Sepsis is a serious worldwide health concern, especially in developing countries. Sepsis, by definition, is severe and fatal organ failure caused by the body's reaction to an infection that it cannot control [1]. Globally, sepsis accounts for an estimated 48.9 million cases and 11 million deaths annually, representing 19.7% of all fatalities worldwide. Furthermore, data analysis across 109 million individual death records underscores the substantial global burden of the condition [2]. Purba et al. reported a case fatality rate among patients receiving treatment in intensive care units of 69% [3]. The mortality rate for severe sepsis and septic shock can range from 25% to 70%, making early identification imperative [4]. The elevated death rate underscores the importance of early identification to promptly and correctly commence therapy. Given the central role of platelet activation and consumption in sepsis-induced coagulopathy, biomarkers reflecting real-time thrombopoietic activity may provide additional diagnostic value. The immature platelet fraction (IPF), which reflects increased bone marrow platelet release in response to peripheral consumption, represents a readily available hematological parameter that might complement existing sepsis biomarkers [5]. However, the diagnostic performance of the IPF for early sepsis identification has not been systematically evaluated.

Timely identification of sepsis necessitates an integration of clinical assessment and laboratory indicators. Frequently employed measures encompass procalcitonin (PCT), C-reactive protein (CRP), lactate, and a complete blood count [6,7]. PCT serves as a measure for systemic bacterial infection, CRP signifies an acute inflammatory response, and lactate reflects tissue hypoperfusion. Nevertheless, the use of these parameters has constraints: PCT and CRP lack specificity for coagulation activity. The platelet count alone indicates the quantity of platelets and does not represent the activity of bone marrow production. All these indicators remain of low efficacy in preventing multiorgan dysfunction syndrome resulting from sepsis. This syndrome is initiated by persistent microcirculatory abnormalities, which ultimately lead to death [8–10].

Among the numerous mechanisms contributing to microcirculatory disorders, dysfunctions in the coagulation system are pivotal in sepsis-induced organ damage [11]. Despite the contentious nature of microthrombi in sepsis, microvascular alterations may transpire even in the absence of evident thrombotic occurrences [12]. The severity of a patient's condition may deteriorate when systemic inflammation triggers coagulation factors and platelets [13]. This highlights the necessity of including coagulation indicators within the laboratory assessment for sepsis diagnosis [5].

Sepsis triggers Tumor Necrosis Factor-alpha (TNF-α), interleukin(IL)-1β, and IL-6 as inflammatory mediators, which activate the vascular endothelium [14]. The activation of endothelial cells leads to the release of tissue factors that trigger the coagulation cascade, resulting in the formation of microthrombi and the consumption of significant quantities of platelets, frequently culminating in disseminated intravascular coagulation. The reduction in platelet count prompts the bone marrow to enhance thrombopoiesis and release an IPF into the bloodstream, resulting in an elevated intravascular platelet count [14,15]. A high IPF value in sepsis signifies that thrombocytopenia results from platelet consumption or destruction, with bone marrow function remaining intact. In contrast, a low IPF shows a failure in bone marrow production.

The IPF is the percentage of reticulated platelets that still contain residual RNA from megakaryocyte formation and is a direct indicator of thrombopoietic activity in the bone marrow [16,17]. IPF testing may be conducted automatically with fluorescence flow cytometry alongside a complete blood count. The benefit of the IPF compared to other metrics is in its capacity to identify alterations in platelet production at an early stage, prior to a substantial decline in total platelet count, hence serving as a biomarker for the early detection of thrombocytopenia in sepsis [18].

Numerous studies indicate that the IPF has great diagnostic accuracy for the early identification of sepsis [19–27]. The results for diagnostic testing are still pending for some individuals; therefore, this study seeks to ascertain the definitive outcomes. However, existing evidence includes both adult and pediatric populations, which may influence diagnostic performance due to age-related hematological differences. This study sought to evaluate the diagnostic precision of IPF testing for the early identification of sepsis. This is, to our knowledge, the first systematic review and meta-analysis addressing this problem.

This meta-analysis demonstrates that the IPF holds considerable promise as a complementary biomarker for sepsis detection in mixed adult and pediatric populations. The IPF exhibited a sensitivity of 74% and a specificity of 70%. These results indicate a moderate diagnostic capacity for both identifying the condition and ruling out health in suspected cases. Clinically, this indicates that the IPF is dependable as an initial screening instrument, although not strong enough to serve as the sole test for diagnostic confirmation. These findings offer the first indication that the IPF might serve as a pertinent supplementary test, particularly when utilized with other known metrics such as PCT and CRP levels.

These findings align with literature reporting that the IPF is increased in sepsis patients due to stimulation of megakaryocytes in the bone marrow in response to platelet destruction and consumption during systemic inflammation [16]. The activation of the inflammatory response, mainly via the production of pro-inflammatory cytokines like IL-6 and TNF-α, stimulates expedited platelet maturation, leading to a notable rise in the quantity of immature platelets discharged into the bloodstream [14,15]. This situation indicates the body's compensatory efforts to maintain hemostasis while simultaneously signaling an ongoing severe inflammatory process.

In the adult population subgroup analysis, without the research on pediatric patients, sensitivity rose to 85% and specificity to 68%. This heightened sensitivity indicates that the IPF may be more effective in identifying sepsis in adult patients than in the pediatric group. The pathophysiological explanation lies in the stability of the adult hematopoietic system, which regularly reveals an increase in immature platelet formation in response to sepsis [30]. In pediatrics, physiological variability in platelet production, the development of the immune system, and varying hematopoietic responses might affect the IPF levels even without infection, hence diminishing diagnostic accuracy [30].

