Personalized Interpretation of CBC and the Role of CRP in Early Detection and Monitoring of Blood Infection or Sepsis: A Diagnostic Perspective

ABSTRACT

Background and Aims

Sepsis remains a leading cause of morbidity and mortality worldwide, particularly in low‐ and middle‐income countries where diagnostic delays are common. The complete blood count (CBC) is widely used as an initial sepsis screening tool due to its availability and affordability. However, reliance on population‐based reference ranges, particularly white blood cell (WBC) counts, often leads to missed or delayed diagnosis, especially in early disease or among immunosuppressed patients. This article examines the diagnostic limitations of conventional CBC interpretation in suspected infection, and propose a personalized, baseline‐informed approach integrating C‐reactive protein (CRP) as an adjunct biomarker for early detection and monitoring.

Approach

This perspective is based on a narrative synthesis of published literature on sepsis diagnostics, CBC parameters, and inflammatory biomarkers, combined with pathophysiological principles and clinical reasoning relevant to resource‐constrained settings. Evidence from diagnostic studies, systematic reviews, and guideline recommendations was conceptually analyzed to identify limitations of static laboratory thresholds and opportunities for personalized interpretation.

Findings

Population‐based CBC reference ranges are limited in early sepsis detection due to inter‐individual variation. Personalized interpretation, considering baseline values and serial trends, improves sensitivity in identifying infection. CRP rises earlier and more consistently than WBC, particularly when hematologic responses are blunted. Integrating serial CRP measurements with baseline‐informed CBC trends enhances diagnostic utility, supports timely recognition, and improves monitoring of clinically significant infection.

Conclusion

Clinicians should shift from interpreting CBC parameters based solely on population reference ranges and instead adopt a baseline‐informed, trend‐based diagnostic approach. In patients with suspected infection, particularly those with normal CBC values or immunosuppression, CRP should be routinely used as an adjunct marker to unmask early or atypical sepsis. In resource‐limited settings, where advanced diagnostics are unavailable, integrated interpretation of personalized CBC trends and serial CRP provides a practical, cost‐effective strategy to improve diagnostic performance.

Summary

• The complete blood count (CBC) parameters vary significantly with age, immune status, comorbidities, medications, and genetic diversity, limiting the reliability of single, population‐based thresholds for infection or sepsis screening.

• Standard reference ranges may fail to detect early or atypical infections, as many septic patients, particularly those with immunosuppression or chronic leukopenia can present with normal WBC counts despite active infection.

• A personalized, trend‐based interpretation that incorporates individual baseline values and clinical context offers superior diagnostic sensitivity and clinical utility compared to static population reference ranges.

• Serial CRP is a reliable adjunct biomarker, rising earlier and more consistently than WBC, and improves diagnostic accuracy when used alongside personalized CBC trends, especially when WBC response is delayed, suppressed, or unreliable.

1. Introduction

Sepsis is a life‐threatening organ dysfunction caused by a dysregulated host response to infection [1]. The syndrome continues to be a major cause of morbidity and mortality globally, particularly in low‐ and middle‐income countries (LMICs) [2, 3]. In 2020, the World Health Organization (WHO) estimated that 20% of all global deaths were related to sepsis, with about 85% of all sepsis cases and deaths occurring in LMICs [3]. The discrepancy in regional distribution of sepsis reflects the widespread gaps in early diagnosis, access to appropriate care, and health system resilience.

Sepsis arises when the release of proinflammatory mediators in response to infection exceeds the boundaries of the local environment, leading to a systemic response [4]. When an infection is not detected and treated promptly, it allows microbial proliferation and sustained inflammatory signaling, which may lead to sepsis [5]. Therefore, early detection of infection remains the mainstay of preventing progression to sepsis.

