Tobacco smoking clusters in households affected by tuberculosis in an individual participant data meta-analysis of national tuberculosis prevalence surveys: Time for household-wide interventions?

Tuberculosis (TB) and non-communicable diseases (NCD) share predisposing risk factors. TB-associated NCD might cluster within households affected with TB requiring shared prevention and care strategies. We conducted an individual participant data meta-analysis of national TB prevalence surveys to determine whether NCD cluster in members of households with TB. We identified eligible surveys that reported at least one NCD or NCD risk factor through the archive maintained by the World Health Organization and searching in Medline and Embase from 1 January 2000 to 10 August 2021, which was updated on 23 March 2023. We compared the prevalence of NCD and their risk factors between people who do not have TB living in households with at least one person with TB (members of households with TB), and members of households without TB. We included 16 surveys (n = 740,815) from Asia and Africa. In a multivariable model adjusted for age and gender, the odds of smoking was higher among members of households with TB (adjusted odds ratio (aOR) 1.23; 95% CI: 1.11-1.38), compared with members of households without TB. The analysis did not find a significant difference in the prevalence of alcohol drinking, diabetes, hypertension, or BMI between members of households with and without TB. Studies evaluating household-wide interventions for smoking to reduce its dual impact on TB and NCD may be warranted. Systematically screening for NCD using objective diagnostic methods is needed to understand the actual burden of NCD and inform comprehensive interventions.

Neutrophil-Lymphocyte and Platelet-Lymphocyte Ratios in Distinguishing Lung Cancer in People with HIV.

Objective: The neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) demonstrate good diagnostic accuracy in distinguishing lung cancer patients from healthy individuals, primarily in HIV-negative populations. We determined the sensitivity (Se), specificity (Sp), and area under the curve (AUC) of the NLR and PLR in discriminating between people living with HIV (PLWH) with and without lung cancer. Methods: This is a comparative analysis of secondary data. Cases were PLWH with lung cancer from a retrospective cohort treated at the Uganda Cancer Institute. Controls were unmatched PLWH without lung cancer who were randomly selected from three HIV clinics in Uganda. Se, Sp, and AUC analysis and determination of optimal cutoffs were performed using receiver operating characteristic (ROC) curves. Results: Of 115 PLWH (18 cases and 97 controls), 83 (72.2%) were female, 110 (95.7) were on ART, and the median (IQR) age was 46 (38-51) years. The median (IQR) NLR was higher among cases than controls (3.53 (3.14-7.71) vs. 0.92 (0.67-1.09), p < 0.001). Similarly, the PLR was higher among cases than controls (237.5 (177.8-361.6) vs. 123.6 (100.6-155.4), p=0.001). At a cutoff of 2.44, the respective Se, Sp, and AUC of the NLR were 87.5% (95% CI: 61.7%-98.4%), 100% (95% CI: 96.2%-100%), and 0.94 (95% CI: 0.85-1.00, p < 0.001). Similarly, the respective Se, Sp, and AUC for the PLR were 75% (95% CI: 47.6%-92.7%), 87.2% (95% CI: 78.8%-93.2%), and 0.81 (95% CI: 0.70-0.93, p < 0.001) at a cutoff of 196.3. Conclusion: The NLR and PLR discriminated PLWH with and without lung cancer and could be useful in PLWH with respiratory symptoms in whom lung cancer can easily be misdiagnosed as other lung pathology.

Association of diabetes, smoking, and alcohol use with subclinical-to-symptomatic spectrum of tuberculosis in 16 countries: an individual participant data meta-analysis of national tuberculosis prevalence surveys.

