The temporal dynamics of relapse and reinfection tuberculosis after successful treatment: a retrospective cohort study.

BACKGROUND: There is increasing evidence from tuberculosis high-burden settings that exogenous reinfection contributes considerably to recurrent disease. However, large longitudinal studies of endogenous reactivation (relapse) and reinfection tuberculosis are lacking. We hypothesize a relationship between relapse vs reinfection and the time between treatment completion and recurrent disease. METHODS: Population-based retrospective cohort study on all smear-positive tuberculosis cases successfully treated between 1996 and 2008 in a suburban setting in Cape Town, South Africa. Inverse gaussian distributions were fitted to observed annual rates of relapse and reinfection, distinguished by DNA fingerprinting of Mycobacterium tuberculosis strains recultured from diagnostic samples. RESULTS: Paired DNA fingerprint data were available for 130 (64%) of 203 recurrent smear-positive tuberculosis cases in the 13-year study period. Reinfection accounted for 66 (51%) of 130 recurrent cases overall, 9 (20%) of 44 recurrent cases within the first year, and 57 (66%) of 86 thereafter (P < .001). The relapse rate peaked at 3.93% (95% confidence interval [CI], 2.35%-5.96%) per annum 0.35 (95% CI, .15-.45) years after treatment completion. The reinfection tuberculosis rate peaked at 1.58% (95% CI, .94%-2.46%) per annum 1.20 (95% CI, .55-1.70) years after completion. CONCLUSIONS: To our knowledge, this is the first study of sufficient size and duration using DNA fingerprinting to investigate tuberculosis relapse and reinfection over a lengthy period. Relapse occurred early after treatment completion, whereas reinfection dominated after 1 year and accounted for at least half of recurrent disease. This temporal relationship may explain the high variability in reinfection observed across smaller studies. We speculate that follow-up time in antituberculosis drug trials should take reinfection into account.

Assessment of clofazimine activity in a second-line regimen for tuberculosis in mice.

RATIONALE: Although observational studies suggest that clofazimine-containing regimens are highly active against drug-resistant tuberculosis, the contribution of clofazimine for the treatment of this disease has never been systematically evaluated. OBJECTIVES: Our goal was to directly compare the activity of a standard second-line drug regimen with or without the addition of clofazimine in a mouse model of multidrug-resistant tuberculosis. Our comparative outcomes included time to culture conversion in the mouse lungs and the percentage of relapses after treatment cessation. METHODS: Mice were aerosol-infected with an isoniazid-resistant (as a surrogate of multidrug-resistant) strain of Mycobacterium tuberculosis. Treatment, which was administered for 5 to 9 months, was initiated 2 weeks after infection and comprised the following second-line regimen: daily (5 d/wk) moxifloxacin, ethambutol, and pyrazinamide, supplemented with amikacin during the first 2 months. One-half of the mice also received daily clofazimine. The decline in lung bacterial load was assessed monthly using charcoal-containing agar to reduce clofazimine carryover. Relapse was assessed 6 months after treatment cessation. MEASUREMENTS AND MAIN RESULTS: After 2 months, the bacillary load in lungs was reduced from 9.74 log10 at baseline to 3.61 and 4.68 in mice treated with or without clofazimine, respectively (P < 0.001). Mice treated with clofazimine were culture-negative after 5 months, whereas all mice treated without clofazimine remained heavily culture-positive for the entire 9 months of the study. The relapse rate was 7% among mice treated with clofazimine for 8 to 9 months. CONCLUSIONS: The clofazimine contribution was substantial in these experimental conditions.

Challenges to the global control of tuberculosis.

