Maia Lesosky

Feasibility, accuracy, and clinical effect of point-of-care Xpert MTB/RIF testing for tuberculosis in primary-care settings in Africa: a multicentre, randomised, controlled trial

BACKGROUND The Xpert MTB/RIF test for tuberculosis is being rolled out in many countries, but evidence is lacking regarding its implementation outside laboratories, ability to inform same-day treatment decisions at the point of care, and clinical effect on tuberculosis-related morbidity. We aimed to assess the feasibility, accuracy, and clinical effect of point-of-care Xpert MTB/RIF testing at primary-care health-care facilities in southern Africa. METHODS In this pragmatic, randomised, parallel-group, multicentre trial, we recruited adults with symptoms suggestive of active tuberculosis from five primary-care health-care facilities in South Africa, Zimbabwe, Zambia, and Tanzania. Eligible patients were randomly assigned using pregenerated tables to nurse-performed Xpert MTB/RIF at the clinic or sputum smear microscopy. Participants with a negative test result were empirically managed according to local WHO-compliant guidelines. Our primary outcome was tuberculosis-related morbidity (measured with the TBscore and Karnofsky performance score [KPS]) in culture-positive patients who had begun anti-tuberculosis treatment, measured at 2 months and 6 months after randomisation, analysed by intention to treat. This trial is registered with Clinicaltrials.gov, number NCT01554384. FINDINGS Between April 12, 2011, and March 30, 2012, we randomly assigned 758 patients to smear microscopy (182 culture positive) and 744 to Xpert MTB/RIF (185 culture positive). Median TBscore in culture-positive patients did not differ between groups at 2 months (2 [IQR 0-3] in the smear microscopy group vs 2 [0·25-3] in the MTB/RIF group; p=0·85) or 6 months (1 [0-3] vs 1 [0-3]; p=0·35), nor did median KPS at 2 months (80 [70-90] vs 90 [80-90]; p=0·23) or 6 months (100 [90-100] vs 100 [90-100]; p=0·85). Point-of-care MTB/RIF had higher sensitivity than microscopy (154 [83%] of 185 vs 91 [50%] of 182; p=0·0001) but similar specificity (517 [95%] 544 vs 540 [96%] of 560; p=0·25), and had similar sensitivity to laboratory-based MTB/RIF (292 [83%] of 351; p=0·99) but higher specificity (952 [92%] of 1037; p=0·0173). 34 (5%) of 744 tests with point-of-care MTB/RIF and 82 (6%) of 1411 with laboratory-based MTB/RIF failed (p=0·22). Compared with the microscopy group, more patients in the MTB/RIF group had a same-day diagnosis (178 [24%] of 744 vs 99 [13%] of 758; p<0·0001) and same-day treatment initiation (168 [23%] of 744 vs 115 [15%] of 758; p=0·0002). Although, by end of the study, more culture-positive patients in the MTB/RIF group were on treatment due to reduced dropout (15 [8%] of 185 in the MTB/RIF group did not receive treatment vs 28 [15%] of 182 in the microscopy group; p=0·0302), the proportions of all patients on treatment in each group by day 56 were similar (320 [43%] of 744 in the MTB/RIF group vs 317 [42%] of 758 in the microscopy group; p=0·6408). INTERPRETATION Xpert MTB/RIF can be accurately administered by a nurse in primary-care clinics, resulting in more patients starting same-day treatment, more culture-positive patients starting therapy, and a shorter time to treatment. However, the benefits did not translate into lower tuberculosis-related morbidity, partly because of high levels of empirical-evidence-based treatment in smear-negative patients. FUNDING European and Developing Countries Clinical Trials Partnership, National Research Foundation, and Claude Leon Foundation.

Long-term outcomes of patients with extensively drug-resistant tuberculosis in South Africa: a cohort study