Background: Non-communicable diseases (NCDs) and NCD risk factors, such as smoking, increase the risk for tuberculosis (TB). Data are scarce on the risk of prevalent TB associated with these factors in the context of population-wide systematic screening and on the association between NCDs and NCD risk factors with different manifestations of TB, where ∼50% being asymptomatic but bacteriologically positive (subclinical). We did an individual participant data (IPD) meta-analysis of national and sub-national TB prevalence surveys to synthesise the evidence on the risk of symptomatic and subclinical TB in people with NCDs or risk factors, which could help countries to plan screening activities. Methods: In this systematic review and IPD meta-analysis, we identified eligible prevalence surveys in low-income and middle-income countries that reported at least one NCD (e.g., diabetes) or NCD risk factor (e.g., smoking, alcohol use) through the archive maintained by the World Health Organization and by searching in Medline and Embase from January 1, 2000 to August 10, 2021. The search was updated on March 23, 2023. We performed a one-stage meta-analysis using multivariable multinomial models. We estimated the proportion of and the odds ratio for subclinical and symptomatic TB compared to people without TB for current smoking, alcohol use, and self-reported diabetes, adjusted for age and gender. Subclinical TB was defined as microbiologically confirmed TB without symptoms of current cough, fever, night sweats, or weight loss and symptomatic TB with at least one of these symptoms. We assessed heterogeneity using forest plots and I2 statistic. Missing variables were imputed through multi-level multiple imputation. This study is registered with PROSPERO (CRD42021272679). Findings: We obtained IPD from 16 national surveys out of 21 national and five sub-national surveys identified (five in Asia and 11 in Africa, N = 740,815). Across surveys, 15.1%-56.7% of TB were subclinical (median: 38.1%). In the multivariable model, current smoking was associated with both subclinical (OR 1.67, 95% CI 1.27-2.40) and symptomatic TB (OR 1.49, 95% CI 1.34-1.66). Self-reported diabetes was associated with symptomatic TB (OR 1.67, 95% CI 1.17-2.40) but not with subclinical TB (OR 0.92, 95% CI 0.55-1.55). For alcohol drinking ≥ twice per week vs no alcohol drinking, the estimates were imprecise (OR 1.59, 95% CI 0.70-3.62) for subclinical TB and OR 1.43, 95% CI 0.59-3.46 for symptomatic TB). For the association between current smoking and symptomatic TB, I2 was high (76.5% (95% CI 62.0-85.4), while the direction of the point estimates was consistent except for three surveys with wide CIs. Interpretation: Our findings suggest that current smokers are more likely to have both symptomatic and subclinical TB. These individuals can, therefore, be prioritised for intensified screening, such as the use of chest X-ray in the context of community-based screening. People with self-reported diabetes are also more likely to have symptomatic TB, but the association is unclear for subclinical TB. Funding: None.

Cross-sectional validation of the COPD Assessment Test (CAT) among chronic obstructive pulmonary disease patients in rural Uganda.

Measuring quality of life is a key component in the management of Chronic Obstructive Pulmonary Disease (COPD). The COPD assessment test (CAT), an easy to administer and shorter instrument than the standard Saint George's respiratory questionnaire (SGRQ), could be an alternative tool for measuring the quality of life of COPD patients in rural Uganda. A cross-sectional study was conducted between June and August 2022, consecutively recruiting 113 COPD patients aged > 40 years from the Low-Dose Theophylline for the management of Biomass-associated COPD (LODOT-BCOPD) study. Upon obtaining consent, participants answered an interviewer administered social demographic, CAT and SGRQ questionnaire. Internal consistency for both SGRQ and CAT was determined using Cronbach's alpha coefficient and values > 0.7 were considered acceptable while correlations were determined using Spearman's rank correlation. Limits of Agreement were visualised using Bland Altman and pair plots. Of the 113 participants, 51 (45.1%) were female. The mean age was 64 ± 12 years, 19 (16.8%) had history of smoking while majority (112 (99.1%)) reported use of firewood for cooking. There was a strong correlation of 0.791 (p < 0.001) between the CAT and SGRQ total scores with a high internal consistency of CAT, Cronbach's alpha coefficient of 0.924 (0.901-0.946). The agreement between the absolute CAT scores and the SGRQ scores was good with a mean difference of -0.932 (95% Confidence Interval: -33.49-31.62). In summary, CAT has an acceptable validity and can be used as an alternative to the SGRQ to assess the quality of life of COPD patients in rural Uganda.

Unmet Diagnostic and Therapeutic Opportunities for Chronic Obstructive Pulmonary Disease in Low- and Middle-Income Countries.

Rationale: Chronic obstructive pulmonary disease (COPD) is a prevalent and burdensome condition in low- and middle-income countries (LMICs). Challenges to better care include more effective diagnosis and access to affordable interventions. There are no previous reports describing therapeutic needs of populations with COPD in LMICs who were identified through screening. Objectives: To describe unmet therapeutic need in screening-detected COPD in LMIC settings. Methods: We compared interventions recommended by the international Global Initiative for Chronic Obstructive Lung Disease COPD strategy document, with that received in 1,000 people with COPD identified by population screening at three LMIC sites in Nepal, Peru, and Uganda. We calculated costs using data on the availability and affordability of medicines. Measurement and Main Results: The greatest unmet need for nonpharmacological interventions was for education and vaccinations (applicable to all), pulmonary rehabilitation (49%), smoking cessation (30%), and advice on biomass smoke exposure (26%). Ninety-five percent of the cases were previously undiagnosed, and few were receiving therapy (4.5% had short-acting ß-agonists). Only three of 47 people (6%) with a previous COPD diagnosis had access to drugs consistent with recommendations. None of those with more severe COPD were accessing appropriate maintenance inhalers. Even when available, maintenance treatments were unaffordable, with 30 days of treatment costing more than a low-skilled worker's daily average wage. Conclusions: We found a significant missed opportunity to reduce the burden of COPD in LMIC settings, with most cases undiagnosed. Although there is unmet need in developing novel therapies, in LMICs where the burden is greatest, better diagnosis combined with access to affordable interventions could translate to immediate benefit.

