Surgery as an Adjunctive Treatment for Multidrug-Resistant Tuberculosis: An Individual Patient Data Metaanalysis.

BACKGROUND: Medical treatment for multidrug-resistant (MDR)-tuberculosis is complex, toxic, and associated with poor outcomes. Surgical lung resection may be used as an adjunct to medical therapy, with the intent of reducing bacterial burden and improving cure rates. We conducted an individual patient data metaanalysis to evaluate the effectiveness of surgery as adjunctive therapy for MDR-tuberculosis. METHODS: Individual patient data, was obtained from the authors of 26 cohort studies, identified from 3 systematic reviews of MDR-tuberculosis treatment. Data included the clinical characteristics and medical and surgical therapy of each patient. Primary analyses compared treatment success (cure and completion) to a combined outcome of failure, relapse, or death. The effects of all forms of resection surgery, pneumonectomy, and partial lung resection were evaluated. RESULTS: A total of 4238 patients from 18 surgical studies and 2193 patients from 8 nonsurgical studies were included. Pulmonary resection surgery was performed on 478 patients. Partial lung resection surgery was associated with improved treatment success (adjusted odds ratio [aOR], 3.0; 95% confidence interval [CI], 1.5-5.9; I(2)R, 11.8%), but pneumonectomy was not (aOR, 1.1; 95% CI, .6-2.3; I(2)R, 13.2%). Treatment success was more likely when surgery was performed after culture conversion than before conversion (aOR, 2.6; 95% CI, 0.9-7.1; I(2)R, 0.2%). CONCLUSIONS: Partial lung resection, but not pneumonectomy, was associated with improved treatment success among patients with MDR-tuberculosis. Although improved outcomes may reflect patient selection, partial lung resection surgery after culture conversion may improve treatment outcomes in patients who receive optimal medical therapy.

Exposure to combustion of solid fuel and tuberculosis: a matched case-control study.

The present study was conducted in Benin to ascertain the association between exposure to combustion of solid fuel (coal and biomass) and tuberculosis. Cases were consecutive, sputum smear-positive tuberculosis patients never previously treated for tuberculosis for as long as 1 month. Two controls were selected from the neighbourhood of each case, matched by age and sex by a predefined procedure. A total of 200 new smear-positive cases and 400 neighbourhood controls were enrolled. In univariate analysis, using solid fuel for cooking (OR 1.7, 95% CI 1.1-2.8), ever smoking (OR 5.5, 95% CI 3.1-9.8), male sex (OR 10.5, 95% CI 1.6-71.1), daily use of alcoholic beverages (OR 2.3, 95% CI 1.2-4.2) and having a family member with tuberculosis in the previous 5 yrs (OR 30.5, 95% CI 10.8-85.8) were all significantly associated with tuberculosis cases. When all significant variables were entered into a multivariate conditional logistic regression model, the association between using solid fuel for cooking and tuberculosis cases was no longer statistically significant (adjusted OR 1.4, 95% CI 0.7-2.7). In conclusion, the association between exposure to combustion of solid fuel and tuberculosis was relatively weak and not statistically significant.

Protecting patients' rights, ensuring safety and quality assurance in tuberculosis prevalence surveys.

The conduct of biomedical studies is guided by statements of internationally recognised principles of human rights. The first principle of the Nuremberg Code was the centrality of voluntary participation of subjects with informed consent. All prevalence surveys should be reviewed by the appropriate ethics review committees. Each potential survey participant should be adequately informed of the aims, methods and sources of funding of the survey, any possible conflicts of interest, the institutional affiliations of the researchers, the anticipated benefits and potential risks of the study, and any discomfort it may entail. Attention should be paid to safety in each component of the survey. Test procedures that require particular attention are chest radiography (CXR) and bacteriological examination. Quality assurance should be applied to all aspects of research and, in particular, to any measurements undertaken, including CXR assessments, laboratory examinations and questionnaire and data management. Furthermore, to ensure comparability of data from different surveys, it is important to apply the same survey design and methodology and to use the same reporting format.

Tuberculosis outcomes in Taipei: factors associated with treatment interruption for 2 months and death.

