Role of C - reactive protein in Fever without focus in children between 1 to 36 months of

age
 INTRODUCTION

Febrile illnesses in infants and children account for 20% of paediatric visits. 1,2There are

less invasive methods to measure temperature as well, such as axillary and aural thermometry.

But, the results produced from these techniques differ from one another.3, 4For this reason, while

taking a child's temperature, rectal thermometry currently the outpatient reference standard

should be utilised. If fever guidelines are to be used, a precise measurement of the patient's

temperature is very important. This is because these recommendations start to be applied the

moment a patient exceeds a set temperature threshold. Interactions between viral and non-

infectious processes and the host's defence system lead to the development of fever. 4

Fever that lasts for less than a week typically has an abrupt start and does not exhibit any

localising signs or symptoms. It is more prevalent in kids less than 36 months. Infants between

the ages of one and thirty-six months who have had vaccinations and do not appear to be feverish

may be considered for a laboratory screening test. On the other hand, newborns under 29 days old

who appear toxic should have a sepsis work-up performed. By carefully analysing the patient's

medical history and doing a physical examination, the majority of febrile episodes in a normal

host can be diagnosed. Laboratory testing is usually not required. Individuals who are

immunocompromised and feverish are at an increased risk of developing a serious bacterial

infection in comparison to newborns, babies under three months old, children aged three to

36 months, and feverish children.5

Though most of these children will have a moderate viral illness, children under three

years old are at risk of developing a serious bacterial infection (SBI) that is clinically undetected.

Roughly 10% to 15% of previously healthy youngsters who present with a rectal fever greater

than 39℃ have a severe bacterial infection. Of these children, occult bacteremia (OB) affects

about 2-3%. UTIs range from 2 to 8%, depending on the age and gender. Occult bacterial

pneumonia, which affects 3% of children under the age of three months, and other infections,
which affect 5% of children, such as bacterial enteritis, meningitis, soft tissue infections, and

bone and combined infections, are other sources of dangerous bacterial infections. Other serious

bacterial infections are caused by bacteria that are resistant to antibiotics. Even though antibiotic

treatment is required for children who have serious bacterial infections, it is vital to limit therapy

in those children who are at the greatest risk.6

Common etiological agents in less than 3 months: Escherichia coli ,Group B Streptococci

and Listeria monocytogenes, Salmonella, Neisseria etc.7

As of right now, no published standard or suggested advanced diagnostic methodology

exists for the identification of FUO. Newer diagnostic methods and a documented change in the

disease pattern have led to a shift in the etiological factors causing FUO.7, 8 Routine diagnostic

testing includes the measurement of white blood cells and differential erythrocyte sedimentation

rate, urine analysis, C reactive protein, morphological alterations in peripheral neutrophils,

microscopic evaluation of buffy coat, and quantitative blood cultures.6

The quintessential acute-phase protein is C-reactive protein (CRP). It was initially

shown to precipitate with the pneumococcus C-polysaccharide fraction. CRP is distinct

among human acute-phase proteins because it often exists in lower concentrations of

nanograms per millilitre and rises dramatically and quickly to hundreds of micrograms per

millilitre in just three days. In contrast to the erythrocyte sedimentation rate, the C-reactive

protein level increases and decreases more quickly following the resolution of the infectious

process.9, 10, 11 When an accident or illness occurs, the concentration of CRP rises 103-fold,

and measuring it in a clinical laboratory is quick, accurate, and simple.12

There are a limited number of studies that have been conducted in India on the use of

CRP in the diagnosis of serious bacterial infections in febrile children who are between 1 and

36 months old. Therefore, the study is aimed in using CRP in children with fever without

focus.
 AIM AND OBJECTIVES

AIM

 To describe the aetiological profile of FWF in children aged one to thirty-six months

and to identify clinical and laboratory predictors of specific aetiologies.

OBJECTIVES

 To know the aetiology of fever of short duration presenting without localising signs in

the age group 1 -36 months.

 To know the common organism causing bacteraemia in our children.

 To evaluate the diagnostic value of C - reactive protein (CRP) by semiquantitative

method in predicting occult serious bacterial infection in febrile children between 1-

36 months of age.
 REVIEW OF LITERATURE

One of the most prevalent clinical symptoms in children treated by paediatricians and

other healthcare professionals is fever, which frequently causes parents to become concerned.

According to certain estimations, it represents one-third of the conditions that youngsters

present with.13

When a kid has a fever, parents frequently call their child's doctor for assistance on

managing the fever, make impromptu doctor appointments, and use over-the-counter

antipyretics extensively. A typical child may experience four to six fever episodes annually

throughout their first two years of life due to the widespread occurrence of fever.14

Since the dawn of recorded history, fever has been understood to be an indication of

sickness. Research indicates that the majority of fever episodes are not harmful and instead

serve to strengthen the immune system's response to an infection.15

The majority of fevers are benign and don't require an out-of-home consultation

unless they are coupled with other concerning symptoms or signs, such as altered mental

state, convulsions, difficulty feeding, or indications of cardiac compromise. The phrase "fever

phobia" was originally used by Shimit in 1980. Numerous studies have been conducted since

then, yet parents' dread of fever has not only persisted but has further grown, rising from 52%

to 76% in 2001.16 It is impacted by low mother education levels, a lack of knowledge about

fever management, and a lack of experience with feverish children. Most parents fear the

more serious consequences of fever, namely seizures or brain damage, which are extremely

uncommon occurrences.13, 14

Upper respiratory tract infections and other viral infections are the most common

causes of fever lasting less than five days. These illnesses usually go away on their own and
don't require emergency medical attention. These children can get care and/or observation at

home. But it's crucial for parents to understand when a child with a fever needs to be

examined by a medical professional, when the fever should be treated, and when it's okay to

just watch the child.15, 16

Since the body's immune response can be boosted at higher temperatures, fever may

be helpful as a defensive mechanism. Nevertheless, there are arguments for and against the

utility of fever, and the topic is contentious.17

Fever without Focus

Fever that typically has an abrupt onset and lasts for less than a week, without any

localised symptoms or indicators. It is more prevalent in children less than 36 months.18

Fever of Unknown origin

Children with fever for whom the cause could not be determined after three weeks of

outpatient evaluation or one week of hospital evaluation.18

A thorough history and physical examination are sufficient for diagnosing the

majority of febrile episodes in a healthy host, and minimal or no laboratory testing is needed.

Patients with immunocompromised conditions, neonates, infants under three months old,

children between three and six months old, and febrile patients are all at higher risk of

developing serious bacterial infections. In children between the ages of three months and

three years, about 30% do not exhibit any localising indications of infection.19, 20

The polysaccharide vaccine has reduced the frequency of invasive pneumococcal

illness in children. A maturational immunological deficit in the development of opsonic IgG

antibodies against the polysaccharide antigens present on encapsulated bacteria may

contribute to the increased incidence of bacteremia in young children.21

 In paediatric outpatient practise, fever is a frequently occurring presenting symptom

in children under 3 years of age. 20% to 30% of the youngsters may have a fever with no

discernible cause following a physical examination and history.22

While the majority of these children will have a benign viral infection, children under

three have a higher chance of developing a significant bacterial infection (SBI) that is

clinically undetected. Approximately 10–15% of previously healthy children who report with

a rectal fever greater than 39°C have a severe bacterial illness. Depending on their age and

gender, 5-13% of these youngsters have UTIs and 1-2% have Occult Bacteremia (OB).23, 24

Occult bacterial pneumonia is one of the additional causes of severe bacterial

infections. Three percent of infants under three months old will experience other type of

illness, such as bacterial enteritis, meningitis, soft tissue infection, or bone and joint infection

(5%). While children with significant bacterial infections require antibiotic treatment, it's

equally critical to restrict therapy for the children who are most at risk.25

Typical causative agents in under three months: Escherichia coli, Listeria

monocytogenes, Neisseria, Salmonella, and group B streptococci, among others.

