Effect of quitting smoking on health outcomes during treatment for tuberculosis: secondary analysis of the TB & Tobacco Trial.

BACKGROUND: Despite treatment, patients with tuberculosis (TB) who smoke have poorer outcomes compared with non-smokers. It is unknown, however, if quitting smoking during the 6 months of TB treatment improves TB outcomes. METHODS: The TB & Tobacco Trial was a double-blind, placebo-controlled randomised trial of cytisine for smoking cessation in 2472 patients with pulmonary TB in Bangladesh and Pakistan. In a secondary analysis, we investigated the hypothesis that smoking cessation improves health outcomes in patients during the TB treatment course. The outcomes included an eight-point TB clinical score, sputum conversion rates, chest X-ray grades, quality of life (EQ-5D-5L), TB cure plus treatment completion rates and relapse rates. These were compared between those who stopped smoking and those who did not, using regression analysis. RESULTS: We analysed the data of 2273 (92%) trial participants. Overall, 25% (577/2273) of participants stopped smoking. Compared with non-quitters, those who quit had better TB cure plus treatment completion rates (91% vs 80%, p<0.001) and lower TB relapse rates (6% vs 14%, p<0.001). Among quitters, a higher sputum conversion rate at week 9 (91% vs 87%, p=0.036), lower mean TB clinical scores (-0.20 points, 95% CI -0.31 to -0.08, p=0.001) and slightly better quality of life (mean EQ-5D-5L 0.86 vs 0.85, p=0.015) at 6 months were also observed. These differences, except quality of life, remained statistically significant after adjusting for baseline values, trial arm and TB treatment adherence rates. CONCLUSION: Patients with TB who stop smoking may have better outcomes than those who don't. Health professionals should support patients in stopping smoking.

Scaling up tobacco cessation within TB programmes: findings from a multi-country, mixed-methods implementation study.

BACKGROUND: Brief behavioural support can effectively help tuberculosis (TB) patients quit smoking and improve their outcomes. In collaboration with TB programmes in Bangladesh, Nepal and Pakistan, we evaluated the implementation and scale-up of cessation support using four strategies: (1) brief tobacco cessation intervention, (2) integration of tobacco cessation within routine training, (3) inclusion of tobacco indicators in routine records and (4) embedding research within TB programmes. METHODS: We used mixed methods of observation, interviews, questionnaires and routine data. We aimed to understand the extent and facilitators of vertical scale-up (institutionalization) within 59 health facility learning sites in Pakistan, 18 in Nepal and 15 in Bangladesh, and horizontal scale-up (increased coverage beyond learning sites). We observed training and surveyed all 169 TB health workers who were trained, in order to measure changes in their confidence in delivering cessation support. Routine TB data from the learning sites were analysed to assess intervention delivery and use of TB forms revised to report smoking status and cessation support provided. A purposive sample of TB health workers, managers and policy-makers were interviewed (Bangladesh n = 12; Nepal n = 13; Pakistan n = 19). Costs of scale-up were estimated using activity-based cost analysis. RESULTS: Routine data indicated that health workers in learning sites asked all TB patients about tobacco use and offered them cessation support. Qualitative data showed use of intervention materials, often with adaptation and partial implementation in busy clinics. Short (1-2 hours) training integrated within existing programmes increased mean confidence in delivering cessation support by 17% (95% CI: 14-20%). A focus on health system changes (reporting, training, supervision) facilitated vertical scale-up. Dissemination of materials beyond learning sites and changes to national reporting forms and training indicated a degree of horizontal scale-up. Embedding research within TB health systems was crucial for horizontal scale-up and required the dynamic use of tactics including alliance-building, engagement in the wider policy process, use of insider researchers and a deep understanding of health system actors and processes. CONCLUSIONS: System-level changes within TB programmes may facilitate routine delivery of cessation support to TB patients. These strategies are inexpensive, and with concerted efforts from TB programmes and donors, tobacco cessation can be institutionalized at scale.

How do private practitioners in Pakistan manage children suspected having tuberculosis? A cross sectional study.

