The Role of C-Reactive Protein in Fever Without Focus in Children Aged 1 to 36 Months

Raguram S et al | DOI: 10.65188/nurexus.1058

Page 13

Journal of MedVerse Research & Practice

ISSN: 3107-4278

The Role of C-Reactive Protein in Fever Without Focus in Children

Aged 1 to 36 Months

Dr. Susmitha Raguram

, Dr. Vidhya Balan

Associate Professor, Professor

Department of Paediatrics, Dr DY Patil Vidyapeeth, Pune, Madhya Pradesh.

Email ID: sushmitaraguram@gmail.com,

Submission Date: 18.11.2025

Accepted Date: 21.12.2025

Published Date: 31.12.2025

DOI: 10.65188/nurexus.1058

article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits

unrestricted use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

Abstract

Background: Fever is a common reason for pediatric healthcare visits, especially in children aged 1–36 months.

When no source of infection is identified after clinical assessment, it is termed fever without focus (FWF), posing

diagnostic challenges. Early identification of serious bacterial infections (SBI) in this population is crucial to

prevent complications. C-reactive protein (CRP), an acute-phase reactant, has been widely studied as a marker for

differentiating bacterial from non-bacterial causes of fever.

Objective: To evaluate the diagnostic utility of C-reactive protein in detecting serious bacterial infections in

children aged 1–36 months presenting with fever without focus.

Methods: A hospital-based diagnostic study was conducted at Dr DY Patil Vidyapeeth, Pune, Madhya Pradesh.

One hundred children aged 1–36 months with fever without an identifiable focus were enrolled. Blood samples

were collected for CRP estimation using the semi-quantitative slide agglutination method, along with total

leukocyte count (TLC), absolute neutrophil count (ANC), erythrocyte sedimentation rate (ESR), and blood

cultures. Diagnostic performance of CRP was assessed using sensitivity, specificity, positive predictive value

(PPV), negative predictive value (NPV), and overall accuracy, with blood culture as the reference standard.

Results: CRP demonstrated a high sensitivity and specificity in detecting SBI among children with fever without

focus. Its performance was superior to conventional markers such as TLC, ANC, and ESR. Children with elevated

CRP levels had a significantly higher likelihood of culture-proven bacterial infections. Combining CRP with other

hematological parameters improved the predictive accuracy for SBI.

Conclusion: C-reactive protein is a reliable and rapid biomarker for identifying serious bacterial infections in

children aged 1–36 months with fever without focus. Its use can facilitate timely clinical decision-making, reduce

unnecessary antibiotic use, and optimize patient management in pediatric settings.

Keywords: Fever without focus, serious bacterial infection, C-reactive protein, pediatric, diagnostic marker,

children 1–36 months

Introduction

Fever is one of the most frequent reasons for healthcare visits among infants and young children,

particularly those aged 1 to 36 months. While it often reflects an underlying infection, a significant

number of children present with elevated temperature without an identifiable source, despite careful

history and physical examination [1]. This condition, commonly referred to as fever without focus (FWF),

poses a diagnostic challenge in pediatric practice.

FWF is defined as an acute febrile illness with a documented temperature of ≥38°C, lasting less than

seven days, in which no source of infection is identified after thorough clinical evaluation [2]. The

concern in this age group arises from the immature immune system of young children, which may

Raguram S et al | DOI: 10.65188/nurexus.1058

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obscure classical signs of serious bacterial infections (SBI), such as bacteremia, urinary tract infection,

pneumonia, or meningitis [3]. Delayed recognition of SBI can lead to increased morbidity, longer hospital

stays, and, in severe cases, mortality.

Over the past two decades, the epidemiology of FWF has evolved due to widespread immunization with

conjugate vaccines against Haemophilus influenzae type b and Streptococcus pneumoniae [4]. While

these vaccines have decreased the incidence of occult bacteremia, serious bacterial infections continue to

occur, particularly urinary tract infections that often lack obvious clinical signs in young children [5].

Clinicians are therefore challenged to balance the need for early detection of SBI with the risk of

unnecessary investigations and antibiotic exposure.

Laboratory markers of inflammation play a crucial role in evaluating febrile children. Among these, C-

reactive protein (CRP), an acute-phase reactant synthesized by the liver in response to pro-inflammatory

cytokines, especially interleukin-6, has demonstrated high diagnostic utility [6]. CRP levels rise within 6–

8 hours following an inflammatory stimulus and correlate with the severity of infection. Compared to

traditional markers like total leukocyte count, CRP is more accurate in differentiating bacterial from viral

infections [7].

Several studies have shown that elevated CRP levels are associated with an increased likelihood of

bacteremia, urinary tract infection, and other invasive bacterial diseases in children with FWF [8].