A controlled rise in body temperature above an individual's typical range is referred to

as a fever. Thermosensitive neurons in the preoptic or anterior hypothalamus control body

temperature by reacting to variations in blood temperature and by directing neuronal

connections with warm and cold sensors in the skin and muscles.

Redirecting blood to or from cutaneous vascular beds, sweating more or less,

controlling the volume of extracellular fluid (via arginine vasopressin), and behavioural

reactions like pursuing a warmer or cooler environment are examples of thermoregulatory

responses. Everyday, the normal body temperature likewise varies according to a regular
schedule. Due to this diurnal oscillation, or circadian temperature rhythm, body temperature

is lower in the early morning and rises by about 10C in the late afternoon and early evening.

Pathogenesis

Exogenous pyrogens are chemicals that cause fever outside the body, such as bacterial

products. For instance, Staphylococcus aureus enterotoxins and lipopolysaccharide

(endotoxin) of gram negative bacteria. Conversely, endogenous pyrogens such as cytokines—

are molecules that originate from the host and cause fever. IL-1, IL-4, IL-6, TNF-α, ciliary

neurotropic factor (CNTF), and IFN-γ are examples of pyrogenic cytokines.

Through prostaglandin E2, the endogenous pyrogenic cytokines mediate the resetting

of the temperature regulation set point. When exposed to exogenous pyrogens, which need

the synthesis and release of pyrogenic cytokines, the fever response to endogenous pyrogens

occurs in 10 to 15 minutes.26

The majority of endogenous pyrogen molecules are too big to effectively pass through

the blood-brain barrier. The blood-brain barrier is absent from circumventricular organs near

the hypothalamus, allowing neurons to communicate with circulating substances via fissured

capillaries.

Exogenous pyrogens, or substances originating from outside the body that cause fever

by stimulating macrophages and other cells to make endogenous pyrogens, are most

frequently microbes.

One can consider fever to be a sign of an infection. One theory is that fever is an early

sign of sepsis.
 Elevated generation of carbondioxide and higher oxygen demand are linked to fever.

Fever should be treated since there is an increased risk of febrile seizures. Sepsis is

characterised by substantial swings in fever that occur intermittently.

It is rare for an axillary temperature to exceed 37.50C during the first two months of

life. According to integrated management of paediatric illnesses, a small infant's fever may be

the only indication of a dangerous bacterial infection.

Physical factors influencing body temperature

Based on his own oral temperature, Gierse (1842) investigated the diurnal rhythm of

core body temperature. The study showed that the early morning is when temperatures are at

their lowest and the early evening, between 4 and 6 PM, is when they are at their highest.

Physical activity (maximum 1.1°C), digestion, changes in ambient temperature, after

ovulation in women, the first three months of pregnancy, and excitement are among the

physical variables that may affect body temperature.27, 28

The comparison table of approximated range of fever for each type of fever is as

follows

Temperature scales based on the fever grade

Fever grade Celsius Fahrenheit

Hypothermia < 36 < 96.8

Subnormal 35 – 36.7 95 - 97

Normal 35.5 – 37.7 96-100

Mild fever 37.7 – 37.8 99 – 100

Moderate fever 37.8 – 39.4 100 – 103

 High fever 39.4 – 40 103 – 105

Hyperpyrexia > 40 > 104

Patterns of fever

Fever patterns often indicate five patterns, yet their clinical utility is still unknown.

The five patterns are chaotic, relapsing, intermittent, recurrent, and continuous. The traits and

illustrations of every pattern

Characteristics and examples of each fever pattern

Fever patterns Characteristics Examples

Continuous fever Temperature >37°C Lobar pneumonia, urinary

throughout the day, does not tract infection, infective

fluctuate > 1° C in 24 hrs

Remittent fever Temperature may persist Typhoid, viral upper

above normal throughout the respiratory tract, legionella,

day, fluctuate > 0.5°C in 24 mycoplasma

hrs

Intermittent fever Elevated temperature persists Pyogenic infection,

for some hours in a day and lymphoma, miliary TB

remits to normal

Relapsing fever Fever spikes are noted with Malaria, kala-azar,

intermittent normal cholangitis, infections with

temperature for days or Borrelia recurrentis,

weeks Hodgkin's disease

  Daily spike- quotidian (PelEbstein fever), and other

 Every alternate day- neoplasms

Tertian

 Every third day –Quartan

IMMUNOLOGY OF FEVER

The body's natural reaction to any internal or external stimulus that upsets normal

homeostasis is inflammation. Although inflammation was first identified as a component of

straightforward clinical symptoms, it has now developed to describe a more complicated

phenomenon. Although our understanding of immunology has advanced recently, the precise

concept of inflammation remains unclear.

Fever is a basic response to infection that has evolved over 600 million years of

evolution and has been retained in vertebrates. Integrated neural and physiological circuitry

provides a survival advantage and is necessary for performing the fever response during

infection. A fever often aids in the body's ability to fight against infections, and new studies

have shown that fever improves the efficiency of some immune cells. But in some cases, the

temperature rise could be excessive, which could be dangerous and result in a number of

issues.29

As with cellulitis, a highly localised inflammatory disease, even the temperature is

elevated. Calor refers to this reaction as one of the primary indicators of inflammation. It is

commonly referred to as a fever. The host's immune system is strengthened and the rate of

spread of infectious agents is reduced by the fever response, which has been recognised as a

characteristic of infections and inflammatory illnesses.29

Effect of Elevated temperature on Immunity

Temperatures in the fever range are critical in initiating multiple critical components

of innate immunity. They do this by stimulating the bone marrow to produce neutrophils

through the granulocyte—colony stimulating factor (G-CSF) pathway. They are in charge of

the CXC-chemokine ligand 8 (CXCL8)-dependent recruitment of neutrophils to the lungs and

other local infection sites. The respiratory burst is further accentuated by the heat stress at the

infection site, which in turn increases neutrophil bacteriolytic activity. Natural killer (NK)

cells' cytolytic activity is enhanced by thermal treatment in two ways: 1) by inducing the

expression of MHC class I polypeptide-related sequence A (MICA) on target cells, such as

tumour cells 2) encouraging NK cell surface clustering of the MICA counter-receptor

NKG2D.

The ability of antigen-presenting cells to trigger an adaptive immune response is

enhanced in temperatures within the feverish range. The heat increases the phagocytic

potential of macrophages and dendritic cells (DCs) and enhances their response to invasive

infections by upregulating the expression of Toll-like receptor 2 (TLR2) and TLR4.

Additionally, the synthesis of certain immunomodulatory chemicals is increased by elevated

temperatures, including cytokines (including TNF), nitric oxide (NO), and heat shock protein

70 (HSP70). Additionally, it increases mature DCs' production of MHC class I and II

molecules as well as costimulatory molecules (CD80 and CD86), which are necessary for the

cells to migrate via the afferent lymphatics in response to the CCR7 chemokine receptor.DCs

are more effective in presenting antigens cross-presentation and polarising T helper 1 (Th1)

cells when exposed to feverish temperatures.