Serum E-selectin and endothelial cell-specific Molecule-1 levels among people living with HIV on long term ART in Uganda: a pilot cross-sectional study.

BACKGROUND: Prolonged exposure to HIV and anti-retroviral therapy (ART) has been linked with endothelial cell activation which subsequently predisposes people living with HIV (PLWH) to cardiovascular diseases. Serum biomarkers of endothelial cell activation such as E-Selectin and endothelial cell-specific molecule-1 (ESM-1) could aid in early detection of PLWH at a risk of cardiovascular diseases. However, there is a paucity of data on these biomarkers like E-selectin and endothelial cell-specific molecule-1 (ESM-1) among PLWH on long term ART (≥ 10 years) in Uganda. The aim of this study is to determine the serum levels of these biomarkers in this population. METHODS: This was a cross-sectional study where we randomly sampled 73 stored serum samples of PLWH who were enrolled in the Infectious Diseases Institute (IDI) ART long term (ALT cohort). We measured serum levels of E-selectin and ESM-1 by ELISA. Data was summarized using median and interquartile range. Inferential statistics were performed to determine predictors of elevated levels of E-selectin. RESULTS: Of the 73 samples analyzed, 38 (52.1%) were from female participants. The mean age was 54 ± 9.0 years. Twenty participants (27.4%) had a history of smoking while 52 (71.2%) had a history of alcohol intake. Twenty-five (34.3%) of the participants were overweight whereas 4 (5.6%) were obese. Fifty-four (74%) had an undetectable viral load (≤ 0 copies/ml) and the mean duration of ART at the time of sampling (2014/2015) was 10.4 ± 0.4 years. While serum levels of ESM-1 were not detectable in any of our samples, the median E-selectin levels was 147.6 µm/L ranging from 8.44 µm/L and 1,979.36 µm/L. Sixty-seven participants (91.8%) had elevated levels of E-selectin (> 39 µm/L). CD4 count > 500 cells/µl compared to lower counts was a predictor of elevated levels of E-Selectin (adjusted Odd Ratio 12.5, 95% CI (1.03 - 149.95, p < 0.05). CONCLUSIONS: The majority (91.8%) of PLWH on long term ART had elevated levels of E-selectin. Having high CD4 count (> 500 cells/µl) was predictive of elevated levels of E-Selectin. Future work should longitudinally assess the trend of levels of E-selectin and ESM-1 while assessing for cardiovascular diseases endpoint.

Mycobacterium tuberculosis infection and cytogenetic abnormalities among people with HIV.

OBJECTIVE: To compare cytogenetic abnormalities among people living with HIV (PLWH) with and without previous exposure to Mycobacterium tuberculosis (Mtb) (both latent tuberculosis infection [LTBI] and active tuberculosis [TB]). METHODS: Adult PLWH (≥18 years) were randomly selected at three HIV clinics in Uganda. Previous active TB was confirmed in the clinics' TB records. LTBI was defined as a positive QuantiFERON-TB Gold Plus assay. Participants' buccal mucosal exfoliated cells were examined (per 2000 cells) using the buccal micronucleus assay for chromosomal aberrations (micronuclei and/or nuclear buds), cytokinetic defects (binucleated cells), proliferative potential (normal differentiated cells and basal cell frequency) and/or cell death (condensed chromatin, karyorrhexis, pyknotic and karyolytic cells). RESULTS: Among 97 PLWH, 42 (43.3%) had exposure to Mtb;16 had previous successfully treated active TB and 26 had LTBI. PLWH with exposure to Mtb had a higher median number of normal differentiated cells (1806.5 [1757.0 - 1842.0] vs. 1784.0 [1732.0 - 1843.0], p = 0.031) and fewer karyorrhectic cells (12.0 [9.0 - 29.0] vs. 18.0 [11.0 - 30.0], p = 0.048) than those without. PLWH with LTBI had fewer karyorrhectic cells than those without (11.5 [8.0 - 29.0] vs. 18.0 [11 - 30], p = 0.006). CONCLUSION: We hypothesized that previous exposure to Mtb is associated with cytogenetic damage among PLWH. We found that exposure to Mtb is associated with more normal differentiated cells and less frequent karyorrhexis (a feature of apoptosis). It is unclear whether this increases the propensity for tumorigenesis.

Implementation of evidence-based multiple focus integrated intensified TB screening to end TB (EXIT-TB) package in East Africa: a qualitative study.

