Sepsis is a serious global public health concern as almost 50 million patients suffer from sepsis each year, leading to 11 million deaths worldwide annually, with an overwhelmingly high proportion of deaths being in low- and middle-income countries.1 Despite significant improvements in early identification and protocolized management of sepsis, risk stratification remains problematic. While biomarkers such as lactate and procalcitonin (PCT) have increased diagnostic accuracy, their unavailability and limited applicability have prompted a resurgence of interest in simple hematological parameters such as neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR), and monocyte–lymphocyte ratio (MLR). The study by Deokate et al. provides additional evidence on this topic, showing the association of high NLR and MLR values with extended hospital stays and necessity for intubation in the intensive care unit (ICU), as well as the role of NLR as a predictor for mortality (area under receiver-operating characteristic curve = 0.797).2 This study is consistent with other evidence available on this issue, but it raises a more general problem: Is it possible to utilize simple and available biomarkers to improve prognosis in septic patients? BIOLOGICAL RATIONALE: INTEGRATING INNATE AND ADAPTIVE IMMUNITY Physiopathological factors that underlie the ratios used in this study include interactions between innate and adaptive immunity during sepsis. While neutrophilia occurs early in innate immune system activation, lymphopenia reflects immune cell exhaustion and impaired adaptive immunity due to immune system activation, apoptosis, and depletion.3 Accordingly, NLR is a combination of these factors that can be considered a summary parameter characterizing immune dysregulation. High levels of NLR have been repeatedly linked with increased severity of the disease, organ dysfunction, and mortality, among other outcomes in different ICUs and cohorts.4,5 Moreover, monocytes serve as mediators involved in presenting antigens and modulating cytokine production. Consequently, MLR can represent immune dysregulation associated with ongoing inflammation and imbalance between the two arms of the immune response.6 Platelets have usually been known as mediators of coagulation and hemostasis. Still, recent studies show that platelets play a role in inflammation and interactions with endothelial cells. Therefore, PLR can be characterized as a link between inflammation and thrombosis.7 Nevertheless, the prognostic value of this ratio was inconsistent as well. CLINICAL INTERPRETATION: SIGNAL VERSUS NOISE Though the biological plausibility of hematological ratios cannot be overstated, their use in the clinical setting is still complex. As reported by Deokate et al., NLR and MLR are positively correlated with extended hospitalization and need for mechanical ventilation, factors that point to the seriousness of the condition and increased resource utilization.2 Nonetheless, no significant correlation was found between NLR and MLR and survival status when categorized. Recent literature further refines this perspective, highlighting the role of dynamic assessment and integrative modeling to provide a comprehensive view of the evolving and dynamic biomarker ecosystem associated with sepsis. Increasing evidence supports the idea that hematologic ratios should not be evaluated in isolation, but rather as part of the dynamic biomarker ecosystem associated with sepsis. Emerging data suggest that the NLR is independently associated with mortality in different ICU populations,8 and that there is consistent correlation between increased NLR values and increased risk of death and organ dysfunction. In addition, studies have shown that early NLR thresholds (e.g., >10–11) are reasonably accurate in predicting hospital mortality, with reported area under curve (AUCs) as high as approximately 0.88 for certain patient cohorts.9 These data support the hypothesis that the NLR may serve as an early warning biomarker, particularly during the initial hyper-inflammatory phase of sepsis. Hematological ratio show superior prognostic capabilities compared to static thresholds. Serial assessment studies have shown that declining NLR values within the first 72 h are associated with better outcomes, whereas persistently elevated or rising trends indicate ongoing immune dysregulation and poor response to treatment.10 The dynamic nature of this relationship correlates with established biomarkers, such as PCT and lactate, supporting the inclusion of NLR into a longitudinal monitoring approach. Importantly, recent investigations have explored the integration of hematological ratios into composite predictive models, demonstrating that combining NLR with clinical scores for example, sequential organ failure assessment (SOFA) and biochemical markers significantly enhances prognostic accuracy, with some models achieving AUC values exceeding 0.90.11 Such approaches align with the broader movement toward multimodal and data-driven risk stratification in critical care. Recent studies have begun to know that how to include hematological ratios in composite predictive models. For example, combining NLR with clinical scores (such as the SOFA score) or with biochemical markers to enhance prognostic accuracy can result in AUC values >0.90.11 These approaches are