Fever-range temperature enhances adaptive immunity in lymphnodes by focusing on

two different elements of T cell activation. Heat increases the pace of lymphocyte trafficking
across high endothelial venules (HEVs) in peripheral lymph nodes by acting on each step of

the adhesion cascade. The frequency of rolling contacts and tethering depending on L-

selectin is increased when lymphocytes are exposed to heat. Temperatures within the febrile

range have an independent effect on HEVs, improving the lymphocytes' transition from

rolling to stable arrest by increasing the intravascular density of CCL21 (CChemokine ligand

21) and ICAM-1 (intracellular adhesion molecule 1). ICAM1 also facilitates transendothelial

migration and lymphocyte crawling to inter-endothelial cell connections.ICAM1 also

facilitates transendothelial migration and lymphocyte crawling to inter-endothelial cell

connections. Raising the temperature within the lymphoid organs directly affects T cells by

causing TCR(3 and CD8) components of the immunological synapse to pre-cluster into lipid

rafts. This helps maintain the interactions with APCs and encourage the differentiation of

CD8* T cells into an effector phenotype characterised by increased cytotoxicity,

downregulation of L-selectin, and interferon-y (IFNy) production. A higher body temperature

contributes to the best possible immune response, albeit at the expense of higher metabolic

and neuroendocrine processes.

DIAGNOSIS

Tachycardia, lethargy, and irritability are examples of subtle indications that can be

used to diagnose dangerous bacterial infections with a thorough history and physical

examination. Clinical findings are insufficiently sensitive and specific to identify latent

bacterial infections on their own.31To diagnose occult bacteremia, laboratory testing is

required.Blood culture is still the gold standard and takes around 24 hours on average.32

Sepsis may be detected by total white blood cell count, band count, blood, urine, and

cerebrospinal fluid (CSF) cultures. The test that is most frequently used to screen for occult

bacteremia is the total white blood cell count.

 The threshold of 15,000 for the total white blood cell count (WBC) may be used to

determine whether to begin antibiotic therapy. Nevertheless, empirical treatment based on a

WBC · 15,000 is not indicated in 85% to 95% of instances due to its low predictive value.33

According to recent research, the absolute neutrophil count (ANC) is a test that is

more reliable for identifying occult bacteremia. Nevertheless, the overall absolute neutrophil

count profile is comparable to the white blood cell count profile. ANC is computed using the

following formula: total neutrophils multiplied by the total WBC count = segmented

neutrophils plus band neutrophils; the absolute neutrophil count is obtained by omitting the

decimal point.34, 35

Formula for calculating the ANC

ANC = 10 × WBC count in 1000’s × (Percentage of polymorphs leukocytes +

Percentage of band cells)

Normal value: More than 1500 cells/ mm3

Mild Neutropenia: More than 1000 – Less than 1500/ mm3

Moderate neutropenia: More than 500 – Less than 1000/ mm3

Severe Neutropenia: < 500/ mm3

The gold standard tests are still blood, urine, and chest X-rays; however, it usually

takes between 15 and 16 hours on average to identify positive cultures, and it can take up to

48 hours on average. In this age group, urinary tract infections (UTIs) are the most frequent

cause of occult severe bacterial infections, and they can be identified and verified using

culture techniques. A colony count of more than 1,00,000(105) is indicative. Distinguishing

between viral and bacterial pneumonia just from a chest radiograph is exceedingly

challenging.36

Rectal temperature > 390 C usually presents with common organism in New born and

Infants between 1 to 3 months.

a. Group B streptococci

b. E. Coli K1

c. Listeria monocytogenes

3 months to 36 months

a. H. Influenza type b

b. S pneumonia

c. N Meningitidis

d. Salmonella

Ninety percent of occult bacteremia is caused by these pathogens. Children who have

a temperature higher than 41 degrees Celsius during the pre-H-influenza B era are linked to

9.3% of occult bacteremia. Temperatures above 40.9 °C are linked to 2.8% of occult

bacteremia in the post-H1N1 period.

Risk factors indicating bacteraemia are

1. Temperature ≥ 390 C

2. WBC count > 1500 cells /µL

3. Elevated ANC more than 1000 cells /µL

4. Elevated Erythrocytes sedimentation rate (ESRF)

5. CRP > 6 mg / dl
Complications

A localised infection such meningitis, pneumonia, cellulitis, pericarditis,

osteomyelitis, or suppurative arthritis may result from occult bacteremia, or it may clear on

its own.

Primary prevention: Immunisation with PRP-OMP (2 doses) at 2, 4 months and a

booster at 12 months, or H. influenza B vaccine (3 doses at 2, 4, and 6 months) and booster at

15 months. There is a decrease in the frequency of H-influenza B infection following primary

immunisation.

It is advised to administer the pneumococcal 7 valent conjugate vaccination (PCV 7)

in three doses, the first at 2, 4, and 6 months of age, and the fourth at 12 to 15 months in

addition to the meningococcal vaccine, meningitis prevention.

Treatment

After collecting a blood culture, children with temperatures higher than 39 °C should

begin empirical antibiotic therapy with ceftrioxone 50 mg/kg. If WBC is greater than 15,000

cells/mL, begin antimicrobial treatment.

Clinical findings are insufficiently sensitive and specific to identify latent bacterial

infections on their own. Acute phase reactants could be useful in this particular clinical

scenario.37, 38, 39

ACUTE PHASE REACTANTS

These are the proteins produced in level under the influence of interleukin – 1 when

inflammation form any cause is present. The most important and widely used is C – reactive

Protein (CRP).
  CRP

 IL-6

 IL-8

 G-CSF

 TNF alpha

 IFN-Beta

 Haptoglobin

C – REACTIVE PROTEIN

It is a non-specific marker of inflammation or tissue necrosis. It was the first protein

to be discovered behaving as acute phase reactant. It was named because of its ability to bind

and precipitate the somatic C – polysaccharide of pneumococci. The binding reaction, which

is calcium dependent, results from the specific capacity of CRP to recognize phosphoryl

choline residues which are present in C – polysaccharide. CRP can also bind to some but not

all other substances which contain phosphoryl choline, for e.g., some phospholipids, plasma

lipoproteins and plasma membranes of damaged but not intact cells. In addition, CRP binds

even more avidly to nuclear chromatin, the DNA – histone complex, when this is exposed in

dead or damaged cells or is isolated from preparation of nuclei.40

CRP activates the classical complement pathway having bound to its various ligands

through Cl and does so as efficiently as IgG antibodies. This means that CRP can induce all

known, inflammatory opsonizing and complex – solubilizing activities of the complement

system. In particular complement activation by CRP – Chromatin complexes promotes their

dissolution and the dissociation of the chromatin. A significant biological function of CRP is

scavenging and promoting clearance of cell and tissue debris promoting its clearance from

the circulation and the tissues.40

 CRP is synthesized in the liver in response to inflammatory cytokines. It is a trace

protein in normal healthy individuals, the median value is 0.8 mg/dl with an inter quartile

range of 0.3 – 1.7 mg/l. About 90% of the individuals have levels of less than 3 mg/l and 99%

of them less than 10 mg /l. The serum concentration of CRP rises rapidly and extensively

reaching levels of over 300 mg/dl by 48 hours after acute severe stimulus such as a

myocardial infarction or major trauma or surgery. The circulating CRP concentration

generally falls equally rapidly with uncomplicated resolution of injury or effective treatment

of infection.40

The scope of practical, clinical application of serum CRP measurements is

exceptionally broad comprising (i) screening for organic disease (ii) objective monitoring of

the extent and activity of known infective, inflammatory, necrotic and neoplastic diseases and