Diagnosis and treatment of tuberculosis (TB) will likely navigate a historical turning point in the 2010s with a new management paradigm emerging. However, global control of TB remains a formidable challenge for the decades to come. The estimated case detection rate of TB globally was 66%, and there were 310 000 estimated multidrug-resistant TB (MDR-TB) cases among the 6.2 million TB patients notified in 2011. Although new tools are being introduced for the diagnosis of MDR-TB, there are operational and cost issues related to their use that require urgent attention, so that the poor and vulnerable can benefit. World Health Organization (WHO) estimated that globally, 3.7% of new cases and 20% of previously treated cases have MDR-TB. However, the scale-up of programmatic management of drug-resistant TB is slow, with only 60 000 MDR-TB cases notified to WHO in 2011. The overall proportion of treatment success of MDR-TB notified globally in 2009 was 48%, far below the global target of 75% success rate. Although new tools and drugs have the potential to significantly improve both case detection and treatment outcome, adequate health systems and human resources are needed for rapid uptake and proper implementation to have the impact required to eliminate TB. Hence, the global TB community should broaden its scope, seek intersectoral collaboration and advocate for cost reduction of new tools, while ensuring that the basics of TB control are implemented to reduce the TB burden through the current 'prevention through case management' paradigm.

Hopelessness as a basis for tuberculosis diagnostic delay in the Arkhangelsk region: a grounded theory study.

BACKGROUND: Data about delayed tuberculosis diagnosis in Northern Russia are scarce yet such knowledge could enhance the care of tuberculosis. The Arkhangelsk region is situated in the north of Russia, where the population is more than one million residents.The aim of the study was to understand factors influencing diagnostic delay among patients with tuberculosis in the Arkhangelsk region and to develop a theoretical model in order to explain diagnostic delay from the patients' perspectives. METHODS: Twenty-three patients who had experienced diagnostic delay of tuberculosis were interviewed in Arkhangelsk. Using a qualitative approach, we conducted focus-group discussions for data gathering using Grounded Theory with the Paradigm Model to analyse the phenomenon of diagnostic delay. RESULTS: The study resulted in a theoretical model of the pathway of delay of tuberculosis diagnosis in the Arkhangelsk region in answer to the question: "Why and how do patients in the Arkhangelsk region delay tuberculosis diagnosis?" The model included categories of causal conditions, context and intervening conditions, action/interaction strategies, and consequences. The causal condition and main concern of the patients was that they were overpowered by hopelessness. Patients blamed policy, the administrative system, and doctors for their unfortunate life circumstances. This was accompanied by avoidance of health care, denial of their own health situations, and self-treatment. Only a deadly threat was a sufficient motivator for some patients to seek medical help. "Being overpowered by hopelessness" was identified as the core category that affected their self-esteem and influenced their entire lives, including family, work and social relations, and appeared even stronger in association with alcohol use. This category reflected the passive position of many patients in this situation, including their feelings of inability to change anything in their lives, to obtain employment, or to qualify for disability benefits. CONCLUSION: The main contributing factor to unsuccessful health-seeking behaviour for patients with tuberculosis was identified as "being overpowered by hopelessness." This should be taken into consideration when creating any preventive programs and diagnostic algorithms aimed at increasing knowledge about TB, improving the health system, decreasing alcohol consumption and reducing the poverty of the people in Arkhangelsk.

Drug-resistant tuberculosis transmission and resistance amplification within families.

Drug-resistant tuberculosis is caused by transmission of resistant strains of Mycobacterium tuberculosis and by acquisition of resistance through inadequate treatment. We investigated the clinical and molecular features of the disease in 2 families after drug-resistant tuberculosis was identified in 2 children. The findings demonstrate the potential for resistance to be transmitted and amplified within families.

Multidrug resistant pulmonary tuberculosis treatment regimens and patient outcomes: an individual patient data meta-analysis of 9,153 patients.

