Fever Without a Focus 

Infants or young children who have a fever with no obvious source of infection present a diagnostic dilemma. Health care providers see these patients on a daily basis. As many as 20% of childhood fevers have no apparent cause.[1] A small but significant number of these patients may have a serious bacterial infection; the risk is greatest among febrile infants and children younger than 36 months, making proper diagnosis and management important. Physical examination and patient history do not always identify patients with occult bacteremia or serious bacterial infection. Serious infections that are not recognized promptly and treated appropriately can cause significant morbidity or mortality.

This article focuses primarily on infants and young children aged 2-36 months and reflects the significant changes in the care of the febrile infant and child over the past 10 years. The article Fever in the Young Infant addresses the diagnosis and treatment of febrile infants younger than 2 months.

Fever is defined as a rectal temperature that exceeds 38°C (100.4°F). Direct the initial evaluation of these patients toward identifying or ruling out serious bacterial infections (SBI), most commonly urinary tract infections. The following questions are important to consider:

• What laboratory studies are indicated for various age ranges?

• Which patients need in-depth evaluation and treatment?

• Which patients need treatment with antibiotics?

• Which patients should be hospitalized?

• Which patients can be sent home safely and what follow-up is appropriate for them?

• Are the diagnosis and treatment modalities for each patient cost-effective?

• What is the potential morbidity associated with testing and treatment?

• What are the parental (and patient) preferences for testing and treatment?

A great deal of time and effort has been spent on research to help identify the febrile infant and young child with a serious bacterial infection. However, evaluation and treatment of febrile infants and young children vary, despite nationally published treatment guidelines.

Note also, this article primarily addresses children who are completely immunized, and in particular who have received full Hib and PCV7 vaccine series. Unimmunized children are at higher risk for bacteremia, pneumonia, and other SBIs.

Meningitis, pneumonia, urinary tract infection (UTI), and bacteremia are serious etiologies of fever in infants and young children.

Neonates' immature immune systems place them at greater risk of systemic infection. Hematogenous spread of infection is most common in this age group or in patients who are immunocompromised or unimmunized. For these same reasons, infants who have a focal bacterial infection have a greater risk of developing metastatic infection or bacteremia.

The following are among the most common bacterial etiologies of serious bacterial infection in this age group:

• Streptococcus pneumoniae

• Streptococcus agalactiae

• Neisseria meningitidis

• Haemophilus influenzae type b

• Listeria monocytogenes

• Escherichia coli

Historically, approximately 2.5-3% of highly febrile children younger than 3 years have occult bacteremia, which is typically caused by S pneumoniae.[3] The advent of conjugate pneumococcal vaccine has resulted in a decrease in pneumococcal occult bacteremia and other disease.[4] Viral infections are common in the young child as well[5] ; however, exclude serious bacterial infection prior to assuming a viral etiology for the fever.[6]

Several common bacteria cause serious bacterial infections, including the following:

• S pneumoniae: S pneumoniae is still the leading cause of nearly all common bacterial upper respiratory tract infections (eg, pneumonia, sinusitis, otitis media). This organism is also still the most common cause of meningitis in the United States, despite use of the conjugate pneumococcal vaccine.[7]

• N meningitidis

• H influenzae type b

• L monocytogenes

• E coli: E coli is the most common cause of UTIs. Among febrile children with UTIs, 75% have pyelonephritis, with consequences that, if missed, include renal scarring in 27-64% of patients, a 23% risk of hypertension, a 10% risk of renal failure, and a 13% risk of preeclampsia as adults. Approximately 13-15% of end-stage renal disease is believed to be related to undertreated childhood UTIs.

• Salmonella

United States statistics

Fever accounts for 10-20% of pediatric visits to health care providers.

Race-, sex-, and age-related demographics

There is no racial difference in incidence of fever.

There is no difference in incidence of fever in males versus females.

This article focuses on the diagnosis and treatment of febrile children aged 2-36 months.

The prognosis for an appropriately treated patient is excellent.

Morbidity/mortality

Patients with no easily identified source of infection have a small but significant risk of a serious bacterial infection. If not recognized and treated appropriately and promptly, a serious bacterial infection can cause morbidity or mortality.

Complications

Although almost all infants, toddlers, and young children with fever without a focus have benign, viral infections, a small number may have serious bacterial infection, which makes good follow-up all the more important.