(iii) sensitive testing for the presence of inter current infection in patients

immunocompromised by another primary disease and / or therapy. Increased awareness of a

number of these applications a range of commercial assay methods have recently become

available, including homogenous enzyme immunoassay, fluorescence polarization

immunoassay and various new light scattering methods in addition to the already established

nephelometric, gel precipitation and latex agglutination methods.40

The elevation of CRP is found in bacterial sepsis and meningitis. A single

determination of CRP at birth lacks both sensitivity and specificity for infection, but serial

CRP determination at birth and at 12 hours and beyond have been used to manage infants at

risk for sepsis.41, 42

CRP levels fall quickly after efficient elimination of microbial stimulus due to its

short half-life of 19 hours. Thus, CRP may be used as a parameter to identify the time period

when antibiotic therapy can safely be discontinued in case of suspected neonatal septicaemia.
TNF – α

The TNF – α test had shown a moderate accuracy of the diagnosis of paediatric sepsis

both in early onset neonatal sepsis and in later onset neonatal sepsis.43

IL – 6 and IL – 8

IL – 6 and IL – 8 plasma concentrations are considered to be sensitive and specific for

the prediction of pediatric sepsis. These indicators can be detected in blood early but their

short half life of about 12 to 24 hours, limits their use in clinical practice.44

PROCALCITONIN

The procalcitonin was first described as marker of the extent and course of the

systemic inflammatory response to bacterial and fungal infections, physiologically produced

by thyroid C cells as precursor of calcitonin. It is an acute phase protein secreted by several

tissues in response to various endogenous and exogenous stimuli such as cytokines and

lipopolysaccharide, acting as a chemoattractant factor on blood monocytes.45

The studies have shown the procalcitonin is detectable in blood of healthy volunteers

after two hours of injection of small amount bacterial endotoxins, increasing rapidly in 6 – 8

hours and reaching a plateau between 12 and 48 hours. PCT levels increase in severe sepsis

and its plasma concentrations is related to the amount endotoxins. It has been shown that a

great amount of PCT is produced in human liver cells after TNF-α and IL-6 stimulation. The

PCT levels remains continuously high despite a decrease in TNF-α and IL-6 levels in parallel

with the severity of the ongoing infection.

PCT levels are usually found to be in lower range (1 ng/ml) in patients with non-

bacterial and nonfungal “SIRS”. PCT levels can be elevated independently of infectious

process early after multiple trauma or major surgery and in severe burns.46
 The induction of PCT can be caused by different stimuli both in vivo and in vitro. The

PCT protein carries leukocyte chemoattractant properties and modulates the production of

NO by endothelial cells. Bacterial endotoxins and pro-inflammatory cytokines are powerful

stimuli for the production of PCT. The procalcitonin levels are shown to increase within 2

hours of an infection episode, peak at 12 hours and normalize within 2 to 3 days in healthy

adult volunteers. Procalcitonin concentrations has a modestly better sensitivity than does CRP

concentrations but it is less specific.

Granulocyte colony stimulating factor

The granulocyte colony stimulating factor was shown to have sensitivity of 95% and

negative predicting value (NPV) of 99% in detecting infection in neonates of all gestational

ages when a cut off level of 200 pg/ mL was used.47

MICRO – ESR

A micro ESR method using 0.2 ml of blood to fill a plastic disposable tube 230 mm

long and with a 1 mm internal bore was described by Barett. Capillary blood values

correlated well with venous blood micro – ESR and Westergren ESR value. It is simple, but

not very reliable and a value of > 15 mm in 1st hour is suggestive of infection.48

Blood culture

Microbial culture examination is the definitive diagnosis of the Paediatric sepsis. The

biological samples for culture can include blood, urine, cerebrospinal fluid for the detection

of bacteraemia or fungemia, despite their limitations of low sensitivity (sepsis due to bacterial

endotoxins induce negative cultures) and time required for results (48 to 72 h) which can

retard the beginning of antibiotic therapy and compromise the life of the newborns. 49 The
yield of a positive blood culture ranges from 8 – 73% as shown in a study.50 The test needed

must be cheap, easily performed with quick availability of reports.

An ideal diagnostic test for neonatal sepsis must have maximum sensitivity and

specificity. Although, inflammatory markers are sensitive and specific, they are sophisticated

and very expensive and impractical for developing countries. A number of cheap but reliable

laboratory tests have been evaluated for the diagnosis of systemic infection in neonates. The

complete blood count (CBC) with the various neutrophil parameters and C – reactive protein

(CRP) are the most frequently asked.51

REVIEW OF RELATED STUDIES

Ramanan PV et al (2022)aimed to describe the aetiological profile of fever without

focus (FWF) in children aged one to thirty-six months and to identify clinical and laboratory

predictors of specific aetiologies, especially serious bacterial infection (SBI). Among 141

children with FWF, 41 (29%) had SBI, and 21(14.9%) had Dengue fever (DF). Leucocytosis,

neutrophilia, and raised CRP levels were good predictors of SBI. Thrombocytopenia was an

excellent predictor of DF. High fever was significantly associated with SBI and Dengue (p=.004),

and fever beyond 3 days at presentation was significantly associated with SBI (p=<.001). Pyuria

had a high specificity (94.5%) for identifying urinary tract infection (UTI). About 50% of UTIs

were caused by extended spectrum beta lactamase (ESBL) producing organisms.52

Hiremath PM et al (2021) conducted a study to evaluate combination of CRP with

Procalcitonin (PCT) as a marker of SBI in children (Three months to 36 months) with fever

without focus in comparison with only PCT or CRP done separately. Among 31 recruited cases,

14 had occult serious bacterial infection with urinary tract infection being the most common

cause. The combination PCT with CRP had sensitivity of 78.5%, specificity of 100%, and

positive predictive value of 100% and negative predictive value of 85%. Diagnostic accuracy was
90.32% which did not have any statistically significant difference compared to PCT alone but

significant compared to CRP alone.53

Mathew D et al (2019) screened children in the age group of 1-3 years presenting with

temperature >39°C. CRP >6mg/d1 was observed in 25 cases of children who had SBI giving rise

to sensitivity of 75.8%, 46 children who did not have SBI have CRP <6mg/d1 giving a specificity

of 39.3%. Among 96 cases with CRP more than 6mg/d1 only 25 (26%) cases had SBI giving

PPV of 26%. Among 54 cases of CRP <6mg/d1 46(85%) cases did not have SBI giving a NPV of

85.2%.54

Chitra S et al (2017)aimed in using CRP as a marker to differentiate contaminated vs.

true positive blood culture, compare it with other diagnostic tests WBC, ANC, ESR. Out of 140

of children, children with serious bacterial infection are 40, and children without serious bacterial

infection are 100. These children were divided into with and without Serial Bacterial Infection

(SBI). Results analyzed using simple statistical proportions and ROC curve. CRP had sensitivity

of 77 %, specificity of 89% PPV of 74%, NPV of 91% and likelihood ratio of 9.6%. While using

