval: 2.2, 3.8). The overall secondary attack rate for tuberculosis infection was 47.4 (95% confidence interval: 44.3, 50.6) and did not vary widely with age, HIV status or BCG vaccination. The risk for progressive primary disease was highest among the young or HIV infected and was reduced by BCG vaccination. Conclusions Early case detection and treatment may limit household transmission of M. tuberculosis. Household members at high risk for disease should be protected through vaccination or treatment of latent tuberculosis infection.

Evidence for a Major Gene Influence on Tumor Necrosis Factor-α Expression in Tuberculosis: Path and Segregation Analysis

Objective: Tuberculosis (TB) is a growing global public health problem. Several studies suggest a role for host genetics in disease susceptibility, but studies to date have been inconsistent and a comprehensive genetic model has not emerged. A limitation of previous genetic studies is that they only analyzed the binary trait TB, which does not reflect disease heterogeneity. Furthermore, these studies have not accounted for the influence of shared environment within households on TB risk, which may spuriously inflate estimates of heritability. Methods: We conducted a household contact study in a TB-endemic community in Uganda. Antigen-induced tumor necrosis factor-α (TNFα) expression, a key component of the underlying immune response to TB, was used as an endophenotype for TB. Results: Path analysis, conducted to assess the effect of shared environment, suggested that TNFα is heritable (narrow sense heritability = 34–66%); the effect of shared environment is minimal (1–14%), but gene-environment interaction may be involved. Segregation analysis of TNFα suggested a major gene model that explained one-third of the phenotypic variance, and provided putative evidence of natural selection acting on this phenotype. Conclusion: Our data further support TNFα as an endophenotype for TB, as it may increase power to detect disease-predisposing loci.

Body Composition among HIV-seropositive and HIV-seronegative Adult Patients with Pulmonary Tuberculosis in Uganda

PURPOSE We determined whether human immunodeficiency virus (HIV) infection affects body cell mass and fat mass wasting among adults with pulmonary tuberculosis (PTB). METHODS We screened 967 Ugandan adults for PTB and HIV infection in a cross-sectional study. We compared anthropometric and bioelectric impedance analysis (BIA) body composition parameters among HIV-seropositive and HIV-seronegative men and women with or without PTB by using a non-parametric test. RESULTS We found that poor nutritional status associated with TB differed among men and women. Anthropometric and BIA body composition did not differ between HIV-seropositive and HIV-seronegative patients regardless of gender. Average weight group difference in men consisted of body cell mass and fat mass in equal proportions of 43%. In women, average weight group difference consisted predominantly of fat mass of 73% and body cell mass of 13%. Compared to individuals without TB, patients with TB had lower body mass index, weight, body cell mass, and fat mass regardless of gender and HIV status. CONCLUSIONS Gender, but not HIV status, was associated with body composition changes in TB. TB appears to be the dominant factor driving the wasting process among co-infected patients.

Lean Tissue Mass Wasting is Associated With Increased Risk of Mortality Among Women With Pulmonary Tuberculosis in Urban Uganda

OBJECTIVES We assessed the impact of wasting on survival in patients with tuberculosis by using a precise height-normalized lean tissue mass index (LMI) estimated by bioelectrical impedance analysis and body mass index (BMI). METHODS In a retrospective cohort study, 747 adult pulmonary patients with tuberculosis who were screened for HIV and nutritional status were followed for survival. RESULTS Of 747 patients, 310 had baseline wasting by BMI (kg/m(2)) and 103 by LMI (kg/m(2)). Total deaths were 105. Among men with reduced BMI, risk of death was 70% greater (hazard ratio [HR] 1.7, 95% confidence interval [95% CI] 1.03-2.81) than in men with normal BMI. Survival did not differ by LMI among men (HR 1.1; 95% CI 0.5-2.9). In women, both the BMI and LMI were associated with survival. Among women with reduced BMI, risk of death was 80% greater (HR 1.8; 95% CI 0.9-3.5) than in women with normal BMI; risk of death was 5-fold greater (HR 5.0; 95% CI 1.6-15.9) for women with low LMI compared with women with normal LMI. CONCLUSIONS Wasting assessed by reduced BMI is associated with an increased risk for death among both men and women whereas reduced LMI is among women with tuberculosis.

