Bruce Kirenga

Prednisolone and Mycobacterium indicus pranii in Tuberculous Pericarditis

BACKGROUND Tuberculous pericarditis is associated with high morbidity and mortality even if antituberculosis therapy is administered. We evaluated the effects of adjunctive glucocorticoid therapy and Mycobacterium indicus pranii immunotherapy in patients with tuberculous pericarditis. METHODS Using a 2-by-2 factorial design, we randomly assigned 1400 adults with definite or probable tuberculous pericarditis to either prednisolone or placebo for 6 weeks and to either M. indicus pranii or placebo, administered in five injections over the course of 3 months. Two thirds of the participants had concomitant human immunodeficiency virus (HIV) infection. The primary efficacy outcome was a composite of death, cardiac tamponade requiring pericardiocentesis, or constrictive pericarditis. RESULTS There was no significant difference in the primary outcome between patients who received prednisolone and those who received placebo (23.8% and 24.5%, respectively; hazard ratio, 0.95; 95% confidence interval [CI], 0.77 to 1.18; P=0.66) or between those who received M. indicus pranii immunotherapy and those who received placebo (25.0% and 24.3%, respectively; hazard ratio, 1.03; 95% CI, 0.82 to 1.29; P=0.81). Prednisolone therapy, as compared with placebo, was associated with significant reductions in the incidence of constrictive pericarditis (4.4% vs. 7.8%; hazard ratio, 0.56; 95% CI, 0.36 to 0.87; P=0.009) and hospitalization (20.7% vs. 25.2%; hazard ratio, 0.79; 95% CI, 0.63 to 0.99; P=0.04). Both prednisolone and M. indicus pranii, each as compared with placebo, were associated with a significant increase in the incidence of cancer (1.8% vs. 0.6%; hazard ratio, 3.27; 95% CI, 1.07 to 10.03; P=0.03, and 1.8% vs. 0.5%; hazard ratio, 3.69; 95% CI, 1.03 to 13.24; P=0.03, respectively), owing mainly to an increase in HIV-associated cancer. CONCLUSIONS In patients with tuberculous pericarditis, neither prednisolone nor M. indicus pranii had a significant effect on the composite of death, cardiac tamponade requiring pericardiocentesis, or constrictive pericarditis. (Funded by the Canadian Institutes of Health Research and others; IMPI ClinicalTrials.gov number, NCT00810849.).

Variability of Infectious Aerosols Produced during Coughing by Patients with Pulmonary Tuberculosis

RATIONALE Mycobacterium tuberculosis is transmitted by infectious aerosols, but assessing infectiousness currently relies on sputum microscopy that does not accurately predict the variability in transmission. OBJECTIVES To evaluate the feasibility of collecting cough aerosols and the risk factors for infectious aerosol production from patients with pulmonary tuberculosis (TB) in a resource-limited setting. METHODS We enrolled subjects with suspected TB in Kampala, Uganda and collected clinical, radiographic, and microbiological data in addition to cough aerosol cultures. A subset of 38 subjects was studied on 2 or 3 consecutive days to assess reproducibility. MEASUREMENTS AND MAIN RESULTS M. tuberculosis was cultured from cough aerosols of 28 of 101 (27.7%; 95% confidence interval [CI], 19.9-37.1%) subjects with culture-confirmed TB, with a median 16 aerosol cfu (range, 1-701) in 10 minutes of coughing. Nearly all (96.4%) cultivable particles were 0.65 to 4.7 μm in size. Positive aerosol cultures were associated with higher Karnofsky performance scores (P = 0.016), higher sputum acid-fast bacilli smear microscopy grades (P = 0.007), lower days to positive in liquid culture (P = 0.004), stronger cough (P = 0.016), and fewer days on TB treatment (P = 0.047). In multivariable analyses, cough aerosol cultures were associated with a salivary/mucosalivary (compared with purulent/mucopurulent) appearance of sputum (odds ratio, 4.42; 95% CI, 1.23-21.43) and low days to positive (per 1-d decrease; odds ratio, 1.17; 95% CI, 1.07-1.33). The within-test (kappa, 0.81; 95% CI, 0.68-0.94) and interday test (kappa, 0.62; 95% CI, 0.43-0.82) reproducibility were high. CONCLUSIONS A minority of patients with TB (28%) produced culturable cough aerosols. Collection of cough aerosol cultures is feasible and reproducible in a resource-limited setting.