CRP and WBC combination, over all sensitivity increased to 57%, specificity increased to 97%,

PPV increased to 86% and NPV increased to 91%.55

Grover A et al (2013) aimed to study the utility of C-Reactive Protein (CRP) in detecting

serious bacterial infection (SBI) in children with fever. One hundred and nine children (1-36

months of age) with fever (≥ 39°C; < 7 days) without any focus of infection were enrolled. Main

organisms found on cultures were Staphylococcus aureus (5), Staphylococcus epidermidis(3),

Enterobacterfaecalis (1) and Klebsiella species (1) for OB; Escherichia coli (5) and Citrobacter

(1) for UTI and Acinetobacter species in meningitis. Duration of temperature, CRP and band

count were significantly higher in children with SBI as compared to those without SBI (P value <

0.05) The two groups were not significantly different in characteristics like age, sex, degree of

fever, TLC, ANC, and Yale observation score. Higher CRP suggests greater inflammatory

response in SBI. CRP had higher sensitivity (95.2%) and negative predictive values (95%) than
TLC, ANC and band count. The area under the Receiver Operating Characteristic curve was

highest for CRP 0.7 and statistically significant. CRP> 12.8 mg/dL was highly significant in

predicting SBI.56

Pulliam PN et al (2001)conducted a study to determine the diagnostic properties of

quantitative C-reactive protein (CRP) associated with clinically undetectable serious bacterial

infection (SBI) in febrile children 1 to 36 months of age. Seventy-seven patients were enrolled in

the study. Fourteen (18%) had a SBI (6 urinary tract infection; 4 pneumonias, including 1 patient

with Streptococcus pneumoniae bacteraemia; and 4 occult S pneumoniae bacteraemia), and 63

had no SBI. The 2 groups were indistinguishable in age, sex, ED temperature, duration of fever,

and Yale observation scale. CRP concentration, WBC, and ANC were significantly different

between the 2 groups. In a multivariate logistic regression analysis, only CRP remained as a

predictor of SBI. Receiver-operating characteristic analysis demonstrated CRP to be superior to

ANC and to WBC. A CRP cut-off point of 7 was determined to maximize both sensitivity and

specificity. Multilevel likelihood ratios and post-test probabilities were calculated for a variety of

CRP levels. A CRP concentration of <5 mg/dL effectively ruled out SBI.57

In a study by Rodriguez et al (2022), there were 137 patients in all. Of the patients,

41 suffered from serious bacterial infections (29.9%; 95% CI, 22%-38%). Urinary tract

infection was the most common diagnosis (78%), among individuals with severe bacterial

infections. Serious bacterial infections were significantly associated with serum C-reactive

protein levels more than 80 mg/L (odds ratio: 2.79 [1.14,6.86]) and total days with fever

(odds ratio: 2.56 [1.81,3.62]).Without signs of a serious bacterial infection, the majority of

newborns with fever without a cause had self-limited febrile syndromes. There was a

correlation between the number of days with fever in the past and C-reactive protein levels

higher than 80 mg/L and the prevalence of serious bacterial infections. It is necessary to

confirm our findings in other tropical nations.58

 In a review by Escadafal et al (2020), as the global health community became

divided over the use of CRP, it became necessary to determine whether the test could be

useful in preventing antimicrobial resistance and promoting universal health coverage. This

document aims to summarise the "good and the bad" of CRP in various settings in LMICs. In

summary, the literature review indicates that CRP testing could be helpful in low-resource

settings to improve the rational use of antibiotics for febrile patients, but that its positive

predictive value is insufficient to support its use as a stand-alone tool. Instead, CRP testing

would be best utilised in conjunction with a panel of diagnostic tests and algorithms.58

In a study by Kuzmanovic et al (2006), useful advice for treating toddlers who are

feverish medically Children's age, clinical presentation (toxic symptoms), and risk for serious

bacterial infection (sepsis, meningitis, pneumonia, urinary tract infection, etc.) are taken into

consideration when prescribing 0-36 months of age. A toxic look is a clinical presentation

that includes cyanosis, hypo/hyperventilation, lethargy, and poor perfusion. Every feverish

child younger than 36 months who appears toxic needs to be admitted to the hospital,

evaluated for sepsis, and given empirical antibiotic therapy. However, all newborns with

fevers need to be admitted to the hospital; blood, urine, and spinal fluid cultures need to be

obtained; empirical antibiotic therapy needs to start very away. Infants who are febrile and

between the ages of 28 and 90 days should be assessed to see if they fall into the low-risk

category for potentially fatal bacterial infections (Rochester Criteria).For the purpose of

determining the risk of occult bacteriemia in febrile children aged three to six months, the

Yale Observation Scale is advised. Children who are febrile, defined as those between the

ages of three and six months and who seem well, should be regularly monitored without the

use of laboratory testing or antibiotics, and they should be reexamined two to three days later.

If the leukocyte count exceeds 15000/mm3 or the absolute neutrophil count is over

10.000/mm3, blood should be cultured and ceftriaxone 50 mg/kg should be administered in a

single dose to febrile infants aged 3 to 36 months who have a temperature of 39 degrees

Celsius and above without any adverse symptoms.59

In a study by Kim et al (2022), 4252 (42.6%) of the 9989 feverish children had their

white blood cell and CRP levels tested. 33 (32.3%; 95% confidence interval [CI], 25.0%-

40.7%) of the 133 (3.1%) recruited children with EL (233 5.5%) developed SBI, which

included 33 cases of pyelonephritis, 5 deep abscesses, 3 lobar pneumonia cases, and 2 soft

tissue infections. The CRP cutoff of 7.8 mg/dL resulted in the following results: 81.4% (95%

CI, 67.4%-90.3%) for sensitivity; 80.0% (95% CI, 70.6%-87.0%) for specificity; 4.1 for

positive likelihood; 66.0% (95% CI, 52.6%-77.3%) for negative predictive value; 90.0%

(95% CI, 81.5%-94.9%) for negative predictive value; and 66.0% (95% CI, 55.6%-75.0%)

for positive predictive value.When the CRP level was 16.1 mg/dL or over, the resulting PP

was 84.2% (95% CI: 62.1%-94.5%) and the LR was 11.2. When the CRP level was less than

3.4 mg/dL, the PP was 2.4% (95% CI: 0.3%–14.6%) and the LR was 0.05.In febrile infants

with EL, there is a substantial correlation between a high CRP content and the occurrence of

SBI.60
 MATERIAL AND METHODS

A hospital based cross sectional study was undertaken in the department of Pediatrics,

District hospital, Ballari among children aged 1 month to 36 months of age during the study

period between September 2022 to September 2023. Clearance from institution ethics

committee was obtained before the study was started. An informed, bilingual and written

consent was obtained before the study was started. The Sample size was calculated as

follows,

Based on the study conducted by Pulliam PN et al19 Prevalence of serious bacterial

infections (SBI) was 18%.

