eMedicine Specialties > Pediatrics: General Medicine > Infectious Disease

Fever Without a Focus

Robert W Tolan Jr, MD, Chief, Division of Allergy, Immunology and Infectious Diseases, The Children's Hospital at Saint Peter's University Hospital; Clinical Associate Professor of Pediatrics, Drexel University College of Medicine

Updated: Jan 22, 2009

Introduction

Background

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 occult bacteremia or other serious bacterial infections. Address the following questions:

• 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.

Pathophysiology

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. 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 typically is caused by S pneumoniae. The advent of conjugate pneumococcal vaccine has resulted in a decrease in pneumococcal occult bacteremia and other disease.² Viral infections are common in the young child as well; however, exclude serious bacterial infection prior to assuming a viral etiology for the fever.

Frequency

United States

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

Mortality/Morbidity

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, this can cause morbidity or mortality.

Age

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

Clinical

History

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.

Physical

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

• Record vital signs.
  • 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.
  • 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 3-36 months, management decisions are mostly based on the degree of toxicity and the height of temperature.
• The Yale Observation Scale is a reliable method for determining degree of illness.^3,4
  • 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.
  • 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 UTI and that white females with that temperature had a 17% incidence of UTI.⁵ In this age group, the prevalence of bacteremia correlates with the height of fever.
  • Children with temperatures from 39-39.5°C (102.2-103°F) have an approximate 2-4% risk of having occult bacteremia. Those with temperatures higher than 39.5°C (103°F) have an approximate 5% chance of having occult bacteremia.
  • The impact of the conjugated pneumococcal vaccine on these findings and predictions has not been evaluated.
  • Summary of the Yale Observation Scale
    
    

    Observation Items	1 (Normal)	3 (Moderate Impairment)	5 (Severe Impairment)
    Quality of cry	Strong with normal tone or contentment without crying	Whimpering or sobbing	Weak cry, moaning, or high-pitched cry
    Reaction to parent stimulation	Brief crying that stops or contentment without crying	Intermittent crying	Continual crying or limited response
    Color	Pink	Acrocyanotic or pale extremities	Pale or cyanotic or mottled or ashen
    State variation	If awake, stays awake; if asleep, wakes up quickly upon stimulation	Eyes closed briefly while awake or awake with prolonged stimulation	Falls asleep or will not arouse
    Hydration	Skin normal, eyes normal, and mucous membranes moist	Skin and eyes normal and mouth slightly dry	Skin doughy or tented, dry mucous membranes, and/or sunken eyes
    Response (eg, talk, smile) to social overtures	Smiling or alert (<2 mo)	Briefly smiling or alert briefly (<2 mo)	Unsmiling anxious face or dull, expressionless, or not alert (<2 mo)

Causes

• S pneumoniae
  • S pneumoniae is the leading cause of nearly all common bacterial upper respiratory tract infections (eg, pneumonia, sinusitis, OM).
  • This organism is the most common cause of meningitis in the United States, although the use of the pneumococcal vaccine will likely change this.
  • It is the most common cause of occult bacteremia, the incidence of which is decreasing.
• 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.

Differential Diagnoses

Workup

Laboratory Studies

• Recommended laboratory studies for children with fever without a focus are based on the child's appearance, age, and temperature.
• 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 a CBC count with manual differential.
  • Obtain and hold blood cultures, pending receipt of CBC count results. Send blood culture for analysis if WBC count exceeds 15,000/μ L or if the absolute neutrophil count exceeds 10,000/μ L.
  • 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 UTI
  • Consider cerebrospinal fluid (CSF) studies and culture. Obtain CSF if meningitis is suspected.
  • Consider obtaining stool for WBC counts and guaiac if diarrhea is present.
• 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/μ L.
  • 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 if meningitis is suspected. Administer antibiotics before performing the lumbar puncture (LP) if any delay is anticipated.
  • 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) may be useful to decrease the need for other studies and/or antibiotic therapy.

Imaging Studies

Chest radiography is part of any thorough evaluation of a febrile child.