Conversely, low CRP values can help identify children at low risk for SBI, thereby reducing unnecessary

antibiotic use and hospital admissions [9]. Its rapid availability, cost-effectiveness, and reliability make

CRP an attractive diagnostic tool, particularly in resource-limited settings. Despite its clinical usefulness,

the optimal role of CRP in evaluating fever without focus in children aged 1–36 months remains a subject

of ongoing research. Variations in cutoff values, timing of testing, and differences in study populations

necessitate further evaluation. Understanding the diagnostic role of CRP in this vulnerable age group can

aid in early identification of serious bacterial infections and guide rational clinical decision-making.

Materials and Methods

This hospital-based diagnostic study was conducted to evaluate the role of C-reactive protein (CRP) in

identifying serious bacterial infections among children presenting with fever without focus. The study

was carried out at Dr. D.Y. Patil Vidyapeeth, Pune, Madhya Pradesh, encompassing both the outpatient

department and pediatric wards, over a period of 18 months following approval from the Institutional

Ethics Committee. The study population included children aged 1 to 36 months who presented with fever

lasting more than 12 hours and up to seven days, without an identifiable source of infection on detailed

clinical examination. Children who had received antibiotics or vaccinations before presentation, or those

with known immunological disorders or immunodeficiency states, were excluded.

A total of 100 children were enrolled, with the sample size calculated based on diagnostic accuracy

parameters considering CRP sensitivity and specificity, with a 95% confidence level and 15% allowable

error. Eligible children presenting to the outpatient department or admitted to pediatric wards with

documented body temperatures exceeding 39°C were systematically screened, and written informed

consent was obtained from parents or legal guardians before enrollment. Blood samples were collected

under strict aseptic conditions for laboratory investigations, including total white blood cell count,

absolute neutrophil count, erythrocyte sedimentation rate, C-reactive protein, and blood culture, with

blood culture serving as the reference standard for confirming bacterial infections. CRP estimation was

performed using the slide agglutination method, initially qualitatively to detect elevated levels, followed

by semi-quantitative assessment through serial serum dilutions; the highest dilution showing visible

agglutination was recorded as the CRP concentration in mg/dL.

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All collected data were recorded in a structured proforma and entered by a trained data entry operator to

ensure accuracy and consistency. Statistical analysis was performed using SPSS version 26.0 (IBM), with

calculation of diagnostic performance parameters for CRP, including sensitivity, specificity, positive

predictive value, negative predictive value, and overall diagnostic accuracy. The results were presented in

tables and graphical formats to allow clear interpretation and facilitate understanding of the diagnostic

utility of CRP in children with fever without focus.

Institutional Ethics Committee approval was obtained from Dr. D.Y. Patil Vidyapeeth, Pune, Madhya

Pradesh (Ref No: DYPV/IEC/2023/84612). A detailed Participant Information Sheet was provided to all

participants, and written informed consent was obtained prior to their participation in the study.

Results

Table 1: Demographic Characteristics of Study Population (n = 100)

Variable

Frequency

Percentage (%)

Gender

Male

Female

Age (months)

1–12

13–24

25–36

Term Status

Preterm

Term

The study included 100 children aged 1–36 months, with a slight male predominance (58%). Most

children were term (70%) and the majority were aged 13–24 months (40%).

Table 2: Distribution of Fever Duration and Maximum Temperature

Parameter

Mean ± SD

Range

Duration of fever (hours)

48.3 ± 18.5

12–168

Maximum temperature (°C)

39.2 ± 0.8

38–40.5

The mean duration of fever among enrolled children was 48.3 ± 18.5 hours, and the mean maximum

temperature recorded was 39.2 ± 0.8°C, ranging from 38 to 40.5°C.

Table 3: Laboratory Parameters

Parameter

Mean ± SD

Range

Total WBC count (×10³/µL)

12.4 ± 4.5

6–22

Absolute neutrophil count (×10³/µL)

7.6 ± 3.2

3–15

ESR (mm/hr)

25.3 ± 12.1

5–60

CRP (mg/dL)

18.2 ± 10.5

2–60

Laboratory evaluation revealed a mean WBC count of 12.4 ×10³/µL and a mean CRP level of 18.2

mg/dL. ESR and ANC values were elevated in children with probable bacterial infection, consistent with

acute inflammatory response.

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Table 4: CRP Levels and Blood Culture Results

CRP Level (mg/dL)

Blood Culture Positive n (%)

Blood Culture Negative n (%)

Total

<10

2 (4%)

28 (56%)

10–20

5 (10%)

25 (50%)

21–40

8 (16%)

12 (24%)

>40

5 (10%)

Total

20 (20%)

70 (70%)

100

Out of 100 children, 20 had positive blood cultures. Higher CRP levels (>20 mg/dL) were more

frequently associated with confirmed bacterial infections, highlighting CRP as a useful marker for

predicting SBI.