INTRODUCTION: Tuberculosis (TB) remains a major cause of morbidity and mortality, especially in sub-Saharan Africa. We qualitatively evaluated the implementation of an Evidence-Based Multiple Focus Integrated Intensified TB Screening package (EXIT-TB) in the East African region, aimed at increasing TB case detection and number of patients receiving care. OBJECTIVE: We present the accounts of participants from Tanzania, Kenya, Uganda, and Ethiopia regarding the implementation of EXIT-TB, and suggestions for scaling up. METHODS: A qualitative descriptive design was used to gather insights from purposefully selected healthcare workers, community health workers, and other stakeholders. A total of 27, 13, 14, and 19 in-depth interviews were conducted in Tanzania, Kenya, Uganda, and Ethiopia respectively. Data were transcribed and translated simultaneously and then thematically analysed. RESULTS: The EXIT-TB project was described to contribute to increased TB case detection, improved detection of Multidrug-resistant TB patients, reduced delays and waiting time for diagnosis, raised the index of TB suspicion, and improved decision-making among HCWs. The attributes of TB case detection were: (i) free X-ray screening services; (ii) integrating TB case-finding activities in other clinics such as Reproductive and Child Health clinics (RCH), and diabetic clinics; (iii), engagement of CHWs, policymakers, and ministry level program managers; (iv) enhanced community awareness and linkage of clients; (v) cooperation between HCWs and CHWs, (vi) improved screening infrastructure, (vii) the adoption of the new simplified screening criteria and (viii) training of implementers. The supply-side challenges encountered ranged from disorganized care, limited space, the COVID-19 pandemic, inadequate human resources, inadequate knowledge and expertise, stock out of supplies, delayed maintenance of equipment, to absence of X-ray and GeneXpert machines in some facilities. The demand side challenges ranged from delayed care seeking, inadequate awareness, negative beliefs, fears towards screening, to financial challenges. Suggestions for scaling up ranged from improving service delivery, access to diagnostic equipment and supplies, and infrastructure, to addressing client fears and stigma. CONCLUSION: The EXIT-TB package appears to have contributed towards increasing TB case detection and reducing delays in TB treatment in the study settings. Addressing the challenges identified is needed to maximize the impact of the EXIT-TB intervention.

Development and validation of an interstitial lung disease exposure questionnaire for sub-Saharan Africa.

Background: American Thoracic Society/European Respiratory Society guidelines recommend context-specific exposure assessments to diagnose interstitial lung disease (ILD). In sub-Saharan Africa, ILD diagnoses are rare, and locally validated ILD exposure questionnaires are not used. Methods: A physician-administered ILD exposure questionnaire was developed using a four-step mixed-methods modified Delphi approach. First, ILD questionnaires from high-income countries and data from Pneumotox were reviewed, compiled and face-validated. Second, a local pilot group of ILD experts ranked item relevance using a Likert scale and suggested additions. Third, the questionnaire format and pilot rankings were addressed in a focus group discussion that was analysed using grounded theory. Finally, following focus group discussion modifications, the resulting items (with three duplicate item groups for evaluation of internal consistency) were ranked for importance by members of the Pan-African Thoracic Society (PATS). Results: Face validation resulted in 82 items in four categories: "Smoking and Drugs", "Environmental Exposures", "Occupations" and "Medications". Pilot group (n=10) ranking revealed 27 outliers and 30 novel suggestions. Focus group (n=12) discussion resulted in 10 item deletions, 14 additions and 22 re-wordings; themes included desire for extensive questionnaires and stigma sensitivity. Final validation involved 58 PATS members (mean±sd age 46±10.6  years, 76% male, from 17 countries) ranking 84 items derived from previous steps and three duplicate question groups. The questionnaire was internally consistent (Cronbach's α >0.80) and ultimately included 73 items. Conclusion: This mixed-methods study included experts from 17 countries in sub-Saharan Africa and successfully developed a 73-item ILD exposure questionnaire for sub-Saharan Africa. African pulmonary experts valued region-specific additions and ranked several items from existing ILD questionnaires as unimportant.

HIV-related lung cancer in Uganda: a cohort study.

BACKGROUND: There are few reports on lung cancer among people with HIV (PWH) in Sub-Saharan Africa. In this report, we describe a cohort of PWH and lung cancer at the Uganda Cancer Institute. METHODS: This retrospective cohort of PWH and lung cancer was managed at the Uganda Cancer Institute between 2008 and 2018. Sociodemographic and clinical data were abstracted from the patient charts. The median survival from diagnosis to death, loss-to-follow up or 31st December 2018, was estimated. RESULTS: There were 18 people with HIV and lung cancer. The median (interquartile range, IQR) age was 49.5 (38.8-56.0) years, 11 (61.1%) were women and 5 (27.8%) were smokers. Of the 18 PWH, 13 (72.2%) were on antiretroviral therapy and the median (IQR) CD4 count (n = 13) was 380 (243.5-595) cells per mm3. Difficulty in breathing (88.9%), chest pain (78.6%, n = 11), cough (76.5%, n = 17) and weight loss (72.2%) were the commonest symptoms while pleural effusions were observed in 12 (66.7%). In this cohort, 8 (44.4%) were presumptively treated for tuberculosis before the diagnosis of lung cancer. Seven (38.9%) had an Eastern Cooperative Oncology Group performance status of 3. Non-small cell lung cancer was the predominant histological type observed in 17 (94.4%) of whom 14 (82.4%) had adenocarcinoma. Majority of PWH had stage IV disease (88.9%). The median (IQR) survival was 3.3 (1.1-13.2) months and all were either dead (72.2%) or lost-to-follow up (27.8%) at five years from diagnosis. CONCLUSION: People with HIV and lung cancer in Uganda report low rates of smoking, present with advanced disease and post very poor survival rates. There is need for biomarkers for early detection of lung cancer in HIV.

