Asthma is a chronic respiratory disease characterized by airway inflammation and reversible airflow obstruction (1), affects over 300 million individuals worldwide and imposes a substantial burden on healthcare systems. Asthma is typically managed with a stepwise approach centered on anti-inflammatory therapy, especially inhaled corticosteroids (ICS) (2), For patients with more severe disease, additional treatments such as long-acting β₂-agonists (LABAs), leukotriene receptor antagonists (LTRAs), or biologic agents may be used (3). However, therapeutic optimization depends on timely and accurate diagnosis, which remains a challenge, highlighting the need for reliable biomarkers. Traditional diagnostic methods, such as spirometry, are useful for assessing airflow limitation but are not effective for early detection or predicting the occurrence of asthma, particularly when symptoms are not yet evident (4), underscoring the urgent need for accessible, cost-effective biomarkers to guide clinical decision-making.

The neutrophil-to-lymphocyte ratio (NLR), a simple and cost-effective marker of systemic inflammation, has emerged as a candidate biomarker for asthma (5). NLR reflects the interplay between neutrophilic and lymphocytic immune pathways-key drivers of asthma heterogeneity (6). While preliminary studies suggest elevated NLR correlates with asthma severity and exacerbations (7, 8), existing evidence is limited by methodological inconsistencies, insufficient exploration of confounding factors (e.g., age, geographic disparities), and a lack of standardized thresholds for clinical application.

This systematic review and meta-analysis aims to compare NLR levels between asthma patients and healthy controls, and to examine its variation across subgroups stratified by asthma severity. Additionally, we will investigate how demographic factors such as age and geographic region influence NLR differences. By synthesizing existing evidence, our findings aim to bridge critical knowledge gaps, offering insights for integrating NLR into standardized diagnostic frameworks to enhance precision in asthma management.

A systematic literature search was conducted in PubMed, EmBase, and the Cochrane Library following PRISMA guidelines. The initial search identified 378 relevant publications. After duplicate removal (n = 21), 357 articles were further evaluated based on title and abstract screening, 321 articles were excluded. Full texts evaluation was conducted for remaining 36 articles, with 5 excluded due to the lack of a control group and 12 excluded for not meeting inclusion criteria. Finally, 19 studies were included in the meta-analysis (Figure 1).

This systematic review and meta-analysis evaluated the NLR as a biomarker reflecting systemic inflammation in asthma and its association with disease severity. Our findings demonstrate that NLR levels are significantly higher in asthma patients compared to healthy controls, with marked differences between severe and non-severe asthma groups. Notably, NLR effectively distinguished mild from moderate asthma, and showed a trend toward significance when comparing mild and severe asthma. However, the difference between moderate and severe asthma did not reach statistical significance.

These results align with previous meta-analyses by Huang et al (27) and Tahseen et al (28), who reported elevated NLR levels in asthma patients, particularly during exacerbations and in severe cases. Huang et al., however, included only six studies and focused primarily on acute exacerbations, while Tahseen et al. found significantly higher NLR levels in severe asthma compared to non-severe cases, suggesting a possible association between NLR and asthma severity. However, both studies were limited by small sample sizes and lacked detailed stratification across multiple severity levels.

The elevated NLR observed in asthma patients, particularly those with severe asthma, can be understood through the pathophysiology of disease. Asthma is characterized by chronic airway inflammation involving both neutrophils and lymphocytes (29, 30). Neutrophils, typically responsible for the innate immune response against infections, are often elevated in the airways of patients with asthma (31, 32). Their accumulation contributes to persistent inflammation, tissue injury, and airway remodeling—features that correlate with increased disease severity. Conversely, lymphocytes mediate allergic responses and adaptive immunity (33). An elevated NLR reflects a shift toward neutrophilic dominance and systemic inflammation, potentially serving as a surrogate marker for asthma severity and immune dysregulation. This pathophysiological relationship is supported by our ROC analysis, which demonstrated high diagnostic performance of NLR in distinguishing asthma patients from healthy controls (AUC = 0.929) and severe asthma from non-severe asthma (AUC = 0.914). However, the lower accuracy observed when differentiating mild from moderate asthma (AUC = 0.800) suggests that NLR may be less sensitive to subtle inflammatory changes in less advanced disease stages. This discrepancy may be attributed to overlapping inflammatory phenotypes in these stages (34), especially in patients with established airway remodeling or chronic neutrophilic burden. Additionally, relatively limited number of direct comparisons may have reduced the statistical power to detect subtle differences.