BACKGROUND: In Pakistan, private providers provide a large portion of health care, including for tuberculosis (TB). All TB patients are supposed to be reported to the National Tuberculosis Program (NTP), which provides drugs free of charge in addition to monitoring, supervision, and support. However, diagnosis of TB in children is difficult. We aimed to assess the private health care providers' investigation practices and management of childhood TB. METHODS: We used a cross-sectional study, which was based on a national survey measuring under-reporting of children with TB in 12 selected districts in Pakistan from April-June, 2016. We explored the practices of the private health care providers, including the health care workers i.e. general practitioners, pediatricians, pulmonologists and chest specialists, who were involved in the diagnosis of TB in children under 15 years for investigating and managing children suspected having TB. RESULTS: Among 6519 presumptive child TB cases, a total of 5193(79.7%) children under 15 years were diagnosed as TB by private health care providers during second quarter, 2016. Only 187(2.9%) were notified to NTP. The majority of presumptive child TB cases reported cough, fever, and failure to thrive; few had TB contacts with pulmonary TB patients. Failure to thrive, loss of body weight and absence of BCG (Bacillus Calmette-Guérin) scar was more common in female children. Private providers relied on chest X-ray in 46.1%, while tuberculin skin test and Gene-Xpert MTB/RIF testing was little utilized. Bacteriological confirmation was present in 7.6%, and clinical assessment was the only basis for diagnosis in 39.3%. Of children with presumptive TB, only 955(14.6%) children were treated by private provider, while 3121(47.9%) cases were referred for diagnosis and 2443(37.5%) were referred after diagnosis for treatment; among all the referred, 3812(68.5%) were sent for investigations to District TB Centre (NTP). CONCLUSION: This study showed that many private providers referred children suspected having TB to laboratories for further diagnosis, but the cases identified in these investigations were often not notified to the NTP. This problem could be resolved by strengthening the referral linkages between private health providers, NTP laboratories and treatment centres through capacity building and training of their staff.

Tuberculosis Preventive Therapy for Individuals Exposed to Drug-resistant Tuberculosis: Feasibility and Safety of a Community-based Delivery of Fluoroquinolone-containing Preventive Regimen.

BACKGROUND: Observational studies have demonstrated the effectiveness of a fluoroquinolone-based regimen to treat individuals presumed to be infected with drug-resistant tuberculosis (DR-TB). We sought to assess the feasibility of this approach in an urban setting in South Asia. METHODS: From February 2016 until March 2017, all household contacts of DR-TB patients enrolled at the Indus Hospital were screened for TB symptoms at home. Children aged 0-17 years, symptomatic adults, and those with an immunocompromising condition (human immunodeficiency virus, diabetes, or malnutrition) were evaluated for TB disease. Contacts diagnosed with TB disease were started on treatment. Contacts without TB disease aged <5 years, contacts aged between 5 and 17 years with either a positive tuberculin skin test or an immunocompromising condition, or contacts aged ≥18 years with an immunocompromising condition were offered 6 months of treatment with a fluoroquinolone. RESULTS: One hundred households with 800 contacts were enrolled: 353 (44.1%) individuals aged ≤17 years with a median age of 19 years (interquartile range, 10-32); 423 (52.9%) were males. In total, 737 (92.1%) individuals were screened, of which 8 were already on treatment for TB (1.1%); another 3 (0.4%) contacts were diagnosed with TB disease and started on treatment. Of 215 eligible for infection treatment, 172 (80.0%) contacts initiated and 121 (70.3%) completed treatment. No TB disease or significant adverse events were observed during 12 months of follow-up. CONCLUSIONS: Fluoroquinolone-based treatment for contacts with presumed DR-TB infection is feasible and well tolerated in a high TB burden setting.

Finding gaps in TB notifications: spatial analysis of geographical patterns of TB notifications, associations with TB program efforts and social determinants of TB risk in Bangladesh, Nepal and Pakistan.

BACKGROUND: In order to effectively combat Tuberculosis, resources to diagnose and treat TB should be allocated effectively to the areas and population that need them. Although a wealth of subnational data on TB is routinely collected to support local planning, it is often underutilized. Therefore, this study uses spatial analytical techniques and profiling to understand and identify factors underlying spatial variation in TB case notification rates (CNR) in Bangladesh, Nepal and Pakistan for better TB program planning. METHODS: Spatial analytical techniques and profiling was used to identify subnational patterns of TB CNRs at the district level in Bangladesh (N = 64, 2015), Nepal (N = 75, 2014) and Pakistan (N = 142, 2015). A multivariable linear regression analysis was performed to assess the association between subnational CNR and demographic and health indicators associated with TB burden and indicators of TB programme efforts. To correct for spatial dependencies of the observations, the residuals of the multivariable models were tested for unexplained spatial autocorrelation. Spatial autocorrelation among the residuals was adjusted for by fitting a simultaneous autoregressive model (SAR). RESULTS: Spatial clustering of TB CNRs was observed in all three countries. In Bangladesh, TB CNR were found significantly associated with testing rate (0.06%, p < 0.001), test positivity rate (14.44%, p < 0.001), proportion of bacteriologically confirmed cases (- 1.33%, p < 0.001) and population density (4.5*10-3%, p < 0.01). In Nepal, TB CNR were associated with population sex ratio (1.54%, p < 0.01), facility density (- 0.19%, p < 0.05) and treatment success rate (- 3.68%, p < 0.001). Finally, TB CNR in Pakistan were found significantly associated with testing rate (0.08%, p < 0.001), positivity rate (4.29, p < 0.001), proportion of bacteriologically confirmed cases (- 1.45, p < 0.001), vaccination coverage (1.17%, p < 0.001) and facility density (20.41%, p < 0.001). CONCLUSION: Subnational TB CNRs are more likely reflective of TB programme efforts and access to healthcare than TB burden. TB CNRs are better used for monitoring and evaluation of TB control efforts than the TB epidemic. Using spatial analytical techniques and profiling can help identify areas where TB is underreported. Applying these techniques routinely in the surveillance facilitates the use of TB CNRs in program planning.