Prevalence of chronic obstructive pulmonary disease and associated risk factors in Uganda (FRESH AIR Uganda): a prospective cross-sectional observational study

BACKGROUND In sub-Saharan Africa, little is known about the damage to respiratory health caused by biomass smoke and tobacco smoke. We assessed the prevalence of chronic obstructive pulmonary disease (COPD) and related risk factors in a rural region of Uganda. METHODS We did this prospective observational cross-sectional study in rural Masindi, Uganda. We randomly selected people above the age of 30 years from 30 villages. Trained local health-care workers asked validated questionnaires and administered spirometry to participants. We defined COPD as FEV1:FVC less than the lower limit of normal. We calculated prevalence of COPD and tested its association with risk factors. FINDINGS Between April 13, and Aug 14, 2012, we invited 620 people to participate, of whom 588 provided acceptable spirometry and were analysed. Mean age was 45 years (SD 13·7); 297 (51%) were women. 546 (93%) were exposed to biomass smoke. The prevalence of COPD was 16·2% (15·4% in men, 16·8% in women). Prevalence was highest in people aged 30-39 years (17 [38%] of 45 men, 20 [40%] of 50 women). 20 (44%) of 45 men with COPD were current smokers (mean age 40 years, SD 7·5), 11 (24%) were former smokers (mean age 49 years, SD 11·0); four [8%] of 50 women were current smokers (mean age 52 years, SD 18·1), nine (18%) were former smokers (mean age 64 years, SD 16·2). Mean Clinical COPD Questionnaire score was 0·81 (SD 0·78), mean Medical Research Council dyspnoea score was 1·33 (SD 0·65); 28 (30%) of 95 patients had had one or more exacerbations past 12 months. COPD was associated with wheeze (odds ratio 2·17, 95% CI 1·09-4·34; p=0·028) and being a former smoker (1·96, 1·07-3·59; p=0·029). INTERPRETATION In this rural district of Uganda, COPD starts early in life. Major risk factors were biomass smoke for both sexes and tobacco smoke for men. In addition to high smoking prevalence in men, biomass smoke could be a major health threat to men and women in rural areas of Uganda. FUNDING International Primary Care Respiratory Group.

Elucidating emergence and transmission of multidrug-resistant tuberculosis in treatment experienced patients by whole genome sequencing

Background Understanding the emergence and spread of multidrug-resistant tuberculosis (MDR-TB) is crucial for its control. MDR-TB in previously treated patients is generally attributed to the selection of drug resistant mutants during inadequate therapy rather than transmission of a resistant strain. Traditional genotyping methods are not sufficient to distinguish strains in populations with a high burden of tuberculosis and it has previously been difficult to assess the degree of transmission in these settings. We have used whole genome analysis to investigate M. tuberculosis strains isolated from treatment experienced patients with MDR-TB in Uganda over a period of four years. Methods and Findings We used high throughput genome sequencing technology to investigate small polymorphisms and large deletions in 51 Mycobacterium tuberculosis samples from 41 treatment-experienced TB patients attending a TB referral and treatment clinic in Kampala. This was a convenience sample representing 69% of MDR-TB cases identified over the four year period. Low polymorphism was observed in longitudinal samples from individual patients (2-15 SNPs). Clusters of samples with less than 50 SNPs variation were examined. Three clusters comprising a total of 8 patients were found with almost identical genetic profiles, including mutations predictive for resistance to rifampicin and isoniazid, suggesting transmission of MDR-TB. Two patients with previous drug susceptible disease were found to have acquired MDR strains, one of which shared its genotype with an isolate from another patient in the cohort. Conclusions Whole genome sequence analysis identified MDR-TB strains that were shared by more than one patient. The transmission of multidrug-resistant disease in this cohort of retreatment patients emphasises the importance of early detection and need for infection control. Consideration should be given to rapid testing for drug resistance in patients undergoing treatment to monitor the emergence of resistance and permit early intervention to avoid onward transmission.

Impact of chronic respiratory symptoms in a rural area of sub-Saharan Africa: an in-depth qualitative study in the Masindi district of Uganda

Background: Chronic obstructive pulmonary disease (COPD), once regarded as a disease of developed countries, is now recognised as a common disease in low- and middle-income countries. No studies have been performed to examine how the community in resource-poor settings of a rural area in sub-Saharan Africa lives with chronic respiratory symptoms. Aims: To explore beliefs and attitudes concerning health (particularly respiratory illnesses), use of biomass fuels, tobacco smoking, and the use of health services. Methods: A qualitative study was undertaken in a rural area of Masindi district in Uganda, using focus group discussions with 10–15 members of the community in 10 randomly selected villages. Results: Respiratory symptoms were common among men, women, and children. In several communities respiratory symptoms were stigmatised and often associated with tuberculosis. Almost all the households used firewood for cooking and the majority cooked indoors without any ventilation. The extent of exposure to tobacco and biomass fuel smoke was largely determined by their cultural tradition and gender, tribal origin and socioeconomic factors. Many people were unaware of the damage to respiratory health caused by these risk factors, notably the disproportionate effect of biomass smoke in women and children. Conclusions: The knowledge of chronic respiratory diseases, particularly COPD, is poor in the rural community in sub-Saharan Africa. The lack of knowledge has created different beliefs and attitudes concerning respiratory symptoms. Few people are aware of the relation between smoke and respiratory health, leading to extensive exposure to mostly biomass-related smoke.

