* This is the Professional Version. *
Fever in Infants and Children
Normal body temperature varies from person to person and throughout the day. Normal body temperature is highest in children who are preschool aged. Several studies have documented that peak temperature tends to be in the afternoon and is highest at about 18 to 24 mo of age when many normal healthy children have a temperature of 101° F. However, fever usually is defined as a core body (rectal) temperature ≥ 38.0° C (100.4° F).
Significance of fever depends on clinical context rather than peak temperature; some minor illnesses cause high fever, whereas some serious illnesses cause only a mild temperature elevation. Although parental assessment is frequently clouded by fear of fever, the history of a temperature taken at home should be considered equivalent to a temperature taken in the office.
Fever occurs in response to the release of endogenous pyogenic mediators called cytokines. Cytokines stimulate the production of prostaglandins by the hypothalamus; prostaglandins readjust and elevate the temperature set point (see Fever).
Fever plays an integral role in fighting infection and, although it may be uncomfortable, does not necessitate treatment in an otherwise healthy child. Some studies even indicate that lowering the temperature can prolong some illnesses. However, fever increases the metabolic rate and the demands on the cardiopulmonary system. Therefore, fever can be detrimental to children with pulmonary or cardiac compromise or neurologic impairment. It can also be the catalyst for febrile seizures, a typically benign childhood condition ( Febrile Seizures).
Causes of fever (see Some Common Causes of Fever in Children) differ based on whether the fever is acute (≤ 14 days ), acute recurrent or periodic (episodic fever separated by afebrile periods), or chronic (> 14 days), which is more commonly referred to as fever of unknown origin (FUO). Response to antipyretics and height of the temperature have no direct relationship to the etiology or its seriousness.
Most acute fevers in infants and young children are caused by infection. The most common are
However, potential infectious causes of acute fever vary with the child’s age. Neonates (infants < 28 days) are considered functionally immunocompromised because they often fail to contain infection locally and, as a result, are at higher risk of serious invasive bacterial infections most commonly caused by organisms acquired during the perinatal period. The most common perinatal pathogens in neonates are group B streptococci, Escherichia coli (and other gram-negative enteric organisms), Listeria monocytogenes, and herpes simplex virus. These organisms can cause bacteremia, pneumonia, pyelonephritis, meningitis, and/or sepsis.
Most febrile children 1 mo to 2 years of age without an obvious focus of infection on examination (fever without source [FWS]) have self-limited viral disease. However, a small number (perhaps < 1% in the post–conjugate vaccine era) of such patients are early in the course of a serious infection (eg, bacterial meningitis). Thus, the main concern in a patient with FWS is whether occult bacteremia (pathogenic bacteria in the bloodstream without focal symptoms or signs on examination) is present. The most common causative organisms of occult bacteremia are Streptococcus pneumoniae and Haemophilus influenzae. The widespread use of vaccinations against both of these organisms has made occult bacteremia much less common.
Noninfectious causes of acute fevers include Kawasaki disease, heatstroke, and toxic ingestions (eg, of drugs with anticholinergic effects). Some vaccinations can cause fever either in the first 24 to 48 h after the vaccine is given (eg, with pertussis vaccination) or 1 to 2 wk after the vaccine is given (eg, with measles vaccination). These fevers typically last from a few hours to a day. If the child is otherwise well, no evaluation is necessary. Teething does not cause significant or prolonged fevers.
Fever that occurs daily for ≥ 2 wk and for which initial cultures and other investigations fail to yield a diagnosis is considered fever of unknown origin (FUO—see also Fever of Unknown Origin (FUO)).
Potential categories of causes (see Table: Some Common Causes of Fever in Children) include localized or generalized infection, connective tissue disease, and cancer. Miscellaneous specific causes include inflammatory bowel disease, diabetes insipidus with dehydration, and disordered thermoregulation. Pseudo FUO is likely much more common than true FUO because frequent, minor viral illness may be overinterpreted. In children, despite the numerous possible causes, true FUO is more likely to be an uncommon manifestation of a common disease rather than an uncommon disease; respiratory infections account for almost one half of cases of infection-associated FUO.
