Kilic SS. The child with fever. Recent Advances in Pediatrics, Jaypee Brothers Medical Publishers, New Delhi, 441 ISBN 81-8061-297-X , pp261-275, 2004





Fever is an important part of the bodys defense against infection and indicates that something is wrong with a child. There is no question that fever is a source of great consternation for parents and also physicians . Febrile infants and children are frequently brought to primary care and emergency physicians. The presentation of a young child with high fever and no obvious focus of infection on evaluation are common problems in emergency departments. It is the role of the physician to determine which of these cases may represent serious illnesses that require further evaluation and treatment. Recent studies, however, have greatly enhanced physicians' understanding of how to manage these young patients best1-4. Physicians in private office settlings tend to adopt strategies involving less diagnostic testing or empiric treatment, whereas hospital-based physicians are most likely to test and treat.

Enhancement of the role of ambulatory pediatrics in the care of febrile children may be more cost-effective than anticipatory hospitalization.

Definition of Fever

Fever is defined in children younger than 2 months of age as body temperature (rectal temperature) greater than or equal to 38 degrees centigrade. In older children, an oral temperature of 37.8C (100F) is considered abnormal (Table 1 gives temperature conversion of Fahrenheit to Celsius). The rectal temperature provides a close approximation to core body temperature, with rectal temperatures of 38.0oC and above generally being regarded as fever. Oral and axillary temperatures are generally lower than rectal temperatures (approximately 0.5 and 0.8 oC, respectively, provided that thermometers are left in place for at least one minute). Normal body temperature changes slightly throughout the dayusually lower in the morning and higher in the evening. Physical activity may cause to increase in body temperatures in children 5.

The majority of children with fever are younger than 3 years of age. Minor and life-threatening infections, including respiratory tract infections, gastroenteritis, sepsis, and meningitis, are common in this age group.


The difference between fever and hyperthermia
Hyperthermia almost never occurs in response to infection (including ARI); it typically arises during heavy physical activity or overdressing in a hot, humid environment. Fever, on the other hand, is an upward adjustment of the set-point. Unlike hyperthermia, therefore, fever does not represent a failure of temperature control, but rather an upward shift of the regulated temperature 6. Fever may be a result of overbundling a small infant. When this is suspected, the child may be unbundled and the temperature retaken in 15 to 30 minutes. If this repeat temperature is normal in a healthy appearing infant, it may be considered that infant is afebrile.



Fever mechanism

The elevation in body temperature is mediated by an increase in the hypothalamic heat regulatory set point. Thermosensitive neurons located in hypothalamus respond to changes in blood temperature as well as to direct neural connections with cold and warm receptors located in skin and muscle. Pyrogens act in the brain to reset the body's thermostat to a higher temperature than normal. In order to raise the body's temperature, the brain spreads a message throughout the body to "conserve heat". Prostaglandin resets the heat regulatory set point, leading to constriction of the blood vessels, heat production, and elevation of temperature 7.

Data from laboratory immunological studies and a limited number of animal studies suggest that a moderate rise in body temperature may improve immune defence against infection and may therefore be desirable. Fever activates the bodys immune system, which speeds-up the production of antibodies, white blood cells, and other infection-fighting agents. Regardless of whether fever is associated with infection, connective tissue disease, or malignancy, the thermostat is reset in response to endogenous pyrogens including the cytokines interleukin-1b (IL-1b) and IL6, tumor necrosis factor-a (TNF- a), and interferon- b (IFN-b) and IFNg. Stimulated leukocytes and other cells produce lipids that also serve as endogenous pyrogens which have a number of direct effects on the immune response, including enhancement of chemotaxis, oxidative activity in neutrophils, B-lymphocyte proliferation and antibody production, and T-lymphocyte activation. One of the well known lipid mediator is prostaglandin E2. Exogenous pyrogens include microbes, microbial toxins, or other products of microbes which stimulate macrophages and other cells to produce endogenous pyrogens7.