Evaluation of Cepheid's Xpert MTB/Rif test on pleural fluid in the diagnosis of pleural tuberculosis in a high prevalence HIV/TB setting.

Background Diagnosis of pleural tuberculosis (TB) using routinely available diagnostic methods is challenging due to the paucibacillary nature of the disease. Histopathology and pleural tissue TB culture involves an invasive procedure which requires expertise and appropriate equipment, both often unavailable in many health units. Xpert MTB/Rif test has been widely evaluated in sputum specimens but data on its performance in pleural TB is scarce. We evaluated the accuracy of Cepheids Xpert MTB/Rif test on pleural fluid in the diagnosis of pleural TB in Uganda. Methods Consenting adult patients with exudative pleural effusions underwent pleural biopsy and the tissue obtained subjected to Lowenstein-Jensen and mycobacterial growth indicator tube MTB cultures and histopathology. Pleural fluid for Xpert MTB/Rif testing was also collected. Data on socio-demographic characteristics, clinical symptoms, HIV status and CD4 count were also collected. Sensitivity, specificity, positive and negative predictive values of Xpert MTB/Rif test on pleural fluid in pleural TB diagnosis were calculated using pleural tissue MTB culture and/or histopathology as the reference standard. Results Of the 116 participants [female 50%, mean age 34 (SD ±13], 87/116 (75%) had pleural TB confirmed on pleural tissue culture and/or histopathology. The Xpert MTB/Rif test identified 25 (28.7%) of the 87 confirmed pleural TB cases. The sensitivity and specificity of Xpert MTB/Rif test were 28.7% and 96.6% respectively while the positive and negative predictive values were 96.1% and 31.1% respectively. Conclusion Xpert MTB/Rif test on pleural fluid does not accurately diagnose pleural TB and therefore cannot be used as an initial evaluation test in patients with suspected pleural TB. New, rapid and accurate tests for the diagnosis of pleural TB are still warranted.

Clinical Predictors and Accuracy of Empiric Tuberculosis Treatment among Sputum Smear-Negative HIV-Infected Adult TB Suspects in Uganda

Introduction The existing diagnostic algorithms for sputum smear-negative tuberculosis (TB) are complicated, time-consuming, and often difficult to implement. The decision to initiate TB treatment in resource-limited countries is often largely based on clinical predictors. We sought to determine the clinical predictors and accuracy of empiric TB treatment initiation in HIV-infected sputum smear-negative TB suspects using sputum culture as a reference standard. Setting Out-patient HIV-TB integrated urban clinic in Kampala, Uganda. Methods HIV-infected TB suspects were screened using sputum smear microscopy, and mycobacterial sputum liquid and solid cultures were performed. Smear results were made available to the clinician who made a clinical decision on empiric TB treatment initiation for sputum smear-negative patients. Clinic records were reviewed for patients whose sputum smears were negative to collect data on socio-demographics, TB symptomatology, chest X-ray findings, CD4 cell counts and TB treatment initiation. Results Of 253 smear-negative TB suspects, 56% (142/253) were females, median age 38 IQR (31–44) years, with a median CD4 cell count of 291 IQR (150–482) cells/mm3. Of the 85 (33.6%) smear-negative patients empirically initiated on TB treatment, 35.3% (n = 30) were sputum culture positive compared to only 18 (10.7%) of the 168 untreated patients (p<0.001). Abnormal chest X-ray [aOR 10.18, 95% CI (3.14–33.00), p<0.001] and advanced HIV clinical stage [aOR 3.92, 95% CI (1.20–12.85), p = 0.024] were significantly associated with empiric TB treatment initiation. The sensitivity and specificity of empiric TB treatment initiation in the diagnosis of TB in HIV-infected patients after negative smear microscopy was 62.5% and 73.7% respectively. Conclusion In resource-limited settings, clinically advanced HIV and abnormal chest X-ray significantly predict a clinical decision to empirically initiate TB treatment in smear-negative HIV-infected patients. Empiric TB treatment initiation correlates poorly with TB cultures. Affordable, accurate and rapid point-of-care diagnostics are needed in resource-limited settings to more accurately determine which HIV-infected TB suspects have smear-negative TB.

Rationale and design of the Investigation of the Management of Pericarditis (IMPI) trial: a 2 × 2 factorial randomized double-blind multicenter trial of adjunctive prednisolone and Mycobacterium w immunotherapy in tuberculous pericarditis.