consistent with a general movement toward multimodal and data-driven risk stratification in the ICU. However, heterogeneity of both cutoff values and study populations presents an obstacle to clinical translation. Reported NLR cutoffs can vary widely; for example, lower cut-offs of 3.5 may be used for patients with severe sepsis, and higher cut-offs of 18 are used for mortality prediction.12 Therefore, there is a need for standardisation and context-specific validation. Until consensus is reached, hematological ratios should be viewed as adjuncts to existing clinical judgement and scoring systems. The inconsistency described above brings attention to the main flaw– static biomarkers can miss the dynamics of sepsis. There are indications that time-related changes, particularly those observed in NLR, give more accurate data on patient outcomes. Thus, continuously increasing or elevated NLR during the first 48–72 h can predict worse prognosis, whereas decreasing values mean better outcomes.13 In addition, only moderate discriminative power (~0.79 AUC) emphasizes that hematological ratios are too weak to predict patient outcomes individually. Traditional scoring systems, such as the SOFA score, include several physiological parameters and show higher predictive accuracy.14 Nonetheless, combining hematological ratios with other parameters will increase the prediction’s reliability. Combining the NLR with other clinical indicators and lactate, researchers were able to achieve better discrimination capacity compared to individual variables.15 STRENGTHS AND LIMITATIONS OF CURRENT EVIDENCE The study carried out by Deokate et al. has a number of strengths, among them being the prospective design, clinically relevant endpoints, and the use of biomarkers that are easily obtainable.2 These characteristics give the study applicability in practical settings, especially in resource-limited circumstances. Nevertheless, there are some weaknesses that should be considered. The one-centre design reduces the applicability of the study, whereas the lack of repeated measurements does not allow insight into the temporal changes in biomarker levels. Moreover, various factors like the presence of comorbidities, origin of the infection, and previous treatment could have confounded the results. Most importantly, there is no comparison made between hematological ratios and other biomarkers such as PCT and interleukin-6. Such a weakness stems from the problem that most studies exhibit in relation to differences in methodology, population, and cutoff levels. RELEVANCE TO GLOBAL CRITICAL CARE PRACTICE The key advantage of hematological ratios comes from their universal availability and applicability. As opposed to expensive and complicated biomarker analysis or genomic evaluation, hematological ratios calculated using complete blood count data are accessible, cheap, and quickly obtained. These features make hematological ratios especially relevant for low-resource countries, where the burden of sepsis is significant. Here, NLR, together with other ratios, may act as an early marker of potential problems, which will trigger increased vigilance. Moreover, the incorporation of hematological ratios into the routine practice does not require any additional equipment. Nonetheless, the issue of overreliance should be mentioned. Namely, the use of hematological ratio as a single marker for decision-making is inappropriate and even dangerous. FUTURE DIRECTIONS: FROM ASSOCIATION TO IMPLEMENTATION The following issues need to be considered to achieve the full potential of hematological ratios: The use of dynamic assessment: Studies should concentrate on serial evaluation and trajectory analysis, which would more accurately capture changes in host physiology during sepsis Setting consensus cut-off values: Great variation between different cut-offs makes these results difficult to apply in practice, and standard cut-offs should be set according to population and disease severity Use of hematological ratios in predictive models: Using these ratios together with scoring systems, biomarker results, and advanced algorithms will provide a better prediction of outcome Multicenter study design: A large cohort of diverse patients is crucial for validation and confirmation of results obtained in smaller cohorts Understanding underlying biology: Understanding of the association between hematological ratios and biological processes will increase their utility. CONCLUSION The findings of the study serve as another reminder of the mounting evidence that simple hematological ratios are capable of offering relevant information on the complicated immunopathogenesis of sepsis. Although their diagnostic accuracy is limited, their easy availability and biological plausibility render them significant complements to the current management of septic patients. As precision medicine becomes more prominent in our modern world and costly tests continue to dominate our healthcare system, we must remember the importance of basic laboratory indicators. Instead of asking ourselves whether these tests should be used, we need to consider how they can best be incorporated into our current practices. This is what could be achieved by combining the advantages of simple and sophisticated tests in hematological ratios.
Gupta et al. (Wed,) studied this question.