SETTING: All individuals reported as being treated for pulmonary tuberculosis (PTB) among citizens of Taipei City, Taiwan, in 2003. OBJECTIVES: To investigate risk factors associated with treatment interruption for at least 2 consecutive months and death. DESIGN: The outcome of PTB cases was determined by consulting medical charts. RESULTS: Of 1127 PTB patients registered, 824 (73.1%) were successfully treated, 189 (16.8%) died, 65 (5.8%) interrupted treatment, 17 (1.5%) were still on treatment 15 months after commencing treatment and 32 (2.8%) failed. The only significant factor associated with treatment interruption was visits to other health facilities after commencing tuberculosis (TB) treatment. TB patients had a standardised mortality ratio of 8.7 (95%CI 7.5-10.0). Factors significantly associated with death were age (adjusted hazard ratio [adjHR] 1.06. 95%CI 1.05-1.08), sputum culture not performed/unknown (adjHR 2.07, 95%CI 1.47-2.92), and comorbidity with respiratory disease (adjHR 1.68, 95%CI 1.24-2.27), infectious disease (adjHR 2.80, 95%CI 2.07-3.78), renal disease (adjHR 2.58, 95%CI 1.82-3.66) or cancer (adjHR 3.31, 95%CI 2.35-4.65), compared with other patients. CONCLUSION: Visits to other health facilities were associated with interruption of treatment for at least 2 months. A high proportion of deaths was due to old age and comorbidity.

Registering initial defaulters and reporting on their treatment outcomes.

This Unresolved Issues article highlights three original articles that appeared last year in the Journal discussing the phenomenon of initial defaulters. There are three important challenges with patients that appear in the laboratory sputum register but are not recorded in the tuberculosis (TB) patient register: the first is how to identify these patients, trace them and get them on to treatment as soon as possible; the second is how to register and report on these cases as part of the case-finding component of TB control; and the third is whether to include these initial default patients in the cohort analysis of treatment outcomes. We recommend a step-wise approach to these challenges and advocate that these patients be included, wherever possible, in the TB patient register and in the cohort analysis of treatment outcomes.

Informed patient consent for defaulter tracing: should we obtain it?

Active default tracing is an integral part of tuberculosis (TB) programmatic control. It can be differentiated into the tracing of defaulters (patients not seen at the clinic for > or =2 months) and 'late patients' (late for their scheduled appointments). Tracing is carried out to obtain reliable information about who has truly died, transferred out or stopped treatment, and, if possible, to persuade those who have stopped treatment to resume. This is important because, unlike routine care for non-communicable diseases, TB has the potential for transmission to other members of the community, and therefore presents the issue of the rights of the individual over the rights of the community. For this reason, default or 'late patient' tracing (defined together as default tracing in this article) has been incorporated into standard practice in most TB programmes and, in many industrialised countries, it is also a part of public health legislation. In resource-poor countries with limited access to phones or e-mails, default tracing involves active home visits. In this Unresolved Issues article, we discuss the need for patient consent within both the programmatic and the research context; we describe how this subject arose during operational research training at the Research Institute of Tuberculosis in Japan; we provide comments from individuals who are experienced and skilled at international and national TB control; and finally we offer some conclusions about the way forward. This is not an easy subject, and we welcome open debate on the issue.

Isoniazid preventive therapy for people living with HIV: public health challenges and implementation issues.

Isoniazid preventive therapy (IPT) is recognised as an important component of collaborative tuberculosis (TB) and human immunodeficiency virus (HIV) activities to reduce the burden of TB in people living with HIV (PLHIV). However, there has been little in the way of IPT implementation at country level. This failure has resulted in a recent call to arms under the banner title of the 'Three I's' (infection control to prevent nosocomial transmission of TB in health care settings, intensified TB case finding and IPT). In this paper, we review the background of IPT. We then discuss the important challenges of IPT in PLHIV, namely responsibility and accountability for the implementation, identification of latent TB infection, exclusion of active TB and prevention of isoniazid resistance, length of treatment and duration of protective efficacy. We also highlight several research questions that currently remain unanswered. We finally offer practical suggestions about how to scale up IPT in the field, including the need to integrate IPT into a package of care for PLHIV, the setting up of operational projects with the philosophy of 'learning while doing', the development of flow charts for eligibility for IPT, the development and implementation of care prior to antiretroviral treatment, and finally issues around procurement, distribution, monitoring and evaluation. We support the implementation of IPT, but only if it is done in a safe and structured way. There is a definite risk that 'sloppy' IPT will be inefficient and, worse, could lead to the development of multidrug-resistant TB, and this must be avoided at all costs.