BACKGROUND Long-term treatment-related outcomes in patients with extensively drug-resistant (XDR) tuberculosis are unknown. We followed up a cohort of patients to address knowledge gaps. METHODS Between March, 2008, and August, 2012, we prospectively followed up a cohort of 107 patients from three provinces in South Africa, who had been diagnosed with XDR tuberculosis between August 2002, and February, 2008. Available isolates from 56 patients were genotyped to establish strain type and used for extended susceptibility testing. FINDINGS All patients were treated empirically as inpatients with a median of eight drugs (IQR six to ten). 44 patients (41%) had HIV. 36 (64%) of 56 isolates were resistant to at least eight drugs, and resistance to an increasing number of drugs was associated with the Beijing genotype (p=0·01). After 24 months of follow-up, 17 patients (16%) had a favourable outcome (ie, treatment cure or completion), 49 (46%) had died, seven (7%) had defaulted (interruption of treatment for at least 2 consecutive months), and 25 (23%) had failed treatment. At 60 months, 12 patients (11%) had a favourable outcome, 78 (73%) had died, four (4%) had defaulted, and 11 (10%) had failed treatment. 45 patients were discharged from hospital, of whom 26 (58%) had achieved sputum culture conversion and 19 (42%) had failed treatment. Median survival of patients who had failed treatment from time of discharge was 19·84 months (IQR 4·16-26·04). Clustering of cases and transmission within families containing a patient who had failed treatment and been discharged were shown with genotypic methods. Net sputum culture conversion occurred in 22 patients (21%) and median time to net culture conversion was 8·7 months (IQR 5·6-26·4). Independent predictors of probability of net culture conversion were no history of multidrug-resistant tuberculosis (p=0·0007) and use of clofazamine (p=0·0069). Independent overall predictors of survival were net culture conversion (p<0·0001) and treatment with clofazamine (p=0·021). Antiretroviral therapy was also a predictor of survival in patients with HIV (p=0·003). INTERPRETATION In South Africa, long-term outcomes in patients with XDR tuberculosis are poor, irrespective of HIV status. Because appropriate long-stay or palliative care facilities are scarce, substantial numbers of patients with XDR tuberculosis who have failed treatment and have positive sputum cultures are being discharged from hospital and are likely to transmit disease into the wider community. Testing of new combined regimens is needed urgently and policy makers should implement interventions to minimise disease spread by patients who fail treatment. FUNDING European and Developing Countries Clinical Trials Partnership, South African National Research Foundation (SARChI), and the South African Medical Research Council.

Vitamin D and Reduced Risk of Breast Cancer: A Population-Based Case-Control Study

Background: Vitamin D, antiproliferative and proapoptotic in breast cancer cell lines, can reduce the development of mammary tumors in carcinogen-exposed rats. Current evidence in humans is limited with some suggestion that vitamin D–related factors may reduce the risk of breast cancer. We conducted a population-based case-control study to assess the evidence for a relationship between sources of vitamin D and breast cancer risk. Methods: Women with newly diagnosed invasive breast cancer were identified from the Ontario Cancer Registry. Women without breast cancer were identified through randomly selected residential telephone numbers. Telephone interviews were completed for 972 cases and 1,135 controls. Odds ratios (OR) and 95% confidence intervals (CI) for vitamin D–related variables were estimated using unconditional logistic regression with adjustment for potential confounders. Results: Reduced breast cancer risks were associated with increasing sun exposure from ages 10 to 19 (e.g., OR, 0.65; 95% CI, 0.50-0.85 for the highest quartile of outdoor activities versus the lowest; P for trend = 0.0006). Reduced risk was also associated with cod liver oil use (OR, 0.76; 95% CI, 0.62-0.92) and increasing milk consumption (OR, 0.62 95% CI 0.45-0.86 for ≥10 glasses per week versus none; P for trend = 0.0004). There was weaker evidence for associations from ages 20 to 29 and no evidence for ages 45 to 54. Conclusion: We found strong evidence to support the hypothesis that vitamin D could help prevent breast cancer. However, our results suggest that exposure earlier in life, particularly during breast development, maybe most relevant. These results should be confirmed. (Cancer Epidemiol Biomarkers Prev 2007;16(3):422–9)

Effect on mortality of point-of-care, urine-based lipoarabinomannan testing to guide tuberculosis treatment initiation in HIV-positive hospital inpatients: a pragmatic, parallel-group, multicountry, open-label, randomised controlled trial

