Tuberculosis (TB) remains a major global health problem, with 8.2 million new and relapse cases notified worldwide in 2023, representing an increase from 7.5 million cases in 2022 and the highest number recorded since global TB surveillance began [1]. Older adults represent an important population in TB because ageing is accompanied by immunological and physiological changes that increase susceptibility to infectious diseases. Immunosenescence and inflammaging may impair the ability of the host immune system to control Mycobacterium tuberculosis (MTB), while age-related decline in respiratory function, including impaired mucociliary clearance and cough reflex, may further compromise pulmonary defense mechanisms. These changes are frequently accompanied by multimorbidity and reduced physiological reserve, potentially influencing the clinical course and host response to TB [1-3].

                Ageing and active TB are both associated with increased cellular stress, inflammation, and disturbances in redox homeostasis. Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine that has been associated with cellular injury, inflammation, metabolic dysfunction, and ageing. Its circulating concentration increases in several chronic conditions and has recently been shown to be elevated among mobility-limited older adults with frailty and sarcopenia, supporting its potential role   as  a marker of systemic biological stress in geriatric

populations. In patients with TB, GDF-15 has also been investigated as a marker of systemic stress with recent evidence demonstrating an association between baseline GDF-15 concentrations and subsequent haemoglobin reduction during linezolid-containing treatment for rifampicin-resistant TB. These findings suggest that GDF-15 may reflect host responses to cellular and inflammatory stress in TB, although its relationship with the extent of pulmonary disease remains uncertain [4,5].

        Oxidative stress is also an important component of the host response to TB. Inflammatory processes and activated macrophages can generate reactive oxygen species, while inadequate nutritional intake and systemic illness may further compromise antioxidant defenses. Total Antioxidant Capacity (TAC) provides an integrated measure of the ability of circulating antioxidants to counteract oxidative stress. Previous research demonstrated that total antioxidant levels were significantly lower in patients with active TB than in community controls and increased during anti-tuberculosis therapy, suggesting an association between systemic antioxidant status and active TB. However, TAC is influenced by multiple factors, including nutritional status, age, dietary intake, and comorbidities, and therefore may not directly reflect oxidative processes occurring within infected pulmonary tissue. In geriatric patients, the interaction between age-related oxidative imbalance and TB-related inflammation may therefore be particularly relevant when evaluating potential biomarkers of disease burden [6,7]

        However, whether circulating GDF-15 and TAC are associated with these different dimensions of disease burden in geriatric patients with active pulmonary TB remains unclear. Because GDF-15 reflects systemic cellular stress and TAC represents systemic antioxidant capacity, evaluating their relationship with both microbiological and radiographic disease burden may provide insight into the interaction between ageing, host response, oxidative balance, and pulmonary TB. Therefore, this study aimed to determine the association of GDF-15 and TAC levels with microbiological and radiographic disease burden in geriatric patients with active pulmonary TB.

Study Design and Settings

This cross-sectional study was conducted at RSUD Raden Mattaher Jambi, Indonesia, from September 2025 to February 2026. The study included geriatric patients aged ≥60 years with newly diagnosed, drug-susceptible active pulmonary tuberculosis. The study assessed the association of GDF-15 and TAC concentrations with microbiological and radiological disease burden in geriatric patients.

        The study was conducted in accordance with the principles of the Declaration of Helsinki. Ethical approval was obtained from the Ethics Committee of Universitas YARSI, Indonesia (Ethical Approval No. 377/KEP-UY/EA.10/X/2025). Written informed consent was obtained from all participants prior to their participation in the study.

Data Collection

Participants were eligible if they were aged ≥60 years according to the Indonesian Ministry of Health definition of older adults, had newly diagnosed drug-susceptible pulmonary tuberculosis confirmed by molecular testing and radiological examination, had initiated anti-tuberculosis treatment (ATT) within ≤7 days before enrollment, and had not received antioxidant supplementation.

        Patients were excluded if they had a previous history of pulmonary tuberculosis, extrapulmonary tuberculosis, baseline plasma calcium >2.6 mmol/L, creatinine >250, or aspartate aminotransferase levels >3 times the upper limit of normal; end-stage kidney disease; active malignancy; corticosteroid use within the preceding 30 days; current use of cytotoxic or immunosuppressive medications; multidrug-resistant tuberculosis; malabsorption syndrome; or refusal to participate.