BACKGROUND: Treatment of multidrug resistant tuberculosis (MDR-TB) is lengthy, toxic, expensive, and has generally poor outcomes. We undertook an individual patient data meta-analysis to assess the impact on outcomes of the type, number, and duration of drugs used to treat MDR-TB. METHODS AND FINDINGS: Three recent systematic reviews were used to identify studies reporting treatment outcomes of microbiologically confirmed MDR-TB. Study authors were contacted to solicit individual patient data including clinical characteristics, treatment given, and outcomes. Random effects multivariable logistic meta-regression was used to estimate adjusted odds of treatment success. Adequate treatment and outcome data were provided for 9,153 patients with MDR-TB from 32 observational studies. Treatment success, compared to failure/relapse, was associated with use of: later generation quinolones, (adjusted odds ratio [aOR]: 2.5 [95% CI 1.1-6.0]), ofloxacin (aOR: 2.5 [1.6-3.9]), ethionamide or prothionamide (aOR: 1.7 [1.3-2.3]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.3 [1.3-3.9]), and three or more likely effective drugs in the continuation phase (aOR: 2.7 [1.7-4.1]). Similar results were seen for the association of treatment success compared to failure/relapse or death: later generation quinolones, (aOR: 2.7 [1.7-4.3]), ofloxacin (aOR: 2.3 [1.3-3.8]), ethionamide or prothionamide (aOR: 1.7 [1.4-2.1]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.7 [1.9-3.9]), and three or more likely effective drugs in the continuation phase (aOR: 4.5 [3.4-6.0]). CONCLUSIONS: In this individual patient data meta-analysis of observational data, improved MDR-TB treatment success and survival were associated with use of certain fluoroquinolones, ethionamide, or prothionamide, and greater total number of effective drugs. However, randomized trials are urgently needed to optimize MDR-TB treatment. Please see later in the article for the Editors' Summary.

Indoor solid fuel use and tuberculosis in China: a matched case-control study.

BACKGROUND: China ranks second among the 22 high burden countries for tuberculosis. A modeling exercise showed that reduction of indoor air pollution could help advance tuberculosis control in China. However, the association between indoor air pollution and tuberculosis is not yet well established. A case control study was conducted in Anhui, China to investigate whether use of solid fuel is associated with tuberculosis. METHODS: Cases were new sputum smear positive tuberculosis patients. Two controls were selected from the neighborhood of each case matched by age and sex using a pre-determined procedure. A questionnaire containing demographic information, smoking habits and use of solid fuel for cooking or heating was used for interview. Solid fuel (coal and biomass) included coal/lignite, charcoal, wood, straw/shrubs/grass, animal dung, and agricultural crop residue. A household that used solid fuel either for cooking and (/or) heating was classified as exposure to combustion of solid fuel (indoor air pollution). Odds ratios and their corresponding 95% confidence limits for categorical variables were determined by Mantel-Haenszel estimate and multivariate conditional logistic regression. RESULTS: There were 202 new smear positive tuberculosis cases and 404 neighborhood controls enrolled in this study. The proportion of participants who used solid fuels for cooking was high (73.8% among cases and 72.5% among controls). The majority reported using a griddle stove (85.2% among cases and 86.7% among controls), had smoke removed by a hood or chimney (92.0% among cases and 92.8% among controls), and cooked in a separate room (24.8% among cases and 28.0% among controls) or a separate building (67.8% among cases and 67.6% among controls). Neither using solid fuel for cooking (odds ratio (OR) 1.08, 95% CI 0.62-1.87) nor using solid fuel for heating (OR 1.04, 95% CI 0.54-2.02) was significantly associated with tuberculosis. Determinants significantly associated with tuberculosis were household tuberculosis contact (adjusted OR, 27.23, 95% CI 8.19-90.58) and ever smoking tobacco (adjusted OR 1.64, 96% CI 1.01-2.66). CONCLUSION: In a population where the majority had proper ventilation in cooking places, the association between use of solid fuel for cooking or for heating and tuberculosis was not statistically significant.

Treatment delay among tuberculosis patients in Tanzania: data from the FIDELIS initiative.