Viral or bacterial infection

During the first two years of life, children experience an average of five acute fevers. The immune system is not completely mature at birth and may not be well developed in some aspects until a child reaches school age, therefore small children are more likely to get infections. The overwhelming majority of nontoxic but febrile infants and young children have a viral infection 8. They can be managed on an outpatient basis. The criteria of the outpatient basis treatment include no evidence of focal infection, a peripheral white blood cell count (WBC) between 5000/mm3 and 15.000 /mm3, with less than 1500 bands/mm3 , and urinalysis yielding normal findings.

Viral illnesses occasionally cause to development of bacteremia. There are a number of reports in the medical literature suggesting an increased risk for bacteremia in patients with varicella. Bacteremia with Group A Streptococcus and Staphylococcus aureus has been most commonly reported in these patient groups.

The incidence of bacterial disease is found to be approximately 10% in febrile infants 1 to 2 months of age and approximately 13% in febrile infants younger than 1 month of age 9. The reason for the relatively high overall rate of bacterial disease in this age is likely related to the lower level of immunocompotence that has been demonstrated in younger infants. The prevalance of bacteremia in children aged 3-36 months with fever without source is reported to be from 3% to 11% with a mean probability of 4.3% in children with a temperature of 39 oC or more 10,11. In the same age group, the prevalance of bacteremia with fever and clinical otitis media or pneumonia has been found as 5%, 2.7%, respectively. Many studies showed that in children under 24 months of age with a fever over 390C who have otitis media or pneumonia a blood culture should be taken 12,13.

In Baraffs extensive study6 , children under 3 months of age and between 3-36 months of ages were analysed. In low risk infants <3 months of age, the prevalance of occult bacteremia is 0.2-1%, bacterial enteritis is 0.2-1%, urinary tract infection is 0.2-1%, and bacterial meningitis is 0%; in the 3-36 month group with a temperature over 390C, the prevalance of occult bacteremia is 2.6-6.1% . The major pathogen was S.pneumonia, followed by Salmonella and N meningitides. Before H. nfluenzae Type b vaccine, the prevalance of occult bacteremia ranged from 2.3 to 11.6%, which has been reduced over 90%. Because of widespread vaccination against Haemophilus influenzae infection, Streptococcus pneumoniae has become the most common cause of bacteremia in infants 14,15. Streptococcal bacteremia affects fewer than 2 percent of well-appearing older infants and young children with a temperature above 39C. Children younger than 24 months also have a poor antibody response to encapsulated bacteria. Approximately 10 percent of infants and young children with fever and S. pneumoniae bacteremia progress to a serious bacterial infection, and from 3 to 6 percent progress to meningitis.The risk of pneumococcal bacteremia varies based on the patient's age, temperature and white blood cell count. The use of the pneumococcal vaccine for the prevention of invasive infection related to Streptococcus pneumonia may radically alter the approach to this clinical problem. Preliminary reports indicate that the vaccine is almost 95 percent effective against the invasive pneumococcal serotypes included in the vaccine 16, 17.

Urinary tract infection (UTI) remains as a significant risk in well-appearing but febrile infants and young children. UTIs are a frequent (15% to 20%) cause of fever in children <3 months of age and occasional (2% to 5 %) cause of fever in boys 3 to 6 months and girls 3 to 12 months of age. Up to 20 percent of febrile young infants have been reported to have positive urine cultures. Urine collected by bag is not sterile and should not be sent for culture. Although suprapubic aspirate is the gold standard for urine culture, many physcians do not routinely perform such an invasive procedure and a catheterized sample is now acceptable. In all boys <6 months and girls <12 months, a urine obtained by bladder catheterization should be sent for urinalysis or Gram stain and culture. Infants with pyuria or bacturia should be treated immediately 18-21.

Infants with bacterial disease are often difficult to identify on the basis of clinical presentation alone.To ensure the early identification of all infants with serious bacterial illness, many physcians routinely use evaluation of sepsis, hospitalization, and expectant treatment with antibiotics for all febrile infants. This approach arguably subjects many infants to excessive testing and exposes them to unnecessary risks and morbidity.

Serious bacterial infection

Serious bacterial infection is defined as bacterial growth of a known pathogen in cultures of blood, urine, spinal fluid, or stool. Sepsis, meningitis, pneumonia, bone and joint infections, urinary tract infections, and enteritis are considered as serious bacterial infections.