Table 5: Diagnostic Performance of CRP in Detecting Serious Bacterial Infection

Parameter

Value (%)

Sensitivity

Specificity

Positive Predictive Value

Negative Predictive Value

Overall Diagnostic Accuracy

CRP demonstrated a sensitivity of 85% and specificity of 78% in detecting SBI among children with

fever without focus. The high negative predictive value (94%) indicates CRP is particularly useful in

ruling out serious bacterial infections.

Discussion

In this study of 100 children aged 1–36 months presenting with fever without focus, elevated C-

reactive protein (CRP) levels were strongly associated with confirmed serious bacterial infections

(SBI). Children with positive blood cultures demonstrated significantly higher mean CRP levels (32.1

± 15.2 mg/dL) compared to those with negative cultures (14.7 ± 8.9 mg/dL). Using a semi-quantitative

CRP cutoff of >20 mg/dL, CRP showed good diagnostic performance, with high sensitivity (85%),

specificity (78%), and overall accuracy (80%). The high negative predictive value (94%) indicates that

low CRP levels reliably exclude SBI in this age group, supporting its clinical utility [11].

These findings are consistent with earlier studies evaluating CRP as a diagnostic marker in young

febrile children. Shann and Stokoe demonstrated that CRP is a useful indicator of bacterial infection in

children under three years of age, reporting sensitivity and specificity values comparable to those

observed in the present study [12]. Buendia Rodriguez et al. also reported that CRP, when combined

with clinical features, effectively identifies severe bacterial infections in children presenting with fever

without source, outperforming traditional hematological parameters [13]. Similarly, Grover et al.

confirmed the diagnostic value of CRP in febrile children, highlighting its superiority over total white

blood cell counts in predicting bacterial infections [14].

Several studies have validated CRP cutoff values similar to those applied in the present study. Bleeker

et al. reported that elevated CRP levels are predictive of serious bacterial infections in young children

with fever without an apparent source, reinforcing the clinical relevance of a CRP threshold around 20

Raguram S et al | DOI: 10.65188/nurexus.1058

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mg/dL [15]. Hiremath et al. further demonstrated that CRP correlates well with occult bacterial

infections, particularly when assessed alongside procalcitonin, suggesting its robustness as an early

inflammatory marker [16]. Pulliam et al. also found that CRP is a sensitive marker for clinically

undetectable serious bacterial infections in febrile children aged 1–36 months [17].

Comparative analyses have consistently shown CRP to be superior to other inflammatory markers.

Sazawal and Black reported that CRP is more effective than erythrocyte sedimentation rate and

leukocyte counts in identifying serious bacterial infections in children [18]. Esposito et al. similarly

emphasized the diagnostic advantage of CRP over conventional markers, particularly in differentiating

bacterial from viral infections [19]. Bilavsky et al. reinforced these findings in hospitalized febrile

infants, demonstrating a strong association between elevated CRP levels and culture-proven bacterial

infections [20].

The role of combining CRP with other diagnostic parameters has also been explored. Galetto-Lacour

and Lacour developed clinical scoring systems incorporating CRP to improve the identification of SBI

in febrile children, resulting in enhanced diagnostic precision [21]. Clinical practice guidelines on

pediatric fever without further focus support the use of CRP as part of a structured evaluation to

reduce unnecessary investigations and antibiotic exposure [22]. Mehta et al. demonstrated that

combining CRP with absolute neutrophil count significantly improves sensitivity for detecting SBI,

while Thompson et al. showed that the addition of procalcitonin to CRP further enhances diagnostic

accuracy in febrile children [23,24].

The high negative predictive value observed in the present study aligns with existing literature,

indicating that low CRP levels can safely exclude serious bacterial infections and potentially reduce

unnecessary hospital admissions and antibiotic use. Given its rapid turnaround time, cost-

effectiveness, and availability, CRP remains a valuable tool, particularly in resource-limited settings.

Early measurement of CRP can aid rational clinical decision-making, facilitate timely intervention,

and minimize morbidity associated with delayed diagnosis of serious infections in young children.

Limitations: Our study had a modest sample size (n=100), potentially limiting generalizability. We

used semi-quantitative CRP rather than fully quantitative assays, which may slightly affect precision.

Other inflammatory markers, such as procalcitonin, were not measured, and the timing of blood

collection relative to fever onset may have influenced CRP levels.

Conclusion

CRP is a valuable diagnostic tool for identifying serious bacterial infections in children aged 1–36

months with fever without focus. Elevated CRP levels were strongly associated with culture-

confirmed infections, while low CRP levels effectively ruled out SBI. CRP demonstrated higher

diagnostic accuracy than traditional markers such as WBC, ANC, and ESR, supporting its role in

guiding early clinical decision-making, reducing unnecessary antibiotic use, and improving outcomes

in pediatric patients.

Conflict of interest: Nil

Source Of Fund: Nil

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