BACKGROUND: Several FIDELIS projects (Fund for Innovative DOTS Expansion through Local Initiatives to Stop TB) in Tanzania were conducted by the National Tuberculosis and Leprosy Programme (NTLP) during the years 2004-2008 to strengthen diagnostic and treatment services. These projects collected information on treatment delay and some of it was available for research purposes. With this database our objective was to assess the duration and determinants of treatment delay among new smear positive pulmonary tuberculosis (TB) patients in FIDELIS projects, and to compare delay according to provider visited prior to diagnosis. METHODS: Treatment delay among new smear positive TB patients was recorded for each patient at treatment initiation and this information was available and fairly complete in 6 out of 57 districts with FIDELIS projects enrolling patients between 2004 and 2007; other districts had discarded their forms at the time of analysis. It was analysed as a cross sectional study. RESULTS: We included 1161 cases, 10% of all patients recruited in the FIDELIS projects in Tanzania. Median delay was 12 weeks. The median duration of cough, weight loss and haemoptysis was 12, 8 and 3 weeks, respectively. Compared to Hai district Handeni had patients with longer delays and Mbozi had patients with shorter delays. Urban and rural patients reported similar delays. Patients aged 15-24 years and patients of 65 years or older had longer delays. Patients reporting contact with traditional healers before diagnosis had a median delay of 15 weeks compared to 12 weeks among those who did not. Patients with dyspnoea and with diarrhoea had longer delays. CONCLUSION: In this patient sample in Tanzania half of the new smear positive pulmonary tuberculosis patients had a treatment delay longer than 12 weeks. Delay was similar in men and women and among urban and rural patients, but longer in the young and older age groups. Patients using traditional healers had a 25% longer median delay.

Operational challenges in managing Isoniazid Preventive Therapy in child contacts: a high-burden setting perspective.

BACKGROUND: The study was conducted at a high TB-HIV burden primary health community clinic in Cape Town, South Africa. We describe the management of children under five years of age in household contact with a smear and/or culture-positive adult TB case. METHODS: This study was a record review of routinely-collected programme data. RESULTS: A total of 1094 adult TB case folders were reviewed. From all identified contacts, 149 children should have received IPT based on local guidelines; in only 2/149 IPT was initiated. Management of child contacts of sputum smear and/or culture-positive compared to sputum-negative TB patients were similar. CONCLUSIONS: IPT delivery to children remains an operational challenge, especially in high TB-HIV burden communities. A tool to improve IPT management and targeting sputum smear and/or culture-positive TB child contacts may overcome some of these challenges and should be developed and piloted in such settings.

Childhood tuberculosis deskguide and monitoring: an intervention to improve case management in Pakistan.

BACKGROUND: Childhood tuberculosis (TB) has been a neglected area in national TB control programme (NTCP) in high burden countries. The NTP Pakistan adapted the global approaches by developing and piloting its policy guideline on childhood TB in ten districts of the country. We developed an intervention package including a deskguide and a monitoring tool and tested with the ongoing childhood TB care in a district. The objective of our study was to measure effectiveness of intervention package with deskguide and monitoring tool by comparing TB case finding and treatment outcomes among districts in 2008, and performance assessment in intervention district. METHOD: An intervention study with cohort design within a routine TB control programme comparing case findings and treatment outcomes before and after the intervention, and in districts with and without intervention. We enrolled all children below 15 years registered at all nine public sector hospitals in three districts of Pakistan. The data was collected from hospital TB records. RESULTS: In eight months during 2007 there were 164 childhood TB cases notified, and after intervention in 2008 a total of 194 cases were notified. In intervention district case finding doubled (110% increase) and correct treatment practice significantly increased in eight months. Successful outcomes were significantly higher in intervention district (37,100%) compared to control district A (18, 18%, p < 0.05) and control district B (41, 72%, p < 0.05). CONCLUSION: Childhood TB deskguide and structured monitoring was associated with improved case management and it augmented NTP policy. More development and implementation in all health services of the district are indicated.