BACKGROUND HIV-associated tuberculosis is difficult to diagnose and results in high mortality. Frequent extra-pulmonary presentation, inability to obtain sputum, and paucibacillary samples limits the usefulness of nucleic-acid amplification tests and smear microscopy. We therefore assessed a urine-based, lateral flow, point-of-care, lipoarabinomannan assay (LAM) and the effect of a LAM-guided anti-tuberculosis treatment initiation strategy on mortality. METHODS We did a pragmatic, randomised, parallel-group, multicentre trial in ten hospitals in Africa--four in South Africa, two in Tanzania, two in Zambia, and two in Zimbabwe. Eligible patients were HIV-positive adults aged at least 18 years with at least one of the following symptoms of tuberculosis (fever, cough, night sweats, or self-reported weightloss) and illness severity necessitating admission to hospital. Exclusion criteria included receipt of any anti-tuberculosis medicine in the 60 days before enrolment. We randomly assigned patients (1:1) to either LAM plus routine diagnostic tests for tuberculosis (smear microscopy, Xpert-MTB/RIF, and culture; LAM group) or routine diagnostic tests alone (no LAM group) using computer-generated allocation lists in blocks of ten. All patients were asked to provide a urine sample of at least 30 mL at enrolment, and trained research nurses did the LAM test in patients allocated to this group using the Alere Determine tuberculosis LAM Ag lateral flow strip test (Alere, USA) at the bedside on enrolment. On the basis of a positive test result, the nurses made a recommendation for initiating anti-tuberculosis treatment. The attending physician made an independent decision about whether to start treatment or not. Neither patients nor health-care workers were masked to group allocation and test results. The primary endpoint was 8-week all-cause mortality assessed in the modified intention-to-treat population (those who received their allocated intervention). This trial is registered with ClinicalTrials.gov, number NCT01770730. FINDINGS Between Jan 1, 2013, and Oct 2, 2014, we screened 8728 patients and randomly assigned 2659 to treatment (1336 to LAM, 1323 to no LAM). 108 patients did not receive their allocated treatment, mainly because they did not meet the inclusion criteria, and 23 were excluded from analysis, leaving 2528 in the final modified intention-to-treat analysis (1257 in the LAM group, 1271 in the no LAM group). Overall all-cause 8-week mortality occurred in 578 (23%) patients, 261 (21%) in LAM and 317 (25%) in no LAM, an absolute reduction of 4% (95% CI 1-7). The risk ratio adjusted for country was 0·83 (95% CI 0·73-0·96), p=0·012, with a relative risk reduction of 17% (95% CI 4-28). With the time-to-event analysis, there were 159 deaths per 100 person-years in LAM and 196 per 100 person-years in no LAM (hazard ratio adjusted for country 0·82 [95% CI 0·70-0·96], p=0·015). No adverse events were associated with LAM testing. INTERPRETATION Bedside LAM-guided initiation of anti-tuberculosis treatment in HIV-positive hospital inpatients with suspected tuberculosis was associated with reduced 8-week mortality. The implementation of LAM testing is likely to offer the greatest benefit in hospitals where diagnostic resources are most scarce and where patients present with severe illness, advanced immunosuppression, and an inability to self-expectorate sputum. FUNDING European Developing Clinical Trials Partnership, the South African Medical Research Council, and the South African National Research Foundation.

Vitamin D From Dietary Intake and Sunlight Exposure and the Risk of Hormone-Receptor-Defined Breast Cancer

Evidence has emerged for a role of vitamin D in the development of breast cancer, and there is some suggestion that its antiproliferative effect is greater in hormone-receptor-positive cells. Few epidemiologic studies have considered the association between vitamin D and hormone-receptor-defined breast cancer, and the results are conflicting. Considering 759 cases and 1,135 controls from a case-control study (Ontario, Canada, 2003-2005), the authors examined the association between vitamin D intake at specific ages and combined estrogen-receptor- (ER) and progesterone-receptor- (PR) defined breast cancer. While increased intake of vitamin D (from the sun and diet) was most consistently associated with a significantly reduced risk of ER+/PR+ tumors (e.g., odds ratio = 0.76, 95% confidence interval: 0.59, 0.97 for use of cod liver oil during adolescence), comparable nonsignificant associations were found for receptor-negative (ER-/PR-) (odds ratio = 0.74, 95% confidence interval: 0.53, 1.04) and mixed (ER+/PR-) (odds ratio = 0.79, 95% confidence interval: 0.51, 1.22) tumors. This study suggests that vitamin D is associated with a reduced risk of breast cancer regardless of ER/PR status of the tumor. Future studies with a larger number of receptor-negative and mixed tumors are required.

Characterization of progressive HIV-associated tuberculosis using 2-deoxy-2-[ 18 F]fluoro- D -glucose positron emission and computed tomography

Tuberculosis is classically divided into states of latent infection and active disease. Using combined positron emission and computed tomography in 35 asymptomatic, antiretroviral-therapy-naive, HIV-1-infected adults with latent tuberculosis, we identified ten individuals with pulmonary abnormalities suggestive of subclinical, active disease who were substantially more likely to progress to clinical disease. Our findings challenge the conventional two-state paradigm and may aid future identification of biomarkers that are predictive of progression.