Clinically, sepsis presents with nonspecific signs such as fever, tachycardia, tachypnea, altered mental status, or hypotension, making early diagnosis particularly challenging in resource‐limited settings [5, 6, 7]. The Sepsis‐3 criteria defines sepsis as an infection accompanied by organ dysfunction, often assessed using the Sequential Organ Failure Assessment (SOFA) score [1]. However, these criteria are primarily suited for confirming established sepsis rather than facilitating early detection [1]. In practice, the diagnosis is often empirical, guided by clinical suspicion, response to antibiotics, or retrospective confirmation via microbiological results [5]. The pathogen identification remains elusive in a significant proportion of patients, even in high‐resource settings, making reliance on clinical judgment and supportive laboratory biomarkers essential for prompt recognition and timely intervention [7, 8, 9].

The complete blood count (CBC) is a widely performed laboratory investigation in patients with suspected infection or sepsis, due to its availability, affordability and rapid turnaround time [10, 11]. Clinicians often use CBC parameters as surrogate markers of infection or systemic inflammation [10, 11, 12]. While these markers offer valuable insights, their diagnostic accuracy is limited when used in isolation [1, 12, 13, 14]. Over‐reliance on CBC parameters without clinical or personalized context and supporting biomarkers can increase the rate of underdiagnosis, overtreatment or both, especially in the early or atypical stages of sepsis. In light of these limitations, this paper aims to: (i) examine the diagnostic challenges and interpretative limitations of CBC in infection and sepsis screening; (ii) advocate for a personalized, context‐specific interpretation of CBC parameters that accounts for individual baseline values and patient‐specific factors, particularly in resource‐limited settings; and (iii) highlight the complementary role of CRP as an adjunct biomarker in early sepsis screening and monitoring response to treatment.

1.1. The Role of CBC Parameters in Sepsis Screening: Current Utility and Limitations

The CBC has historically been a cornerstone in the initial evaluation of suspected infection or sepsis. Early sepsis criteria incorporated abnormalities in the white blood cell (WBC) count, specifically leukocytosis and leukopenia, as part of the systemic inflammatory response syndrome (SIRS) criteria used to identify sepsis [15]. However, the updated Sepsis‐3 criteria no longer include WBC count abnormalities as diagnostic requirements. Instead, they frame leukocytosis within the context of SIRS as a supportive screening tool rather than a definitive diagnostic parameter for sepsis [1]. Generally, the diagnostic utility of CBC in sepsis has been shown to be low. For instance, when assessed upon presentation in the emergency department, both leukocytosis and leukopenia yielded modest diagnostic performance, with reported sensitivity and specificity values of approximately 57.1% and 78.7%, respectively, for distinguishing severe sepsis or septic shock from non‐septic states [13].

Despite its limited utility as a standalone infectious marker, leukocytosis frequently prompts further investigations for potential infection [10]. Although both leukocytosis and leukopenia are recognized features of sepsis, a substantial proportion of patients with sepsis exhibit normal WBC counts at presentation [14]. Additionally, numerous non‐infectious conditions, such as trauma, corticosteroid therapy, dehydration, and hematologic disorders can produce similar hematologic changes and symptomatology, increasing the risk of overdiagnosis when WBC count is interpreted independently [16, 17, 18]. Conversely, normal WBC parameters do not rule out infection. In early sepsis or in immunosuppressed patients (e.g., elderly, those undergoing chemotherapy, or individuals living with HIV infection), the immune response may be blunted, resulting in normal WBC counts despite an active infection [19].

Another important component of the CBC is the presence of a “left shift,” characterized by an increased proportion of immature granulocytes, such as myelocytes, metamyelocytes, and band neutrophils in peripheral blood [20]. This hematologic response is driven by pro‐inflammatory cytokines release during infection [21, 22]. While the presence of bandemia is relatively specific for infection, its sensitivity is low [10, 20]. Importantly, the release of immature cells typically occurs 12–24 hours after the onset of infection. This delay may hinder early detection, allowing the infection to progress to sepsis if clinicians rely solely on bandemia at the time of initial presentation [14, 20].