Development and implementation of a national programme for the management of severe and very severe pneumonia in children in Malawi.

Penelope Enarson and colleagues describe the development, scale-up, and achievements of a national pneumonia program in Malawi, which is based on a successful anti-tuberculosis service delivery model.

No decrease in annual risk of tuberculosis infection in endemic area in Cape Town, South Africa.

OBJECTIVE: To estimate the change in annual risk of tuberculosis infection (ARTI) in two neighbouring urban communities of Cape Town, South Africa with an HIV prevalence of approximately 2%, and to compare ARTI with notification rates and treatment outcomes in the tuberculosis (TB) programme. METHODS: In 1998-1999 and 2005, tuberculin skin test surveys were conducted to measure the prevalence of Mycobacterium tuberculosis infection and to calculate the ARTI. All 6 to 9-year-old children from all primary schools were included in the survey. Notification rates and treatment outcomes were obtained from the TB register. RESULTS: A total of 2067 children participated in the survey from 1998 to 1999 and a total of 1954 in 2005. Based on a tuberculin skin test cut-off point of 10 mm, the ARTI was 3.7% (3.4-4.0%) in the 1998-1999 survey and 4.1% (3.8-4.5%) in 2005. The notification rate for pulmonary TB increased significantly from 646 per 100 000 in 1998 to 784 per 100,000 in 2002. In Ravensmead, there was no significant change in ARTI [first survey: 3.5% (3.1-3.9%), second survey: 3.2% (2.9-3.6%)], but in Uitsig the ARTI increased significantly from 4.1% (3.6-4.6%) to 5.8% (5.2-6.5%). The difference in ARTI between the two areas was associated with differences in reported case rates and the proportion of previously treated cases. CONCLUSION: Tuberculosis transmission remains very high in these two communities and control measures to date have failed. Additional measures to control TB are needed.

Health systems that serve: what's the bottom line?

SETTING: Health services in low- and middle-income countries. BACKGROUND: The Global Plan to Stop TB, 2006-2015. OBJECTIVE: Using a framework for evaluation of public health systems, to evaluate evidence that tuberculosis (TB) services contribute to strengthening the health systems. DESIGN: Critical evaluation of published material. RESULTS: The Global Plan to Stop TB 2006-2015 identifies strengthening the health systems as one of its components. Published material illustrates substantial improvement of quality of TB services over the past decade. However, even where these services have achieved a high level of quality, there is little evidence to indicate that other health services in the same locations show similar quality. CONCLUSION: Policies, strategies and actions to strengthen health systems through TB services will require specific plans and priorities to achieve their objectives; this will not occur as a natural effect of improving TB services.

Radiographic signs and symptoms in children treated for tuberculosis: possible implications for symptom-based screening in resource-limited settings.

BACKGROUND: The World Health Organization advises active tracing of children younger than 5 years old in household contact with a sputum smear-positive tuberculosis index case. This study compared radiographic disease manifestations in 2 groups of children treated for tuberculosis in an endemic setting: those who presented with suspicious symptoms; and those actively traced as household contacts of an adult index case. METHODS: We conducted a prospective descriptive study from February 2003 through October 2004 at 5 primary health care clinics in Cape Town South Africa, including all children (younger than 5 years old) treated for tuberculosis (TB). RESULTS: A total of 326 children (younger than 5 years old) received antituberculosis treatment; 190 (58.3%) presented with suspicious symptoms, and 136 (41.7%) were actively traced contacts. Children were categorized as; "not TB" 71 (22%), intrathoracic tuberculosis 230 (70%) and extrathoracic tuberculosis 25 (8%). Significantly more actively traced contacts were categorized as "not TB" (odds ratio, 7.4; 95% confidence interval, 3.8-14.3), or demonstrated elements of the primary complex only on the chest radiograph (odds ratio, 26.2; 95% confidence interval, 8.6-89.2), compared with children who presented with suspicious symptoms. Of all children diagnosed with intrathoracic tuberculosis, 20 of 230 (9%) reported no symptoms, all of whom demonstrated elements of the primary complex only. CONCLUSIONS: The majority of actively traced contacts had minimal disease. Symptom-based screening would have identified all but 9% of children diagnosed with intrathoracic tuberculosis, all of whom demonstrated elements of the primary complex only. Further investigation is required to establish whether symptom-based screening can be justified to improve access to preventive chemotherapy in resource-limited endemic settings.