Prevalence of tuberculosis, HIV/AIDS, and hepatitis; in a prison of Balochistan: a cross-sectional survey.

BACKGROUND: Human Immunodeficiency Virus (HIV), Hepatitis, and Tuberculosis (TB) are three primary communicable infections have the likely potential to cause severe morbidity in prison settings. The prison has the most favorable environment for the transmission of infections. We conducted this survey to determine the prevalence and feasibility of rapid diagnostic tests in an active screening of these infectious diseases in prison. METHODS: This cross-sectional survey conducted in central Jail Gaddani, one of the largest prisons in the Balochistan province of Pakistan. All prisoners, jail staffs, and staff's family members participated. Informed consent obtained from each participant before the screening. Van equipped with digital X-ray linked with Computer-Aided Detection for TB (CAD4TB) software used for testing. Sputum samples tested on Xpert for MTB/RIF assay and blood specimens collected for HIV and hepatitis serology. Diagnosed TB patients enrolled for treatment at Basic Management Unit (BMU), reactive on hepatitis Rapid Diagnostic Tools (RDTs) were referred for further testing and management, while HIV reactive referred to Anti Retro Viral (ARV) center for Anti Retro Viral Treatment (ART). RESULTS: A total of 567 participants offered screening, 63% (356) prisoners, 23% (129) staff's family members, and 14% (82) jail staffs. Among tested 10.3% (58/562) were hepatitis seropositive (Hepatitis-C 41 [7.29%] Hepatitis-B, 16 [2.84%] Hepatitis B&C both, 01 [0.17%]). In reactive participants, 49 were prisoners, 08 were jail staffs, and 01 was the staff's family member. HIV seropositive was 4% (24/566), and all were prisoners. Almost 99% (565/567) screened by digital X-ray, 172 (30%) were with abnormal CAD4TB suggestion (score > 50), out of them sputum of 26% (148) tested on Xpert, and 2% (03) found Mycobacterium tuberculosis Positive (MTB+). A total of five TB patients were detected; out of two were diagnosed clinically. Co-morbidities observed in 15 patients, (01 TB/HIV co-infected, 12 HIV/HCV, 01 HIV/HBV, and 01 HBV/HCV). CONCLUSION: The high frequency of infectious diseases in prison is alarming. For limiting the transmission of infections among prison and community, immediate steps are needed to be taken for improvement of prisons condition by application of recommended screening protocols at the time of the first entry of prisoners in prisons.

Delivering Patient-Centered Care in a Fragile State: Using Patient-Pathway Analysis to Understand Tuberculosis-Related Care Seeking in Pakistan.

Background: Pakistan has the sixth largest population in the world and boasts the fifth greatest burden of tuberculosis. The Government of Pakistan has set the ambitious goal of zero deaths due to tuberculosis and universal access to tuberculosis care by 2020. Successfully reaching these goals is dependent on the country's capacity to diagnose and successfully treat an estimated 200000 unnotified or missing patients with tuberculosis. Methods: A patient-pathway analysis (PPA) was conducted at the national level, as well as for each of the 4 provinces, to assess the alignment between patient care seeking and the availability of tuberculosis diagnostic and treatment services. Results: Almost 90% of patients initiated care in the private sector, which accounts for only 15% of facilities with the capacity for tuberculosis diagnosis and treatment. Across the country, nearly 50% of tuberculosis microscopy laboratories were located in public-sector-basic health units and regional health centers. However, very few patients initiated care in these facilities. Overall, tuberculosis case detection was high given the low likelihood of patients reaching facilities with the capacity for tuberculosis service delivery during their first visit. Discussion: Improving the engagement of the informal sector and lower-level clinicians will improve the efficiency and timeliness of tuberculosis diagnosis for patients in Pakistan. Concurrently, the apparent strength of the referral networks connecting community-level workers and private clinicians to the public sector for tuberculosis diagnosis and treatment suggests that strengthening the capacity of the public sector could be valuable.