Toxic appearance

Toxic is defined as a clinical picture consistent with the sepsis syndrome. Toxic appearing children are pale or cyanotic, lethargic or irritable and may have tachypnea and tachycardia with poor capillary refill. Infants less than 12 weeks of age who appear toxic have a 17% probability of serious bacterial infections including an 11% probability of bacteremia and a 4% probability of meningitis 22. The probability of serious bacterial infections in older toxic-appearing febrile children has been reported to range from approximately 10% to 90% depending on the criteria used to define toxic.

Risk criteria of infants with fever

Fever in the first two months of life may be a sign of possible serious bacterial infection and referral to hospital is indicated for further investigation and treatment. All toxic-appearing infants, children and all febrile infants less than 28 days of age should be hospitalized for parenteral antibiotic therapy. Febrile infants between 28 to 90 days of age defined at low risk by specific clinical and laboratory criteria may be managed as outpatient if close follow-up is assured.

Among the non-toxic appearing febrile infants, clinical evaluation and laboratory investigations can be used to define a population of low-risk infants who can be managed safely as outpatients. There are several tools that may be useful in evaluating febrile infants. The Rochester criteria were developed by Dagan et al 23 in 1985 to determine a group of infants ≤60 days of age who are less at risk of occult bacterial infection and can be managed on an outpatient basis. These low risk criteria which are known as the Rochester criteria are presented in Table 2. Jaskiewicz et al24 reported that the negative predictive value of this low risk criteria was 98.9% for serious bacterial infections (SBI), and 99.5% for bacteremia. They suggested that infants who meet the low risk criteria can be carefully observed without administering antimicrobial agents. An alternative strategy for the management of the low risk febrile infant is to administer a single dose of intramuscular ceftriaxone following a complete laboratory evaluation for suspected sepsis (a culture of blood, cerebrospinal fluid-CSF, and urine, a complete blood cell and differential count, urine analysis, examination of cerebrospinal fluid for cells, glucose, and protein) and to provide as careful outpatient follow-up as possible. It is important to know that the administration of parenteral antibiotics to a febrile infant is not substitute for careful observation. The decision to observe a low risk febrile infant at home with or without parenteral antibiotics should be made only after careful assessment of the caregiver. Caregivers should have a telephone, have a telephone number of the physician, and if the infants condition changes, be able to meet the physician within 30 minutes. Infants who meet the Rochester criteria but who cannot be adequately observed at home should be hospitalized.

Baker et al9 subsequently developed alternative criteria in 1993, the Philadelphia Criteria, to detemine which infants more than 28 days of age are at high risk of bacterial infection. These criteria are white blood cell count of at least 15.000/mm3 , a spun urine specimen that has 10 or more white blood cells per high-power field or that is positive on bright-field, cerebrospinal fluid (CSF) with a white-cell count 8 /mm3 or a positive Grams stain, or a chest X-ray revealed an infiltrate. The Philadelphia protocol for outpatient management without antibiotics of febrile infants at low risk for bacteremia remains practical, reliable, and safe. The avoidance of the unnecessary use of antibiotics, reduces costs and decreases the risk for antibiotic-resistant pathogens.

Both criteria (the Rochester and the Philadelphia) have been widely used in the evaluation of the young febrile infants. However, screening tools do not seem to be fully effective in identifying febrile infants younger than 1 month who are at low risk for bacterial disease. Therefore, most physicians agreed to continue to be conservative and prefer to hospitalize febrile infants younger than 1 month of age and emprically administer antibiotics to them.

Fever- WBC count and risk of bacteremia

The risk of serious bacterial infection is greater in younger children and in those with higher temperatures and white blood cell counts. But little evidence regarding what temperature significantly increases the risk for serious bacterial infection in younger infants with lower fevers. The positive predictive value of a high temperature (> 38.5 0C) in predicting bacterial infection has been found as 40% in febrile infants ≤60 days of age by Jaskiewicz et al. In the same study group, the negative and positive predictive values for neutrophilia (> 10 x 109/L) have been found as 47% and 77% respectively, and 2.5% of patients blood cultures were positive for a pathogenic organism24 . Another study pointed out that an infant or a young child with a temperature higher than 40.9C (105.6F) is more than three times more likely to harbor bacteremia than an infant or a young child with a temperature of 39C4.