Comparing Tuberculosis Diagnostic Yield in Smear/Culture and Xpert® MTB/RIF-Based Algorithms Using a Non-Randomised Stepped-Wedge Design.

SETTING: Primary health services in Cape Town, South Africa. STUDY AIM: To compare tuberculosis (TB) diagnostic yield in an existing smear/culture-based and a newly introduced Xpert® MTB/RIF-based algorithm. METHODS: TB diagnostic yield (the proportion of presumptive TB cases with a laboratory diagnosis of TB) was assessed using a non-randomised stepped-wedge design as sites transitioned to the Xpert® based algorithm. We identified the full sequence of sputum tests recorded in the electronic laboratory database for presumptive TB cases from 60 primary health sites during seven one-month time-points, six months apart. Differences in TB yield and temporal trends were estimated using a binomial regression model. RESULTS: TB yield was 20.9% (95% CI 19.9% to 22.0%) in the smear/culture-based algorithm compared to 17.9% (95%CI 16.4% to 19.5%) in the Xpert® based algorithm. There was a decline in TB yield over time with a mean risk difference of -0.9% (95% CI -1.2% to -0.6%) (p<0.001) per time-point. When estimates were adjusted for the temporal trend, TB yield was 19.1% (95% CI 17.6% to 20.5%) in the smear/culture-based algorithm compared to 19.3% (95% CI 17.7% to 20.9%) in the Xpert® based algorithm with a risk difference of 0.3% (95% CI -1.8% to 2.3%) (p = 0.796). Culture tests were undertaken for 35.5% of smear-negative compared to 17.9% of Xpert® negative low MDR-TB risk cases and for 82.6% of smear-negative compared to 40.5% of Xpert® negative high MDR-TB risk cases in respective algorithms. CONCLUSION: Introduction of an Xpert® based algorithm did not produce the expected increase in TB diagnostic yield. Studies are required to assess whether improving adherence to the Xpert® negative algorithm for HIV-infected individuals will increase yield. In light of the high cost of Xpert®, a review of its role as a screening test for all presumptive TB cases may be warranted.

The Impact of a Line Probe Assay Based Diagnostic Algorithm on Time to Treatment Initiation and Treatment Outcomes for Multidrug Resistant TB Patients in Arkhangelsk Region, Russia.