In addition to WBC counts, platelet levels can also serve as important hematological indicators in the context of infection and sepsis [10, 14]. Platelets are acute‐phase reactants and their levels may rise or fall in response to infectious stimuli [10]. Thrombocytosis can occur during early or mild infections as part of the inflammatory response, whereas thrombocytopenia is more commonly observed in severe infections, particularly in cases of sepsis and septic shock [14]. This reduction in platelet count is largely attributed to increased platelet consumption, sequestration, and destruction in the setting of systemic inflammation and disseminated intravascular coagulation (DIC), which often accompany severe sepsis [14]. Despite its utility in sepsis, platelet count should be interpreted with caution, as thrombocytosis and thrombocytopenia may also arise from non‐infectious conditions [23]. Thrombocytosis can occur in iron deficiency anemia, chronic inflammatory disorders, or malignancies, while thrombocytopenia may result from hematologic diseases, liver dysfunction, or certain medications, independent of infection [23, 24]. Therefore, a personalized approach to interpretation is essential, and repeat testing may be warranted to confirm the findings and assess trends over time. Table 1 summarizes key CBC parameters along with their potential confounding factors, highlighting considerations for accurate interpretation in the context of infection and sepsis [10, 13, 14, 20].

Table 1.

Diagnostic performance of CBC parameters in suspected infection/sepsis.

Biomarker	Typical time to change (h)	Sensitivity (%)	Specificity (%)	Confounders
WBC count	12–24	~57	~78	Dehydration, corticosteroid therapy, trauma, hematological disorders, immunosuppression
Neutrophil count	12–24	~60	~75	Dehydration, corticosteroid therapy, trauma, hematological disorders, immunosuppression
Bandemia	12–24	~45	~85	Immunosuppression, bone marrow disorders
Platelet count	24–48	~50	~70	Iron deficiency anemia, chronic inflammatory diseases, liver diseases

Generally, the common CBC indicators of infection or systemic inflammation include leukocytosis, leukopenia, thrombocytosis, thrombocytopenia, and bandemia [10, 15]. While these parameters are valuable for initial triage and raising suspicion of infection or sepsis, they are not sufficient on their own to confirm or rule out a sepsis diagnosis [1]. Their interpretation must therefore be contextualized within the individual's baseline parameters, medical history and overall clinical presentation, underscoring the need for a more comprehensive diagnostic approach that incorporates individualized clinical assessment and additional biomarkers.

2. Personalized Interpretation of CBC Parameters in Sepsis or Infection Screening

Interpreting CBC results in the context of suspected infection or sepsis requires more than simply comparing values to standard reference ranges. It demands an individualized approach that considers the patient's clinical background, comorbidities, immune status, and historical laboratory data. Baseline hematologic parameters, particularly the WBC count can vary widely among individuals due to factors such as age, chronic illness, medication use, underlying hematological disorders and inborn physiological or immunological variation due to genetic diversity [25, 26, 27]. Moreover, inter‐individual inborn and acquired variation in hematological parameters becomes more apparent during immune responses [25, 26]. For instance, elderly patients or those with immunosuppressive conditions like HIV, malignancy, or those receiving long‐term corticosteroids or chemotherapy may exhibit chronically low or blunted WBC responses, even in the setting of severe infection [19, 28, 29]. Similarly, individuals with congenital or acquired leukopenia may have a baseline WBC below normal limits, making a “normal” WBC count potentially misleading if interpreted without context. In such cases, a relative increase in WBC count from an individual's baseline, even if the absolute value remains within population reference ranges may signal an early infection or systemic inflammation [19]. For example, a chronically neutropenic patient with a baseline WBC of 3.0 × 10⁹/L may present with a count of 9.5 × 10⁹/L during sepsis. Although this value falls within the normal standard reference range, it represents more than three‐fold increase from baseline, indicating a significant clinical change. Without reference to prior values, such changes may be overlooked, underscoring the limitations of population‐based reference ranges and reinforcing the need for personalized interpretation of hematologic parameters.