Some Common Causes of Fever in Children
History of present illness should note degree and duration of fever, method of measurement, and the dose and frequency of antipyretics (if any). Important associated symptoms that suggest serious illness include poor appetite, irritability, lethargy, and change in crying (eg, duration, character). Associated symptoms that may suggest the cause include vomiting, diarrhea (including presence of blood or mucus), cough, difficulty breathing, favoring of an extremity or joint, and strong or foul-smelling urine. Drug history should be reviewed for indications of drug-induced fever.
Factors that predispose to infection are identified. In neonates, these factors include prematurity, prolonged rupture of membranes, maternal fever, and positive prenatal tests (usually for group B streptococcal infections, cytomegalovirus infections, or sexually transmitted diseases). For all children, predisposing factors include recent exposures to infection (including family and caregiver infection), indwelling medical devices (eg, catheters, ventriculoperitoneal shunts), recent surgery, travel and environmental exposures (eg, to endemic areas, to ticks, mosquitoes, cats, farm animals, or reptiles), and known or suspected immune deficiencies.
Review of systems should note symptoms suggesting possible causes, including runny nose and congestion (viral URI), headache (sinusitis, Lyme disease, meningitis), ear pain or waking in the night with signs of discomfort (otitis media), cough or wheezing (pneumonia, bronchiolitis), abdominal pain (pneumonia, strep pharyngitis, gastroenteritis, UTI, abdominal abscess), back pain (pyelonephritis), and any history of joint swelling or redness (Lyme disease, osteomyelitis). A history of repeated infections (immunodeficiency) or symptoms that suggest a chronic illness, such as poor weight gain or weight loss (TB, cancer), is identified. Certain symptoms can help direct the evaluation toward noninfectious causes; they include heart palpitations, sweating, and heat intolerance (hyperthyroidism) and recurrent or cyclic symptoms (a rheumatoid, inflammatory, or hereditary disorder).
Past medical history should note previous fevers or infections and known conditions predisposing to infection (eg, congenital heart disease, sickle cell anemia, cancer, immunodeficiency). A family history of an autoimmune disorder or other hereditary conditions (eg, familial dysautonomia, familial Mediterranean fever) is sought. Vaccination history is reviewed to identify patients at risk of infections that can be prevented by a vaccine.
Vital signs are reviewed, noting abnormalities in temperature and respiratory rate. In ill-appearing children, BP should also be measured. Temperature should be measured rectally in infants for accuracy. Any child with cough, tachypnea, or labored breathing requires pulse oximetry.
The child’s overall appearance and response to the examination are important. A febrile child who is overly compliant or listless is of more concern than one who is uncooperative. However, an irritable infant or child who is inconsolable is also of concern. The febrile child who looks quite ill, especially when the temperature has come down, is of great concern and requires in-depth evaluation and continued observation. However, children who appear more comfortable after antipyretic therapy do not always have a benign disorder.
The remainder of the physical examination seeks signs of causative disorders (see Examination of the Febrile Child).
Examination of the Febrile Child
Although serious illness does not always cause high fever and many high fevers result from self-limited viral infections, a temperature of ≥ 39° C in children < 2 yr indicates higher risk of occult bacteremia.
Other vital signs also are significant. Hypotension should raise concern about hypovolemia, sepsis, or myocardial dysfunction. Tachycardia in the absence of hypotension may be caused by fever (10 to 20 beats/min increase for each degree above normal) or hypovolemia. An increased respiratory rate may be a response to fever, indicate a pulmonary source of the illness, or be respiratory compensation for metabolic acidosis.