Prioritising primary care respiratory research needs: results from the 2020 International Primary Care Respiratory Group (IPCRG) global e-Delphi exercise.

Respiratory diseases remain a significant cause of global morbidity and mortality and primary care plays a central role in their prevention, diagnosis and management. An e-Delphi process was employed to identify and prioritise the current respiratory research needs of primary care health professionals worldwide. One hundred and twelve community-based physicians, nurses and other healthcare professionals from 27 high-, middle- and low-income countries suggested 608 initial research questions, reduced after evidence review by 27 academic experts to 176 questions covering diagnosis, management, monitoring, self-management and prognosis of asthma, COPD and other respiratory conditions (including infections, lung cancer, tobacco control, sleep apnoea). Forty-nine questions reached 80% consensus for importance. Cross-cutting themes identified were: a need for more effective training of primary care clinicians; evidence and guidelines specifically relevant to primary care, adaption for local and low-resource settings; empowerment of patients to improve self-management; and the role of the multidisciplinary healthcare team.

Discriminative Accuracy of Chronic Obstructive Pulmonary Disease Screening Instruments in 3 Low- and Middle-Income Country Settings.

Importance: Most of the global morbidity and mortality in chronic obstructive pulmonary disease (COPD) occurs in low- and middle-income countries (LMICs), with significant economic effects. Objective: To assess the discriminative accuracy of 3 instruments using questionnaires and peak expiratory flow (PEF) to screen for COPD in 3 LMIC settings. Design, Setting, and Participants: A cross-sectional analysis of discriminative accuracy, conducted between January 2018 and March 2020 in semiurban Bhaktapur, Nepal; urban Lima, Peru; and rural Nakaseke, Uganda, using a random age- and sex-stratified sample of the population 40 years or older. Exposures: Three screening tools, the COPD Assessment in Primary Care to Identify Undiagnosed Respiratory Disease and Exacerbation Risk (CAPTURE; range, 0-6; high risk indicated by a score of 5 or more or score 2-5 with low PEF [<250 L/min for females and <350 L/min for males]), the COPD in LMICs Assessment questionnaire (COLA-6; range, 0-5; high risk indicated by a score of 4 or more), and the Lung Function Questionnaire (LFQ; range, 0-25; high risk indicated by a score of 18 or less) were assessed against a reference standard diagnosis of COPD using quality-assured postbronchodilator spirometry. CAPTURE and COLA-6 include a measure of PEF. Main Outcomes and Measures: The primary outcome was discriminative accuracy of the tools in identifying COPD as measured by area under receiver operating characteristic curves (AUCs) with 95% CIs. Secondary outcomes included sensitivity, specificity, positive predictive value, and negative predictive value. Results: Among 10 709 adults who consented to participate in the study (mean age, 56.3 years (SD, 11.7); 50% female), 35% had ever smoked, and 30% were currently exposed to biomass smoke. The unweighted prevalence of COPD at the 3 sites was 18.2% (642/3534 participants) in Nepal, 2.7% (97/3550) in Peru, and 7.4% (264/3580) in Uganda. Among 1000 COPD cases, 49.3% had clinically important disease (Global Initiative for Chronic Obstructive Lung Disease classification B-D), 16.4% had severe or very severe airflow obstruction (forced expiratory volume in 1 second <50% predicted), and 95.3% of cases were previously undiagnosed. The AUC for the screening instruments ranged from 0.717 (95% CI, 0.677-0.774) for LFQ in Peru to 0.791 (95% CI, 0.770-0.809) for COLA-6 in Nepal. The sensitivity ranged from 34.8% (95% CI, 25.3%-45.2%) for COLA-6 in Nepal to 64.2% (95% CI, 60.3%-67.9%) for CAPTURE in Nepal. The mean time to administer the instruments was 7.6 minutes (SD 1.11), and data completeness was 99.5%. Conclusions and Relevance: This study demonstrated that screening instruments for COPD were feasible to administer in 3 low- and middle-income settings. Further research is needed to assess instrument performance in other low- and middle-income settings and to determine whether implementation is associated with improved clinical outcomes.

Mapping low-resource contexts to prepare for lung health interventions in four countries (FRESH AIR): a mixed-method study.