Additionally, the clinician needs to recognize that serious and life threatening infectious diseases occasionally may be present in an infant without fever to this degree and that hypothermia (rectal temperature of less than 360C or 96.80F) may be associated with serious infectious diseases in young infants.

Harmful effects of fever

A fever in a young child can be very frightening to a parent. But as time goes by, even new parents begin to realize that fever is a common problem for young children. Harmful effects of fever alone are rare and are found mainly in children who are extremely debilitated or who have severe pulmonary or cardiovascular disease because of the increased oxygen consumption and cardiac output. This might be particularly relevant in a child with very severe pneumonia, who may suffer from hypoxemia.

High fevers or rapid rise in temperature in young children (especially between 6 months of age and 3 years of age) are associated with febrile convulsions but these generally resolve spontaneously and are not associated with long-term neurological complications. In addition there is no evidence that they can be prevented with antipyretic treatment. One controlled trial has shown that even aggressive antipyretic treatment of fevers has been associated with very high recurrence rates of febrile convulsions and suggests that antipyretic treatment is unlikely to be of major preventive benefit 25,26 .

Fever above 42 0C can lead to neurological damage, but this is a very rare event. There is no evidence the fevers below 42 0C cause neurological damage, even in young infants. High fevers may also be associated with listlessness and reduced appetite in children.

History and examination

The evaluation of a febrile illness is guided by the history and physical examination, along with judiciously selected screening tests. The history of a febrile illness may suggest a likely cause. Skin, soft tissue, skeletal, and ear infections in young infants have been associated with serious bacterial infections (SBI). Respiratory symptoms such as cough or tachypnea may suggest pneumonia. However, it is kept in mind that young children with pneumonia may have little or no cough. Abdominal pain may suggest UTI or enteritis, etc.

Recent antibiotic treatment should be questioned and physicians must always keep in their memory the possibility of partially treated meningitis when they are evaluating febrile infants and young children who have recently been prescribed antibiotics. Additionally, vaccine reactions, animal contact, eg. cat-scratch, foreign travel can account for fever; therefore, parents should be questioned regarding recent history.

Laboratory investigations

Nonspecific tests have been recommended as basic screening to determine which children are bacteremic. These are WBC count, absolute neutrophil and band count, C-reactive protein and erythrocyte sedimentation rate. The risk of bacteremia increases from 0.5 percent for WBC counts less than 15.000/ mm3 to greater than 18 percent for WBC counts over 30 000 mm3. The WBC count can be used with absolute band count, C-reactive protein and erythrocyte sedimentation rate to assess which children 3 to 36 months of age with fever without source should have a blood culture 6 .

Urinalysis should be a part of the evaluation of febrile infants. When fresh urine (<10 minutes after collection) is evaluated for the presence of bacteria by Gram stain or phase microscopy in addition to testing for either nitrite and leukocyte esterase or WBC, most urinary tract infections can be diagnosed. The microscopic urinalysis fails to detect 10 to 20 percent of urinary tract infections in infants and young children, therefore, only a urine culture obtained by bladder catheterization can estabilish or exclude the diagnosis of a urinary tract infection27.

A lumbar puncture is indicated in any child in whom the physcian considers the diagnosis of sepsis or meningitis based on clinical assessment. Additionally, in infants younger than 3 months of age, a lumbar puncture should be performed if the patient is inconsolable, lethargic, has a change in behavior. However, if the patient is unstable or the lumbar puncture is technically difficult to perform, then antibiotics should be started before obtaining specimens of CSF28,29.

The need for obtaining chest radiographs as part of the initial screening for bacterial disease in febrile infants has generated considerable debate. Chest radiographs are usually negative in children with fever without source who have no symptoms of pulmonary infection (eg, tachypnea, cough, rales or rhonchi). For that reason, several investigators believe that chest radiographs should be obtained only for febrile infants who have clinical indications of pulmonary disease29.

Stool culture is recommended only in febrile infants and children who have diarrhea.