Formula: n = Zα2 * pq / d2 Where, n is the required sample size. Zα is the standard normal

deviate, which is equal to 1.96 at 95% confidence interval. p is the prevalence in the

population of the factor under study.

q = 100-p d = Absolute precision taken as 6% p = 18% q = 82% n = number of samples is to

be studied n = Zα2 * pq / d2 = (1.96)2* 18* 82 / (6)2

= 5670.20/36

= 158

The inclusion and exclusion criteria were as follows,

INCLUSION CRITERIA:

 Children aged 1-36 months

 Fever more than 12 hours up to 7 days

 Without obvious focus of infection on clinical examination

EXCLUSION CRITERIA:

 Children who have received prior antibiotics and vaccines

  Children with underlying immunological disease

METHODOLOGY

 Children in the age group of 1-36 months presenting to the outpatient department was

screened for temperature >39°C and who satisfied inclusion criteria were included in

the study. Temperatures will be recorded either in the axillary or rectal areas.

 Informed consent was obtained from parents or guardian & clearance of Institutional

Ethical Committee Review Board.

 On admission complaints, history and treatment for present illness, past history,

socioeconomic status and immunisation status was recorded in the reliable Informant.

 Nutritional status and vitals will be recorded.

 A thorough clinical examination was done. Positive findings and relevant negative

findings regarding general examination, cardiovascular systems, respiratory systems,

gastrointestinal and central nervous system were noted.

 Blood samples were taken for total WBC count, ANC, ESR and CRP and at the same

time samples for blood culture.

 Blood cultured in various media incubated overnight and colony morphology was

read.

 Urine analysis, urine culture, colony count, chest radiograph was done.

 CSF analysis was done for selected cases (children who had altered sensorium and

seizures).

 Patients were reviewed thereafter.

 CRP was done by slide agglutination method. Qualitative CRP followed by Semi-

quantitative CRP was performed. CRP-Agglutination in highest serum dilution

corresponds to amount of CRP in mg/dl. The findings were recorded.

  CRP Estimation: It is based on the principle of agglutination. One drop of test

specimen is placed on a slide after centrifugation using a disposable pipette to which a

drop of CRP reagent was added. Both test specimen and the reagent to be uniformly

mixed over the entire circle, using a mixing stick. The slide is gently rocked to and fro

and considered Negative if no agglutination occurs, if positive CRP concentration is

more than 0.6 mg/dL. Dilution and semiquantitative test was done for all cases. S x D

= mg/dl =Quantitative CRP was calculated for all cases.

Statistical Analysis:

Data entry was done using M.S. Excel and it will be statistically analysed using Statistical

package for social sciences (SPSS Version 16) for M.S Windows.

Descriptive statistical analysis was carried out to explore the distribution of several

categorical and quantitative variables. Categorical variables were summarized with n (%), while

quantitative variables were summarized by mean ± S.D. All results were presented in tabular

form and are also shown graphically using bar diagram or pie diagram as appropriate.

Inferential Statistics: The difference in the two groups was tested for Statistical

Significance using Parametric tests such as t-test and categorical variables tested by chi square

test. P-value less than 0.05 was considered to be statistically significant.

 RESULTS

Table 1. Distribution of the study groups according to age group

Age in months Frequency Percent

1 – 12 months 64 40.5

13 – 24 months 44 27.8

25 – 36 months 50 31.6

Total 158 100

Chart 1. Distribution of the study groups according to age group

45
40.5
40

35 31.6
30 27.8

25

20 Percent

15

10

0
1 – 12 months 13 – 24 months 25 – 36 months

In this study about 40.5% of the cases were aged between 1 – 12 months and 31.6%

were aged between 25 – 36 months.

 Table 2. Distribution of the study groups according to Sex

Sex Frequency Percent

Male 82 51.9

Female 76 48.1

Total 158 100

Chart 2. Distribution of the study groups according to Sex

51.9
52

51

50
Percent
49 48.1

48

47

46
Male Female

About 51.9% of the cases were males and 48.1% were females.
 Table 3. Distribution of the study groups according to Duration of fever

Duration of fever Frequency Percent

1 – 24 hours 48 30.4

25 – 48 hours 55 34.8

49 – 72 hours 55 34.8

Total 158 100

Chart 3. Distribution of the study groups according to Duration of fever

34.8 34.8
35

34

33

32
Percent
31 30.4

30

29

28
1 – 24 hours 25 – 48 hours 49 – 72 hours

The duration of fever was between 25 – 48 hours and 49 – 72 hours in 34.8% of the

cases each in this study.

 Table 4. Distribution of the study groups according to total leukocyte count

TLC CRP

< 6 mg/dl > 6 mg/dl

< 15000 18 (81.8) 90 (66.2)

> 15000 4 (18.2) 46 (33.8)

Total 22 (100) 136 (100)

χ2 Value=2.142 df=1 p value, sig= 0.143, NS

Chart 4. Distribution of the study groups according to total leukocyte count

90 81.8
80
70 66.2

60
50
40 33.8 < 15000
30 > 15000
18.2
20
10
0
< 6 mg/dl > 6 mg/dl
CRP

About 66.2% of the cases with CRP values of more than 6 mg had leukocyte count of

less than 15000 and 33.8% had count of more than 15,000. This difference was not

statistically significant.
 Table 5. Distribution of the study groups according to Absolute neutrophil count

ANC CRP

< 6 mg/dl > 6 mg/dl

< 1000 10 (45.5) 67 (49.3)

> 1000 12 (54.5) 69 (50.7)

Total 22 (100) 136 (100)

χ2 Value=0.110 df=1 p value, sig= 0.74, NS

Chart 5. Distribution of the study groups according to Absolute neutrophil count

56 54.5

54
50.7
52
49.3
50
48 < 1000
45.5
46 > 1000

44
42
40
< 6 mg/dl > 6 mg/dl
CRP

This study had shown that, about 54.5% of the cases with CRP value of more than 6

mg/dl had absolute neutrophil count of less than 1000 and 45.5% had count of more than

1000. This difference was not statistically significant.

 Table 6. Distribution of the study groups according to Erythrocyte sedimentation rate

ESR CRP

< 6 mg/dl > 6 mg/dl

< 15 9 (40.9) 41 (30.1)

> 15 13 (59.1) 95 (69.9)

Total 22 (100) 136 (100)

χ2 Value=1.014 df=1 p value, sig= 0.314, NS

Chart 6. Distribution of the study groups according to Erythrocyte sedimentation rate

69.9
70 59.1
60
50 40.9
40 30.1 < 15
30 > 15
20
10
0
< 6 mg/dl > 6 mg/dl
CRP

About 59.1% of the cases with CRP levels of more than 6 mg/dl had Erythrocyte

sedimentation rate of less than 15 and 40.9% had level of more than 15 mg/dl. This difference

was not statistically significant.

 Table 7. Distribution of the study groups according to blood culture results and CRP

levels

Blood culture CRP

< 6 mg/dl > 6 mg/dl

Negative 15 (68.2) 97 (71.3)

Positive 7 (31.8) 39 (28.7)

Total 22 (100) 136 (100)

χ2 Value=0.091 df=1 p value, sig= 0.763, NS

Chart 7. Distribution of the study groups according to blood culture results and CRP

levels

80
71.3
68.2
70

60

50

40
31.8 Negative
28.7
30
Positive
20

10

0
< 6 mg/dl > 6 mg/dl
CRP

This study had shown that, about 31.8% of the cases with CRP of less than 6 mg/dl

and 28.7% with CRP levels of more than 6 mg/dl had positive blood cultures. This difference

was not statistically significant.