BACKGROUND: Effectiveness of health programmes can be undermined when the implementation misaligns with local beliefs and behaviours. To design context-driven implementation strategies, we explored beliefs and behaviours regarding chronic respiratory disease (CRD) in diverse low-resource settings. METHODS: This observational mixed-method study was conducted in Africa (Uganda), Asia (Kyrgyzstan and Vietnam) and Europe (rural Greece and a Roma camp). We systematically mapped beliefs and behaviours using the SETTING-tool. Multiple qualitative methods among purposively selected community members, health-care professionals, and key informants were triangulated with a quantitative survey among a representative group of community members and health-care professionals. We used thematic analysis and descriptive statistics. FINDINGS: We included qualitative data from 340 informants (77 interviews, 45 focus group discussions, 83 observations of community members' households and health-care professionals' consultations) and quantitative data from 1037 community members and 204 health-care professionals. We identified three key themes across the settings; namely, (1) perceived CRD identity (community members in all settings except the rural Greek strongly attributed long-lasting respiratory symptoms to infection, predominantly tuberculosis); (2) beliefs about causes (682 [65·8%] of 1037 community members strongly agreed that tobacco smoking causes symptoms, this number was 198 [19·1%] for household air pollution; typical perceived causes ranged from witchcraft [Uganda] to a hot-cold disbalance [Vietnam]); and (3) norms and social structures (eg, real men smoke [Kyrgyzstan and Vietnam]). INTERPRETATION: When designing context-driven implementation strategies for CRD-related interventions across these global settings, three consistent themes should be addressed, each with common and context-specific beliefs and behaviours. Context-driven strategies can reduce the risk of implementation failure, thereby optimising resource use to benefit health outcomes. FUNDING: European Commission Horizon 2020. TRANSLATIONS: For the Greek, Russian and Vietnamese translations of the abstract see Supplementary Materials section.

Perceptions of Adolescents and Health Workers Towards Adolescents' TB Diagnosis in Central Uganda: A Cross-Sectional Qualitative Study.

PURPOSE: Prompt diagnosis of TB among adolescents may reduce transmission and improve individual outcomes. However, TB diagnosis in adolescents is challenging. This study sought to understand challenges to adolescent TB diagnosis. METHODS: We conducted qualitative focus group discussions (FGDs) to explore adolescents' and health workers' perspectives on challenges to TB diagnosis among adolescents seeking care at four secondary health care facilities in Uganda. Eight FGDs were conducted: four with 32 adolescents consulting for medical care and four with 34 health workers involved in TB care. RESULTS: Adolescents were aware of TB and associated risk factors and believed behaviours like smoking and alcohol use are risk factors for TB. They reported school schedules limit them from seeking TB care and have to miss school or wait for holidays to seek TB diagnosis. They noted school nurses do not take much interest in diagnosing TB and do not refer them to hospitals for further evaluation when they present with TB symptoms. Furthermore, adolescents reported cross-cutting issues like loss of trust in public health systems, encountering unfriendly, judgmental and uncooperative health workers. Health workers mentioned the school environment exposes adolescents to TB as the dormitories they sleep in are overcrowded. They indicated that it was difficult to make a diagnosis of TB in adolescents as the adolescents do not disclose health information. They reported fellow health workers perceive adolescents as being at low risk of TB as they believe most often adolescents are HIV negative and thus have reduced risk of TB. CONCLUSION: Adolescents present unique challenges that need to be addressed if TB diagnosis is to improve. These challenges could be handled by interventions that lead to minimal disruptions on school schedules, provision of adolescent-friendly services and intervention to build capacity of health care workers in the provision of adolescent-friendly services.

Strategies for the prevention, diagnosis and treatment of COPD in low- and middle- income countries: the importance of primary care.

INTRODUCTION: Low- and middle-income countries (LMICs) bear a high proportion of the global morbidity and mortality caused by COPD. Increased exposure to risk factors throughout life (e.g. malnutrition, indoor and outdoor air pollution, and smoking) is associated with higher COPD prevalence in LMICs and the lack of treatment availability increases avoidable harm. AREAS COVERED: This review covers the epidemiology and burden of COPD in LMICs, and challenges and recommendations related to health-care systems, prevention, diagnosis, and treatment. Main challenges are related to under-resourced health-care systems (such as limited availability of spirometry, rehabilitation, and medicines). Lack of policy and practical local guidelines on COPD diagnosis and management further contribute to the low diagnostic and treatment rates. In the absence of, or limited number of respiratory specialists, primary care practitioners (general practitioners, nurses, pharmacists, physiotherapists, and community health workers) play an even more pivotal role in COPD management in LMICs. EXPERT OPINION: Raising awareness on COPD, educating health-care workers, patients, and communities on cost-effective preventive measures as well as improving availability, affordability and proper use of diagnostic and pharmacological and non-pharmacologic treatment in primary care are the key interventions needed to improve COPD prevention, diagnosis, and care in LMICs.

Undernutrition and Treatment Success in Drug-Resistant Tuberculosis in Uganda.