For excellent patient education resources, visit eMedicineHealth's Children's Health Center. Also, see eMedicineHealth's patient education article Fever in Children.

In addition, see the following WebMD resources:

• Fever Facts
• Fever in Babies
• When to Call a Pediatrician

Obtaining an accurate history from the parent or caregiver is important when assessing fever without a focus; the history obtained should include the following information:

• Fever history: What was child's temperature prior to presentation and how was temperature measured? Consider fever documented at home by a reliable parent or caregiver the same as fever found upon presentation. Accept parental reports of maximum temperature.

• Fever at presentation: If the physician believes the infant has been excessively bundled, and if a repeat temperature taken 15-30 minutes after unbundling is normal, the infant should be considered afebrile. Always remember that normal or low temperature does not preclude serious, even life-threatening, infectious disease.

• Current level of activity or lethargy

• Activity level prior to fever onset (ie, active, lethargic)

• Current eating and drinking pattern

• Eating and drinking pattern prior to fever onset

• Appearance: Fever sometimes makes a child appear rather ill

• Vomiting or diarrhea

• Ill contacts

• Medical history

• Immunization history (especially recent immunizations)

• Urinary output: Inquire as to the number of wet diapers

While performing a complete physical examination, pay particular attention to assessing hydration status and identifying the source of infection.[8, 9]  Physical examination of every febrile child should include the following:

Record vital signs as follows:

• Temperature: Rectal temperature is the standard. Temperature obtained via tympanic, axillary, or oral methods may not truly reflect the patient's temperature.

• Pulse rate

• Respiratory rate

• Blood pressure

Measure pulse oximetry levels as follows:

• Pulse oximetry may be a more sensitive predictor of pulmonary infection than respiratory rate in patients of all ages, but especially in infants and young children.

• Pulse oximetry is mandatory for any child with abnormal lung examination findings, respiratory symptoms, or abnormal respiratory rate, although keep in mind that the respiratory rate increases when children are febrile.

Record an accurate weight on every chart:

• All pharmacologic and procedural treatments are based on the weight in kilograms.

• In urgent situations, estimating methods (eg, Broselow tape, weight based on age) may be used.

During the examination, concentrate on identifying any of the following:

• Toxic appearance, which suggests possible signs of lethargy, poor perfusion, hypoventilation or hyperventilation, or cyanosis (ie, shock)

• A focus of infection that is the apparent cause of the fever

• Minor foci (eg, otitis media [OM], pharyngitis, sinusitis, skin or soft tissue infection)

• Identifiable viral infection (eg, bronchiolitis, croup, gingivostomatitis, viral gastroenteritis, varicella, hand-foot-and-mouth disease)

• Petechial or purpuric rashes, often associated with bacteremia

• Purpura, which is associated more often with meningococcemia than is the presence of petechiae alone

For all patients aged 2-36 months, management decisions are based on the degree of toxicity and the identification of serious bacterial infection.

The Yale Observation Scale is a reliable method for determining degree of illness.[10, 11]  It consists of 6 variables: quality of cry, reaction to parent stimulation, state variation, color, hydration, and response. A score of 10 or less has a 2.7% risk of serious bacterial infection. A score of 16 or greater has a 92% risk of serious bacterial infection. It is important to remember that this scale was validated in the occult bacteremia era, prior to widespread pneumococcal conjugate vaccination.

Regarding the height of temperature, Hoberman et al found that 6.5% of patients with a temperature of 39.0°C (102.2°F) or more had a urinary tract infection (UTI) and that white females with that temperature had a 17% incidence of UTI.[12]

Table. Summary of the Yale Observation Scale (Open Table in a new window)

Recommended laboratory studies for children with fever without a focus are based on the child's appearance, age, and temperature.[2]

Begin intravenous (IV) or intramuscular (IM) antibiotic administration for all infants who appear ill once urine and blood specimens are obtained.

Perform the following for children who do not appear toxic:

• Perform urinalysis (UA) by bladder catheterization and urine culture based on the following criteria: all males younger than 6 months and all uncircumcised males younger than 12 months; all females younger than 24 months and older female children if symptoms suggest a urinary tract infection (UTI).

• Rapid testing for viruses (eg, influenza, respiratory syncytial virus) may be useful to decrease the need for other studies and/or antibiotic therapy. Newer multiplex PCR-based panels are available in many ER and inpatient settings that can detect multiple viruses at once, including RSV, influenza, adenovirus, parainfluenza, metapneumovirus, and rhinovirus.