 Table 8. Distribution of the study groups according to urine culture results and CRP

levels

Urine culture CRP

< 6 mg/dl > 6 mg/dl

Negative 21 (95.5) 124 (91.2)

Positive 1 (4.5) 12 (8.8)

Total 22 (100) 136 (100)

χ2 Value=0.459 df=1 p value, sig= 0.498, NS

Chart 8. Distribution of the study groups according to urine culture results and CRP

levels

95.5
100 91.2
90
80
70
60
50 Negative
40 Positive
30
20 8.8
4.5
10
0
< 6 mg/dl > 6 mg/dl
CRP

About 4.5% of the cases with CRP levels of less than 6 mg/dl and 8.8% of the cases

with CRP levels of more than 6 mg/dl had positive urine cultures. This difference was not

statistically significant.
Table 9. Distribution of the study groups according to duration of fever and CRP levels

Duration of fever CRP

< 6 mg/dl > 6 mg/dl

1 – 24 hour 6 (27.3) 42 (30.9)

25 – 48 hours 10 (45.5) 45 (33.1)

49 – 72 hours 6 (27.3) 49 (36.0)

Total 22 (100) 136 (100)

χ2 Value=1.330 df=2 p value, sig= 0.514, NS

Chart 9. Distribution of the study groups according to duration of fever and CRP levels

50 45.5
45
40 36
33.1
35 30.9
27.3 27.3
30
CRP < 6 mg/dl
25
CRP > 6 mg/dl
20
15
10
5
0
1 – 24 hour 25 – 48 hours 49 – 72 hours

About 30.9% of the cases with fever duration of 1 – 24 hours, 33.1% with 25 – 48

hours and 36.0% with fever of 49 – 72 hours had CRP levels of more than 6 mg/dl. This

difference was not statistically significant.

 Table 10. Distribution of the study groups according to age in months and CRP levels

Age in months CRP

< 6 mg/dl > 6 mg/dl

1 – 12 months 10 (45.5) 54 (39.7)

13 – 24 months 6 (27.3) 38 (27.9)

25 – 36 months 6 (27.3) 44 (32.4)

Total 22 (100) 136 (100)

χ2 Value=0.312 df=2 p value, sig= 0.856, NS

Chart 10. Distribution of the study groups according to age in months and CRP levels

50
45.5
45
39.7
40
35 32.4
30 27.3 27.9 27.3
25 CRP < 6 mg/dl

20 CRP > 6 mg/dl

15
10
5
0
1 – 12 months 13 – 24 months 25 – 36 months

About 39.7% of the cases aged between 1 – 12 months, 27.9% of the cases aged

between 13 – 24 months and 32.4% of the cases aged between 25 – 36 months had CRP

values of more than 6 mg/dl. This difference was not statistically significant.
Chart 11. Receiver operating characteristic curve of different test in comparison with

blood culture

Table 11. Area under curve

Area Under the Curve

Test Result Variable(s) Area

TLC .447
ANC .600
ESR .441
CRP .512

The test result variable(s): TLC, ANC,

ESR, CRP has at least one tie
between the positive actual state
group and the negative actual state
group. Statistics may be biased.
 The area under curve for Total leukocyte count was low (44.7%), Absolute neutrophil

count was 60%, ESR was 44.1% and CRP was 51.2%.
 Table 12. Predictive accuracy of different tests in comparison with blood culture

Cut off point Sensitivity Specificity PPV NPV

WBC 11250 52.2 38.4 22.0 67.6

ESR 17 65.2 34.8 28.7 70.0

CRP 6 97.8 97.3 93.75 99.1

ANC 1000 63.04 53.6 35.8 77.9

The sensitivity was WBC at a cut off value of 112.5 was 52.2%, specificity was

38.4%, PPV was 22.0% and NPV was 67.6%. The Sensitivity for ESR with a cut off value of

17 was 65.2%, specificity was 34.8%, PPV was 28.7% and NPV was 70.0%. The sensitivity

of CRP at a cut off value of 6 was 97.8%, specificity was 97.3%, PPV was 93.75% and NPV

was 99.1%. The sensitivity of ANC at a cut off value of 1000 was 63.04%, specificity was

53.6%, PPV was 35.8% and NPV was 77.9%.

 DISCUSSION

Feverish ailments in young children make up 20% of paediatric visits. 1,2 Aural and

axillary thermometry are two less invasive ways to take a person's temperature. However, the

outcomes generated by these methods are not interchangeable. 3, 4 Rectal thermometry is now the

outpatient reference standard, so it should be used when assessing a child's temperature. A precise

measurement of the patient's temperature is crucial if fever criteria are to be followed. This is due

to the fact that these suggestions take effect as soon as a patient's temperature rises above a

predetermined level. Fever is caused by interactions between the host's immune system and viral

and non-infectious processes.4

Less than week-long fevers usually start suddenly and don't show any localising

symptoms or indicators. In children under 36 months old, it is more common. If an infant is

between one and thirty-six months old, has received all of their vaccines, and doesn't seem to be

feverish, they can be a good candidate for a laboratory screening test. Conversely, if a newborn

appears toxic and is younger than 29 days, a sepsis work-up should be done. Most fever bouts in

a normal host can be diagnosed by carefully reviewing the patient's medical history and doing a

physical examination. Typically, laboratory testing is not necessary. Typically, laboratory

testing is not necessary. Those who are immunocompromised and feverish are more likely

than newborns, babies under three months old, children three to 36 months old, and feverish

youngsters to get a serious bacterial illness.5

There is currently no published advanced diagnostic methodology that is standard or

recommended for the detection of FUO. An alteration in the illness pattern and improved

diagnostic techniques have resulted in a change in the etiological components that cause FUO. 7, 8

Measuring white blood cells and differential erythrocyte sedimentation rate, urine analysis, C

reactive protein, morphological changes in peripheral neutrophils, microscopic assessment of

buffy coat, and quantitative blood cultures are examples of routine diagnostic tests. 6
 C-reactive protein (CRP) is the classic acute-phase protein. It was first demonstrated

to precipitate in conjunction with the C-polysaccharide fraction of pneumococcus. Among

human acute-phase proteins, CRP is unique in that it frequently occurs at lower

concentrations of nanograms per millilitre and rises sharply to hundreds of micrograms per

millilitre in a matter of three days. The C-reactive protein level rises and falls more quickly

after the infectious process is resolved than the erythrocyte sedimentation rate.9, 10, 11, The

concentration of CRP increases 103-fold after an injury or illness, and it is easy, rapid, and

accurate to measure in a clinical laboratory.12

A hospital based cross sectional study was undertaken in the department of Pediatrics,

District hospital, Ballari among children aged 1 month to 36 months of age.

Age group

Approximately 40.5% of the cases in this study were between the ages of 1 and 12

months, and 31.6% were between the ages of 25 and 36 months. In a study by Buendia

Rodriguez et al, the median age of the children was 14 months.58 In a study by Pulliam et al,

age was significantly different in cases with and without SBI.57 In a study by Chiu et al, the

mean age was 46.8 days and invasive bacterial infections was 45.4 days.61

Sex

Males made up about 51.9% of the cases, while females made up 48.1%. In contrary

to these results, Buendia Rodriguez et al reported that, about 57% of the cases were

females.58 In a study by Pulliam et al, there was a significant difference in sex between the

cases with or without SBI.57 In a study by Chiu et al, males outnumbered females.61

Duration of fever
 In 34.8% of the cases in this study, the fever lasted between 25 and 48 hours and 49

and 72 hours, respectively. In a study by Buendia Rodriguez et al, the median duration of

fever 3 days in cases without SBI and 7 days in cases with SBI.58 A study by Pulliam et al

had shown a significant difference between the cases with or without SBI.57

Total leukocyte count

Leukocyte counts of fewer than 15,000 and more than 15,000 were found in

approximately 66.2% and 33.8%, respectively, of the cases with CRP values more than 6 mg.

