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.

Measuring and addressing the childhood tuberculosis reporting gaps in Pakistan: The first ever national inventory study among children.

INTRODUCTION: Tuberculosis in children may be difficult to diagnose and is often not reported to routine surveillance systems. Understanding and addressing the tuberculosis (TB) case detection and reporting gaps strengthens national routine TB surveillance systems. OBJECTIVE: The present study aimed to measure the percentage of childhood TB cases that are diagnosed but not reported to the national surveillance system in Pakistan. DESIGN: The study design was cross sectional. The study was nationwide in 12 selected districts across Pakistan, each representing a cluster. Health facilities that diagnose and treat childhood TB from all sectors were mapped and invited to participate. Lists of child TB cases were created for the study period (April-June 2016) from all study facilities and compared against the list of child TB cases notified to the national TB surveillance system for the same districts and the same period. RESULTS: All public and private health facilities were mapped across 12 sampled districts in Pakistan and those providing health services to child TB cases were included in the study. From all private health facilities, 7,125 children were found with presumptive TB during the study period. Of them, 5,258 were diagnosed with tuberculosis: 11% were bacteriologically-confirmed and 89% clinically-diagnosed; only 4% were notified to National TB Control Program. An additional 1,267 children with TB were also registered in the National TB Control Program. Underreporting was measured to be 78%. CONCLUSION: This is the first nationwide childhood TB inventory study globally and confirmed that childhood TB underreporting is very high in Pakistan. TB surveillance in the country must be strengthened to address this, with particular attention to guiding and supporting general practitioners and pediatricians to notify their TB cases.

Building sustainable operational research capacity in Pakistan: starting with tuberculosis and expanding to other public health problems.

Background: For many years, operational research capacity has been a challenge and has remained a low priority for the health sector in Pakistan. Building research capacity for developing a critical mass of researchers in Pakistan was done through Structured Operational Research and Training Initiative (SORT IT) courses in Paris and Asia between 2010 and 2016. Objective: The aim of this paper is to describe the journey of SORT-IT in Pakistan from its inception to progressive expansion and discuss the challenges and ways forward. Methods: The journey began with the training of the Pakistan NTP research team lead in 2010 in an international SORT IT course at Paris. This was followed by training of two team members in Asia SORT IT courses in 2014 and 2015. These three then worked together to conceive and implement the first national Pakistan SORT IT course supported by WHO/TDR and the Global Fund in 2016. This was facilitated by international facilitators and local trained SORT-IT participants from Paris and Asia. This was followed by two further national SORT IT courses in 2017 and 2018. Results: Between 2010 and 2017, a total of 34 participants from Pakistan had been enrolled in national and international SORT IT courses. Of the 23 participants from completed courses, 18(78%) successfully completed the course. In total 18 papers were submitted and up until June 2018, 15(83%) have been published and 21 institutions in Pakistan involved with operational research as a result of the SORT IT initiative. Conclusions: The SORT IT course has been an effective way to build operational research capacity at national level and this has resulted in a large number of published papers providing local evidence for decision making on TB and other disease control programmes. The experience from Pakistan should stimulate other countries to adopt the SORT-IT model.

Yield of facility-based verbal screening amongst household contacts of patients with multi-drug resistant tuberculosis in Pakistan.

BACKGROUND: Household contacts of multidrug-resistant tuberculosis (MDR-TB) patients are at a high risk of getting infected with TB/MDR-TB, therefore symptomatic or vulnerable individuals should be screened and treated early. METHODS: A cross-sectional study was conducted among household contacts of MDR-TB patients in three high-burden TB sites in Pakistan from July 2013 to June 2014. MDR-TB index patients were asked to provide a list of all members of their household and were asked whether any of them had TB symptoms such as productive cough, fever, weight loss and night sweat ("facility-based verbal screening"). Symptomatic contacts were defined as presumptive TB cases and were invited for investigations at the facility. Those who did not come were paid a home-visit. Confirmed TB/MDR-TB patients were registered in the nearest treatment facility. RESULTS: Of 209 MDR-TB index patients, 1467 household contacts were identified and screened, 95 of them children < 5 years. Of these 172 (12%) were symptomatic. Most common symptoms were cough 157 (91%) and fever 107 (62%). 58 (34%) presumptive TB contacts were not investigated. Of total contacts, 56 (3.8%) were diagnosed with TB, among them 54(96%) with MDR-TB and 2(4%) with drug-susceptible-TB. The number needed to screen (NNS) to identify a new MDR-TB case among adult household contacts was 27 and among presumptive adult and pediatric TB contacts was three. All 56 confirmed patients were registered for treatment. CONCLUSION: Screening household contacts of MDR-TB index cases may be considered a feasible and high yield option, in high-burden, low-resource settings within Pakistan. The number of presumptive TB contacts required to screen to identify a new MDR-TB case was unusually low, indicating an effective strategy that could easily be scaled-up. The screening and management of vulnerable adults and children living with patients having TB of any form is a major priority in the combined efforts to end TB.