• Consider obtaining stool for WBC counts and guaiac if diarrhea is present.

• For unimmunized patients, consider performing a CBC and blood culture in addition to the workup above, regardless of how ill-appearing the patient is.

Perform the following for children who appear toxic:

• Perform a CBC count with manual differential.

• Obtain blood cultures.

• Consider obtaining a chest radiograph. Chest radiography should be performed for patients with a WBC count greater than 20,000/μL.

• Perform UA by bladder catheterization and urine culture based on the following criteria: all males younger than 6 months and all uncircumcised males younger than 12 months; all females younger than 24 months and older female children if symptoms suggest a UTI.

• Obtain CSF and perform studies and culture. Administer antibiotics before performing the lumbar puncture (LP) if any delay is anticipated.

  • A study by Martinez et al analyzed the prevalence of bacterial meningitis in infants younger than 90 days with fever without a source. The study found that lumbar puncture was performed in 639 (27.0%) of the 2362 infants with fever without a source and the rate was higher in not well appearing infants (60.9%) and in those ≤21 days old (70.1%). 9 infants ≤21 days old and 5 not well-appearing infants were diagnosed with bacterial meningitis and none of the well-appearing infants were diagnosed. ^[13]

• Consider obtaining stool for WBCs and guaiac if diarrhea is present.

• Admit these patients for further treatment; pending culture results, administer parenteral antibiotics (see Treatment).

• Rapid testing for viruses (eg, influenza, respiratory syncytial virus, etc.) may be useful to decrease the need for other studies and/or antibiotic therapy, as above

• The role of measurement of C-reactive protein and procalcitonin in the evaluation of these infants is under investigation but is unclear at present.[14, 15, 16] Some newer unpublished data presented at national meetings suggests a negative procalcitonin may be a useful marker for ruling out SBI but further work is needed. A systematic review and meta-analysis found that procalcitonin had high diagnostic accuracy in detecting invasive bacterial infection in children with fever without an apparent source but had lower accuracy in the diagnosis of SBI.[17]

Imaging studies

Chest radiography is part of any thorough evaluation of a febrile child.[14]  Chest radiography is indicated when the patient has tachypnea, retractions, focal auscultatory findings, or oxygen saturation level on room air of less than 95%.

Although viral etiologies are considered the cause of most pediatric pneumonias, establishing a viral or bacterial etiology may be challenging.

Procedures

The following procedures may be included in the workup:

• Bladder catheterization
• Suprapubic aspiration
• Lumbar puncture

For children with fever without a focus who appear ill, conduct a complete evaluation to identify occult sources of infection. Follow the evaluation with empiric antibiotic treatment and admit the patient to a hospital for further monitoring and treatment pending culture results. Because children presenting with fever and leukopenia are also a concern, consider leukocytosis and leukopenia in making decisions about empiric antibiotic therapy. According to a study by Gomez et al, isolated leukopenia, especially in children without leukocyturia suggestive of a UTI, may not be a significant risk factor for SBI and viral etiologies may be considered more strongly.[18]

Patients aged 2-36 months may not require admission if they meet the following criteria:

• Patient was healthy prior to onset of fever.

• Patient is fully immunized.

• Patient has no significant risk factors.

• Patient appears nontoxic and otherwise healthy.

• Patient's parents (or caregivers) appear reliable and have access to transportation if the child's symptoms should worsen.

Treatment recommendations for children with fever without a focus are based on the child's appearance, age, and temperature.

For children who do not appear toxic, treatment recommendations are as follows:

• Schedule a follow-up appointment within 24-48 hours and instruct parents to return with the child sooner if the condition worsens.

• Hospital admission is indicated for children whose condition worsens or whose evaluation findings suggest a serious infection.

For children who appear toxic, treatment recommendations are as follows:

• Admit child for further treatment; pending culture results, administer parenteral antibiotics.

• Initially administer ceftriaxone, cefotaxime, or ampicillin/sulbactam (50 mg/kg/dose).

Consultations

The need to consult with specialists depends on the specialty of the physician who initially evaluated the patient and the ultimate source of fever. Typically, general pediatricians easily manage febrile infants on both an inpatient and outpatient follow-up basis.

Diet

Patient tolerance is the only restriction on diet. Physicians should monitor intake and output as an indication of the patient's status because these measurements may provide the first evidence of a disturbance that indicates illness.