Predictors of unsuccessful interim treatment outcomes of multidrug resistant tuberculosis patients.

BACKGROUND: Interim treatment outcomes at 6-months for multidrug-resistant tuberculosis (MDR-TB) treatment are among the most basic performance monitoring and key evaluation indicators in the Stop and End TB strategy of the World Health Organization (WHO). Therefore, this study was conducted to evaluate the interim treatment outcomes of MDR-TB patients in Pakistan. METHODS: This study was conducted at the Programmatic Management Unit for Drug-resistance TB (PMDT) site of the National Tuberculosis Program (NTP), Pakistan. It is located in the Chest Disease Unit (CDU) of the Bahawal Victoria Hospital (BVH), Bahawalpur, Punjab, Pakistan. Data was collected between April 1, 2014 and December 31, 2015. The medical records, Electronic Nominal Recording Reporting System (ENRS) data and MRD-TB notification forms of the MDR-TB patients registered at the PMDT site were reviewed to obtain data. For reporting and calculation of interim treatment outcomes, standardized WHO methodology was adopted. Simple logistic regression analysis was used to examine the possible association between the dependent variable (i.e. unsuccessful interim treatment outcome) and selected socio-demographic and clinical variables. RESULTS: A total of 100 drug-resistant TB (DR-TB) patients (all types) were registered during the study period. Out of these, 80 were MDR-TB patients for whom interim results were available. Out of the 80 MDR-TB cases, 48 (60%) were classified under the successful interim treatment outcome category. The remaining 40% had unsuccessful 6-month treatment outcomes and 12 (15%) patients died, while nine (11.3%) were lost to follow-up by six months. The final predictors of unsuccessful interim treatment outcomes were; being resistant to ofloxacin (AOR 3.23, 95% CI 0.96-10.89; p-value = 0.04), having above normal baseline serum creatinine levels (AOR 6.49, 95% CI 1.39-30.27; p-value = 0.02), and being culture positive at the second month of treatment (AOR 6.94, 95% CI 2-24.12; p-value = 0.01). CONCLUSIONS: Despite free treatment and programmatic efforts to ensure patient adherence, the high rate of unsuccessful interim treatment outcomes is concerning. The identified risk factors for unsuccessful interim treatment outcomes in the current study provides clinicians an opportunity to identify high-risk patients and ensure enhanced clinical management and greater treatment success rates.

Subnational tuberculosis burden estimation for Pakistan.

Global tuberculosis (TB) burden estimates are aggregated at the national level, despite the likelihood of uneven distribution across and within regions in the same country. Subnational estimates are crucial to producing informed policies and informing budget allocation at more granular levels. In collaboration with the National TB Programme (NTP), we applied a simple and transparent tool to estimate the subnational TB burden in Pakistan. We tailored the SUBnational Burden Estimation for TB (SUBsET) tool to account for the district-level hierarchy of Pakistan. Districts were assigned weighted scores based on population size, level of urbanisation, households with one room, and food insecurity levels. Using the 2022 national TB incidence estimate, we first allocated the burden across administrative units based on data from the 2010-11 TB prevalence survey and subsequently refined this distribution to reflect weighted scores specific to each district. The estimated TB incidence was compared with pulmonary TB notifications to calculate the case detection rate (CDR) for each district. Utilising the updated SUBsET model, we assigned weight scores to 150 districts spanning seven provinces/regions in Pakistan. The estimated TB incidence varied significantly, ranging from 110 (95%CI: 80-145) to 462 (95%CI: 337-607) per 100,000 inhabitants per year. The provinces bearing the highest burden was Sindh (292; 95%CI: 213-384), followed by Khyber Pakhtunkhwa (269; 95%CI: 196-354) and Punjab (243; 95%CI: 177-320). The CDR was below 70% in three-quarters of the districts and over-reporting (>100%) was observed in 10 districts, primarily within Punjab, which suggests that individuals with TB may be crossing district lines to access care. The application of the SUBsET tool through active collaboration with the NTP revealed high heterogeneity in subnational TB incidence in Pakistan, urging a more granular and tailored approach to TB prevention and care. This approach ensured transparency and acceptance of the findings for wider in-country dissemination.

Efficacy and safety of bedaquiline and delamanid in the treatment of drug-resistant tuberculosis in adults: A systematic review and meta-analysis.