Acute fever is infectious in most cases, and of these, most are viral. History and examination are adequate to make a diagnosis in children > 2 yr who are otherwise well and not toxic-appearing. Typically, they have a viral respiratory illness (recent ill contact, runny nose, wheeze, or cough) or GI illness (ill contact, diarrhea, and vomiting). Other findings also suggest specific causes (see Examination of the Febrile Child).
However, in infants < 24 mo, the possibility of occult bacteremia, plus the frequent absence of focal findings in neonates and young infants with serious bacterial infection, necessitates a different approach. Evaluation varies by age group. Accepted categories are neonates (≤ 28 days), young infants (1 to 3 mo), and older infants and children (3 to 24 mo). Regardless of clinical findings, a neonate with fever requires immediate hospitalization and testing to rule out a dangerous infection. Young infants may require hospitalization depending on screening laboratory results and the likelihood that they will be brought in for follow-up.
Acute recurrent or periodic fever and chronic fever (FUO) require a high index of suspicion for the many potential causes. However, certain findings can suggest the disorder: aphthous stomatitis, pharyngitis and adenitis (PFAPA); intermittent headaches with runny nose or congestion (sinusitis); weight loss, high-risk exposure, and night sweats (TB); weight loss or difficulty gaining weight, heart palpitations, and sweating (hyperthyroidism); and weight loss, anorexia, and night sweats (cancer).
Testing depends on age, appearance of the child and whether the fever is acute or chronic.
For acute fever , testing for infectious causes is directed by the age of the child. Typically, children < 36 mo, even those who do not appear very ill and those who have an apparent source of infection (eg, otitis media), require a thorough search to rule out serious bacterial infections (eg, meningitis, sepsis). In this age group, early follow-up (by phone and/or outpatient visit) is important for all those managed at home.
All febrile children < 1 mo require a WBC count with a manual differential, blood cultures, urinalysis and urine culture (obtained by catheterization, not an external bag) and CSF evaluation with culture and appropriate PCR testing (eg, for herpes simplex, enterovirus) as indicated by historical risk factors. Chest x-ray is done in those with respiratory manifestations, and stool swabs for WBCs and stool cultures are done in those with diarrhea. Neonates are hospitalized and given empiric IV antibiotic coverage for the most common neonatal pathogens (eg, using ampicillin and gentamycin or ampicillin and cefotaxime); antibiotics are continued until blood, urine, and CSF cultures have been negative for 48 to 72 h. Acyclovir also should be given if neonates are ill-appearing, have mucocutaneous vesicles, have a maternal history of genital herpesvirus (HSV) infection, or have seizures; acyclovir is stopped if results of CSF HSV PCR testing are negative.
Febrile children between 1 and 3 mo are differentiated based on their temperature, clinical appearance, and laboratory results. Typically, all should have a WBC count with a manual differential, blood cultures, and urinalysis and urine culture (obtained by catheterization, not an external bag). Chest x-ray is done in those with respiratory manifestations, and stool swabs for WBCs and stool culture are done in those with diarrhea. Lumbar puncture with CSF evaluation, including culture, is also done except in infants aged 61 to 90 days who appear well, have a rectal temperature < 38.5° C, have a normal urinalysis and a normal WBC count (5,000 to 15,000/μL), and who have knowledgeable caregivers, reliable transportation, and well-established follow-up; some experts also defer CSF testing in similar well-appearing infants aged 29 to 60 days, although there are no firm guidelines regarding minimum necessary testing in this age group.
Febrile infants between 1 and 3 mo who are ill-appearing, have an abnormal cry, or have rectal temperature ≥ 38.5° C have a high risk of serious bacterial infection (SBI) regardless of initial laboratory results. Such infants should be hospitalized and given empiric antibiotic therapy using ampicillin and cefotaxime in those aged 29 to 60 days or ceftriaxone in those aged 61 to 90 days, pending the results of blood, urine and CSF cultures.