Activity

Patient tolerance also determines activity level, which should be monitored for changes (eg, lethargy, irritability).

Clinical practice guidelines on the evaluation and management of febrile infants were published in August 2021 by the American Academy of Pediatrics (AAP).[19, 20]  The guidelines cover the assessment and treatment of well-appearing term infants aged 8-60 days who have a fever of at least 100.4°F (38°C).

Infants Aged 8-21 Days

Urinalysis, blood culture, and analysis of cerebrospinal fluid (CSF) are strongly recommended for infants in this age group. Parenteral antimicrobial therapy and active monitoring by nurses and hospital staff with experience in neonatal care are also strongly recommended. Infants with positive results of urine, blood, or CSF testing for bacterial pathogens should receive targeted antimicrobial therapy. Parenteral antibiotics can be discontinued and patients can be discharged when culture results have been negative for 24-36 hours and the infant appears clinically well or is improving.

Infants Aged 22-28 Days

Urinalysis, blood culture, and assessment of inflammatory markers are strongly recommended for infants in this age group. If more than one inflammatory marker level is abnormal, CSF analysis and bacterial culture are recommended. When CSF analysis has not been performed or the results are uninterpretable, the infant should be hospitalized. Antimicrobial agents can be discontinued and patients can be discharged when culture results have been negative for 24-36 hours, the infant appears clinically well or is improving, and no other infection requiring treatment is present.

Infants may be managed at home if they have negative CSF analysis and urinalysis results and no abnormal inflammatory marker levels. Infants who will be treated at home should receive parenteral antimicrobial therapy. In addition, home care should involve verbal and written instructions for caregivers, plans for re-evaluation in 24 hours, and plans for access to emergency care if the patient’s clinical status changes.

Infants Aged 29-60 Days

Urinalysis, blood culture, and assessment of inflammatory markers are recommended for infants in this age group. If all inflammatory marker levels are normal, CSF analysis and culture are not necessary. However, CSF testing may be performed if any inflammatory marker level is abnormal. If CSF analysis suggests bacterial meningitis, parenteral antimicrobial therapy is strongly recommended. Antimicrobial therapy is not required for patients with normal CSF analysis results, negative urinalysis results, and normal results of testing for inflammatory markers.

Treatment with antipyretics is somewhat controversial because fever is a defensive response to infection.[21] Base the decision to treat a fever without a focus on age, presentation, and laboratory results. If antibiotics are administered empirically, close follow-up is required. Parenteral antibiotics are the drugs of choice.

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover likely pathogens in the clinical setting.

Ceftriaxone (Rocephin)

Third-generation cephalosporin with broad-spectrum, gram-negative activity; lower efficacy against gram-positive organisms; higher efficacy against resistant organisms; arrests bacterial growth by binding to one or more penicillin-binding proteins.

Cefotaxime (Claforan)

For septicemia and treatment of gynecologic infections caused by susceptible organisms. Arrests bacterial cell wall synthesis, which, in turn, inhibits bacterial growth. Third-generation cephalosporin with gram-negative spectrum. Lower efficacy against gram-positive organisms. Useful in pediatric infections as an alternative to ceftriaxone in infants in the first month or two of life, in whom bilirubin displacement from protein-binding sites by the latter antibiotic may be harmful.

Ampicillin/sulbactam (Unasyn)

Drug combination of beta-lactamase inhibitor with ampicillin. Covers skin, enteric flora, and anaerobes. Not ideal for nosocomial pathogens.

Class Summary

These agents inhibit central synthesis and release of prostaglandins that mediate the effect of endogenous pyrogens in the hypothalamus and, thus, promote the return of the set-point temperature to normal.

Ibuprofen (Advil, Motrin)

Among the few NSAIDs indicated for reduction of fever; produces anti-inflammatory, antipyretic, and analgesic effects by inhibiting prostaglandin synthesis.

Acetaminophen (Tempra, Tylenol)

Reduces fever by acting directly on hypothalamic heat-regulating centers, which increases dissipation of body heat via vasodilation and sweating.

All children and infants with a febrile illness without a focus of bacterial infection require close follow-up care and instructions to return if the patient's condition deteriorates. Follow-up visits should be arranged within 24-48 hours after the initial visit.

Tailor medication choice to the source of infection, if known. Administer empiric treatment based on the most likely organisms.

Patients with fever without a focus who fail to improve with outpatient treatment may require hospital admission for further evaluation and treatment.