Association of Vitamin D–Related Information from a Telephone Interview with 25-Hydroxyvitamin D

Vitamin D may be associated with reduced risks of several types of cancer, including colon, prostate, and breast. We examined the relationship between vitamin D–related questions administered in a telephone interview and serum 25-hydroxyvitamin D [25(OH)D]. Three hundred and eight eligible women were randomly selected from controls in a breast cancer case-control study. Questions pertaining to sun exposure and dietary sources of vitamin D over the previous 4 weeks were asked in both summer and winter. We assessed the association between questionnaire-derived items and 25(OH)D using multiple linear regression. There were 217 participating women, 203 in summer and 213 in winter. Models were adjusted for age, body mass index, and skin color. Number of days when more than 0.5 hour was spent outdoors per week (“7” versus “<7” β = 11.12; P = 0.01), limb coverage (“no” β = 24.90 and “partial” β = 8.15 versus “yes”; P = 0.0001), and milk intake (glasses/wk; “>10” β = 18.94, “>5-10” β = 9.16, and “1-5” β = 7.90 versus “<1”; P = 0.02) best predicted 25(OH)D in the summer. The best predictors in the winter were sunlamp use (“yes” β = 27.97 versus “no”; P = 0.01), milk intake (glasses/wk; “>10” β = 14.54, “>5-10” β = 11.54, and “1-5” β = 2.15 versus “<1”; P = 0.01), and vitamin D–containing supplements (“high” β = 17.30 and “moderate” β = 13.82 versus “none”; P = 0.0006). The R2 was 0.29 for the summer model and was 0.21 for the winter model. Overall, there was evidence to suggest that questions designed to assess vitamin D exposure were in fact related to serum 25(OH)D. (Cancer Epidemiol Biomarkers Prev 2008;17(1):232–8)

Effect of patterns of transferring patients among healthcare institutions on rates of nosocomial methicillin-resistant Staphylococcus aureus transmission: a Monte Carlo simulation.

OBJECTIVE To determine the effect of the rate and pattern of patient transfers among institutions within a single metropolitan area on the rates of methicillin-resistant Staphylococcus aureus (MRSA) transmission among patients in hospitals and nursing homes. METHODS A stochastic, discrete-time, Monte Carlo simulation was used to model the rate and spread of MRSA transmission among patients in medical institutions within a single metropolitan area. Admission, discharges, transfers, and nosocomial transmission were simulated with respect to different interinstitutional transfer strategies and various situational scenarios, such as outlier institutions with high transmission rates. RESULTS The simulation results indicated that transfer patterns and transfer rate changes do not affect nosocomial MRSA transmission. Outlier institutions with high transmission rates affect the system wide rate of nosocomial infections differently, depending on institution type. CONCLUSION It is worth effort to understanding disease-transmission dynamics and interinstitutional transfer patterns for the management of recently introduced diseases or strains. Once endemic in a system, other strategies for transmission control need to be implemented.

Antibiotic stewardship ward rounds and a dedicated prescription chart reduce antibiotic consumption and pharmacy costs without affecting inpatient mortality or re-admission rates

Background Antibiotic consumption is a major driver of bacterial resistance. To address the increasing burden of multi-drug resistant bacterial infections, antibiotic stewardship programmes are promoted worldwide to rationalize antibiotic prescribing and conserve remaining antibiotics. Few studies have been reported from developing countries and none from Africa that report on an intervention based approach with outcomes that include morbidity and mortality. Methods An antibiotic prescription chart and weekly antibiotic stewardship ward round was introduced into two medical wards of an academic teaching hospital in South Africa between January-December 2012. Electronic pharmacy records were used to collect the volume and cost of antibiotics used, the patient database was analysed to determine inpatient mortality and 30-day re-admission rates, and laboratory records to determine use of infection-related tests. Outcomes were compared to a control period, January-December 2011. Results During the intervention period, 475.8 defined daily doses were prescribed per 1000 inpatient days compared to 592.0 defined daily doses/1000 inpatient days during the control period. This represents a 19.6% decrease in volume with a cost reduction of 35% of the pharmacy’s antibiotic budget. There was a concomitant increase in laboratory tests driven by requests for procalcitonin. There was no difference in inpatient mortality or 30-day readmission rate during the control and intervention periods. Conclusions Introduction of antibiotic stewardship ward rounds and a dedicated prescription chart in a developing country setting can achieve reduction in antibiotic consumption without harm to patients. Increased laboratory costs should be anticipated when introducing an antibiotic stewardship program.

Neutrophil-Associated Central Nervous System Inflammation in Tuberculous Meningitis Immune Reconstitution Inflammatory Syndrome

Tuberculous meningitis immune reconstitution inflammatory syndrome (TBM-IRIS) is characterized by severe, compartmentalized cerebral inflammation, involving mediators of innate and adaptive immune responses. A high baseline cerebrospinal fluid bacillary load predisposes to recurrent inflammation during antiretroviral therapy, manifesting as TBM-IRIS.