The appropriate management of febrile infants has been debated. The fact is that fever does not necessarily need to be treated. For example: if a child is playful, comfortable, able to sleep, and drinking plenty of fluids, then medical treatment is not likely to be needed. On the other hand, steps should be taken to decrease fever in a child who is uncomfortable, dehydrated, vomiting, of having difficulty sleeping. All febrile children less than 36 months of age who are toxic appearing should be hospitalized for evaluation and treatment of possible sepsis or meningitis30-32.

There is in most circumstances no indication to give antipyretic treatment for fever below 39 0C (rectal). Other than providing symptomatic relief, antipyretics therapy does not change the course of infectious diseases in normal children. Each child should be assessed individually, however, it is reasonable to offer antipyretic treatment to any child who appears to be in discomfort as a consequence of fever. Efforts should be made to identify the specific infection and initiate appropriate treatment.

Physcians should take both the age of infant and the degree of fever into account when deciding whether a CBC and blood culture should be obtained before treating focal infections, as an initial dose of parenteral antibiotics and close follow-up may be preferable in younger infants who are younger than 6 months of age. In the 2-36 month age group, management depends on laboratory test results and care is more patient-specific with regards to the need for chest X-ray, CSF studies, and antibiotic administration32-38.

The management of febrile infants younger than 29 days requires complete evaluation for bacterial disease including blood, urine, cerebrospinal fluid speciments for culture, be hospitalized for parenteral administration of antibiotics pending culture results. In the absence of a suggestion of an unusual pathogen, infants can be treated with ampicillin and gentamycin. If an infant is suspected to have meningitis, cefotaxime or ceftriaxone should substituted for gentamycin39-42. The conservative management of febrile infants 1-2 months of age also demands a full evaluation for bacterial disease, hospitalization, and parenteral antimicrobial therapy for a minimum of 48 hours. However, infants meeting all low risk criteria can be considered for outpatient management. The current guidelines for evaluation of a febrile child with a WBC count greater than 15.000 cells/mm3 recommend parenteral ceftriaxone be given empirically with follow-up in 24 hours. Empiric outpatient therapy with ceftriaxone of febrile young infants should be undertaken only if a lumbar puncture and blood culture are obtained to help distinguish viral from bacterial meningitis and partial treatment of occult bacteremia29 . It seems reasonable to treat the patients who are in high risk group with an initial dose of paranteral antibiotics, and if S.pneumonia is found on blood culture, to consider outpatient treatment with appropriate oral antibiotics for 7-12 days in children over 2-3 months of age. It is pointed out that orally administered antibiotics have not been shown to prevent meningitis43,44.

Control of fever is a major issue for physcians caring for children. The World Health Organization (WHO) 45 recommends, in the guidelines for standard acute fever management, that treatment with paracetamol in children 2 months up to 5 years of age be limited to those with high fever (39 0C rectal or above). Supportive care with additional fluids, appropriate clothing and environmental conditions should be emphasized.

Acetaminophen (paracetamol) is one of the most widely used of all drugs, with a wealth of experience clearly establishing it as the standard antipyretic and analgesic for mild to moderate pain states. It is a paraamenophol derivative that inhibits cyclooxygenase and, therefore, the formation and release of prostaglandin. For routine clinical use, it is administered in a dose of 10-15 mg/kg/dose every 4-6 hours regardless of whether the route of administration is oral or rectal forms, as a tablet, liquid, or suppository. The rectal route is especially useful in several specific circumstances in which the oral route poses difficulties, such as with the child who is vomiting or spitting up oral medications46,47.

However, the American Academy of Pediatrics does not recommend this route because of potential for inadequate therapeutic effect from poor absorption as well as cumulative toxic effects from excessive or too frequently repeated rectal doses. The antipyretic effect of single-dose rectal and oral acetaminophen is 15 mg/kg and doubling the dose of rectal acetaminophen has not produced additional benefit48. Advers effects include development of allergic reaction resulting in a pruritic rash seen in <1% of cases and hepatotoxicity. A major overdose could be complicated by severe and sometimes fatal liver damage. The acute toxic dose of acetaminophen is generally considered to be more than 150 mg/kg in children younger than 12 years. A single ingestion of more than 7.5 gram is considered a minimum toxic dose in adolescents and adults. Medications and fasting may cause impairment of glutathione pathway and production of toxic metabolites, which may lead to liver toxicity49.