Extending 'Contact Tracing' into the Community within a 50-Metre Radius of an Index Tuberculosis Patient Using Xpert MTB/RIF in Urban, Pakistan: Did It Increase Case Detection?

BACKGROUND: Currently, only 62% of incident tuberculosis (TB) cases are reported to the national programme in Pakistan. Several innovative interventions are being recommended to detect the remaining 'missed' TB cases. One such intervention involved expanding contact investigation to the community using the Xpert MTB/RIF test. METHODS: This was a before and after intervention study involving retrospective record review. Passive case finding and household contact investigation was routinely done in the pre-intervention period July 2011-June 2013. Four districts with a high concentration of slums were selected as intervention areas; Lahore, Rawalpindi, Faisalabad and Islamabad. Here, in the intervention period, July 2013-June 2015, contact investigation beyond household was conducted: all people staying within a radius of 50 metres (using Geographical Information System) from the household of smear positive TB patients were screened for tuberculosis. Those with presumptive TB were investigated using smear microscopy and the Xpert MTB/RIF test was performed on smear negative patients. All the diagnosed TB patients were linked to TB treatment and care. RESULTS: A total of 783043 contacts were screened for tuberculosis: 23741(3.0%) presumptive TB patients were identified of whom, 4710 (19.8%) all forms and 4084(17.2%) bacteriologically confirmed TB patients were detected. The contribution of Xpert MTB/RIF to bacteriologically confirmed TB patients was 7.6%. The yield among investigated presumptive child TB patients was 5.1%. The overall yield of all forms TB patients among investigated was 22.3% among household and 19.1% in close community. The intervention contributed an increase of case detection of bacteriologically confirmed tuberculosis by 6.8% and all forms TB patients by 7.9%. CONCLUSION: Community contact investigation beyond household not only detected additional TB patients but also increased TB case detection. However, further long term assessments and cost-effectiveness studies are required before national scale-up.

Population-based resistance of Mycobacterium tuberculosis isolates to pyrazinamide and fluoroquinolones: results from a multicountry surveillance project.

BACKGROUND: Pyrazinamide and fluoroquinolones are essential antituberculosis drugs in new rifampicin-sparing regimens. However, little information about the extent of resistance to these drugs at the population level is available. METHODS: In a molecular epidemiology analysis, we used population-based surveys from Azerbaijan, Bangladesh, Belarus, Pakistan, and South Africa to investigate resistance to pyrazinamide and fluoroquinolones among patients with tuberculosis. Resistance to pyrazinamide was assessed by gene sequencing with the detection of resistance-conferring mutations in the pncA gene, and susceptibility testing to fluoroquinolones was conducted using the MGIT system. FINDINGS: Pyrazinamide resistance was assessed in 4972 patients. Levels of resistance varied substantially in the surveyed settings (3·0-42·1%). In all settings, pyrazinamide resistance was significantly associated with rifampicin resistance. Among 5015 patients who underwent susceptibility testing to fluoroquinolones, proportions of resistance ranged from 1·0-16·6% for ofloxacin, to 0·5-12·4% for levofloxacin, and 0·9-14·6% for moxifloxacin when tested at 0·5 µg/mL. High levels of ofloxacin resistance were detected in Pakistan. Resistance to moxifloxacin and gatifloxacin when tested at 2 µg/mL was low in all countries. INTERPRETATION: Although pyrazinamide resistance was significantly associated with rifampicin resistance, this drug may still be effective in 19-63% of patients with rifampicin-resistant tuberculosis. Even though the high level of resistance to ofloxacin found in Pakistan is worrisome because it might be the expression of extensive and unregulated use of fluoroquinolones in some parts of Asia, the negligible levels of resistance to fourth-generation fluoroquinolones documented in all survey sites is an encouraging finding. Rational use of this class of antibiotics should therefore be ensured to preserve its effectiveness. FUNDING: Bill & Melinda Gates Foundation, United States Agency for International Development, Global Alliance for Tuberculosis Drug Development.

Structured performance monitoring of TB-care at facility, district and province levels - Pakistan experience.