Multi and extensively drug-resistant tuberculosis is a grave cause of global public health concern due to its high mortality and limited treatment options. We conducted this systemic review and meta-analysis to evaluate the efficacy and safety of bedaquiline and delamanid, which have been added to the WHO-recommended regimen for treating drug-resistant tuberculosis. Electronic databases were searched from their inception until December 1st, 2021, for eligible studies assessing the efficacy and safety of bedaquiline and delamanid for treating drug-resistant tuberculosis. Binary outcomes were pooled using a DerSimonian-Laird random-effects model and arcsine transformation and reported on a log scale with a 95% confidence interval (CIs). Twenty-one studies were shortlisted in which bedaquiline, delamanid, and a combination of both were administered in 2477, 937, and 169 patients. Pooled culture conversion at 6 months was 0.801 (p < 0.001), 0.849 (p = 0.059) for bedaquiline and delamanid, respectively, and 0.823 (p = 0.017), concomitantly. In the bedaquiline cohort, the pooled proportion of all-cause mortality at 6 months was reported as 0.074 (p < 0.001), 0.031 (p = 0.372) in the delamanid cohort, and 0.172 in the combined cohort. The incidence of adverse events in the bedaquiline cohort ranged from 11.1% to 95.2%, from 13.2% to 86.2% in the delamanid cohort, and 92.5% in a study in the combined cohort. The incidence of QTC prolongation reported in each cohort is as follows: bedaquiline 0.163 (p < 0.001), delamanid 0.344 (p = 0.272) and combined 0.340 (p < 0.001). Our review establishes the efficacy of delamanid, bedaquiline, and their combined use in treating drug-resistant tuberculosis with reasonable rates of culture conversion, low mortality rates, and safety of co-administration, as seen with their effect on the QTc interval.

Geographical targeting of active case finding for tuberculosis in Pakistan using hotspots identified by artificial intelligence software (SPOT-TB): study protocol for a pragmatic stepped wedge cluster randomised control trial.

INTRODUCTION: Pakistan has significantly strengthened its capacity for active case finding (ACF) for tuberculosis (TB) that is being implemented at scale in the country. However, yields of ACF have been lower than expected, raising concerns on its effectiveness in the programmatic setting. Distribution of TB in communities is likely to be spatially heterogeneous and targeting of ACF in areas with higher TB prevalence may help improve yields. The primary aim of SPOT-TB is to investigate whether a policy change to use a geographically targeted approach towards ACF supported by an artificial intelligence (AI) software, MATCH-AI, can improve yields in Pakistan. METHODS AND ANALYSIS: SPOT-TB will use a pragmatic, stepped wedge cluster randomised design. A total of 30 mobile X-ray units and their field teams will be randomised to receive the intervention. Site selection for ACF in the intervention areas will be guided primarily through the use of MATCH-AI software that models subdistrict TB prevalence and identifies potential disease hotspots. Control areas will use existing approaches towards site selection that are based on staff knowledge, experience and analysis of historical data. The primary outcome measure is the difference in bacteriologically confirmed incident TB detected in the intervention relative to control areas. All remaining ACF-related procedures and algorithms will remain unaffected by this trial. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Health Services Academy, Islamabad, Pakistan (7-82/IERC-HSA/2022-52) and from the Common Management Unit for TB, HIV and Malaria, Ministry of Health Services, Regulation and Coordination, Islamabad, Pakistan (26-IRB-CMU-2023). Findings from this study will be disseminated through publications in peer-reviewed journals and stakeholder meetings in Pakistan with the implementing partners and public-sector officials. Findings will also be presented at local and international medical and public health conferences. TRIAL REGISTRATION NUMBER: NCT06017843.

Prevalence of subclinical pulmonary tuberculosis in adults in community settings: an individual participant data meta-analysis.

