Open research questions in Tuberculosis Research and Epidemiology

What the literature leaves open

• ABSTRACT The serine/threonine protein kinase F (PknF) of Mycobacterium tuberculosis (Mtb) has poorly defined targets and functions but is involved in limiting NLRP3 inflammasome activation in murine macrophages and dendritic cells in vitro .

  Protein kinase F regulates the virulence of <i>Mycobacterium tuberculosis</i> · 2026 · DOI

• Overall, these results highlight mNGS as a valuable supplementary tool for challenging TB cases, especially when conventional tests are inconclusive, and provide strong evidence for integrating it into diagnostic algorithms to optimize clinical decision-making and resource allocation.

  Metagenomic next-generation sequencing for tuberculosis diagnosis: enhanced performance and cost-effectiveness · 2026 · DOI

• Addressing gaps in the literature and developing targeted interventions may thereby better guide health- care providers and policymakers in efforts to improve treatment adherence among patients with TB worldwide. There could be further research into whether peer support groups or community- based interventions improve adherence.

  Determinants of treatment adherence in children and adolescents for tuberculosis: a study from Pakistan · 2026 · DOI

• Mbarara, Kabale, and Fort Portal Regional Referral Hospitals should strengthen integrated TB and HIV services by ensuring routine HIV management, counselling, nutritional assessment, and psychosocial support are provided alongside MDR-TB treatment. This will address the multiple physical and psychological challenges experienced by patients. Health facilities managing MDR-TB patients should incorporate quality of life assessments into routine care to identify patients experiencing difficulties with physical functioning, mental health, social relationships, and financial challenges. Early identification will allow timely referral for appropriate support. MDR-TB programmes should establish structured counselling services, peer-support groups, and family support interventions to address stigma, emotional distress, social isolation, and reduced self-confidence among patients.

  Quality of Life among Multidrug-Resistant Tuberculosis Patients in Southwestern Uganda · 2026 · DOI

• The care pathway in the analysis includes the standard course of antibiotics and associated nursing and hospitalisation costs but does not account for variations in care or post-TB care should patients fail to respond to treatment or relapse.

  A micro-costing analysis of tuberculosis care in England: a bottom-up evaluation of treatment and service delivery costs · 2026 · DOI

• should focus on titled “Estimation of Cost-Effectiveness and Turnaround Time (TAT) of the TB-LAMP Assay Compared with TrueNat and Conventional Methods” to address these limitations and assess practical utility in resource-limited settings.

  Validation of the loop-mediated isothermal amplification compared with real-time micro-PCR and conventional methods for the detection of pulmonary tuberculosis · 2026 · DOI

• Laboratory studies show that mycobacteria utilize host lipid stores at the cellular level, but it remains unclear how—or whether—these cellular events are consistently mirrored in serum lipid panels (29). Lipid measurements were performed at a single time point near diagnosis, so we could not assess longitudi- nal trends or recovery-related changes. reported mixed findings: some document poorer out- comes in NTM, while others do not observe a differ- ence (30-32). A similar, though weaker, trend was observed for tri- glyceride levels in survival analyses; however, its biological plausibility and clinical relevance remain uncertain. Further pro- spective studies with longitudinal assessments and comprehensive adjustment for nutritional and meta- bolic factors are warranted to clarify the clinical rel- evance of lipid-inflammation interactions in TB.

  The relationship between lipid biomarkers, inflammation and mortality in patients with tuberculosis · 2026 · DOI

• Previous studies in mice have shown that stimulating type I interferon (IFN) signaling during BCG vaccination can bolster protection against Mycobacterium tuberculosis, yet clinically feasible delivery strategies for this approach are lacking.

  Replication-deficient Adenovirus 5 Serotypes Induce Type I Interferon and enhance BCG-mediated Immune Response in Co-infected Murine Macrophages · 2026 · DOI

• Future research is recommended to use prospective cohort designs to further investigate the causal relationship between malnutrition and TB drug resistance, as well as to evaluate the effectiveness of nutritional supplementation interventions in reducing resistance rates among malnourished TB patients.

  Analysis of Risk Factors for Comorbidities in Tuberculosis Patients and Resistance Patterns of Mycobacterium Tuberculosis at Gunung Jati Regional Hospital · 2026 · DOI

• Given the supporting role of TRM in early control of Mtb infection (24), this trend warrants further investigation with larger sample sizes to assess TRM persistence and functional capacity.