OBJECTIVE: To develop and evaluate a more structured process for effective tuberculosis control monitoring. METHODS: The quasi-experimental exploratory study was conducted from April 2007 to January 2008 in the Punjab province of Pakistan. Eight intervention districts were compared with eight control districts. Intervention consisted of managers using performance monitoring guidelines and tools for monitoring meetings at the facility and district levels. Proportion of tuberculosis suspects among outpatients, registered confirmed cases and patients' default rate were monitored. Semi-structured interviews were done to assess the experience of the participants. RESULTS: The proportion of TB suspects among outpatient attendees was significantly higher in the intervention districts (95% confidence interval 1.6-1.8%). The pre-registration default also showed difference (p=0.07). The case finding during 9 months of the intervention showed 96.3% increase compared to the 9 months of the preceding year. CONCLUSIONS: The new process was effective in improving tuberculosis case finding. The process may be used to improve tuberculosis monitoring systems and other such healthcare services.

Population Based National Tuberculosis Prevalence Survey among Adults (>15 Years) in Pakistan, 2010-2011.

BACKGROUND: We aimed to determine the prevalence of pulmonary tuberculosis (TB) amongst the adult population in 2010-2011 in Pakistan. METHOD: A nationwide cross-sectional survey with multistage cluster sampling was conducted among adults (≥15 years) in 95 clusters in 2010-2011. All consenting participants were screened for cough and by chest X-ray. Participants with presumptive TB submitted two sputum samples for smear microscopy, culture, and molecular testing if needed. The TB prevalence estimates were adjusted for missing data and the cluster design. RESULT: Of 131,329 eligible individuals, 105,913 (81%) participated in the survey, of whom 10,471 (9.9%) were eligible for sputum examination. We found 341 bacteriologically positive TB cases of whom 233 had sputum smear-positive TB. The adjusted prevalence estimates for smear and bacteriologically positive TB were 270/100,000 (95% confidence interval (CI) 217-323), and 398/100,000 (95% CI 333-463), respectively. Only 61% of the diagnosed TB cases screened positive on symptoms (cough >2wks), whereas the other TB cases were detected based on X-ray abnormalities. The TB prevalence increased with age and was 1.8 times higher among men than women. The prevalence-to-notification ratio of smear-positive TB was 3.1 (95% CI 2.5-3.7), was higher among men than women, and increased with age. CONCLUSION: Our data suggest that there is under-detection and/or -notification of TB, especially among men and elderly. TB control should be strengthened specifically in these risk groups. X-ray examination should be combined with symptom screening to enhance case detection.

Knowledge and perceptions of national and provincial tuberculosis control programme managers in Pakistan about the WHO Stop TB strategy: a qualitative study.

OBJECTIVE: To understand how national and provincial tuberculosis programme managers in Pakistan perceive and engage with the Stop TB strategy, its strengths, weaknesses and their experience in its implementation. National and provincial tuberculosis programme managers play an important role in effective implementation of the Stop TB strategy. DESIGN: A qualitative interview study was conducted with 10 national and provincial tuberculosis programme managers to understand how they perceive and engage with the Stop TB strategy, its strengths, weaknesses and their experience in its implementation. Managers were selected purposively; 10 managers were interviewed (six national staff and four from provincial level). PARTICIPANTS: National and provincial tuberculosis programme managers in Pakistan. Managers were selected purposively; 10 managers were interviewed (six national staff and four from provincial level). SETTING: National and provincial tuberculosis programmes in Pakistan. MAIN OUTCOME MEASURES: 1. Knowledge and perceptions of national and provincial tuberculosis programme managers about the Stop TB strategy 2. Progress in implementing the strategy in Pakistan 3. Significant success factors 4. Significant implementation challenges 5. Lessons learnt to scale up successful implementation. RESULTS: The managers reported that most progress had been made in extending DOTS, health systems strengthening, public -private mixed interventions, MDR-TB care and TB/HIV care. The four factors that contributed significantly to progress were the availability of DOTS services, the public-private partnership approach, comprehensive guidance for TB control and government and donor commitment to TB control. CONCLUSION: This study identified three main challenges as perceived by national and provincial tuberculosis programme managers in terms of implementing the Stop TB strategy: 1. Inadequate political commitment, 2. Issue pertaining to prioritisation of certain components in the TB strategy over others due to external influences and 3. Limitations in the overall health system. To improve the tuberculosis control programme in the country political commitment needs to be enhanced and public -private partnerships increased. This can be done through government prioritisation of TB control at both national and provincial levels; donor-funded components should not receive undue attention; and partnerships with the private health sector, health institutions not yet covered by DOTS services, non-governmental organisations and patient coalitions should be increased.

Good quality locally procured drugs can be as effective as internationally quality assured drugs in treating multi-drug resistant tuberculosis.