Knowledge of ACR Thoracic Imaging Appropriateness Criteria® among Trainees: One Institution's Experience

RATIONALE AND OBJECTIVES Providing evidence-based appropriate imaging potentially increases diagnostic yield and prevents unnecessary imaging. The American College of Radiologys (ACR) evidence-based Appropriateness Criteria(®) (ACR-AC) were developed to provide imaging guidelines given various clinical scenarios. The goal of this study was to evaluate the knowledge level of the appropriate thoracic imaging study to be performed, given a clinical scenario. METHODS An online survey comprising 20 multiple-choice questions was developed on the basis of excerpts from the ACR-AC for thoracic imaging. The survey was piloted and invitations were sent out to resident trainees in radiology (n = 32), medicine (n = 119), and surgery (n = 40) and to pulmonary and critical medicine fellows (n = 16). RESULTS Sixty-nine trainees (33%) completed the survey. The trainees among those who completed the survey included 14 (20%) in radiology, 32 (46%) in medicine, eight (12%) in surgery, and 15 (22%) in pulmonary and critical medicine. Of the 69 trainees, most were male (n = 47 [68%]), aged 25 to 35 years (n = 65 [94%]), and in postgraduate years 1 to 3 (n = 44 [64%]). The overall median and percentage number of correct responses were 13 (interquartile range [IQR], 11-15) and 65% (n = 44), respectively. As would be expected, radiology residents performed better, with a median number of correct responses of 15 (IQR, 11-16) compared to 10 (IQR, 9-12) for medicine trainees, nine (IQR, 9-12) for surgery trainees, and 13 (IQR, 12-15) for pulmonary and critical medicine trainees. There was an increase in the median number of correct responses with years of training, ranging from 10 for postgraduate year 1 to 12 for postgraduate year 6. CONCLUSIONS This study shows an opportunity to increase the awareness of the ACR-AC. Increasing the awareness of the ACR-AC among trainees will likely increase their use in practice and ultimately improve patient care.

Finding the best examples of healthcare quality improvement in Sub-Saharan Africa

Background The purpose of this study was to summarise the current state of healthcare quality improvement literature focusing on sub-Saharan Africa. Methods Conventional methods of searching the literature were quickly found to be inadequate or inappropriate, given the different needs of practitioners in sub-Saharan Africa, and the inaccessibility of the literature. Results The group derived a core list of what were deemed exemplary quality improvement articles, based on consensus and a search into the “grey” literature of quality improvement. Conclusions Quality improvment articles from sub-Saharan Africa are difficult to find, and suffer from a lack of centrality and organisation of literature. Efforts to address this are critical to fostering the growth of quality improvement literature in developing country settings.

Health services research in sub-Saharan Africa: thirty recommended examples

While there is good health services research work beingperformed in and concerning sub-Saharan Africa, it ischallenging and time-consuming to identify and locateit in print. To that end, the Society for Health ServicesResearch in sub-Saharan Africa was founded five yearsago among faculty and graduate students in theDepartment of Epidemiology and Biostatistics at CaseWestern Reserve University. About half the membersare from sub-Saharan Africa while the others haveresearch interests in that region. One of the initial activi-ties was to compile a list of recommended articles fromthe region.The selection criteria were influenced by HisExcellency the Vice President of Uganda, Dr GilbertBukenya, who during a visit to the Department in2006 expressed the view that: ‘We know that we haveproblems. What we need are solutions’. Therefore,our selection criteria for articles were that they had to:demonstrate solutions to problems; provide a clearand replicable description of an intervention; describeoutcome measures; and have at least one Africanauthor. We aimed to cover a wide range of illnessesand health conditions, methods and countries.Individual members of the Society adopted a varietyof search methods to identify articles including systema-tic searches conducted through Google and Medline.This produced over 1500 articles for consideration.In addition, reviews of regional journals, reviews ofwebsites for organizations undertaking health relatedworkintheregion,andmembers’knowledgeofprojectsand unpublished research were all employed.Agreement on which potential articles should beincluded was reached by having each member indepen-dently review and rank them based on the above cri-teria. The 30 highest ranked articles were included inthe recommended list (Box 1).