Well-appearing infants between 1 and 3 mo with CSF pleocytosis, an abnormal urinalysis or chest x-ray, or a peripheral WBC ≤ 5000/μL or ≥ 15,000/μL should be admitted to the hospital for treatment with age-specific empiric antibiotics as described above. If empiric antibiotics are to be given, CSF analysis should be done (if not already done).
Well-appearing febrile infants between 1 and 3 mo with a rectal temperature < 38.5° C, and a normal WBC count and urinalysis (and CSF analysis and chest x-ray, if done) are at low risk of SBI. Such infants can be managed as outpatients if reliable follow-up is arranged within 24 h either by telephone or by return visit, at which time preliminary culture results are reviewed. If the family's social situation suggests that follow-up within 24 h is problematic, infants should be admitted to the hospital and observed. If infants are sent home, any deterioration in clinical status or worsening of fever, a positive blood culture not thought to be a contaminant, or a positive urine culture in an infant who remains febrile warrants immediate hospitalization with repeat cultures and age-specific empiric antibiotic therapy as described above.
Febrile children between 3 mo and 36 mo who have an apparent source of fever on examination and who do not appear ill or toxic can be managed based on this clinical diagnosis. Children who are ill-appearing should be fully evaluated for SBI with WBC count, cultures of blood, urine, and, when meningitis is suspected, CSF. Those with tachypnea or a WBC count > 20,000/μL should have a chest x-ray. These children should be given parenteral antibiotic therapy (usually using ceftriaxone) targeting the likely pathogens in this age group ( S. pneumoniae, Staphylococcus aureus, Neisseria meningitidis, H. influenzae type b) and be admitted to the hospital pending culture results.
Well-appearing children in this age group who have a temperature > 39° C and no identifiable source on examination (fever without source [FWS]) and who are not fully immunized have a risk of occult bacteremia as high as 5% (equal to the risk before the pneumococcal and H. influenzae conjugate vaccines came into use). These children should have a CBC with differential, blood culture, and urinalysis and urine culture. A chest x-ray should be done if the WBC count is ≥ 20,000/μL. Children who have a WBC count ≥ 15,000/μL should be given parenteral antibiotics pending blood and urine culture results. Ceftriaxone (50 mg/kg IM) is preferred because of its broad antimicrobial spectrum and prolonged duration of action. Children who received parenteral antibiotics should have follow-up within 24 h by telephone or by return visit, at which time preliminary culture results are reviewed. If the social situation suggests that follow-up within 24 h is problematic, children should be admitted to the hospital. Children who are not treated with antibiotics should be brought for reevaluation if they are still febrile (≥ 38° C) after 48 h (or earlier if they become sicker or if new symptoms or signs develop).
For well-appearing children who have a temperature > 39° C and FWS and who are completely immunized, risk of bacteremia is < 0.5%. At this low-risk level, most laboratory testing and empiric antibiotic therapy are not indicated or cost-effective. However, UTI can be an occult source of infection in fully immunized children in this age group. Girls < 24 mo, circumcised boys < 6 mo, and uncircumcised boys < 12 mo should have a urinalysis and urine culture (obtained by catheterization, not an external bag) and be appropriately treated if UTI is detected. For other completely immunized children, urine testing is done only when they have symptoms or signs of UTI, they have a prior history of UTI or urogenital anomalies, or fever has lasted > 48 h. For all children, caregivers are instructed to return immediately if fever becomes higher, the child looks sicker, or new symptoms or signs develop.
For febrile children > 36 mo, testing is directed by history and examination. In this age group, a child's response to serious illnesses is sufficiently developed to be recognized clinically (eg, nuchal rigidity is a reliable finding of meningeal irritation), so empiric testing (eg screening WBC counts, urine and blood cultures) is not indicated.