BACKGROUND: Owing toGiven the high costs of drugs to treat multi-drug resistant tuberculosis (MDR-TB), the Green Light Committee (GLC) initiative enables TB programs to procure quality-assured drugs at reduced prices. Despite price reductions, internationally quality assured (IQA) drugs can be more expensive than locally procured drugs. There is little evidence to inform decision-makers about whether IQA drugs are more effective than local drugs. This is the first study to compare outcomes between MDR-TB patients treated using IQA, and locally procured drugs in the same hospitals during the same time period. METHODS/FINDINGS: A retrospective cohort study was conducted in three hospitals across Pakistan. Data on baseline characteristics and treatment outcomes during the first six months of treatment were extracted from hospital records of adult culture-positive pulmonary MDR-TB patients starting treatment between January 2011 and June 2012. Two cohorts were defined: patients receiving IQA drugs, and patients receiving locally procured non-IQA drugs. Data were analysed using Kaplan-Meier curves and Cox proportional hazards regression. The primary outcome compared between cohorts was time to culture conversion. Of 231 patients, 90 were in the IQA and 141 in the non-IQA cohorts. Baseline characteristics were similar except for higher frequency of quinolone resistance in the IQA cohort. Overall, 193 patients (84%) culture converted. Culture conversion was not faster in the IQA cohort; the median time was 81 and 68 days in the IQA and non-IQA cohorts, respectively. Unadjusted and adjusted hazard ratios for culture conversion in IQA verses non-IQA cohorts were 0.82 (95%-CI, 0.62-1.10) and 0.95 (95%-CI, 0.66-1.36) respectively. CONCLUSIONS: Use of good quality, locally procured drugs can be effective in treating MDR-TB, may involve lower costs than using IQA drugs and could strengthen developing country drug quality assurance systems. This may be a suitable alternative in lieu of or whilst awaiting arrival of internationally procured medicines.

A systematic review of the effectiveness of hospital- and ambulatory-based management of multidrug-resistant tuberculosis.

A systematic review of the literature was conducted on the effectiveness of MDR-TB management. A meta-analysis of treatment outcomes of patients treated in hospitals versus ambulatory-based models was performed in accordance with PRISMA guidelines. The pooled treatment success rate was 66.4% (95% confidence interval [CI] 61.4-71.1%), with no statistical difference between ambulatory (65.5%; 55.1-74.6%) and hospital-based models (66.7%; 61.0-72.0%). The pooled death rate was 10.4% (6.3-16.5%), the pooled treatment failure rate was 9.5% (7.3-12.4%), and the defaulter rate was 14.3% (10.5-19.1%). None of the differences between the two models were statistically significant for any of the outcomes considered. This work improves the quality of the evidence available supporting the World Health Organizations (WHO) recommendation that patients be treated using mainly ambulatory care, conditional on infection control measures in the home and clinic, clinical condition of the patient, availability of treatment support to facilitate adherence to treatment, and provisions for backup facility to manage patients who need inpatient treatment care.

Barriers in the management of tuberculosis in rawalpindi, pakistan: a qualitative study.

BACKGROUND: Tuberculosis (TB) is a contagious, airborne disease and remains a major global public health hazard. TB is a major cause of mortality and is affecting millions of people in low-income and middle-income countries. Worldwide, one person out of three is infected with the Mycobacterium tuberculosis. Timely diagnosis and treatment are the two key factors for better outcomes. Non-adherence to TB treatment is an important barrier for TB control programs. This study was designed to understand the barriers encountered by TB patients when seeking health care. MATERIALS AND METHODS: A qualitative study was conducted during the months of August and December 2010 on 15 health facilities. In-depth interviews were conducted with 23 TB patients (13 males and 10 females) aged 15-65 years. In addition, 15 health personnel were also interviewed. RESULTS: Most patients were found to be well informed about the idea of taking TB medications under direct supervision and its overall importance. However, many of them were not convinced with either drugs or treatment protocols. We found that limited knowledge of patients, loss of employment, financial burden, social stigma and long distance from health facility were the main barriers for TB adherence. CONCLUSION: More patient-centred interventions and attention to the barriers are required to improve the treatment adherence. Direct observation of patients and regular home visits by health workers can reduce the risk of non-adherence.

Gender disparity in tuberculosis cases in eastern and western provinces of Pakistan.