        Blood samples were obtained at baseline for measurement of GDF-15 and TAC. GDF-15 concentration was measured in serum or plasma using a validated enzyme-linked immunosorbent assay (ELISA) according to the manufacturer's instructions and was expressed in pg/mL or ng/mL. TAC was assessed in serum or plasma using a validated colorimetric or ELISA-based assay according to the manufacturer's instructions, with results expressed in mmol/L or µmol Trolox equivalents.

        Molecular testing was performed using the GeneXpert MTB assay, which detects MTB genetic material and provides simultaneous information regarding drug resistance. Microbiological disease burden was categorized according to the semi-quantitative GeneXpert MTB results as trace, very low, low, medium, or high. Radiological assessment was performed primarily using standard posteroanterior (PA) chest radiography. Additional radiographic projections or computed tomography were performed when clinically indicated. Radiological disease burden was categorized according to the extent of pulmonary involvement as minimal, moderate, or extensive.

Statistical Analysis

Data were recorded using a standardized data collection form and analyzed using SPSS version 30.0 (IBM Corp., Armonk, NY, USA). Continuous variables were assessed for distribution and presented as mean ± standard deviation or median and interquartile range, as appropriate. Categorical variables were summarized as frequencies and percentages. Differences in GDF-15 and TAC concentrations across microbiological and radiological disease-burden categories were assessed using appropriate parametric or non-parametric statistical tests based on data distribution. Statistical significance was defined as a two-sided p value <0.05.

A total of 40 patients diagnosed with TB were included in this study. The median age of participants was 66 years (IQR 63–69), with a predominance of males (35; 87.5%) compared     with    females    (5; 12.5%).    The  overall demographic, microbiological, radiographical, and biomarker characteristics of the study population are summarised in Table 1.

Table 1: Characteristics of Participants

Abbreviations, IQR: Interquartile Range, WBC: White Blood Cell, GDF-15: Growth Differentiation Factor 15, TAC: Total Antioxidant Capacity

        Based on microbiological disease burden assessed using GeneXpert MTB, the majority of participants had a low bacterial burden (18; 45.0%), followed by high burden (10; 25.0%), medium burden (6; 15.0%), trace burden (4; 10.0%), and very low burden (2; 5.0%). Regarding radiographic disease burden on chest X-ray, more than half of the participants had extensive disease (22; 55.0%), while 9 (22.5%) had minimal and 9 (22.5%) had moderate radiographic involvement.

        Table 2 presents the comparison of WBC count, GDF-15 levels, and TAC according to microbiological burden based on GeneXpert MTB results. The median WBC count showed a decreasing trend across the microbiological burden categories, from 12.04 in the Trace group to 7.67 in the High group; however, this difference was not statistically significant (p = 0.205). Similarly, median GDF-15 levels varied across the groups, ranging from 406.72 in the Trace group to 476.36 in the Very Low group, with no statistically significant difference among groups (p = 0.873). Median TAC levels also varied across microbiological burden categories, ranging from 14.82 in the Medium group to 21.82 in the Very Low group, but the difference was not statistically significant (p = 0.570). Overall, neither GDF-15 nor TAC demonstrated a significant difference across the Gene pert MTB microbiological burden categories.

Table 2: WBC, GDF-15, and Total Antioxidant Capacity According to Microbiological Burden

*Kruskal-Wallis, #IQR was not calculated because only two observations were available. Abbreviations, WBC: White Blood Cell, GDF-15: Growth Differentiation Factor 15, TAC: Total Antioxidant Capacity

        As shown in Table 3, there were no statistically significant differences in WBC, GDF-15, or TAC levels across the categories of radiographic disease burden on chest X-ray. Median WBC counts were 7.46 (5.94–10.02) in the minimal group, 6.44 (5.80–10.64) in the moderate group, and 8.96 (8.05–9.82) in the extensive group (p = 0.120). Similarly, median GDF-15 levels were 484.66 (367.52–699.05), 394.55 (363.02–519.97), and 441.83 (403.19–596.80) in the minimal, moderate, and extensive groups, respectively (p = 0.386). Median TAC levels were 13.88 (8.14–20.57) in the minimal group, 18.31 (16.37–29.72) in the moderate group, and 17.21 (13.56–22.82) in the extensive group (p = 0.207). Thus, neither GDF-15 nor TAC demonstrated a significant association with radiographic disease burden in this population of geriatric patients with active pulmonary tuberculosis.