Cost minimization analysis of line probe assay for detection of multidrug-resistant tuberculosis in Arkhangelsk region of Russian Federation.

BACKGROUND: The development of new diagnostic tools allows for faster detection of both tuberculosis (TB) and multidrug-resistant (MDR) TB and should lead to reduced transmission by earlier initiation of anti TB therapy. The research conducted in the Arkhangelsk region of the Russian Federation in 2012-14 included economic evaluation of Line Probe Assay (LPA) implementation in MDR-TB diagnostics compared to existing culture-based diagnostics of Löwenstein Jensen (LJ) and BacTAlert. Clinical superiority of LPA was demonstrated and results were reported elsewhere. STUDY AIM: The PROVE-IT Russia study aimed to report the outcomes of the cost minimization analysis. METHODS: Costs of LPA-based diagnostic algorithm (smear positive (SSm+) and for smear negative (SSm-) culture confirmed TB patients by Bactec MGIT or LJ were compared with conventional culture-based algorithm (LJ-for SSm- and SSm+ patients and BacTAlert-for SSm+ patients). Cost minimization analysis was conducted from the healthcare system, patient and societal perspectives and included the direct and indirect costs to the healthcare system (microscopy and drug susceptibility test (DST), hospitalization, medications obtained from electronic medical records) and non-hospital direct costs (patient's travel cost, additional expenses associated with hospitalization, supplementary medicine and food) collected at the baseline and two subsequent interviews using the WHO-approved questionnaire. RESULTS: Over the period of treatment the LPA-based diagnostic corresponded to lesser direct and indirect costs comparing to the alternative algorithms. For SSm+ LPA-based diagnostics resulted in the costs 4.5 times less (808.21 US$) than LJ (3593.81 US$) and 2.5 times less than BacTAlert liquid culture (2009.61 US$). For SSm- LPA in combination with Bactec MGIT (1480.75 US$) vs LJ (1785.83 US$) showed the highest cost minimization compared to LJ (2566.09 US$). One-way sensitivity analyses of the key parameters and threshold analyses were conducted and demonstrated that the results were robust to variations in the cost of hospitalization, medications and length of stay. CONCLUSION: From the perspective of Russian Federation healthcare system, TB diagnostic algorithms incorporating LPA method proved to be both more clinically effective and less expensive due to reduction in the number of hospital days to the correct MDR-TB diagnosis and treatment initiation. LPA diagnostics comparing conventional culture diagnostic algorithm MDR-TB was a cost minimizing strategy for both patients and healthcare system.

COPD management. Part II. Relevance for resource-poor settings.

Chronic obstructive pulmonary disease (COPD) is a preventable disease and its prevalence, already high in middle- and low-income countries, is expected to increase in the next decade. Global initiatives, including those against the tobacco industry to stop the tobacco epidemic, are fundamental to reduce the expected morbidity and mortality due to COPD. National health expenditure is generally low in the majority of developing countries, where financial and human resources are lacking and are primarily devoted to infectious diseases. To face these challenges, it is essential to strengthen political commitment to prioritising resource allocation to discourage tobacco use and to implement cost-effective standardised case management. The management of COPD could be more affordable in resource-poor countries if the cheaper spirometers currently on the market were made available and by the use of generic essential drugs. The organisation within clinical services of integrated management of respiratory diseases, including tuberculosis, as recommended by the World Health Organization in its Practical Approach to Lung Health, and by the International Union Against Tuberculosis and Lung Disease in its Comprehensive Approach to Lung Health, would help to improve health systems and skills of health personnel, reduce health costs and improve the quality of care of patients with chronic respiratory diseases.

How to identify tuberculosis cases in a prevalence survey.