  Immunogenicity and protective potential of a mucosal protein-only vaccine candidate for tuberculosis · 2026 · DOI

• While oxidative stress is a hallmark of the host-pathogen interface, the deliberate use of reactive oxygen and nitrogen species (RONS) to modulate antigen immunogenicity remains underexplored.

  Oxidative modifications of tuberculosis antigen Ag85B alter its T cell antigenicity · 2026 · DOI

• The bioinformatic thresholds that distinguish low-frequency variants from sequencing noise vary widely across published TB studies and are rarely empirically justified, thus reshaping which patients are reported as harboring detectable within-host diversity.

  Replicate-anchored calibration of within-host single nucleotide variant detection in Mycobacterium tuberculosis whole genome sequencing · 2026 · DOI

• We report two cases of active pulmonary TB developing despite negative baseline screening, highlighting nutritional vulnerability and crowded living environments as underrecognized contributing factors.

  Pulmonary tuberculosis and nutritional vulnerability during anti-tumor necrosis factor therapy for inflammatory bowel disease: Two case reports · 2026 · DOI

• Measurements and Main ResultsDepending on the target used, projected clinical doses varied widely--both within and across compounds--highlighting the importance of target selection for dose projection and go/no-go decisions.

  Establishing a framework for human dose prediction in anti-tuberculosis drug development · 2026 · DOI

• Background: Despite rising enthusiasm for active case-finding for TB, there have been concerns about conducting simultaneous HIV screenings due to perceived stigma, although the evidence to support this concern is scarce.

  Unmet demand, not reluctance: integrated HIV tuberculosis community screening is highly acceptable in socioeconomically vulnerable adults in South India · 2026 · DOI

• Ethambutol (EMB) is a vital drug for treating Mycobacterium avium-intracellulare (MAI) infections; however, the genomic mutations underlying EMB resistance in MAI remain unclear.

  Analysis of publicly available genomic data · 2026 · DOI

• (NEB, The sequencing libraries were multiplexed and loaded on the flowcell on the Illumina NovaSeq X Plus instrument according to the manufacturer’s instructions.

  Mycobacterium tuberculosis VadK is required for the regulation of the methylcitrate cycle and virulence · 2026 · DOI

• Although the exact mechanism of growth inhibition remains unknown, propionate toxicity is correlated with reduced flux through the TCA, reduced energy production and inhibition of the PPP in Mtb (Dolan et al, 2018; Eoh and Rhee, 2014).

  Mycobacterium tuberculosis VadK is required for the regulation of the methylcitrate cycle and virulence · 2026 · DOI

• Brigden G, Nyang’wa BT, du Cros P, Varaine F, Hughes J, Rich ML. Principles for designing future regimens for multidrug-resistant tuberculosis. Bull World Health Organ, 2014; 92: 68–74. guidelines on tuberculosis. Module 5: Management of drug-resistant tuberculosis. Geneva: WHO., 2023. 4. Tostmann A, Boeree MJ, Aarnoutse RE, de Lange der Ven AJ, Dekhuijzen R.

  ADVERSE DRUG REACTIONS IN LONG-DURATION ANTI-TUBERCULAR THERAPY: RISK FACTORS, CLINICAL MANIFESTATIONS, AND MANAGEMENT · 2026 · DOI

• This study recommends that future research be conducted with larger sample sizes and a multicenter approach to better represent the diverse populations affected by PTB. Additional data can also be collected to further characterize patients with PTB. A randomized controlled trial is suggested to more definitively establish a causal relationship between HRQOL and treatment outcomes. Additionally, conducting a pre- and post- treatment HRQOL analysis can help evaluate the impact of successful PTB treatment on patients’ HRQOL. Given the observed association between the physical and psychological dimensions of HRQOL and treatment outcomes, we advocate the integration of additional support services aimed at improving these aspects during TB treatment. Such interventions would be particularly beneficial for patients with low baseline HRQOL. Furthermore, since a low level of education was found to significantly impact psychological well-being, we recommend implementing targeted health education campaigns and community programs to enhance health literacy and reduce stigma related to PTB. Lastly, we propose long-term follow-up assessments of HRQOL even after treatment completion, to identify ongoing challenges and to inform the development of sustained support strategies for PTB survivors. CONCLUSIONS This study highlights that better physical and psychological well-being are associated with favorable treatment outcomes. Improving HRQOL, particularly these domains, may contribute to more successful treatment outcomes for PTB patients. The analyzed sociodemographic characteristics have a limited association with HRQOL, underscoring the multifaceted nature of HRQOL and the importance of addressing not only clinical but also non-clinical factors, such as psychological support, socioeconomic conditions, education, and social support, to achieve comprehensive improvements in the well-being of patients undergoing treatment for PTB.