Where prior CBC records are accessible, clinicians should prioritize a relative increase from individual's baseline values and identifying patient‐specific trends over single time‐point measurements. Monitoring dynamic changes such as progressive leukocytosis, rising neutrophil or band counts, or platelet trends can provide more meaningful insight into the patient's clinical trajectory. This personalized interpretation model is particularly critical in settings where access to advanced biomarkers such as serial procalcitonin and CRP testing are limited. Ultimately, personalizing CBC interpretation enhances diagnostic sensitivity and helps mitigate the risks of both underdiagnosis and overtreatment. It allows clinicians to move beyond rigid laboratory thresholds toward a more biologically informed and contextualized approach to sepsis recognition, especially in low‐ and middle‐income countries (LMICs) where clinical judgment remains a cornerstone of effective clinical decision‐making.

3. The Role of CRP as an Adjunct Biomarker in Early Sepsis Screening and Monitoring

The early detection of sepsis requires rapid, reliable, and context‐sensitive biomarkers to guide clinical decision‐making. While CBC remains a routine investigation in febrile and potentially septic patients, its limitations in sensitivity and specificity necessitate adjunctive diagnostic biomarkers. One such biomarker is CRP, a well‐established acute‐phase reactant synthesized exclusively in the liver as a response to inflammatory cytokines [30, 31]. Under infectious stimuli, CRP begins to rise within 6–12 hours, typically peaking at 48–72 hours [31]. Unlike WBC counts, which can be influenced by bone marrow reserve, immune status, or concurrent medications, CRP levels are regulated solely by production, making it a more stable and direct reflection of systemic inflammation [31]. Notably, elevated CRP levels correlate well with the severity of infection and often decline in response to effective antibiotic therapy, making it useful in treatment monitoring and prognosis [32, 33, 34, 35].

From a diagnostic standpoint, CRP demonstrates moderate accuracy in distinguishing bacterial infections from non‐infectious causes of inflammation. A systematic review and meta‐analysis estimated a pooled sensitivity of 75% and specificity of 67% for CRP in identifying bacterial infections [36]. Its performance improves substantially at higher thresholds reaching to diagnostic yield of up to 88% for infection at a threshold > 500 mg/L [37]. Although useful as an adjunct marker of infection, CRP has a nonspecific rise in various non‐infectious inflammatory conditions such as surgery, trauma, systemic lupus erythematosus, and rheumatoid arthritis [38]. Its reliability is further reduced in patients with advanced liver cirrhosis, where production may be impaired [39]. Therefore, CRP should be interpreted cautiously, using a personalized approach with emphasis on serial measurements and clinical context to enhance diagnostic accuracy.

The diagnostic value of CRP becomes particularly evident in scenarios where WBC count may fail to reflect an active infection. For example, in a retrospective study by Liu et al. conducted at a Taiwanese emergency department found that among 5628 febrile adult patients, 214 (3.8%) presented with elevated CRP ( > 100 mg/L) despite having normal WBC counts [19]. Remarkably, over 82% of these patients were ultimately diagnosed with infections, and the majority required hospitalization [19]. Notably, most patients did not have underlying hematologic malignancies, challenging the common assumption that such discordance only occurs in immunosuppressed individuals. This reinforces the fact that CRP can unmask clinically significant infections that might otherwise be missed. The study also found that patients with high CRP and normal WBC counts were more likely to be hospitalized, suggesting that CRP influenced clinical decision‐making and reflected a significant infectious burden [19]. These findings support CRP as a more sensitive marker of acute infection, particularly in settings where WBC response is delayed, suppressed, or unreliable.