Ibuprofen, a nonsteroidal anti-inflammatory propionic acid derivative, inhibits prostaglandin synthesis, and prevents temperature elevation. The side effects reported with therapeutic use of ibuprofen are gastrointestinal tract irritation, reduced renal blood flow, and platelet dysfunction. When acetaminophen and ibuprofen are given in equal doses (mg/kg), ibuprofen provides greater temperature reduction and longer duration of antipyresis. The rate of temperature decline and maximal reduction of fever has been found to be equivalent for patients receiving acetaminophen (15 mg/kg) and ibuprofen (10 mg/kg).

Many physcians frequently alternated acetaminophen and ibuprofen, especially in cases of persistent fever. There is presently no scientific evidence that this combination is safe or achieves faster antipyresis than either agent used alone. Another reason for fever control is to prevent febrile seizures. All children have fevers, but a small number of them have a brief convulsion due to the fever. However, controlled studies showed that both acetaminophen and ibuprofen have been found as ineffective to prevent febrile seizures in febrile children.
Both acetaminophen and ibuprofen act via similar mechanism of action; they are both absorbed by the gastrointestinal tract, metabolized by the liver, and excreted in the urine. In hypovolemic patients, this two agents may lead to tubular toxicity by impairing renal perfusion via inhibition of prostaglandin synthesis. Additionally, alternated acetaminophen and ibuprofen can be confusing to the caregivers, potentially leading to incorrect dosing of either product.


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Summary and Conclusion

Fever is defined as a rectal temperature over 38C (100.4 F) and an oral temperature of 37.8 C (100F). In general, how a child looks and acts during a fever is more important that the actual temperature reading. The evaluation of infants and young children with fever will probably remain controversial. Physcians may differ in their approach to laboratory testing and treatment based on their perspectives regarding the risk of disease prevalence, the risk of morbidity resultant from untreated disease, the reliability of follow-up, and the concerns regarding side effects connected with potential treatment. The major effort should be the timely identification and treatment of a bacterial infection (eg, pneumonia, otitis media, streptococcal pharyngitis, meningitis or generalized sepsis) and the referral and admission to hospital of children requiring parenteral antibiotic therapy, or further investigation. Most children's fevers are caused by infection from common viruses. In infants younger than 2 months of age, fever might be the only indicator of bacterial disease. Because of the greater probability of serious

bacterial infection, a more aggressive approach to the evaluation and management of fever is warranted in these young infants. Although clinical scoring systems have been developed to help identify infants and toddlers at low risk for bacterial disease, they have not been found to be reliable when applied to infants younger than 2 months. S. pneumoniae is the pathogen in approximately 90 percent of cases of occult bacteremia in febrile older infants and young children. With the increasing rate of H influenzae and S pneumoniae vaccination, the rate of bacteremia is decreasing; therefore, the rate of empiric testing and treatment for occult bacteremia in febrile children will probably be decreased in the future.

Reduction of fever should be oriented towards relieving the child's discomfort and this is generally best achieved by the oral administration of paracetamol to children with high fever only.


















Table 1.Temperature conversion Fahrenheit to Celsius




























































































































































































Table 2. The Rochester Criteria

1)       Infant appears generally well

2)       Infant has been previously healthy

         born at term (≥37 weeks gestation)

         did not receive perinatal antimicrobial therapy

         was not treated for unexplained hyperbilirubinemia

         had not received and was not receiving antimicrobial agents

         had not been previously hospitalized

         had no chronic or underlying illness

         was not hospitalized longer than mother

3)       No evidence of skin, soft tissue, bone, joint, or ear infection

4)       Laboratory values

         peripheral blood WBC count 5.0 to 15.0x109 cells/L (5000 to 15 000/mm3)

         absolute band form count ≤ 1.5x 109 cells/L (≤1500/ mm3)

         ≤10 WBC per high power field (x40) on microscopic examination of a spun urine sediment

         ≤5 WBC per high power field (x40) on microscopic examination of a stool smear (only for infants with diarrhea)















Vital Learning Points

         Factors are known to increase the risk of serious bacterial infection, including newborn, high fever, high blood total white cell count, toxic appearance of the child.