BACKGROUND In spite of antituberculosis chemotherapy, tuberculous (TB) pericarditis causes death or disability in nearly half of those affected. Attenuation of the inflammatory response in TB pericarditis may improve outcome by reducing cardiac tamponade and pericardial constriction, but there is uncertainty as to whether adjunctive immunomodulation with corticosteroids and Mycobacterium w (M. w) can safely reduce mortality and morbidity. OBJECTIVES The primary objective of the IMPI Trial is to assess the effectiveness and safety of prednisolone and M. w immunotherapy in reducing the composite outcome of death, constriction, or cardiac tamponade requiring pericardial drainage in 1,400 patients with TB pericardial effusion. DESIGN The IMPI trial is a multicenter international randomized double-blind placebo-controlled 2 × 2 factorial study. Eligible patients are randomly assigned to receive oral prednisolone or placebo for 6 weeks and M. w injection or placebo for 3 months. Patients are followed up at weeks 2, 4, and 6 and months 3 and 6 during the intervention period and 6-monthly thereafter for up to 4 years. The primary outcome is the first occurrence of death, pericardial constriction, or cardiac tamponade requiring pericardiocentesis. The secondary outcome is safety of immunomodulatory treatment measured by effect on opportunistic infections (eg, herpes zoster) and malignancy (eg, Kaposi sarcoma) and impact on measures of immunosuppression and the incidence of immune reconstitution disease. CONCLUSIONS IMPI is the largest trial yet conducted comparing adjunctive immunotherapy in pericarditis. Its results will define the role of adjunctive corticosteroids and M. w immunotherapy in patients with TB pericardial effusion.

COPD: early diagnosis and treatment to slow disease progression.

SummaryAims Chronic obstructive pulmonary disease (COPD) is usually a progressive condition. Undiagnosed early-stage disease, particularly in symptomatic patients, is likely to become more severe with time. Hence, prevention or reduction in disease progression is highly relevant. We evaluated the published data and discussed the potential impact of early intervention on the course of COPD. Methods We performed PubMed searches of studies in early or mild COPD, focusing on those relating to lung function decline. Results Smoking cessation reduced lung function decline at all stages of COPD, and the earlier the intervention, the greater the impact on lung function. Accumulating data from placebo-controlled trials suggested that long-acting bronchodilators can slow the decline in lung function, as well as reduce exacerbation and mortality rates and improve health-related quality of life (HRQoL) in patients with mild-to-moderate COPD. Inhaled corticosteroids (ICS) do not impact lung function in early COPD, and further research is needed on the role of long-acting β2-agonist-ICS combination therapy in these patients. Conclusions Initiating treatment early in the course of COPD is likely to slow disease progression and improve HRQoL. Current data support maintenance treatment with a long-acting bronchodilator in this patient group. However, many questions remain unanswered regarding the optimal treatment of mild COPD, and further research is required to develop evidence-based recommendations in this field.

Treatment Outcomes of New Tuberculosis Patients Hospitalized in Kampala, Uganda: A Prospective Cohort Study

Background In most resource limited settings, new tuberculosis (TB) patients are usually treated as outpatients. We sought to investigate the reasons for hospitalisation and the predictors of poor treatment outcomes and mortality in a cohort of hospitalized new TB patients in Kampala, Uganda Methods and findings Ninety-six new TB patients hospitalised between 2003 and 2006 were enrolled and followed for two years. Thirty two were HIV-uninfected and 64 were HIV-infected. Among the HIV-uninfected, the commonest reasons for hospitalization were low Karnofsky score (47%) and need for diagnostic evaluation (25%). HIV-infected patients were commonly hospitalized due to low Karnofsky score (72%), concurrent illness (16%) and diagnostic evaluation (14%). Eleven HIV uninfected patients died (mortality rate 19.7 per 100 person-years) while 41 deaths occurred among the HIV-infected patients (mortality rate 46.9 per 100 person years). In all patients an unsuccessful treatment outcome (treatment failure, death during the treatment period or an unknown outcome) was associated with duration of TB symptoms, with the odds of an unsuccessful outcome decreasing with increasing duration. Among HIV-infected patients, an unsuccessful treatment outcome was also associated with male sex (P = 0.004) and age (P = 0.034). Low Karnofsky score (aHR = 8.93, 95% CI 1.88 – 42.40, P = 0.001) was the only factor significantly associated with mortality among the HIV-uninfected. Mortality among the HIV-infected was associated with the composite variable of CD4 and ART use, with patients with baseline CD4 below 200 cells/µL who were not on ART at a greater risk of death than those who were on ART, and low Karnofsky score (aHR = 2.02, 95% CI 1.02 – 4.01, P = 0.045). Conclusion Poor health status is a common cause of hospitalisation for new TB patients. Mortality in this study was very high and associated with advanced HIV Disease and no use of ART.