  Health-Related Quality of Life and Sociodemographic Factors as Predictors of Treatment Outcomes in Pulmonary Tuberculosis Patients in a Tertiary Hospital in Cebu City · 2026 · DOI

• Healthcare providers at Tuberculosis (TB) clinics should adopt integrated clinical management protocols that combine TB and HIV care with nutritional support. Regular screening for malnutrition, co-morbidities, and advanced disease stages should be incorporated into clinical workflows. This includes training healthcare workers on the importance of nutritional interventions as part of holistic TB care. Implication to Theory, Practice and Policy The clinical factors such as advanced TB disease stage, HIV co-infection, and under-nutrition supports theories where the disease–nutrition interaction model, which states that infections contribute to malnutrition while malnutrition weakens immune response hence worsening disease progression. This study finding points out the important of incorporating regular assessment of nutritional status into TB protocols. The study recommends screening for HIV and other co-morbidities early and consistently, monitoring of patients with advanced TB disease closely for nutritional decline, counseling into TB treatment plans. Finding of this study may contribute to formulation of policies to promote collaboration between TB programs, HIV programs, and nutrition services to ensure continuity of care. 65 Journal of Health, Medicine and Nursing ISSN 2520-4025 (Online) Vol.12, Issue 2. No.5, pp 54 – 68, 2026 www.iprjb.org REFERENCES Adane, H. T., Howe, R. C., Wassie, L., & Magee, M. J. (2023). Diabetes mellitus is associated with an increased risk of unsuccessful treatment outcomes among drugsusceptible tuberculosis patients in Ethiopia: A prospective health facility-based study. Journal of Clinical Tuberculosis and Other Mycobacterial Diseases, 31, 100368. https://doi.org/10.1016/j.jctube.2023.100368 Atake, E.-H. (2023). Health system productivity in sub-Saharan Africa: tuberculosis control in high burden countries. Cost Effectiveness and Resource Allocation, 21(1), 90. https://doi.org/10.1186/s12962-023-00485-1 Burusie, A., Enquesilassie, F., Salazar-Austin, N., & Addissie, A. (2024). The magnitude of unfavorable tuberculosis treatment outcomes and their relation with baseline undernutrition and sustained undernutrition among children receiving tuberculosis treatment in central Ethiopia. Heliyon, 10(6), e28040. https://doi.org/10.1016/j.heliyon.2024.e28040 CDC. (2016). Tuberculosis Adverse Events During Treatment.

  Clinical Factors Associated with Under-Nutrition among Adult Tuberculosis Patients in Nairobi County, Kenya · 2026 · DOI

• This study was limited by its sample size and the reliance on a prov- ince-specific dataset, which may not be representative of the broader population. The isolates were obtained from a defined clinical reposi- tory, introducing potential sampling bias and limiting the ability to infer prevalence at the population level. Furthermore, a substantial propor- tion of isolates were excluded from the final analysis due to duplication, contamination, and loss of viability during subculture. These exclusions may have introduced selection bias, as the analyzed dataset may not be fully representative of the original sample population. Clinical outcome data were not available to correlate MIC and genotypic results with treat- ment success or failure. Additionally, socio-economic and adherence factors that may influence resistance development were not assessed. Despite these limitations, the findings provide valuable insights into the BDQ resistance landscape in Limpopo and highlight the importance of robust population-level surveillance to detect and circumvent resistance.

  Bedaquiline resistance-associated genetic mutations and minimum inhibitory concentrations in drug-resistant tuberculosis clinical isolates from Limpopo province, South Africa · 2026 · DOI

• This study has several limitations inherent to descriptive cross-sectional designs. Recall bias may have affected guardian responses, given the 3-year study period. Selection bias is possible due to convenience sampling of health care providers, which limits representativeness. Self-reported data may be subject to social desirability bias. Moreover, the study was conducted in 5 diagnostic centers within Kabondo Dianda and may not reflect practices in other health zones. Despite these limitations, exhaustive sampling of guardians and inclusion of all active health care providers strengthen internal validity.