This finding aligns with previous reports that other inflammatory biomarkers, such as PCT and CRP, also show differences in diagnostic performance across age groups [31]. Physiological PCT levels exhibit variations across age groups, with healthy pediatric individuals presenting higher levels than healthy adults, although healthy newborns have the lowest levels. The variations in baseline levels may affect the interpretation of PCT values in sepsis diagnosis, indicating that the appropriate cut-off may differ between age groups [31]. Likewise, CRP levels may be increased owing to non-infectious reasons in young patients, including vaccinations or minor inflammatory conditions. CRP levels may rise substantially post-vaccination, with up to 85% of preterm newborns exhibiting an increase, and adults experiencing an average elevation of around 30% following influenza vaccination. This indicates that an elevation in CRP does not invariably signify infection, particularly during the post-immunization phase [32,33]. This meta-analysis aligns with many studies indicating that the IPF was considerably elevated in septic patients exhibiting neutrophilia compared to non-septic controls [34,35]. The IPF could distinguish thrombocytopenia resulting from peripheral damage (e.g., in sepsis) from thrombocytopenia caused by bone marrow hypoproduction [36–39].

Sepsis triggers massive immune system activation accompanied by activation of the coagulation system [40]. A crucial mechanism is the production of microthrombi resulting from disseminated intravascular coagulation or subclinical coagulation events. This disease markedly elevates platelet consumption. Consequently, the bone marrow enhances thrombopoiesis, characterized by the discharge of immature platelets (platelet reticulocytes) into the bloodstream [40,41]. The IPF, measured by fluorescent flow cytometry on modern hematology analyzers, reflects the proportion of immature platelets in the blood and is a direct indicator of thrombopoietic activity [42].

From a clinical standpoint, the IPF offers numerous advantages: it is readily accessible and can be concurrently measured with a complete blood count on most contemporary hematology instruments; it is expeditious, yielding results within minutes, thereby facilitating prompt clinical decision-making in emergency departments or intensive care units; and it is non-invasive, negating the necessity for additional blood sampling [37]. Consequently, the data of the present study suggest that the IPF should be included in a sepsis diagnostic panel rather than utilized as an independent test. Integrating the IPF with PCT, CRP, or a clinical score like the quick Sequential Organ Failure Assessment (qSOFA) could enhance diagnostic precision and assist in patient risk stratification [23,43]. The interpretation of the IPF necessitates the evaluation of confounding circumstances, including acute bleeding, postoperative states, significant trauma, autoimmune diseases, and hematologic illnesses such as idiopathic thrombocytopenic purpura (ITP), all of which may elevate the IPF in the absence of sepsis [44]. Conversely, decreased bone marrow production resulting from chemotherapy, certain viral infections, or dietary deficits might lower the IPF count. In pediatrics, characteristics such as hematopoietic maturation, comorbidities, and nutritional conditions may further influence this value [45,46].

Several limitations must be acknowledged. The number of papers fulfilling the inclusion criteria was small (n = 3), resulting in a low strength of evidence. Secondly, discrepancies in research design, sepsis definitions, IPF measurement techniques, and applied cutoffs may affect the heterogeneity of the findings. Third, two of the three studies were observational, and subgroup analyses were constrained since just one study investigated a pediatric population, rendering adult-pediatric comparisons exploratory.

This meta-analysis should be interpreted with caution as the small number of included studies may reduce the precision of pooled estimates and limit generalizability. Additionally, heterogeneity may arise from differences in sepsis definitions, patient age groups, hematology analyzers, IPF measurement techniques, and applied cut-off values. Consequently, the data of this study suggest that the IPF should be included in a sepsis diagnostic panel rather than utilized as an independent test. This complementary role is consistent with the intended use of the IPF as an adjunct to established biomarkers and clinical assessment rather than a replacement. Further research should highlight the need for future standardization of IPF measurement, including harmonization of analytical platforms, calibration procedures, and clinically validated cut-off values. Establishing standardized protocols is essential to facilitate broader clinical implementation and improve the reliability of the IPF as a diagnostic adjunct in sepsis. Research should encompass a fair representation of pediatric and adult populations to elucidate variations in diagnostic performance attributable to age. Assessing the interplay of the IPF with additional biomarkers in multivariate predictive models may enhance its application in comprehensive diagnostic algorithms.

The IPF may serve as a complementary diagnostic biomarker for sepsis due to its rapid availability and integration into routine hematological testing. However, the limited number of studies and methodological heterogeneity warrant cautious interpretation. Future large-scale prospective studies using standardized sepsis definitions, IPF measurement techniques, and validated cut-off values are needed to confirm its clinical utility.

Conceptualization: SW, IPYP; Data curation: IBAPM, IGPS; Formal analysis: SW, IPYP; Investigation: IBAPM, IGPS; Methodology: IBAPM, IGPS, AAWL; Resources: SW, IPYP; Software: IBAPM, IGPS; Supervision: AAWL; Validation: IBAPM, IGPS, AAWL; Visualization: IBAPM, IGPS, AAWL; Writing–original draft: SW, IPYP; Writing–review & editing: all authors. All authors read and approved the final manuscript.

The data that support the findings of this study are available from the corresponding author upon reasonable request.