Table 3: WBC, GDF-15, and TAC Levels According to Radiographic Disease Burden on Chest X-Ray

*Kruskal-Wallis. Abbreviations, WBC: White Blood Cell, GDF-15: Growth Differentiation Factor 15, TAC: Total Antioxidant Capacity

This study evaluated the association of circulating GDF-15 and total antioxidant capacity (TAC) with microbiological and radiographic disease burden in geriatric patients with active pulmonary tuberculosis. The principal finding was that neither GDF-15 nor TAC differed significantly across microbiological disease-burden categories based on semi-quantitative GeneXpert results. Similarly, no significant differences were observed across radiographic disease-burden categories. Specifically, GDF-15 and TAC were not significantly associated with microbiological burden (p=0.873 and p=0.570, respectively), or with radiographic burden (p=0.386 and p=0.207, respectively). These findings suggest that, although GDF-15 and TAC reflect important aspects of systemic stress and host redox biology, their circulating concentrations at a single time point may not adequately represent the extent of pulmonary tuberculosis burden in older adults. Similar investigations in other respiratory infections have demonstrated that disease severity may be associated with alterations in circulating hematological and biochemical parameters. For instance, a study of patients with COVID-19 reported significant associations between disease severity and neutrophil count, lymphocyte count, C-reactive protein, D-dimer, and ferritin, highlighting the relevance of systemic laboratory markers in assessing infectious disease severity [8].

        The absence of an association between GDF-15 and disease burden may be explained by the biological characteristics of this cytokine. GDF-15 is a stress-responsive member of the transforming growth factor-β superfamily and is induced by cellular stress, inflammation, infection, mitochondrial dysfunction and tissue injury. Rather than being specific to tuberculosis or microbial load, GDF-15 represents a broader systemic response to physiological and pathological stress. Its biological effects are also context-dependent, with evidence suggesting roles in immune regulation, tissue tolerance and modulation of inflammatory responses. Therefore, an elevated or variable GDF-15 concentration does not necessarily indicate a greater mycobacterial burden. This interpretation is particularly relevant in the present geriatric population because GDF-15 concentrations increase with ageing and are associated with frailty, sarcopenia and declining physical function. Consequently, age-related cellular stress and geriatric conditions may contribute substantially to inter-individual variation in GDF-15 and potentially obscure its relationship with tuberculosis burden [4,9-11].

        The findings concerning TAC should also be interpreted within the broader biology of oxidative stress in tuberculosis. Active tuberculosis is characterized by increased production of reactive oxygen species as part of the host immune response, while nutritional deficiency, inflammation and disease-related metabolic alterations may simultaneously reduce antioxidant defenses. Previous research has demonstrated that total antioxidant status is significantly lower in patients with active tuberculosis than in community controls and increases during antituberculosis treatment. However, TAC represents the integrated antioxidant capacity of circulating plasma and is influenced by multiple factors, including dietary intake, micronutrient availability, enzymatic antioxidant activity, age and systemic metabolic conditions. Thus, a single TAC measurement may reflect overall systemic redox status rather than the intensity of oxidative stress occurring specifically within pulmonary lesions. This may explain why TAC was not significantly different across the microbiological or radiographic disease-burden categories in the present study [6,12].

        The lack of association with microbiological burden should also be considered in relation to the nature of the GeneXpert measurement. Semi-quantitative GeneXpert categories provide an indirect estimate of the amount of M. tuberculosis DNA detected in respiratory specimens, with categories ranging from trace and very low to low, medium and high; higher categories generally correspond to greater bacillary burden. However, microbiological burden and host-response biomarkers represent different biological dimensions of tuberculosis. GeneXpert primarily reflects the amount of detectable mycobacterial DNA in sputum, whereas GDF-15 reflects systemic cellular stress and TAC reflects systemic antioxidant capacity. Recent evidence also indicates that higher semi-quantitative GeneXpert categories are associated with greater microbiological positivity and other indicators of bacillary burden, supporting its use as a microbiological rather than host-response measure. Therefore, the absence of a correlation in the present study does not necessarily indicate that either biomarker lacks biological relevance; rather, it suggests that systemic host-response markers may not serve as direct surrogates for sputum bacillary burden [13-15].