  Knowledge, Perceptions, and Practices Regarding Pediatric Tuberculosis: Cross-Sectional Study Among Guardians and Health Care Providers in Kabondo Dianda Health Zone, Democratic Republic of the Congo · 2026 · DOI

• Although individuals who seroconverted during follow-up showed particularly high odds of recurrence, this estimate should be interpreted with caution due to the small size of this subgroup (n = 88) and warrants further investigation.

  The role of neighborhood factors in the cumulative number of episodes of recurrent tuberculosis in Cape Town · 2026 · DOI

• longer follow-up, active emphasize screening, and addressing social issues such as overcrowding and poverty to reduce exposure risks. The analysis of TB data in London from 2002 to 2015 shows that 1.4% of TB cases were due to relapse, while 3.8% were from reinfection. Relapse rates dropped from 2.3% in 2002 to 1.3% in 2015, while reinfection rates stayed stable around 4% each year. Risk factors for relapse include recent migration, social issues like homelessness, and specific health conditions.

  Tuberculosis recurrence rates in various World Health Organization regions from 2010 to 2023 · 2026 · DOI

Most-cited papers in Tuberculosis Research and Epidemiology

• The Social Determinants of Tuberculosis: From Evidence to Action · American Journal of Public Health · 2011 · 421 citations
• Tuberculosis and Stigmatization: Pathways and Interventions · Public Health Reports · 2010 · 362 citations
• Global burden of chronic pulmonary aspergillosis as a sequel to pulmonary tuberculosis · Bulletin of the World Health Organization · 2011 · 344 citations
• Trends in tuberculosis incidence and their determinants in 134 countries · Bulletin of the World Health Organization · 2009 · 247 citations
• Antibiotic resistance prediction for Mycobacterium tuberculosis from genome sequence data with Mykrobe · Wellcome Open Research · 2019 · 187 citations
• Global Epidemiology of Tuberculosis and Progress Toward Meeting Global Targets — Worldwide, 2018 · MMWR Morbidity and Mortality Weekly Report · 2020 · 173 citations
• Maternal and perinatal mortality and morbidity associated with tuberculosis during pregnancy and the postpartum period: a systematic review and meta‐analysis · BJOG An International Journal of Obstetrics & Gynaecology · 2016 · 134 citations
• Updates on the Treatment of Drug-Susceptible and Drug-Resistant Tuberculosis: An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline · American Journal of Respiratory and Critical Care Medicine · 2024 · 122 citations
• Tuberculosis in times of COVID-19 · Journal of Epidemiology & Community Health · 2021 · 115 citations
• Global, regional, and national age-specific progress towards the 2020 milestones of the WHO End TB Strategy: a systematic analysis for the Global Burden of Disease Study 2021 · The Lancet Infectious Diseases · 2024 · 111 citations

Most recent work

• High-throughput characterization of Mycobacterium tuberculosis gene function across diverse conditions · PLOS Biology · 2026
• Development of a Rapid Automated Point-of-Care Test for Mycobacterium tuberculosis Detection from Tongue Swabs and Sputum Specimens on the DASH(R) Rapid PCR System · medRxiv · 2026
• The role of neighborhood factors in the cumulative number of episodes of recurrent tuberculosis in Cape Town · Journal of Clinical Tuberculosis and Other Mycobacterial Diseases · 2026
• Expanding Xpert MTB/RIF Ultra and lateral flow urine lipoarabinomannan testing for diagnosis of tuberculosis among adults living with HIV admitted to hospitals in Tanzania and Mozambique (EXULTANT): a randomised controlled trial · The Lancet Infectious Diseases · 2026
• Tyloxapol inhibits ESX-1 secretion in <i>Mycobacterium marinum</i> · Journal of Bacteriology · 2026
• Estimating tuberculosis-related patient costs in KwaZulu-Natal, South Africa · medRxiv · 2026
• A single mycobacterial ligand organizes multi-receptor signaling to reprogram macrophage lipid metabolism · bioRxiv · 2026
• Immortal genome assumption significantly underestimates replication and death rates of Mycobacterium tuberculosis in mice and monkeys · bioRxiv · 2026
• Strong sustained type I IFN signaling acts cell intrinsically to impair IFNγ responses and cause tuberculosis susceptibility · bioRxiv · 2026
• Benchmarking within-sample minority variant detection with short-read sequencing in M. tuberculosis · bioRxiv · 2026

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