BACKGROUND: Although globally, the number of notified TB cases is higher for males, a few countries in the Eastern Mediterranean Region (Afghanistan; Lebanon; Iran and Pakistan) of the World Health Organization have a relatively higher number of female cases. Pakistan ranks fifth amongst the highest TB burden countries and poses a rich ground for exploratory research to address the gender differences in TB cases. It is uniquely neighboured by India on the East, having higher number of cases in males than in females, and by Afghanistan and Iran on the West, having higher number of cases in females than in males. The objective is to see whether these gender differences are evenly distributed across the country or vary by geographies, to enable effective targeting of TB control strategies. METHODS: Cross-sectional analysis was carried out on secondary data, obtained from National Tuberculosis Program. Disaggregated at the provincial level, the sex-specific case notification rates (CNR) were calculated and trends over a 10-year span (2001-2010) were examined. Sex-specific differences for the four Pakistani provinces were analyzed using chi-square test and odds ratios with corresponding confidence intervals. Cumulative countrywide sex-specific notification rates were used as the reference group. RESULTS: The trends for 2001-2010 in the western provinces of Pakistan show higher female CNR as compared to those seen in the eastern provinces having slightly higher male CNR. The proportions of female notified TB cases are approximately twice as high in the western provinces when compared to the eastern provinces and Pakistan over all. CONCLUSIONS: These findings suggest that females are particularly affected by TB disease burden in the west parts of Pakistan. This gender disparity requires a coordinated regional and international effort to further explore triggers and moderators of increased acquisition and progression of TB disease among females in the region to guarantee effective TB control.

Treatment supporters and their impact on treatment outcomes in routine tuberculosis program conditions in rawalpindi district, pakistan.

BACKGROUND: Tuberculosis (TB) is a major cause of mortality affecting millions of people in third world countries. In DOTS monitoring of patients is facility-based and treatment supporter-based; by these two ways patients' compliance to treatment is monitored. The aim of this study was to evaluate the role of treatment supporters and their impact on patients' treatment outcomes. MATERIALS AND METHODS: The study was a cross-sectional survey in the routine TB control program operational context. All sputum smear positive TB patients that were diagnosed and registered by the public sector in the urban and rural diagnostic centers in 2008 with available outcomes were included in the study. Data of 451 patients were collected during August-October 2010 from 15 health facilities. RESULTS: The majority of patients (89.6%) were provided with treatment supporters. Of 404 (89.6%) cases with treatment supporters, in 203 (50.2%) the supporters were lady health workers, in 46 (11.4%) were community health workers and health facility workers, and in 155 (38.4%) were family members and community volunteers. A total of 384 (85.1%) were categorized as "treatment success", 31 (6.9%), as "transferred out", 17 (3.8%), as "expired", 16 (3.5%) as "defaulted" and three (0.7%) as "treatment failure". The treatment success rates in patients supervised by Lady health workers, community health workers and health facility workers, and family members and community volunteers were 93.1%, 89.1% and 73.5%, respectively. CONCLUSION: We found a significantly higher treatment success rate (93.1%) in patients supervised by lady health workers compared to others. The overall treatment success rate was 85.1%.

Characterization of mutations conferring extensive drug resistance to Mycobacterium tuberculosis isolates in Pakistan.

The increasing incidence of extensively drug-resistant (XDR) Mycobacterium tuberculosis in high-tuberculosis-burden countries further highlights the need for improved rapid diagnostic assays. An increasing incidence of XDR M. tuberculosis strains in Pakistan has been reported, but drug resistance-associated mutations in these strains have not been evaluated previously. We sequenced the "hot-spot" regions of rpoB, katG, inhA, ahpC, gyrA, gyrB, and rrs genes in 50 XDR M. tuberculosis strains. It was observed that 2% of rifampin, 6% of isoniazid, 24% of fluoroquinolone, and 32% of aminoglycoside/capreomycin resistance in XDR M. tuberculosis strains would be undetected if only these common hot-spot regions were tested. The frequencies of resistance-conferring mutations were found to be comparable among all XDR M. tuberculosis strain families present, including the Central Asian Strain, Beijing, and East African Indian genogroups and the Unique isolates. Additional genetic loci need to be tested for detection of mutations conferring fluoroquinolone, aminoglycoside, and capreomycin resistance in order to improve molecular diagnosis of regional XDR M. tuberculosis strains.

Short report: Gender differences in tuberculosis notification in Pakistan.

Worldwide, the male to female ratio of new smear-positive tuberculosis (TB) cases is approximately two to one. However, in Pakistan, this is not the case. Rates of notified TB cases are 20-30% higher in young females compared with males, and female rates remain high regardless of increasing age. This is in stark contrast to neighboring India, which is characterized by an excess of male TB cases. It is currently unknown why rates of notified TB are so high in females in Pakistan, but it is clear that this epidemiology is a public health issue of importance that impacts transmission dynamics and disease control initiatives.