• Chest radiography is indicated when the patient has tachypnea, retractions, focal auscultatory findings, or oxygen saturation level in 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.
• Chest radiographs should be obtained if the WBC count is more than 20,000/μ L. One study found a high correlation with WBC greater than 20,000/μ L and pneumonia, even with a lack of clinical findings suggestive of pneumonia.⁶

Procedures

• Bladder catheterization
• Suprapubic aspiration
• LP
  

Treatment

Medical Care

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.

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

• Patient was healthy prior to onset of fever.
• Patient has no significant risk factors.
• Patient appears nontoxic and otherwise healthy.
• Patient's laboratory results are within reference ranges defined as low risk.
• 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:
  • Consider no antibiotics; however, if absolute neutrophil count is greater than 10,000/μ L, consider ceftriaxone (50 mg/kg/dose).
  • 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).

Medication

Treatment with antipyretics is somewhat controversial because fever is a defensive response to infection. 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.

Antibiotics

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.

Dosing

Adult

1-2 g IV q12-24h; not to exceed 4 g/d

Pediatric

>1-2 months and children: 50-100 mg/kg/d IV/IM divided q12h; not to exceed 2 g/d

Interactions

Probenecid may increase levels; coadministration with ethacrynic acid, furosemide, or aminoglycosides may increase nephrotoxicity

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Adjust dose in renal impairment; caution in breastfeeding women and those allergic to penicillin; displaces bilirubin from serum protein-binding sites and should be used with caution in infants <2 mo and in those with hyperbilirubinemia or gallbladder problems

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.

Dosing

Adult

Moderate-to-severe infections: 1-2 g IV/IM q6-8h
Life-threatening infections: 1-2 g IV/IM q4h

Pediatric

Infants and children: 50-200 mg/kg/d IV/IM divided q4-6h
>12 years: Administer as in adults

Interactions

Probenecid may increase levels; coadministration with furosemide and aminoglycosides may increase nephrotoxicity

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Use with caution in patients with documented hypersensitivity to beta-lactams; adjust dose in severe renal impairment; has been associated with severe colitis

Ampicillin/sulbactam (Unasyn)

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

Dosing

Adult

1.5 (1 g ampicillin + 0.5 g sulbactam) to 3 g (2 g ampicillin + 1 g sulbactam) IV/IM q6-8h; not to exceed 4 g/d sulbactam or 8 g/d ampicillin

Pediatric

3 months to 12 years: 100-200 mg ampicillin/kg/d (150-300 mg Unasyn) IV divided q6h
>12 years: Administer as in adults; not to exceed 4 g/d sulbactam or 8 g/d ampicillin

Interactions

Probenecid and disulfiram elevate ampicillin levels; allopurinol decreases ampicillin effects and has additive effects on ampicillin rash; may decrease effects of PO contraceptives

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Adjust dose in renal failure; evaluate rash and differentiate from hypersensitivity reaction

Antipyretic agents

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.

Dosing

Adult

200-800 mg PO q6-8h prn; not to exceed 3.2 g/d

Pediatric

4-10 mg/kg/dose PO tid/qid; not to exceed 40 mg/kg/d or 2.4 g/d
>12 years: Administer as in adults

Interactions

Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effects of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently

Contraindications

Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency; high risk of bleeding

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in congestive heart failure, hypertension, and decreased renal and hepatic function; caution in anticoagulation abnormalities or during anticoagulant therapy

Acetaminophen (Tempra, Tylenol)

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

Dosing

Adult

325-650 mg PO q4-6h or 1000 mg PO tid/qid; not to exceed 4 g/d

Pediatric

<12 years: 10-15 mg/kg/dose PO q4-6h prn; not to exceed 2.6 g/d
>12 years: Administer as in adults

Interactions

Rifampin can reduce analgesic effects; coadministration with barbiturates, carbamazepine, hydantoins, or isoniazid may increase hepatotoxicity

Contraindications

Documented hypersensitivity; known G-6-PD deficiency

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Hepatotoxicity possible following various dose levels in individuals with chronic alcoholism; severe or recurrent pain or high or continued fever may indicate a serious illness; contained in many OTC products; combined use with these products may result in cumulative doses exceeding recommended maximum dose

Follow-up

Further Inpatient Care

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

Further Outpatient Care

• 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.