The identification of pulmonary tuberculosis (TB) cases in a prevalence survey is a challenge, as diagnostic methods are labour-intensive and large numbers of individuals need to be screened because the prevalence rate is low (almost never greater than 1,200 per 100,000 population). Three testing methods are used: questionnaires, chest radiography (CXR) and bacteriological tests, including sputum smear microscopy and culture. These methods can be applied in four strategies to identify cases. The most sensitive strategy is to apply all methods to each eligible individual. The next most sensitive option is to apply the questionnaire, CXR and sputum smear microscopy to each eligible individual and obtain sputum for culture from those individuals with symptoms, abnormalities on the CXR or a positive smear. If laboratory capacity is limited, screening using symptom enquiry and CXR can be used to select those individuals at highest risk of TB. These individuals are then requested to submit sputum for smear microscopy and culture. If neither CXR nor culture is available, sputum samples may be collected from all eligible individuals and examined by an enhanced microscopy method such as fluorescence microscopy. Case definitions are ideally based on the combined results of symptom enquiry, CXR and bacteriology.

Factors associated with a clinician's decision to stop anti-tuberculosis treatment before completion.

OBJECTIVES: To investigate the diagnosis of pulmonary tuberculosis (PTB) and factors associated with a clinician's decision to stop anti-tuberculosis treatment before completion. DESIGN: The medical charts of all citizens of Taipei City, Taiwan, reported to have received treatment for PTB in 2003 were investigated. RESULTS: Of 1126 PTB patients, 512 (45.5%) started treatment immediately based solely on chest X-ray (CXR) findings; treatment for 214 (19.0%) was based on a positive sputum smear for acid-fast bacilli, for 261 (23.2%) it was based on other findings and for 139 (12.3%) it was based on a positive mycobacterial culture. Of the 1126 PTB patients, 156 (13.9%) had their diagnosis of TB changed by a clinician. Multivariate analysis shows that patients whose diagnosis was based on CXR or other findings, female patients, patients who interrupted treatment for 2 months, patients who continued care at other health facilities (transfer) and patients with lung cancer were significantly more likely to have their diagnosis changed than other groups. CONCLUSION: A substantial proportion of patients were prescribed anti-tuberculosis treatment based on CXR findings alone, and a considerable proportion were advised to stop treatment before completing a full course, findings that require the immediate attention of Taiwan's National Tuberculosis Programme.

Initial default from tuberculosis treatment: how often does it happen and what are the reasons?

A study in 11 primary health care facilities in and around Cape Town determined the proportion of bacteriologically confirmed tuberculosis (TB) cases who did not start treatment (initial default) and identified reasons for it. Databases from centralised laboratories were compared with electronic TB treatment registers. Fourteen per cent (373/2758) of TB suspects were TB cases. Of the 58 (16%) initial defaulters, 14 (24%) died, while 26 (45%) could not be interviewed for address-related reasons. The 18 subjects who were interviewed indicated reasons for initial default that were (56%) or were not (44%) directly linked to services. High initial default rates require improvement in the quality of health services.

From suspect to patient: tuberculosis diagnosis and treatment initiation in health facilities in South Africa.

SETTING: Thirteen primary health care (PHC) facilities in the Stellenbosch District, South Africa. OBJECTIVE: To assess the use of a sputum register to evaluate the tuberculosis (TB) diagnostic process and the initiation of TB treatment in selected PHC facilities in a country with a centralised laboratory system. DESIGN: This prospective study was conducted between April 2004 and March 2005. The names of all individuals submitting sputum samples for TB testing were noted in a newly introduced sputum register. We classified all TB suspects with two positive smears as TB cases and consulted TB treatment registers until 3 months after sputum submission to determine how many had started treatment. RESULTS: A total of 4062 persons aged > or =15 years submitted sputum samples, of whom 2484 were TB suspects. There were 2037 suspects with at least two results, 367 (18%) had at least two positive smears and 64 (17%) of these did not start treatment (initial defaulters). Over the entire diagnostic process, up to 5% of TB cases were missed, and up to 26% did not start treatment and were not reported. CONCLUSION: By correcting diagnostic weaknesses identified in the sputum register, PHC facilities will be able to detect, treat and cure a higher percentage of TB patients.

Tuberculosis prevalence surveys: rationale and cost.

This article is the first of the educational series 'Assessing tuberculosis (TB) prevalence through population-based surveys'. The series will give overall guidance in conducting cross-sectional surveys of pulmonary TB (PTB) disease. TB prevalence surveys are most valuable in areas where notification data obtained through routine surveillance are of unproven accuracy or incomplete, and in areas with an estimated prevalence of bacteriologically confirmed TB of more than 100 per 100,000 population. To embark on a TB prevalence survey requires commitment from the national TB programme, compliance in the study population, plus availability of trained staff and financial resources. The primary objective of TB prevalence surveys is to determine the prevalence of PTB in the general population aged >or=15 years. Limitations of TB prevalence surveys are their inability to assess regional or geographic differences in prevalence of TB, estimate the burden of childhood TB or estimate the prevalence of extra-pulmonary TB. The cost of a prevalence survey is typically US$ 4-15 per person surveyed, and up to US$ 25 per person with radiographic screening. A survey of 50,000 people, of limited precision, would typically cost US$ 200,000-1,250,000.