BACKGROUND: Undernutrition is associated with unfavourable treatment outcomes among people with drug-resistant tuberculosis (DRTB). Factors influencing the treatment outcomes among undernourished people with DRTB are not well characterised. The aim of this study was to determine factors associated with treatment success among undernourished people with DRTB in Uganda. METHODS: We analysed data from a retrospective cohort of people with DRTB from 16 treatment sites in Uganda. We included participants with a pre-treatment body mass index (BMI) of <18.5 kilograms/meters2 (kg/m2). Participants were categorised as having mild (BMI of 18.5-17 kg/m2), moderate (BMI of 16.9-16.0 kg/m2) or severe (BMI of <16.0 kg/m2) undernutrition. We performed logistic regression analysis to determine factors associated with treatment success. RESULTS: Among 473 people with DRTB, 276 (58.4%) were undernourished (BMI < 18.5 Kg/m2) and were included in the study. Of these, 92 (33.3%) had mild, 69 (25.0%) had moderate and 115 (41.7%) had severe undernutrition. The overall treatment success rate (TSR) for the undernourished was 71.4% (n = 197). Although the TSR was similar among participants with mild (71.7%), moderate (78.3%) and severe (67.0%) undernutrition (p = 0.258), all treatment failure cases (n =6) were among participants with severe undernutrition (p = 0.010). Cigarette smoking (odds ratio (OR) = 0.19, 95% CI 0.07-0.47, p < 0.001), urban residence (OR = 0.31, 95% CI 0.14-0.70, p = 0.005) and moderate (OR = 0.14, 95% CI 0.06-0.35, p < 0.001) and severe anaemia (OR = 0.06, 95% CI 0.01-0.29, p = 0.001) were associated with lower odds of treatment success. CONCLUSION: Most undernourished people with DRTB have severe undernutrition. Smoking and anaemia are modifiable factors which upon appropriate intervention could improve treatment success. The effect of urban residence on the TSR needs to be evaluated further.

Chronic obstructive pulmonary disease prevalence and associated factors in an urban HIV clinic in a low income country.

INTRODUCTION: In the last decade, survival of people living with HIV (PLHIV) has dramatically increased due wide availability of effective antiretroviral therapy. However, PLHIV remain at a comparatively higher risk of non-communicable comorbidities. We sought to determine the burden of COPD and its associations in an urban tertiary HIV clinic in Uganda. METHODS AND FINDINGS: HIV-infected adults attending the Makerere University Joint AIDS program; aged ≥30 years without acute ailments were screened for COPD using study questionnaires and spirometry (post-bronchodilator FEV1/FVC<0.7). We determined its prevalence and association with demographic characteristics, body mass index (BMI) and known risk factors. Of 288 participants enrolled, 177 (61%) were female; 253 (88%) were from urban residences, median age was 45 years (IQR: 39-51), 71(25%) were 'ever' smokers, 284(99%) reported biomass fuel use and 72(25%) had a history of tuberculosis. All except 1 participant were on antiretroviral therapy, median current CD4 (cells/mm3) was 558 (IQR 402-753) and 275(96%) were virologically suppressed. Nearly half (130/288, 45%) had recurrent respiratory symptoms. The prevalence of COPD was 3.1% (9/288) [95% CI: 1.63-5.92]. COPD was associated with: previous tuberculosis, (adjusted odds ratio (AOR): 6.36, [95% CI 1.64-35.84], P = 0.036), self-reported chronic shortness of breath (AOR: 9.06, [95% CI 1.34-61.10], P = 0.024) and a BMI <21 Kg/m2 (AOR: 10.42 [95% CI: 1.61-100.00], P = 0.013). CONCLUSION: In this HIV population, COPD prevalence was low and was associated with previous tuberculosis, self-reported chronic shortness of breath and BMI <21 Kg/m2.

Challenges in the Implementation of Chronic Obstructive Pulmonary Disease Guidelines in Low- and Middle-Income Countries: An Official American Thoracic Society Workshop Report.

There is a substantial burden of chronic respiratory diseases, including chronic obstructive pulmonary disease (COPD), in low- and middle-income countries (LMICs). LMICs have particular challenges in delivering cost-effective prevention, diagnosis, and management of COPD. Optimal care can be supported by effective implementation of guidelines. This American Thoracic Society workshop considered challenges to implementation of COPD guidelines in LMICs. We make 10 specific recommendations: 1) relevant organizations should provide LMIC-specific COPD management guidance; 2) patient and professional organizations must persuade policy-makers of the importance of lung function testing programs in LMICs; 3) healthcare education and training should emphasize the early-life origins of COPD; 4) urgent action is required by governments to reduce airborne exposures, including exposures to tobacco smoke and indoor and outdoor air pollution; 5) guidance for COPD in LMICs should explicitly link across Essential Medicine Lists and the World Health Organization package of essential noncommunicable disease interventions for primary health care in low-resource settings and should consider availability, affordability, sustainability, and cost-effective use of medicines; 6) the pharmaceutical industry should work to make effective COPD and tobacco-dependence medicines globally accessible and affordable; 7) implementation of locally adapted, cost-effective pulmonary rehabilitation programs should be an international priority; 8) the World Health Organization Global Action Plan for the Prevention and Control of Noncommunicable Diseases should specify how improvements in respiratory health will be achieved; 9) research funders should increase the proportion of funding allocated to COPD in LMICs; and 10) the respiratory community should leverage the skills and enthusiasm of earlier-career clinicians and researchers to improve global respiratory health.