Inpatient & Outpatient Medications

• Tailor medication choice to the source of infection, if known. Administer empiric treatment based on the most likely organisms.
• A second dose of long-acting parenteral antibiotic may be given at the follow-up visit pending culture results.

Complications

• When an occult infection is not suspected and diagnosed in a timely manner, a small but very real possibility that the infection may progress to bacteremia, meningitis, or other life-threatening illness is present.

Prognosis

• Prognosis for an appropriately treated patient is excellent.

Patient Education

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

Miscellaneous

Medicolegal Pitfalls

• The biggest pitfall in treating patients with fever without a focus is failing to consider the possibility of a life-threatening illness. Physicians who approach their patients as if this is a possibility and who provide appropriate evaluation and treatment have done their best to avoid a poor outcome.
• Stress to parents the criticality of their child returning for follow-up care and stress that they must seek immediate medical attention if their child's condition worsens.
• Failure to evaluate and/or treat an ill-appearing infant or child because of a CBC count within the reference range considered normal is a serious pitfall.

Special Concerns

• Even low-risk infants who meet criteria for discharge require close follow-up care. Instruct parents or caregivers to return before the next scheduled appointment if the infant's condition should worsen.
• Admit to the hospital all 2-month to 36-month-old febrile patients who have sickle cell anemia.

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Keywords

fever without a focus, bronchiolitis, childhood fever, croup, cyanosis, end-stage renal disease, Escherichia coli, fever without a source, fever without localizing signs, gingivostomatitis, Haemophilus influenzae type b, hand-foot-and-mouth disease, hyperventilation, hypoventilation, Listeria monocytogenes, meningitis, Neisseria meningitidis, occult bacteremia, otitis media, pediatric fever, pharyngitis, pneumonia, pyelonephritis, renal failure, renal scarring, sinusitis, Streptococcus agalactiae, Streptococcus pneumoniae, urinary tract infection, UTI, varicella, viral gastroenteritis

Contributor Information and Disclosures

Author

Robert W Tolan Jr, MD, Chief, Division of Allergy, Immunology and Infectious Diseases, The Children's Hospital at Saint Peter's University Hospital; Clinical Associate Professor of Pediatrics, Drexel University College of Medicine
Robert W Tolan Jr, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, Phi Beta Kappa, and Physicians for Social Responsibility
Disclosure: GlaxoSmithKline Honoraria Speaking and teaching; MedImmune Honoraria Consulting; MedImmune Honoraria Speaking and teaching; Merck Honoraria Speaking and teaching; Novartis Honoraria Speaking and teaching; sanofi pasteur Grant/research funds Unrestricted research grant; sanofi pasteur  Consulting; sanofi pasteur Honoraria Speaking and teaching; Tap Honoraria Speaking and teaching; Baxter Healthcare Honoraria Speaking and teaching

Medical Editor

Ashir Kumar, MBBS, MD, FAAP, Professor, Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University; Consulting Staff, Department of Pediatrics, EW Sparrow Hospital
Ashir Kumar, MBBS, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics, American Association of Physicians of Indian Origin, American Federation for Clinical Research, American Society for Microbiology, Infectious Diseases Society of America, and Pediatric Infectious Diseases Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Mark R Schleiss, MD, American Legion Chair of Pediatrics, Professor of Pediatrics, Division Director, Division of Infectious Diseases and Immunology, Department of Pediatrics, University of Minnesota School of Medicine
Mark R Schleiss, MD is a member of the following medical societies: American Pediatric Society, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, and Society for Pediatric Research
Disclosure: Nothing to disclose.

CME Editor

Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine
Daniel Rauch, MD, FAAP is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, and Society of Hospital Medicine
Disclosure: Baxter Honoraria Consulting; Pfizer Honoraria Consulting

Chief Editor

Russell W Steele, MD, Head, Division of Pediatric Infectious Diseases, Ochsner Children's Health Center; Clinical Professor, Department of Pediatrics, Tulane University School of Medicine
Russell W Steele, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Microbiology, Infectious Diseases Society of America, Louisiana State Medical Society, Pediatric Infectious Diseases Society, Society for Pediatric Research, and Southern Medical Association
Disclosure: None None None

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