BACKGROUND: In the Arkhangelsk region of Northern Russia, multidrug-resistant (MDR) tuberculosis (TB) rates in new cases are amongst the highest in the world. In 2014, MDR-TB rates reached 31.7% among new cases and 56.9% among retreatment cases. The development of new diagnostic tools allows for faster detection of both TB and MDR-TB and should lead to reduced transmission by earlier initiation of anti-TB therapy. STUDY AIM: The PROVE-IT (Policy Relevant Outcomes from Validating Evidence on Impact) Russia study aimed to assess the impact of the implementation of line probe assay (LPA) as part of an LPA-based diagnostic algorithm for patients with presumptive MDR-TB focusing on time to treatment initiation with time from first-care seeking visit to the initiation of MDR-TB treatment rather than diagnostic accuracy as the primary outcome, and to assess treatment outcomes. We hypothesized that the implementation of LPA would result in faster time to treatment initiation and better treatment outcomes. METHODS: A culture-based diagnostic algorithm used prior to LPA implementation was compared to an LPA-based algorithm that replaced BacTAlert and Löwenstein Jensen (LJ) for drug sensitivity testing. A total of 295 MDR-TB patients were included in the study, 163 diagnosed with the culture-based algorithm, 132 with the LPA-based algorithm. RESULTS: Among smear positive patients, the implementation of the LPA-based algorithm was associated with a median decrease in time to MDR-TB treatment initiation of 50 and 66 days compared to the culture-based algorithm (BacTAlert and LJ respectively, p<0.001). In smear negative patients, the LPA-based algorithm was associated with a median decrease in time to MDR-TB treatment initiation of 78 days when compared to the culture-based algorithm (LJ, p<0.001). However, several weeks were still needed for treatment initiation in LPA-based algorithm, 24 days in smear positive, and 62 days in smear negative patients. Overall treatment outcomes were better in LPA-based algorithm compared to culture-based algorithm (p = 0.003). Treatment success rates at 20 months of treatment were higher in patients diagnosed with the LPA-based algorithm (65.2%) as compared to those diagnosed with the culture-based algorithm (44.8%). Mortality was also lower in the LPA-based algorithm group (7.6%) compared to the culture-based algorithm group (15.9%). There was no statistically significant difference in smear and culture conversion rates between the two algorithms. CONCLUSION: The results of the study suggest that the introduction of LPA leads to faster time to MDR diagnosis and earlier treatment initiation as well as better treatment outcomes for patients with MDR-TB. These findings also highlight the need for further improvements within the health system to reduce both patient and diagnostic delays to truly optimize the impact of new, rapid diagnostics.

Assessment of a revolving drug fund for essential asthma medicines in Benin.

OBJECTIVES: Benin established a revolving drug fund (RDF) for essential asthma medicines in 2008. We evaluated the operation of the RDF and assessed whether there was interruption of supply of asthma medicine from 2008 to 2013. METHODS: We reviewed the process in establishing the RDF. We assessed cost and sale price of asthma medicines, expenditure of the RDF in procuring asthma medicines and other tools, revenue generated by sales of medicines to patients, and balance of capital as of 31 January 2013. We investigated whether there was interruption of supply of essential asthma medicines from 2008-2013. RESULTS: The total amount of grants initially injected into the RDF was 24,101€. As of 31 January 2013, the capital of the RDF, including the deposit in the RDF bank account (8,114€) and the value of inhalers in stock (12,172€), was equivalent to 20,586€, slightly less than the initial capital (24,101€). The decrease of capital was mainly because a number of inhalers were expired or provided free-of-charge (6,091€) and because part of the fund was used to procure other elements required for the management of asthma (4,338€). Thanks to a RDF, Benin maintained an uninterrupted supply of essential asthma medicines in asthma pilot sites from 2008-2013. CONCLUSION: The Benin experience demonstrated that in countries where universal health coverage was not yet in place, establishment of a RDF may help maintain an uninterrupted supply of essential medicines.

The influence of diabetes, glycemic control, and diabetes-related comorbidities on pulmonary tuberculosis.