The combination of CBC and CRP offers a more robust diagnostic framework for detecting infection, guiding early sepsis management and therapeutic monitoring. While CBC remains a first‐line investigation, its limitations in sensitivity, particularly in elderly, immunosuppressed or early‐stage septic patients can lead to missed or delayed diagnosis [28]. CRP, in contrast, offers dynamic responsiveness, reasonable specificity, and enhanced utility when interpreted in conjunction with clinical findings and CBC trends. When used together, CRP and CBC offer a synergistic diagnostic advantage. Their combined use increases the sensitivity and negative predictive value for infection detection, particularly in ambiguous clinical cases [40]. For instance, in febrile patients with normal WBC counts, an elevated CRP level may prompt clinicians to consider infection even in the absence of leukocytosis or neutrophilia [19]. This dual‐biomarker strategy is especially valuable in resource‐limited settings, where access to cultures, imaging, or advanced biomarkers (e.g., procalcitonin) may be limited. Based on this approach, we propose a baseline‐informed CBC/CRP algorithm for infection and sepsis screening as illustrated in Figure 1 below.

Figure 1.

The proposed baseline‐informed CBC and CRP algorithm for infection/sepsis detection.

4. Conclusion

The early detection of sepsis remains a critical challenge, particularly in low‐resource settings. While CBC is a widely accessible first‐line test, its diagnostic accuracy is limited when interpreted in isolation. Therefore, a personalized interpretation, one that considers individual baselines where available and dynamic trends is essential for improving diagnostic sensitivity. C‐reactive Protein (CRP) serves as a valuable adjunct in this context. It rises early in infection, correlates with disease severity, and retains diagnostic utility even when WBC counts are within normal limits. Studies show that elevated CRP levels can help uncover clinically significant infections that CBC alone may miss. Together, CBC and CRP offer complementary strengths. Their combined use enhances diagnostic accuracy, supports early intervention and ensure effective therapeutic monitoring, especially in resource‐constrained settings.

5. Recommendations

To enhance early detection and management of infections and sepsis, we propose the following actionable recommendations based on our insights. These recommendations prioritize practical strategies that can be implemented in clinical practice and health systems, particularly in resource‐limited settings.

• 1. Prioritize access to prior CBC data where possible: Health systems should promote centralized record‐keeping and electronic medical records to enable comparison of current WBC values with individual baselines. Clinicians should be trained to assess relative changes in WBC counts rather than relying solely on static population reference intervals.
• 2. Conduct quantitative studies on baseline‐informed CBC interpretation: Future research should evaluate the diagnostic performance of patient‐specific, baseline‐informed CBC interpretation in early detection of infections and sepsis. Generating quantitative evidence will guide clinical adoption and validate improvements in sensitivity and specificity.
• 3. Train clinicians in personalized interpretation strategies: Clinical training curricula should include instruction on contextual and personalized diagnostic reasoning, emphasizing integration of patient history, hydration status, comorbidities, and baseline laboratory values into sepsis risk assessment.
• 4. Routinely include CRP in sepsis screening panels: Where available, CRP should be added as a standard biomarker alongside CBC for patients with suspected infection, especially in patients presenting with fever and normal CBC results or in early‐stage sepsis where inflammatory markers may precede hematologic changes.
• 5. Scale up CRP testing capacity in LMICs: Policy‐makers and healthcare administrators should invest in low‐cost CRP testing platforms to support early sepsis detection in resource‐limited settings. Given its reliability and affordability, CRP can serve as an essential bridge between clinical suspicion and laboratory confirmation.
• 6. Develop simplified sepsis screening algorithms using CBC and CRP: In the absence of advanced diagnostics, tailored algorithms that combine personalized CBC trends and CRP thresholds can serve as effective tools to guide empirical management, particularly in emergency and primary care settings.

Author Contributions

Study conceptualization and design by David Muhunzi and Harold L. Mashauri. Literature search and analysis by all authors. Writing – original draft preparation by David Muhunzi. Writing – reviewing and editing by Emanuel Mrema, Fredrick Banda and Harold L. Mashauri. Project administration by David Muhunzi and Harold L. Mashauri. Supervision by Harold L. Mashauri.

Funding

The authors received no specific funding for this work.

Ethics Statement

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Consent

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Transparency Statement

The lead author, David Muhunzi, affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

Data Availability Statement

Data sharing is not applicable to this article as no data sets were generated or analyzed during the current study.