BACKGROUND: Subclinical pulmonary tuberculosis, which presents without recognisable symptoms, is frequently detected in community screening. However, the disease category is poorly clinically defined. We explored the prevalence of subclinical pulmonary tuberculosis according to different case definitions. METHODS: We did a one-stage individual participant data meta-analysis of nationally representative surveys that were conducted in countries with high incidence of tuberculosis between 2007 and 2020, that reported the prevalence of pulmonary tuberculosis based on chest x-ray and symptom screening in participants aged 15 years and older. Screening and diagnostic criteria were standardised across the surveys, and tuberculosis was defined by positive Mycobacterium tuberculosis sputum culture. We estimated proportions of subclinical tuberculosis for three case definitions: no persistent cough (ie, duration ≥2 weeks), no cough at all, and no symptoms (ie, absence of cough, fever, chest pain, night sweats, and weight loss), both unadjusted and adjusted for false-negative chest x-rays and uninterpretable culture results. FINDINGS: We identified 34 surveys, of which 31 were eligible. Individual participant data were obtained and included for 12 surveys (620 682 participants) across eight countries in Africa and four in Asia. Data on 602 863 participants were analysed, of whom 1944 had tuberculosis. The unadjusted proportion of subclinical tuberculosis was 59·1% (n=1149/1944; 95% CI 55·8-62·3) for no persistent cough and 39·8% (773/1944; 36·6-43·0) for no cough of any duration. The adjusted proportions were 82·8% (95% CI 78·6-86·6) for no persistent cough and 62·5% (56·6-68·7) for no cough at all. In a subset of four surveys, the proportion of participants with tuberculosis but without any symptoms was 20·3% (n=111/547; 95% CI 15·5-25·1) before adjustment and 27·7% (95% CI 21·0-36·4) after adjustment. Tuberculosis without cough, irrespective of its duration, was more frequent among women (no persistent cough: adjusted odds ratio 0·79, 95% CI 0·63-0·97; no cough: adjusted odds ratio 0·76, 95% CI 0·62-0·93). Among participants with tuberculosis, 29·1% (95% CI 25·2-33·3) of those without persistent cough and 23·1% (18·8-27·4) of those without any cough had positive smear examinations. INTERPRETATION: The majority of people in the community who have pulmonary tuberculosis do not report cough, a quarter report no tuberculosis-suggestive symptoms at all, and a quarter of those not reporting any cough have positive sputum smears, suggesting infectiousness. In high-incidence settings, subclinical tuberculosis could contribute considerably to the tuberculosis burden and to Mycobacterium tuberculosis transmission. FUNDING: Mr Willem Bakhuys Roozeboom Foundation.

Feasibility, enablers and challenges of using timeliness metrics for household contact tracing and TB preventive therapy in Pakistan.

INTRODUCTION: Screening household contacts of TB patients and providing TB preventive therapy (TPT) is a key intervention to end the TB epidemic. Global and timely implementation of TPT in household contacts, however, is dismal. We adapted the 7-1-7 timeliness metric designed to evaluate and respond to infectious disease outbreaks or pandemics, and assessed the feasibility, enablers and challenges of implementing this metric for screening and management of household contacts of index patients with bacteriologically-confirmed pulmonary TB in Karachi city, Pakistan. METHODS: We conducted an explanatory mixed methods study with a quantitative component (cohort design) followed by a qualitative component (descriptive design with focus group discussions). RESULTS: From January-June 2023, 92% of 450 index patients had their household contacts line-listed within seven days of initiating anti-TB treatment ("first 7"). In 84% of 1342 household contacts, screening outcomes were ascertained within one day of line-listing ("next 1"). In 35% of 256 household contacts eligible for further evaluation by a medical officer (aged ≤5 years or with chest symptoms), anti-tuberculosis treatment, TPT or a decision for no drugs was made within seven days of symptom screening ("second 7"). The principal reason for not starting anti-tuberculosis treatment or TPT was failure to consult a medical officer: only 129(50%) of 256 contacts consulted a medical officer. Reasons for poor performance in the "second 7" component included travel costs to see a medical officer, loss of daily earnings and fear of a TB diagnosis. Field staff reported that timeliness metrics motivated them to take prompt action in household contact screening and TPT provision and they suggested these be included in national guidelines. CONCLUSIONS: Field staff found "7-1-7" timeliness metrics to be feasible and useful. Integration of these metrics into national guidelines could improve timeliness of diagnosis, treatment and prevention of TB within households of index patients.

Are patients with pulmonary tuberculosis identified by active and by passive case detection different? A cross-sectional study in Pakistan.

OBJECTIVES: Our objective was to compare the characteristics of patients with pulmonary tuberculosis (TB) identified through "extended contact screening" (ECS) with those of patients identified through routine passive case finding (PCF). METHODS: Active TB case finding by ECS was tested from 2013-2015. This was a cross-sectional study based on data collected from ECS and routine program data from Lahore, Faisalabad, and Rawalpindi districts, and Islamabad in 2015. Characteristics of patients identified through ECS and PCF were compared. RESULTS: Of the 12,114 patients with pulmonary TB in the study, 4604 (38%) were identified through ECS, of whom 4052 (88%) had bacteriological confirmation. Male patients comprised 56.2% (95% confidence interval [CI] 54.8-57.6) of patients with pulmonary TB identified through ECS and 49.7% (95% CI 48.6-50.8) of those identified through PCF. The proportion of bacteriologically confirmed cases was 88.0% (95% CI 87.1-88.9) in the ECS group and 50.3% (95% CI 49.2-51.4) in the PCF group. By regression analysis we found that compared with patients aged 15-44 years, children aged <15 years had higher chances of being identified through ECS (adjusted odds ratio 2.69; 95% CI 2.21-3.28). There was a higher chance of cases being detected by ECS in Faisalabad (adjusted odds ratio 2.57; 95% CI 2.01-3.29) than in Islamabad. CONCLUSION: ECS identified a higher proportion of male and child patients with pulmonary TB than routine case finding; both of these groups are more often unidentified through routine TB control.

