Diagnostic utility of leukocyte volume, conductivity, and scatter (VCS) parameters in febrile neutropenia among pediatric oncology patients: A prospective observational study

INTRODUCTION

Globally, approximately 400,000 children are diagnosed with cancer every year, while 76805 new cases of malignancy are estimated in India annually.^[1,2] Chemotherapy remains a cornerstone of pediatric cancer management but is frequently associated with prolonged neutropenia, predisposing patients to febrile neutropenia (FN), a medical emergency with a reported mortality of 2–13% varying based on prompt treatment versus delayed treatment.^[3-6] FN not only increases the risk of sepsis and multi-organ failure but also prolongs hospitalization, delays chemotherapy, and adds to treatment costs.

The Infectious Diseases Society of America (IDSA) defines FN as an oral or axillary temperature >38.3°C or two consecutive readings >38.0°C within 12 hours, lasting at least 1 hour, in the presence of an absolute neutrophil count (ANC) <500/mm³ or <1000/mm³ with an anticipated decline.^[7] Both hematological malignancies and solid tumors (e.g., high-risk neuroblastoma, osteosarcoma, Ewing sarcoma) carry FN risk, although incidence is higher in leukemia and post-hematopoietic stem cell transplant settings.^[8-10]

Blood cultures remain the diagnostic gold standard but have a positivity rate of only 10–20% in FN episodes.^[9-11] Common biomarkers such as C-reactive protein (CRP) and procalcitonin (PCT) demonstrate variable sensitivity and specificity and are influenced by non-infectious inflammatory conditions. Therefore, there is an unmet need for inexpensive, widely available, and rapid biomarkers to aid early diagnosis and therapeutic decision-making in FN.

Modern automated hematology analyzers, beyond enumerating blood cells, provide morphometric and structural data through volume, conductivity, and scatter (VCS) parameters, collectively termed cell population data (CPD).^[12-14] The Coulter LH system measures:

Volume (V): Via electrical impedance

Conductivity (C): Using radiofrequency opacity (reflecting nuclear-cytoplasmic ratio and internal composition)

Scatter (S): Based on laser light diffraction (indicative of granularity and cytoplasmic complexity)

Previous studies indicate that VCS parameters, particularly mean neutrophil volume (MNV), increase significantly in septic patients, even in those with leukopenia, and may outperform conventional markers like white blood cells (WBC) count, CRP, and PCT for early sepsis detection.^[15-18] However, data on their role in pediatric FN is limited.

MATERIAL AND METHODS

This was a prospective observational study carried out at a tertiary care cancer center affiliated with a medical teaching institution in North India. The study formed part of a postgraduate research project and received prior approval from the Institutional Research Committee (SRHU/HIMS/ETHICS/2025/81)

RESULTS

During the study period, 50 episodes of febrile neutropenia (FN) were recorded among 34 pediatric oncology patients. Of these, 29% (n = 10) occurred in children aged <5 years, 39% (n = 13) in those aged 6–10 years, and 32% (n = 12) in children >10 years. The study cohort comprised 61% males (n = 21) and 39% females (n = 13).

Blood culture positivity and VCS parameters

Among the 50 FN episodes, 28% (n = 14) yielded positive blood cultures, while 72% (n = 36) were sterile. The distribution of isolated organisms is illustrated in Figure 1.

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Figure 1:

Presents the spectrum of organisms identified in febrile neutropenia (FN) episodes that showed positive blood cultures

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When comparing VCS parameters between culture-positive and culture-negative cases, no statistically significant differences were observed. For instance MN-V-NE median was 169.50 (IQR: 152.75–180.50) in culture-positive cases versus 162.50 (IQR: 148.00–180.50) in sterile cases (P = 0.753). MN-C-NE medians were identical (145) in both groups (P = 0.829).

Predictive value of VCS parameters for FN

ROC curve analysis demonstrated that certain VCS parameters—particularly MN-V-NE, MN-V-MO, and MNC-MO—showed good predictive value for FN [Figure 2 and Table 2]. The predictive value of VCS parameters for culture-proven sepsis or outcome was not significant.