Subgroup analyses revealed significant geographic and age-related disparities in NLR levels Asthma patients in developed countries exhibited larger NLR differences compared to controls than those in developing regions, likely due to higher detection of severe phenotypes, greater environmental pollutant exposure (e.g., PM2.5), and improved healthcare access (35, 36). Conversely, underdiagnosis and limited treatment in developing areas may attenuate NLR elevations. Age stratification showed pediatric patients had markedly higher NLR differences than adults, potentially reflecting immature immune regulation favoring neutrophilic inflammation. Adults’ lower NLR differences may result from long-term anti-inflammatory therapy or adaptive immune modulation (16, 37). High heterogeneity across subgroups (I² > 97%) underscores the influence of individual and environmental confounders. In addition to geographic and age-related factors, the variability in how asthma severity was defined across the included studies may also have contributed to the observed heterogeneity. Although all studies applied objective or guideline-based criteria, such as pulmonary function (FEV₁%), FeNO levels, bronchial provocation tests, reversibility testing, or adherence to GINA guidelines, there was no single unified standard across studies. Nonetheless, the consistent use of standardized clinical tools ensures a reasonable level of comparability and supports the validity of the pooled findings.

Several biomarkers have been integrated into clinical practice to guide treatment decisions in asthma, particularly in patients with severe or treatment-resistant disease. Among these, blood eosinophils, serum IgE, fractional exhaled nitric oxide (FeNO), and periostin are the most established and widely used, especially in identifying type 2 (T2)-high phenotypes that may benefit from corticosteroids or biologic therapies (38, 39). However, these biomarkers have limitations, including variable availability, higher cost, and limited utility in certain asthma phenotypes, such as those with non-eosinophilic or mixed inflammatory patterns. In this context, there is growing interest in identifying practical, affordable, and broadly applicable biomarkers to support individualized asthma management.

The NLR, derived from routine blood tests, has been proposed as an accessible marker of systemic inflammation. Although not specific to asthma, our meta-analysis demonstrates a consistent association between elevated NLR and greater disease severity. While this study did not stratify patients by inflammatory endotype, these findings support the potential utility of NLR as a supplementary tool, particularly in settings where conventional biomarkers are unavailable or less informative.

Despite these efforts, several limitations should be acknowledged. First, the overall heterogeneity observed in the pooled analyses was substantial, which may affect the generalizability of the findings. While we employed a random-effects model and conducted subgroup and sensitivity analyses to explore potential sources, residual variability likely remains. Second, although NLR levels increased with asthma severity, its ability to clearly differentiate between moderate and severe asthma stages was limited, suggesting that NLR alone may not fully capture nuanced inflammatory changes across disease progression. Third, most of the included studies were retrospective in design, introducing potential selection and information biases and underscoring the need for future prospective studies to validate and refine the clinical applicability of NLR in asthma management.

This systematic review and meta-analysis confirms that the NLR is elevated in asthma patients compared to healthy controls, with levels increasing alongside disease severity. Subgroup analyses revealed more pronounced NLR differences in pediatric populations and studies from developed countries. While NLR effectively distinguished asthma and severe cases, its ability to differentiate between moderate and severe asthma was limited. These findings support the potential role of NLR as a biomarker for asthma identification and severity stratification. Future prospective studies are needed to validate standardized thresholds and to explore its combined use with other indicators for improved precision across all severity stages.