        A similar explanation may apply to the absence of an association with radiographic disease burden. Chest radiography provides information about the anatomical and structural consequences of pulmonary tuberculosis, including the distribution and extent of pulmonary abnormalities, and remains an important component of TB evaluation. Radiographic severity, however, represents a different dimension of disease from circulating biomarkers. Pulmonary lesions may persist or progress as a consequence of cumulative tissue injury, granulomatous inflammation and cavitation, whereas circulating concentrations of GDF-15 and TAC may fluctuate according to systemic physiological conditions. Previous studies have demonstrated that radiographic extent and cavitary disease can be associated with higher sputum bacillary loads, but the relationship is not necessarily linear across all patients. Thus, radiographic burden and microbiological burden should not be regarded as interchangeable measures, and neither necessarily has to correspond closely with a systemic biomarker measured at a single time point [16-17].

        The geriatric characteristics of the study population may further contribute to the observed findings. Ageing is accompanied by immunosenescence, inflammaging, mitochondrial dysfunction and changes in antioxidant defenses, all of which can alter baseline concentrations of stress-related biomarkers independently of the severity of an acute infectious disease. Recent studies have shown that GDF-15 is consistently elevated in older adults with frailty and sarcopenia, although its diagnostic performance for individual geriatric conditions remains limited. A 2026 systematic review similarly concluded that GDF-15 is associated with frailty, functional decline and sarcopenia across diverse populations, while emphasizing substantial heterogeneity between studies and the influence of age-related factors [4,9-11,19].

        This study has several strengths. First, it specifically focused on geriatric patients with newly diagnosed, drug-susceptible active pulmonary tuberculosis, a population that is frequently underrepresented in biomarker studies despite having distinct age-related changes in immune, metabolic and antioxidant responses. Second, the study assessed two complementary dimensions of tuberculosis disease burden: microbiological burden using semi-quantitative GeneXpert results and radiographic burden using chest radiography. This allowed the relationships between systemic biomarkers and different manifestations of pulmonary disease to be examined simultaneously. Third, the study evaluated both GDF-15, a stress-responsive cytokine, and TAC, an integrated marker of systemic antioxidant capacity, providing complementary information on host cellular stress and redox status. These characteristics strengthen the biological relevance of the study and provide a basis for further investigation of host-response biomarkers in older adults with tuberculosis.

        Several limitations should also be considered when interpreting these findings. First, the sample size was relatively small (n = 40), and the distribution across microbiological categories was uneven, particularly in the trace and very-low GeneXpert groups. This may have limited the statistical power to detect modest associations. Second, the cross-sectional design allowed assessment of associations at diagnosis but did not permit evaluation of temporal changes or causal relationships between biomarker concentrations and tuberculosis disease progression. Third, GDF-15 and TAC were measured systemically in blood and may not directly reflect biological processes within pulmonary lesions. Fourth, GDF-15 and TAC can be influenced by factors other than tuberculosis, including ageing, frailty, nutritional status, metabolic conditions, inflammation and other comorbidities. Therefore, the absence of significant associations should be interpreted cautiously and should not be considered evidence that GDF-15 or TAC has no role in tuberculosis pathophysiology.

In geriatric patients with active pulmonary tuberculosis, circulating GDF-15 and total antioxidant capacity were not significantly associated with either microbiological disease burden assessed by semi-quantitative GeneXpert or radiographic disease burden assessed by chest radiography. These findings suggest that, at the time of diagnosis, GDF-15 and TAC may not serve as standalone surrogate biomarkers of pulmonary tuberculosis disease burden. Further longitudinal studies with larger sample sizes are warranted to determine whether changes in GDF-15 and TAC during antituberculosis treatment are associated with microbiological response, radiographic improvement, and clinical outcomes in older adults with tuberculosis.

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