Providing and monitoring quality service for smoking cessation in tuberculosis care.

All tobacco smokers should be identified and provided with a smoking cessation intervention (SCI) during tuberculosis (TB) treatment. To ensure that this occurs, the intervention process should be recorded and monitored. Monitoring is the best guarantee that care is standardised and offered equitably to all patients. It allows for evaluation of processes and outcomes so that population needs can be identified and appropriate techniques added or updated. In this article we propose steps for brief intervention as a part of the monitoring process, using model forms and suggested procedures for filling them in. The suggested forms are a modified TB treatment card that includes information about tobacco use, an SCI patient card to be added to the patient's TB treatment folder, SCI registers and SCI quarterly report forms and a tobacco use questionnaire for evaluation of services.

Associations between tobacco and tuberculosis.

The association between smoking and tuberculosis (TB) has been investigated since 1918. Both passive and active exposure to tobacco smoke have been shown to be associated with tuberculous infection and with the transition from being infected to developing TB disease. The association between smoking and developing TB disease (without separating the risk of transition from being exposed to being infected and that from being infected to developing TB disease) has been reported substantially. Smoking affects the clinical manifestations of TB. It has been shown that ever smokers are more likely to have cough, dyspnoea, chest radiograph appearances of upper zone involvement, cavity and miliary appearance, and positive sputum culture, but are less likely to have isolated extra-pulmonary involvement than non-smokers. Smoking has been found to be associated with both relapse of TB and TB mortality. There appears to be enough evidence to conclude that smoking is causally associated with TB disease. Patients with TB need and should receive counselling and assistance in stopping smoking.

Tobacco cessation and brief advice.

Patients who are enrolled on tuberculosis (TB) treatment are often ill and are seeking ways to get better. They are more likely at that time to adopt risk-reducing health behaviours. Interventions that are neither complicated nor time-consuming are available to health service personnel to help patients undertake smoking cessation. Brief advice to patients repeated at various times throughout their TB care can increase cessation rates. All tobacco use needs to be identified and reasons for quitting enunciated. Patients are thus given a framework for considering smoking cessation. If patients then choose not to stop currently, they can be asked to reconsider at a later visit, and also be cautioned to avoid smoking in the presence of others. Smokers who want to stop can discuss strategies for avoiding craving and withdrawal, and pharmacological agents can be recommended if they are available. Because the brief advice is repeated, patients are reinforced either for having stopped or for their progress towards stopping.

Introducing brief advice in tuberculosis services.

There are individual and contextual barriers to the adoption of new routines in health care. Health professionals working in tuberculosis (TB) care are unlikely to adopt smoking cessation interventions unless they understand the importance of such interventions, feel that doing them will produce results and are convinced that the interventions should be used. Health professionals need to know what they are expected to do and to feel they have the skills or tools necessary. But beyond informed, willing and ready health care providers, the health care service also needs to provide an encouraging infrastructure. Tobacco cessation has to be included in standard practice guidelines on TB case management, and information about smoking should be included in the standard monitoring process, with appropriate forms. Programme managers and technical advisors need to ask about, encourage and support the inclusion of smoking cessation interventions. It is advisable for one staff member to coordinate tobacco cessation activities to ensure that needed materials are available and to provide assistance and feedback to other staff.

Tobacco use and tobacco control.

Smoking begins when tobacco is readily available and others smoke. It easily becomes something more than experimentation, as the symptoms of nicotine dependence can develop rapidly. The social and environmental cues to smoke, the personal perceptions of smoking and the physiological effects of nicotine create strong links that are difficult to break. Programmes should be put in place to help people to stop smoking, but these programmes cannot reach their potential for success if the wider social and environmental factors are not also changed through strengthened anti-tobacco social values and tobacco control legislation, as exemplified in the WHO Framework Convention on Tobacco Control.