BACKGROUND: To assess the influence of diabetes mellitus (DM), glycemic control, and diabetes-related comorbidities on manifestations and outcome of treatment of pulmonary tuberculosis (TB). METHODOLOGY/PRINCIPAL FINDINGS: Culture positive pulmonary TB patients notified to health authorities in three hospitals in Taiwan from 2005-2010 were investigated. Glycemic control was assessed by glycated haemoglobin A1C (HbA1C) and diabetic patients were categorized into 3 groups: HbA1C<7%, HbA1C 7-9%, HbA1C>9%. 1,473 (705 with DM and 768 without DM) patients were enrolled. Of the 705 diabetic patients, 82 (11.6%) had pretreatment HbA1C<7%, 152 (21.6%) 7%-9%, 276 (39.2%) >9%, and 195 (27.7%) had no information of HbA1C. The proportions of patients with any symptom, cough, hemoptysis, tiredness and weight loss were all highest in diabetic patients with HbA1C>9%. In multivariate analysis adjusted for age, sex, smoking, and drug resistance, diabetic patients with HbA1C>9% (adjOR 3.55, 95% CI 2.40-5.25) and HbA1C 7-9% (adjOR 1.62, 95% CI 1.07-2.44) were significantly more likely to be smear positive as compared with non-diabetic patients, but not those with HbA1C<7% (adjOR 1.16, 95% CI 0.70-1.92). The influence of DM on outcome of TB treatment was not proportionately related to HbA1C, but mainly mediated through diabetes-related comorbidities. Patients with diabetes-related comorbidities had an increased risk of unfavorable outcome (adjOR 3.38, 95% CI 2.19-5.22, p<0.001) and one year mortality (adjOR 2.80, 95% CI 1.89-4.16). However, diabetes was not associated with amplification of resistance to isoniazid (p = 0.363) or to rifampicin (p = 0.344). CONCLUSIONS/SIGNIFICANCE: Poor glycemic control is associated with poor TB treatment outcome and improved glycemic control may reduce the influence of diabetes on TB.

Potentially Modifiable Factors Associated with Death of Infants and Children with Severe Pneumonia Routinely Managed in District Hospitals in Malawi.

OBJECTIVE: To investigate recognised co-morbidities and clinical management associated with inpatient pneumonia mortality in Malawian district hospitals. METHODS: Prospective cohort study, of patient records, carried out in Malawi between 1st October 2000 and 30th June 2003. The study included all children aged 0-59 months admitted to the paediatric wards in sixteen district hospitals throughout Malawi with severe and very severe pneumonia. We compared individual factors between those that survived (n = 14 076) and those that died (n = 1 633). RESULTS: From logistic regression analysis, predictors of death in hospital, adjusted for age, sex and severity grade included comorbid conditions of meningitis (OR =2.49, 95% CI 1.50-4.15), malnutrition (OR =2.37, 95% CI 1.94-2.88) and severe anaemia (OR =1.41, 95% CI 1.03-1.92). Requiring supplementary oxygen (OR =2.16, 95% CI 1.85-2.51) and intravenous fluids (OR =3.02, 95% CI 2.13-4.28) were associated with death while blood transfusion was no longer significant (OR =1.10, 95% CI 0.77-1.57) when the model included severe anaemia. CONCLUSIONS: This study identified a number of challenges to improve outcome for Malawian infants and children hospitalised with pneumonia. These included improved assessment of co-morbidities and more rigorous application of standard case management.

Transmission of tuberculosis in a high incidence urban community in South Africa.

BACKGROUND: The objective of this study was to identify risk factors for ongoing community transmission of tuberculosis (TB) in two densely populated urban communities with a high incidence rate of TB in Cape Town, South Africa. METHODS: Between 1993 and 1998 DNA fingerprints of mycobacterial isolates from TB patients were determined by restriction fragment length polymorphism (RFLP). Cases whose isolates shared identical fingerprint patterns were considered to belong to the same cluster and to be attributable to ongoing community transmission. RESULTS: The average annual notification rate of new smear positive TB was 238/100000. In all, 1023/1526 reported patients were culture positive, and RFLP was available for 768 (75%) of the isolates from these patients. Since some patients experienced more than one infection during the study period, 797 cases were included in the analysis. Of the cases, 575/797 (72%) were clustered. Smear-positive cases and those who were retreated after default were more likely to be clustered than smear-negative and new cases, respectively. Patients from Uitsig were more often part of large clusters than were patients from Ravensmead. Age, sex, year of diagnosis, and outcome of disease were not risk factors for clustering, nor for being the first case in a cluster, although various analytical approaches were used. CONCLUSIONS: The incidence and proportion of cases that are clustered in this area are higher than reported elsewhere. An overwhelming majority of TB cases in this area is attributed to ongoing community transmission, and only very few to reactivation. This may explain the lack of demographic risk factors for clustering.