Geographic accessibility to childhood tuberculosis care in Pakistan.

BACKGROUND: Tuberculosis (TB) in children is difficult to detect and often needs specialists to diagnose; the health system is supposed to refer to higher level of health care when diagnosis is not settled in a sick child. In Pakistan, the primary health care level can usually not diagnose childhood TB and will refer to a paediatricians working at a secondary or tertiary care hospital. We aimed to determine the health services access to child TB services in Pakistan. OBJECTIVE: We aimed to determine the geographical access to child TB services in Pakistan. METHOD: We used geospatial analysis to calculate the distance from the nearest public health facility to settlements, using qGIS, as well as population living within the World Health Organization's (WHO) recommended 5-km distance. RESULT: At primary health care level, 14.1% of facilities report child TB cases to national tuberculosis program and 74% of the population had geographical access to general primary health care within 5-km radius. To secondary- and tertiary-level health care, 33.5% of the population had geographical access within 5-km radius. The average distance from a facility for diagnosis of childhood TB was 26.3 km from all settlement to the nearest child TB sites. The population of one province (Balochistan) had longer distances to health care services. CONCLUSION: With fairly good coverage of primary health care but lower coverage of specialist care for childhood TB, the health system depends heavily on a good referral system from the communities.

Cost-utility of cytisine for smoking cessation over and above behavioural support in people with newly diagnosed pulmonary tuberculosis: an economic evaluation of a multicentre randomised controlled trial.

OBJECTIVES: To assess the cost-effectiveness of cytisine over and above brief behavioural support (BS) for smoking cessation among patients who are newly diagnosed with pulmonary tuberculosis (TB) in low-income and middle-income countries. DESIGN: An incremental cost-utility analysis was undertaken alongside a 12-month, double-blind, two-arm, individually randomised controlled trial from a public/voluntary healthcare sector perspective with the primary endpoint at 6 months post randomisation. SETTING: Seventeen subdistrict hospitals in Bangladesh and 15 secondary care hospitals in Pakistan. PARTICIPANTS: Adults (aged ≥18 years in Bangladesh and ≥15 years in Pakistan) with pulmonary TB diagnosed within the last 4 weeks who smoked tobacco daily (n=2472). INTERVENTIONS: Two brief BS sessions with a trained TB health worker were offered to all participants. Participants in the intervention arm (n=1239) were given cytisine (25-day course) while those in the control arm (n=1233) were given placebo. No significant difference was found between arms in 6-month abstinence. PRIMARY AND SECONDARY OUTCOME MEASURES: Costs of cytisine and BS sessions were estimated based on research team records. TB treatment costs were estimated based on TB registry records. Additional smoking cessation and healthcare costs and EQ-5D-5L data were collected at baseline, 6-month and 12-month follow-ups. Costs were presented in purchasing power parity (PPP) adjusted US dollars (US$). Quality-adjusted life years (QALYs) were derived from the EQ-5D-5L. Incremental total costs and incremental QALYs were estimated using regressions adjusting for respective baseline values and other baseline covariates. Uncertainty was assessed using bootstrapping. RESULTS: Mean total costs were PPP US$57.74 (95% CI 49.40 to 83.36) higher in the cytisine arm than in the placebo arm while the mean QALYs were -0.001 (95% CI -0.004 to 0.002) lower over 6 months. The cytisine arm was dominated by the placebo arm. CONCLUSIONS: Cytisine plus BS for smoking cessation among patients with TB was not cost-effective compared with placebo plus BS. TRIAL REGISTRATION NUMBER: ISRCTN43811467.

A cohort study analyzing the impact of socioeconomic and spatial characteristics alongside treatment regimens on the environmental-health outcomes of the MDR-TB treatment in Pakistan.

This study identifies and analyzes a number of factors that correlate with the environmental-health outcome of multi-drug resistance tuberculosis (MDR-TB) treatment in Pakistan. Survival analysis is carried out by applying the multivariable Cox Proportional Hazard model on secondary data of 369 patients registered at three main MDR-TB sites in Pakistan during 2012-2017. Results show that there is no difference in survival of patients between the two treatment arms, hospital and ambulatory care. Male gender and travel expenditure are found to be negatively associated with the environmental-health outcome, whereas spatial characteristic of time expenditure is positively related to it supporting distance bias approach. Medical expenditure is also positively related to the environmental-health outcome. The study concludes that availability of affordable and accessible health services, better environmental conditions, and ambulatory care based on WHO recommendation as well as health education along with social protection schemes should be ensured by the government to improve environmental-health outcome in the resource-scarce setting in Pakistan.

