Systemic inflammation and adjacent segment disease after lumbar fusion: the importance of biomarker timing

Ji et al. present an important and thoughtfully designed study addressing adjacent segment disease (ASD) after posterior lumbar interbody fusion (PLIF) through a multidimensional lens that integrates systemic inflammation, bone quality, paraspinal muscle degeneration, and postoperative mechanical factors (1). The strength of this work lies in its attempt to move beyond traditional demographic and radiographic predictors and toward an individualized, biologically informed risk model—an approach that aligns well with contemporary spine surgery practice and precision-based perioperative decision-making. The large cohort, detailed imaging analyses, and inclusion of modifiable factors such as muscle quality and bone density represent meaningful contributions to the ASD literature. Among the reported findings, the identification of the neutrophil-to-lymphocyte ratio (NLR) as an independent predictor of ASD is particularly intriguing, as it suggests a potential systemic and modifiable biological component to a complication traditionally viewed through a mechanical lens (1). However, the interpretation of NLR as a risk factor suitable for preoperative optimization warrants careful reconsideration based on the timing of biomarker acquisition relative to outcome definition.

Primary scientific concern: temporal misalignment of NLR measurement and ASD outcome

In the Methods section describing laboratory indicators, the authors state that blood tests were obtained during hospitalization for surgery and at postoperative follow-up, but that platelet, neutrophil, and lymphocyte counts recorded from the patients’ final follow-up test results were used to calculate NLR and systemic immune-inflammation index (SII) (1).

At the same time, ASD in this study is defined not solely by radiographic degeneration, but by new-onset back and/or leg pain with functional impairment in addition to imaging changes (1). This definition, while clinically meaningful, introduces an important temporal and causal ambiguity when inflammatory biomarkers measured at final follow-up are treated as antecedent risk factors. Specifically, elevated NLR at final follow-up may reasonably reflect a physiological response to ASD, rather than a predisposing condition that existed before ASD development.

From a biological and clinical standpoint, several pathways could explain this reverse directionality. Chronic pain and functional limitation are well recognized to be associated with persistent inflammatory activation and physical deconditioning. In the postoperative spine population, ongoing inflammatory processes related to pseudarthrosis, cage subsidence, or micromotion at the fusion site may further elevate systemic inflammatory markers. Importantly, cage subsidence and nonunion—both identified as significant predictors of ASD in the present study—are themselves known to contribute to chronic pain and inflammatory responses after lumbar fusion (1,2). In this context, a final-follow-up NLR may function more as a consequence or correlate of symptomatic ASD than as a true etiologic predictor.

This distinction is not semantic. The Discussion suggests that inflammatory optimization may represent a preventive strategy for ASD (1). Such a conclusion implicitly assumes that NLR elevation precedes ASD onset and is identifiable early enough to influence surgical planning, perioperative optimization, or postoperative surveillance. If, however, NLR elevation primarily reflects established ASD-related pathology, its clinical role would be limited to disease association or postoperative monitoring rather than prevention.

Biological plausibility does not overcome temporal bias

The concept that inflammation contributes to degenerative spinal pathology is biologically plausible and supported by prior work. However, plausibility alone does not establish predictive validity when exposure timing overlaps with or follows outcome development. In prognostic modeling, the temporal relationship between exposure and outcome is fundamental, particularly when the outcome definition includes symptomatic components that may themselves influence systemic inflammatory markers.

Methodological refinements that would strengthen clinical interpretability

The dataset presented by Ji et al. appears well suited to address this issue with feasible secondary analyses that would substantially strengthen the clinical relevance of their conclusions:

• Use of preoperative NLR values: if baseline laboratory data obtained during surgical hospitalization include preoperative counts, reanalysis using preoperative NLR would directly test whether systemic inflammation truly predicts future ASD (1).
• Landmark or time-to-event analysis: given the presence of postoperative mediators such as cage subsidence and nonunion, a time-to-event framework with landmark analysis would help distinguish baseline predictors from downstream consequences and reduce the risk of reverse causation (3).
• Sensitivity analysis using radiographic-only ASD: because the current ASD definition incorporates pain and functional impairment, an imaging-only endpoint could reduce circularity between inflammation-driven symptoms and inflammatory biomarkers (1).

Supporting clinical consideration: baseline adjacent segment degeneration

Extensive spine literature consistently identifies pre-existing adjacent segment degeneration as one of the strongest predictors of postoperative ASD after lumbar fusion (4,5). The absence of explicit grading or adjustment for baseline adjacent-level disc or facet degeneration raises the possibility that systemic markers such as NLR may partially act as proxies for underlying degenerative burden rather than independent biological risk factors. Incorporating baseline adjacent segment status into multivariable modeling or stratified analyses would further clarify the independent contribution of inflammatory biomarkers.

Implications for spine surgeons

The appeal of NLR lies in its simplicity, low cost, and theoretical modifiability. For spine surgeons, the key question is whether NLR can inform decisions before surgery—such as patient counseling, construct selection, bone health optimization, or postoperative surveillance intensity. Clarifying the temporal role of NLR would determine whether it belongs in the category of preoperative risk stratification tools or postoperative disease correlates.

Conclusions

Ji et al. should be commended for advancing a comprehensive and biologically informed framework for understanding ASD after lumbar fusion. Clarifying the timing and role of systemic inflammatory markers—particularly NLR—would significantly enhance the translational impact of this work and strengthen its implications for preventive spine surgery strategies. Addressing this issue through baseline or time-aware analyses would allow readers to better distinguish modifiable preoperative risk factors from postoperative disease consequences.

The authors’ contribution meaningfully enriches the ongoing discussion on individualized ASD prevention, and we appreciate the opportunity to engage constructively with this important study.

Acknowledgments

None

Footnote

Provenance and Peer Review: This article was a standard submission to the journal. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2026-1-0128/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

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