Serum TNF-α and the future of biomarker-enhanced prognostication in bronchiectasis: An Indian perspective
Year: 2025
Type: article
Abstract: Bronchiectasis (BE) has emerged as a major chronic respiratory disease in India and across Asia, characterised by significant heterogeneity in aetiology, microbiology, and clinical course. Importantly, this profile differs markedly from the Western cohorts in which widely used prognostic tools such as the Bronchiectasis Severity Index (BSI) and FACED score were developed.[1,2] A study published in this issue of Lung India by Ramachandaran et al. concludes that serum tumour necrosis factor-alpha (TNF-α) levels are a potential biomarker for assessing BE severity, with elevated levels linked to exacerbations, microbial colonisation, and severe disease presentations, underscoring its clinical relevance in guiding prognosis and management strategies.[3] The study offers valuable early insights into biomarker-based risk stratification and disease behaviour in India. Although BSI and FACED remain the most validated prognostic systems globally, their precision in predicting outcomes in Indian populations remains unclear. The derivation cohorts for these scores predominantly included older European patients, where aetiologies such as idiopathic disease, post-infective BE, and immune deficiency were common.[4] In contrast, Indian populations demonstrate a distinctly different clinical spectrum, with post-tuberculosis BE as a leading cause and with younger patients, divergent microbiology, and variable access to specialist care due to socioeconomic barriers.[1,5] Data from the Indian arm of the EMBARC registry reinforce these differences, suggesting that the predictive performance of these scores may vary locally and may benefit from supplementation with biologically relevant markers.[2] Analysis of the EMBARC data further showed that the BSI was more valid than FACED in the Indian cohort of BE. This raises the question of whether biomarkers are needed to enhance prognostication in BE. Given the disease’s heterogeneity, it is unlikely that clinical scoring tools alone can comprehensively capture disease biology. The latest 2025 European Respiratory Society guidelines advocate for the use of severity scoring tools to identify patients most likely to experience complications.[6] However, due to the limitations of the scoring tools and potential misclassification of patients leading to under- or overtreatment, the guidance opines that these scores be employed to guide clinicians towards more intensive monitoring and management.[6] Asian and Indian expert consensus has increasingly emphasised the need for biomarkers that reflect inflammatory activity, microbial interactions, and disease trajectory, particularly in low- and middle-income settings where diverse phenotypes coexist and standardised care pathways may be inconsistent.[1,7] TNF-α is a central cytokine in neutrophilic inflammation, a hallmark of BE pathogenesis. It is produced by macrophages, epithelial cells, and neutrophils and plays a key role in amplifying airway inflammation, promoting tissue injury, and perpetuating the cycle of infection and structural damage.[8] Several studies have demonstrated elevated TNF-α levels in severe BE, especially during exacerbations and in patients with higher bacterial loads.[9] Recently, sputum and serum inflammatory markers have been shown to identify molecular endotypes in patients with stable BE that are associated with distinct microbiome profiles and future exacerbation risk.[10] Evidence regarding TNF-α in BE remains limited globally, and even more so in India. Much of the available cytokine-based literature originates from European and East Asian cohorts with markedly different aetiological profiles.[11] This makes Indian studies particularly important as biomarker behaviour may vary in populations where post-TB and environmentally driven disease predominate. Reviews focussed on Asian disease patterns consistently highlight the critical gap in biomarker research and the need for region-specific validation.[1] How does TNF-α compare with other biomarkers? Multiple candidates—such as IL-8, CRP, fibrinogen, neutrophil elastase, proteinase e, cathepsin G and S, serum procalcitonin, sputum microbiome signatures, and calprotectin—have been explored.[11,12] Among these, neutrophil elastase remains the strongest predictor of exacerbations and disease progression. Due to the extensive role of neutrophilic inflammation in the pathogenesis and progression of BE, neutrophil serine proteases currently present as promising, treatment-responsive biomarkers in the disease.[12] TNF-α is less extensively validated and exhibits greater biological variability. Nevertheless, its central role in inflammation provides a rationale for further exploration, especially in combination with other markers. Immunomodulatory effects of procalcitonin induce an inflammatory cascade, particularly involving TNF-α.[13] A pertinent question is whether TNF-α could be integrated into existing prognostic tools such as BSI or FACED. Conceptually, biomarker-enhanced scoring systems are attractive but require rigorous multi-centre evidence demonstrating incremental predictive benefit. Existing Indian registry platforms, such as EMBARC-India, offer ideal infrastructure for such validation studies.[14] At this stage, available evidence does not support modifying BSI or FACED, but TNF-α may well serve as a supplementary parameter in future hybrid models combining clinical and biological data. However, the specificity of TNF-α must be interpreted carefully as it may be elevated in co-existing inflammatory or infectious conditions that are not uncommon in Indian settings. Perhaps the greatest promise of TNF-α lies in its potential contribution to precision medicine. Identifying patients with heightened inflammatory activity could enable targeted intensification of therapy—ranging from airway clearance strategies and antimicrobial regimens to potential anti-inflammatory approaches. Lessons from asthma management in LMIC settings show that biomarker-guided stratification can help optimise resource utilisation and improve outcomes.[15] If validated prospectively, TNF-α could help identify patients with more aggressive disease trajectories and guide closer follow-up or tailored therapeutic interventions, while addressing India’s diagnostic inequities. In conclusion, the present study is an important early contribution towards understanding inflammatory biomarkers in Indian BE. While preliminary, it highlights the need for systematic biomarker research and offers a platform for future work. TNF-α should not yet be incorporated into prognostic scoring systems but could evolve into a meaningful component of precision-based care as evidence matures. Strengthening multi-centre collaborations and embedding biomarker research within national registries like EMBARC-India will be essential steps towards improving BE prognostication in India. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
Source: Lung India
Authors: Raja Dhar, Parvaiz A. Koul
Institution: Sher-i-Kashmir Institute of Medical Sciences
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7117648470