There was no statistically significant difference. In a study by Chitra et al, WBC of more than

or equal to 15000 was observed in 15 cases with serious bacterial infection.55 In a study by

Buendia Rodriguez et al, total leukocyte count was more than 15000 in 49% of the cases

without and 53% with SBI.58 In a study by Chiu et al, TLC was 11500 in controls and 12200

in cases with invasive bacterial infections.61

Absolute neutrophil count and CRP

Leukocyte counts were fewer than 15000 in roughly 66.2% of individuals with CRP

values greater than 6 mg, and higher than 15000 in 33.8% of cases. The difference was not

significant in terms of statistics. In a study by Chitra et al, the ANC more than 10000 was

observed in 15 cases with serious bacterial infection.55 In a study by Chiu et al, the neutrophil

percentage was 41.6% in controls and 48.6% in cases with invasive bacterial infections.61

Erythrocyte sedimentation rate and CRP

About 40.9% of individuals with CRP levels above 15 mg/dl and 59.1% of cases with

CRP levels over 6 mg/dl had erythrocyte sedimentation rates below 15. There was no

statistically significant difference. ESR of more than or equal to 15 mm was observed in 22

cases in a study by Chitra et al.55

Blood culture and CRP

According to this study, blood cultures were positive in roughly 31.8% of the cases

with CRP levels less than 6 mg/dl and 28.7% of the cases with CRP levels more than 6 mg/dl.

There was no statistically significant difference. In a study by Chitra et al, serious bacterial

infection was observed in 31 cases with serious bacterial infection.55

Urine culture and CRP

Urine cultures were positive in 4.5% of individuals with CRP levels less than 6 mg/dl

and 8.8% of cases with CRP levels more than 6 mg/dl. There was no statistically significant

difference.

Duration of fever and CRP

More than 6 mg/dl of CRP was found in about 30.9% of cases with fevers lasting one

to 24 hours, 33.1% with fevers lasting 25 to 48 hours, and 36.0% with fevers lasting 49 to 72

hours. There was no statistically significant difference. A study by Buendia Rodriguez et al

had observed that, the median duration of fever in cases without serious bacterial infections

was 2.52 days and in cases with SBO was 2.67 days.58

Age and CRP

CRP values greater than 6 mg/dl were present in about 39.7% of cases between the

ages of 1 and 12 months, 27.9% of cases between the ages of 13 and 24 months, and 32.4%

of cases between the ages of 25 and 36 months. There was no statistically significant

difference.

Predictive accuracy
 The absolute neutrophil count was 60%, the CRP was 51.2%, the ESR was 44.1%,

and the total leukocyte count had a low area under the curve (44.7%). 52.2% was the

sensitivity, 38.4% was the specificity, 22.0% was the PPV, and 67.6% was the NPV for WBC

at a cutoff value of 112.5. With a cut-off value of 17, the sensitivity for ESR was 65.2%,

specificity was 34.8%, PPV was 28.7%, and NPV was 70.0%. At a cutoff value of 6, CRP

had a 97.8% sensitivity, 97.3% specificity, 93.75% PPV, and 99.1% NPV. At a cut-off value

of 1000, ANC's sensitivity was 63.04%, specificity was 53.6%, PPV was 35.8%, and NPV

was 77.9%. A study by Pulliam et al had noted that, ROC for CRP was 0.905 which was

superior to ANC and Total Leukocyte count. A CRP cutoff of 7 determined to maximize the

sensitivity and specificity. The sensitivity was 79% and specificity was 91% at a cut off level

of 7.57 In a study by Chiu et al, the area under curve for neutrophil percentage was 0.583 and

CRP was 0.743.61

According to this study, CRP is more sensitive and specific than other markers in

identifying children who have an undetected serious bacterial infection from children who do

not have a bacterial disease. Based on the CRP concentration curve where a value greater

than 4.5 mg% maximises sensitivity. Rather than a total WBC of more than or equal to

15,000, a CRP concentration of more than 6 mg/dl is beneficial.62, 63, 64

 CONCLUSION

This study was undertaken in order to determine the usefulness of C Reactive Protein

in cases fever without focus in children. This study had demonstrated that, the C reactive

protein is useful in prediction of fever in children without any focus. It has been considered

as better predictive test than ANC and TLC. But this study is not without limitations where

this is a cross sectional study which is weaker by methodology. The sampling method was

not followed in this study. But this study was able to bring out many important aspects of

usefulness of C reactive protein in diagnosis of Occult bacterial infections. Further studies in

this direction can bring out more facts about the usefulness of CRP in diagnosis of fever

without focus.
 SUMMARY

 Approximately 40.5% of the cases in this study were between the ages of 1 and 12

months, and 31.6% were between the ages of 25 and 36 months.

 Males made up about 51.9% of the cases, while females made up 48.1%.

 In 34.8% of the cases in this study, the fever lasted between 25 and 48 hours and 49

and 72 hours, respectively.

 Leukocyte counts of fewer than 15,000 and more than 15,000 were found in

approximately 66.2% and 33.8%, respectively, of the cases with CRP values more

than 6 mg.

 Leukocyte counts were fewer than 15000 in roughly 66.2% of individuals with CRP

values greater than 6 mg, and higher than 15000 in 33.8% of cases. The difference

was not significant in terms of statistics.

 About 40.9% of individuals with CRP levels above 15 mg/dl and 59.1% of cases with

CRP levels over 6 mg/dl had erythrocyte sedimentation rates below 15. There was no

statistically significant difference.

 According to this study, blood cultures were positive in roughly 31.8% of the cases

with CRP levels less than 6 mg/dl and 28.7% of the cases with CRP levels more than

6 mg/dl. There was no statistically significant difference.

 Urine cultures were positive in 4.5% of individuals with CRP levels less than 6 mg/dl

and 8.8% of cases with CRP levels more than 6 mg/dl. There was no statistically

significant difference.

 More than 6 mg/dl of CRP was found in about 30.9% of cases with fevers lasting one

to 24 hours, 33.1% with fevers lasting 25 to 48 hours, and 36.0% with fevers lasting

49 to 72 hours. There was no statistically significant difference.

 CRP values greater than 6 mg/dl were present in about 39.7% of cases between the

ages of 1 and 12 months, 27.9% of cases between the ages of 13 and 24 months, and

32.4% of cases between the ages of 25 and 36 months.

 The absolute neutrophil count was 60%, the CRP was 51.2%, the ESR was 44.1%,

and the total leukocyte count had a low area under the curve (44.7%). 52.2% was the

sensitivity, 38.4% was the specificity, 22.0% was the PPV, and 67.6% was the NPV

for WBC at a cutoff value of 112.5.

 With a cut-off value of 17, the sensitivity for ESR was 65.2%, specificity was 34.8%,

PPV was 28.7%, and NPV was 70.0%.

 At a cutoff value of 6, CRP had a 97.8% sensitivity, 97.3% specificity, 93.75% PPV,

and 99.1% NPV.

 At a cut-off value of 1000, ANC's sensitivity was 63.04%, specificity was 53.6%,

PPV was 35.8%, and NPV was 77.9%.

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