For acute recurrent or periodic fever, laboratory tests and imaging should be directed toward likely causes based on findings from the history and physical examination. PFAPA should be considered in young children who have periodic high fever at intervals of about 3 to 5 wk with aphthous ulcers, pharyngitis, and/or adenitis. Between episodes and even during the episodes, the children appear healthy. Diagnosis requires 6 mo of stereotypic episodes, negative throat cultures during episodes, and exclusion of other causes (eg, specific viral infections). In patients with attacks of fever, arthralgia, skin lesions, mouth ulcers, and diarrhea, IgD levels should be measured to look for hyperimmunoglobulinemia D syndrome (HIDS). Laboratory features of HIDS include elevated C-reactive protein (CRP) and ESR and markedly elevated IgD (and often IgA). Genetic testing is available for the hereditary periodic fever syndromes including familial Mediterranean fever (FMF), TNF receptor–associated periodic syndrome (TRAPS) and HIDS.
For chronic fever (FUO), laboratory tests and imaging should be directed toward likely causes of fever based on the patient's age and findings from the history and physical examination. Indiscriminate ordering of laboratory tests is unlikely to be helpful and can be harmful (ie, because of adverse effects of unnecessary confirmatory testing of false positives). The pace of the evaluation is dictated by the appearance of the child. The pace should be rapid if the child is ill-appearing, but can be more deliberate if the child appears well.
All children with FUO should have
The results of these studies in conjunction with findings from the history and physical examination can focus further diagnostic tests.
Anemia may be a clue to malaria, infective endocarditis, inflammatory bowel disease, SLE, or TB. Thrombocytosis is a nonspecific acute-phase reactant. The total WBC and the differential generally are less helpful, although children with an absolute neutrophil count >10,000 have a higher risk of SBI. If atypical lymphocytes are present, a viral infection is likely. Immature white cells should prompt further evaluation for leukemia. Eosinophilia may be a clue to parasitic, fungal, neoplastic, allergic, or immunodeficiency disorders.
The ESR and CRP are nonspecific acute-phase reactants that are general indicators of inflammation; an elevated ESR or CRP makes factitious fever less likely. A normal ESR or CRP can slow the pace of the evaluation. However, ESR or CRP may be normal in noninflammatory causes of FUO (see Table: Some Causes of FUO).
Blood cultures should be done in all patients with FUO at least once and more often if suspicion of SBI is high. Three blood cultures should be done over 24 h in patients who have any manifestations of infective endocarditis. A positive blood culture, particularly for S. aureus, should raise suspicion for occult skeletal or visceral infection or endocarditis and lead to performance of a bone scan and/or echocardiography.
Urinalysis and urine culture are important because UTI is among the most frequent causes of FUO in children. Patients with FUO should have a chest x-ray to check for infiltrates and lymphadenopathy even if lung examination is normal. Serum electrolytes, BUN, creatinine, and hepatic enzymes are measured to check for renal or hepatic involvement. HIV serologic tests and PPD testing are done because primary HIV infection or TB can manifest as FUO.
Other tests are done selectively based on findings:
Stool cultures or examination for ova and parasites may be warranted in patients with loose stools or recent travel. Salmonella enteritis can infrequently manifest as FUO without diarrhea.
Bone marrow examination in children is most useful in diagnosing cancer (especially leukemia) or other hematologic disorders (eg, hemophagocytic disease) and may be warranted in children with otherwise unexplained hepatosplenomegaly, lymphadenopathy or cytopenias.
Serologic testing that may be warranted, depending on the case, include but are not limited to Epstein-Barr virus infection, cytomegalovirus infection, toxoplasmosis, bartonellosis (cat-scratch disease), syphilis, and certain fungal or parasitic infections.
An antinuclear antibody (ANA) test should be done in children > 5 yr with a strong family history of rheumatologic disease. A positive ANA test suggests an underlying connective tissue disorder, particularly SLE. Immunoglobulin levels (IgG, IgA, and IgM) should be measured in children with a negative initial evaluation. Low levels may indicate an immunodeficiency. Elevated levels can occur in chronic infection or an autoimmune disorder.