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Figure 2:

ROC curve- to determine predictive value of VCS parameters for febrile neutropenia. ROC: Receiver operating characteristics, VCS: Volume, conductivity, scatter, V-NE: Volume neutrophil, C-NE: Conductivity neutrophil, MALS: Mean axila light scatter, LMALS: Low-angle MALS, UMALS- Upper-angle MALS, LALS: Low-ngle light scatter, V-MO: Volume monocytes, C-MO: conductivity monocytes

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Table 2: VCS parameters ROC cut-off for FN episode

VCS Parameters	Cutoff	Sensitivity	Specificity	AUC	P Value
MN-V-NE	142.50	0.94	0.54	0.78	0.000
MN-V-MO	166.50	0.90	0.62	0.67	0.003
MN-C-MO	117.50	0.94	0.84	0.63	0.017

VCS: Volume, conductivity, scatter, ROC: Receiver operating characteristic, FN: Febrile neutropenia, MN-V-NE: Mean neutrophil volume, MN-V-MO: Mean monocyte volume, MN-C-MO: Mean monocyte conductivity, AUC: Area under curve, P value significance <0.05

DISCUSSION

This study evaluated changes in VCS parameters from baseline to the onset of febrile neutropenia (FN) in pediatric oncology patients. We observed a significant increase in mean neutrophil volume (MN-V-NE; p = 0.001), mean monocyte volume (MN-V-MO; p = 0.009), and mean monocyte conductivity (MN-C-MO; p = 0.028) during FN episodes. These findings suggest that specific VCS parameters, particularly those reflecting cellular volume and conductivity, may serve as early indicators of FN. Other parameters, including scatter-related metrics, did not demonstrate statistically significant changes, indicating limited diagnostic relevance in this context.

The potential diagnostic utility of VCS parameters in FN prediction has been previously suggested in the literature, though data remains scarce. Our results are consistent with the hypothesis that neutrophil and monocyte activation during infectious or inflammatory states contributes to changes in cell volume and conductivity, which are measurable through automated hematology analyzers.^[12,15,18]

When comparing blood culture-positive episodes to sterile cases, no statistically significant differences were observed in any VCS parameter. This suggests that while VCS parameters change during FN, they may not differentiate between microbiologically confirmed infections and culture-negative episodes. Similar findings were reported by Bharti A et al., who found limited utility of certain VCS parameters in diagnosing sepsis.^[15] In contrast, Sudhakar et al. reported that specific VCS indices could predict bacterial infection and its severity, and Zhou et al. demonstrated that a combined panel of VCS parameters improved diagnostic accuracy for bacterial infections in chemotherapy recipients.^[16,17] This discrepancy underscores the need for larger, multicentric studies to validate these observations.

Furthermore, no significant correlations were found between VCS parameters and established inflammatory markers such as C-reactive protein (CRP) or procalcitonin (PCT). While CRP and PCT remain established biomarkers for sepsis, their lack of association with VCS parameters in our study suggests that morphological changes detected by VCS may represent a distinct biological phenomenon, potentially reflecting early cellular activation rather than systemic inflammatory responses. Previous studies reported significant but variable associations between VCS indices and sepsis biomarkers, highlighting possible differences in patient populations or study methodologies.^[18,19]

Importantly, baseline VCS parameters did not correlate with clinical outcomes, such as survival versus mortality. This finding suggests that while VCS parameters may be useful for early detection of FN, they are not reliable prognostic indicators in pediatric oncology patients. Their inability to predict adverse outcomes limits their role in risk stratification or therapeutic decision-making at present.

Receiver Operating Characteristic (ROC) curve analysis demonstrated that MN-V-NE exhibited the highest discriminative ability for FN diagnosis, with an area under the curve (AUC) of 0.78, indicating good diagnostic performance. Monocyte-related parameters, including MNC-MO and MN-V-MO, also showed moderate diagnostic accuracy. A review of literature has found variable ROC analysis results. While Kannan & Selvam noted poor specificity of MN-V-NE and poor sensitivity of MN-V-MO (40% and 42.29% respectively), Mardi et al noted a better sensitivity and specificity of MN-V-NE (76%, 63%) and for MN-V-MO (86%, 40%).^[20,21]A Recent study by Nesagri et al showed unusually high sensitivity and specificity of MNV-NE (97%, 96%) and MN-V-MO (95%,86%) for FN.^[22]

These observations are clinically relevant, as they point to the possibility of using automated cell analyzer-derived indices as adjunct tools for FN diagnosis, particularly in resource-limited settings where advanced biomarkers may not be readily available.

CONCLUSION

Overall, the study highlights the potential of VCS parameters as rapid, cost-effective markers for identifying FN episodes. However, their lack of correlation with infection severity, culture positivity, or outcomes indicates that they should be interpreted cautiously and in conjunction with clinical findings and standard biomarkers.