Latent Tuberculosis Infection Status of Pregnant Women in Uganda Determined Using QuantiFERON TB Gold-Plus.

BACKGROUND: The risk of progression of latent tuberculosis infection (LTBI) to active disease increases with pregnancy. This study determined the prevalence and risk factors associated with LTBI among pregnant women in Uganda. METHODS: We enrolled 261 pregnant women, irrespective of gestational age. Participants who had known or suspected active tuberculosis (TB) on the basis of clinical evaluation or who had recently received treatment for TB were excluded. LTBI was defined as an interferon-γ concentration ≥0.35 IU/mL (calculated as either TB1 [eliciting CD4+ T-cell responses] or TB2 [eliciting CD8+ T-cell responses] antigen minus nil) using QuantiFERON TB Gold-Plus (QFT-plus) assay. RESULTS: LTBI prevalence was 37.9% (n = 99) (95% confidence interval [CI], 32.3-44.0). However, 24 (9.2%) subjects had indeterminate QFT-plus results. Among participants with LTBI, TB1 and TB2 alone were positive in 11 (11.1%) and 18 (18.2%) participants, respectively. In multivariable analysis, human immunodeficiency virus (HIV) infection (adjusted odds ratio [aOR], 4.4 [95% confidence interval {CI}, 1.1-18.0]; P = .04) and age 30-39 years (aOR, 4.0 [95% CI, 1.2-12.7]; P = .02) were independently associated with LTBI. Meanwhile, smoking status, alcohol use, nature of residence, crowding index, and TB contact were not associated with LTBI. CONCLUSIONS: Our findings are in keeping with the evidence that HIV infection and advancing age are important risk factors for LTBI in pregnancy. In our setting, we recommend routine screening for LTBI and TB preventive therapy among eligible pregnant women.

Effectiveness of low-dose theophylline for the management of biomass-associated COPD (LODOT-BCOPD): study protocol for a randomized controlled trial.

BACKGROUND: COPD is a leading cause of death globally, with the majority of morbidity and mortality occurring in low- and middle-income country (LMIC) settings. While tobacco-smoke exposure is the most important risk factor for COPD in high-income settings, household air pollution from biomass smoke combustion is a leading risk factor for COPD in LMICs. Despite the high burden of biomass smoke-related COPD, few studies have evaluated the efficacy of pharmacotherapy in this context. Currently recommended inhaler-based therapy for COPD is neither available nor affordable in most resource-limited settings. Low-dose theophylline is an oral, once-a-day therapy, long used in high-income countries (HICs), which has been proposed for the management of COPD in LMICs in the absence of inhaled steroids and/or bronchodilators. The Low-dose Theophylline for the Management of Biomass-Associated COPD (LODOT-BCOPD) trial investigates the clinical efficacy and cost-effectiveness of low-dose theophylline for the management of biomass-related COPD in a low-income setting. METHODS: LODOT-BCOPD is a randomized, double-blind, placebo-controlled trial to test the efficacy of low-dose theophylline in improving respiratory symptoms in 110 participants with moderate to severe COPD in Central Uganda. The inclusion criteria are as follows: (1) age 40 to 80 years, (2) full-time resident of the study area, (3) daily biomass exposure, (4) post-bronchodilator FEV1/FVC below the 5th percentile of the Global Lung Initiative mixed ethnic reference population, and (5) GOLD Grade B-D COPD. Participants will be randomly assigned to receive once daily low-dose theophylline (200 mg ER, Unicontin-E) or placebo for 52 weeks. All participants will receive education about self-management of COPD and rescue salbutamol inhalers. We will measure health status using the St. George's Respiratory Questionnaire (SGRQ) and quality of life using the EuroQol-5D (EQ-5D) at baseline and every 6 months. In addition, we will assess household air pollution levels, serum inflammatory biomarkers (fibrinogen, hs-CRP), and theophylline levels at baseline, 1 month, and 6 months. The primary outcome is change in SGRQ score at 12 months. Lastly, we will assess the cost-effectiveness of the intervention by calculating quality-adjusted life years (QALYs) from the EQ-5D. TRIAL REGISTRATION: ClinicalTrials.gov  NCT03984188 . Registered on June 12, 2019 TRIAL ACRONYM: Low-dose Theophylline for the Management of Biomass-Associated COPD (LODOT-BCOPD).