Building better tuberculosis control systems in a post-COVID world: learning from Pakistan during the COVID-19 pandemic.

OBJECTIVES: All countries impacted by COVID-19 have had to change routine health service delivery. Although this has reversed some of the progress made in reducing the global burden of tuberculosis (TB) disease, there is an opportunity to incorporate lessons learned to improve TB programmes going forward. APPROACH: We use Pakistan as a case study to discuss three important adaptations in light of COVID-19: bringing care closer to patients; strengthening primary health care systems; and proactively addressing stigma and fear. FINDINGS: COVID-19 control in Pakistan has restricted people's ability to travel and this has forced the TB programme to reduce the need for in-person health facility visits and bring care closer to patients' homes. Strategies that may be useful for providing more convenient care to patients in the future include: : remote treatment support using telemedicine; collaborating with private healthcare providers; and establishing community medicine collection points. As part of the response to COVID-19 in Pakistan, the out-patient departments of major tertiary and secondary care hospitals were closed, and this highlighted the importance of strengthening primary healthcare for both better pandemic and TB control. Finally, stigma associated with COVID-19 and TB can be addressed using trusted community-based health workers, such as Lady Health Workers in Pakistan.

Diagnosis of childhood tuberculosis in Pakistan: Are national guidelines used by private healthcare providers?

BACKGROUND: The National Tuberculosis Control Program (NTP) in Pakistan developed, with the Pakistan Paediatric Association, a pediatric scoring chart to aid diagnosis of childhood tuberculosis (TB). Our study compared the diagnostic practice of private healthcare providers in Pakistan with the NTP guidelines. METHODS: A cross-sectional study comparing diagnosis of TB in children <15 years by Non-NTP private providers with the NTP's pediatric scoring chart. A generalized linear model was used to determine the difference in adherence by Non-NTP private providers to the NTP guidelines for childhood TB diagnosis by associated factors. RESULTS: A total of 5193 (79.7% of presumptive childhood TB cases identified in the selected districts during the study) children were diagnosed with TB by Non-NTP private providers. A strong clinical suspicion of TB was present in 17.3%, and chest x-ray was suggestive of TB in 34.3%. The Kappa score between Non-NTP private providers and the NTP guidelines for diagnosing TB was 0.152. Only 47.8% of cases were diagnosed in line with the NTP guidelines. Children <5 years old with a history of TB contact had a higher chance of being diagnosed according to the NTP guidelines. CONCLUSION: This study indicates a low adherence of NTP guidelines for diagnosing childhood TB by private providers in Pakistan.

Public-Private Mix Models of Tuberculosis Care in Pakistan: A High-Burden Country Perspective.

Introduction: Pakistan ranks fifth in the globally estimated burden of tuberculosis (TB) case incidence. Annually, a gap of 241,688 patients with TB exists between estimated TB incidence and actual TB case notification in Pakistan. These undetected/missed TB cases initiate TB care from providers in the private healthcare system who are less motivated to notify patients to the national database that leads to significant underdetection of actual TB cases in the Pakistani community. To engage these private providers in reaching out to missing TB cases, a national implementation trial of the Public-Private Mix (PPM) model was cohesively launched by National TB Control Program (NTP) Pakistan in 2014. The study aims to assess the implementation, contribution, and relative treatment outcomes of cohesively implemented PPM model in comparison to the non-PPM model. Methods: A retrospective record review of all forms (new and relapse) patients with TB notified from July 2015 to June 2016 was conducted both for PPM- and non-PPM models. Results: The PPM model was implemented in 92 districts in total through four different approaches and contributed 25% (81,016 TB cases) to the national TB case notification. The PPM and non-PPM case notification showed a strong statistical difference in proportions among compared variables related to gender (p < 0.001), age group (p < 0.000), and province (p < 0.000). Among PPM approaches, general practitioners and non-governmental-organization facilities achieve a treatment success of 94-95%; private hospitals achieve 82% success, whereas Parastatals are unable to follow more than half of their notified TB cases. Discussion: The PPM model findings in Pakistan are considerably consistent with countries that have prioritized PPM for an increasing trend in the TB case notification to their national TB control programs. Different PPM approaches need to be scaled up in terms of PPM implemented districts, PPM coverage, PPM coverage efficiency, and PPM coverage outcome in the Pakistani healthcare system in the future.