Imaging of the nasal sinuses, mastoids, and GI tract should be done initially only when children have symptoms or signs related to those areas but may be warranted in children in whom FUO remains undiagnosed after initial testing. Children with elevated ESR or CRP, anorexia, and weight loss should have studies to exclude inflammatory bowel disease, particularly if they also have abdominal complaints with or without anemia. However, imaging of the GI tract should be done eventually in children whose fevers persist without other explanation and may be caused by disorders such as psoas abscess or cat-scratch disease. Ultrasonography, CT, and MRI can be useful in evaluating the abdomen and can detect abscesses, tumors, and lymphadenopathy. Imaging of the CNS is generally not helpful in the evaluation of children with FUO. Lumbar puncture may be warranted in children with persistent headache, neurologic signs, or an indwelling ventriculoperitoneal shunt. Other imaging techniques, including bone scan or tagged WBC scan, can be helpful in selected children whose fevers persist without other explanation when suspicion for a source that could be detected by these tests exists. Ophthalmologic examination by slit lamp is useful in some patients with FUO to look for uveitis (eg, as occurs in juvenile idiopathic arthritis [JIA]) or leukemic infiltration. Biopsy (eg, of lymph nodes or liver) should be reserved for children with evidence of involvement of specific organs.
Empiric treatment with anti-inflammatory drugs or antibiotics should not be used as diagnostic measures except when JIA is suspected; in such cases, a trial of NSAIDs is the recommended first-line therapy. Response to anti-inflammatory drugs or antibiotics does not help distinguish infectious from noninfectious causes. Also, antibiotics can cause false-negative cultures and mask or delay the diagnosis of important infections (eg, meningitis, parameningeal infection, endocarditis, osteomyelitis).
Treatment is directed at the underlying disorder.
Fever in an otherwise healthy child does not necessarily require treatment. Although antipyretics can provide comfort, they do not change the course of an infection. In fact, fever is an integral part of the inflammatory response to infection and can help the child fight the infection. However, most clinicians use antipyretics to help alleviate discomfort and to reduce physiologic stresses in children who have cardiopulmonary disorders, neurologic disorders, or a history of febrile seizures.
Antipyretic drugs that are typically used include
Acetaminophen tends to be preferred because ibuprofen decreases the protective effect of prostaglandins in the stomach and, if used chronically, can lead to gastritis. However, recent epidemiologic studies have found an association between the use of acetaminophen and the prevalence of asthma in children and adults; so some clinicians suggest that children with asthma or a strong family history of asthma should avoid using acetaminophen. The dosage of acetaminophen is 10 to 15 mg/kg po, IV, or rectally q 4 to 6 h. Ibuprofen dosage is 10 mg/kg po q 6 h. Use of one antipyretic at a time is preferred. Some clinicians alternate the 2 drugs to treat high fever (eg, acetaminophen at 6 AM, 12 PM, and 6 PM and ibuprofen at 9 AM, 3 PM, and 9 PM); this approach is not encouraged because caregivers may become confused and inadvertently exceed the recommended daily dose. Aspirin should be avoided in children because it increases the risk of Reye syndrome ( Reye Syndrome) if certain viral illnesses such as influenza and varicella are present.
Nondrug approaches to fever include putting the child in a warm or tepid bath, using cool compresses, and undressing the child. Caregivers should be cautioned not to use a cold water bath, which is uncomfortable and which, by inducing shivering, may paradoxically elevate body temperature. As long as the temperature of the water is slightly cooler than the temperature of the child, a bath provides temporary relief.
Most acute fever is caused by viral infections.
Causes and evaluation of acute fever differ depending on the age of a child.
A rare but real number of children <24 mo with fever without localizing signs (primarily those who are incompletely immunized) can have pathogenic bacteria in their bloodstream (occult bacteremia) and be early in the course of a potentially life-threatening infection.
Teething does not cause significant fever.
Antipyretics do not alter the outcome but may make children feel better.
* This is the Professional Version. *