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Fever in Infants and Children

By

Deborah M. Consolini

, MD, Sidney Kimmel Medical College of Thomas Jefferson University

Last full review/revision Jun 2020| Content last modified Jun 2020
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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 months 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.

Pathophysiology

Fever occurs in response to the release of endogenous pyogenic mediators called cytokines (in particular interleukin-1 [IL-1]). Cytokines stimulate the production of prostaglandins by the hypothalamus; prostaglandins readjust and elevate the temperature set point.

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.

Etiology

Causes of fever (see Table: 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.

Acute fever

Most acute fevers in infants and young children are caused by infection. The most common are

  • Viral respiratory or gastrointestinal infections (most common causes overall)

  • Certain bacterial infections (otitis media, pneumonia, urinary tract infections)

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 (viremia with herpes simplex), pneumonia, pyelonephritis, meningitis, and/or sepsis.

Most febrile children 1 month 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 postconjugate 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 hours after the vaccine is given (eg, with pertussis vaccination) or 1 to 2 weeks 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.

Acute recurrent or periodic fever

Acute recurrent or periodic fever is episodes of fever alternating with periods of normal temperature (see Table: Some Common Causes of Fever in Children).

Chronic fever

Fever that occurs daily for ≥ 2 weeks and for which initial cultures and other investigations fail to yield a diagnosis is considered 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.

Table
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Some Common Causes of Fever in Children

Type

Examples

Acute

Viral infections

< 1 month: TORCH infections (toxoplasmosis, other pathogens [syphilis, varicella-zoster, parvovirus B19], rubella, cytomegalovirus [CMV], herpes simplex virus [HSV]), coxsackievirus, HIV

Bacterial infections (most common pathogens vary by age)

< 1 month: Group B streptococci, Escherichia coli and other enteric pathogens, Listeria monocytogenes (these organisms can cause bacteremia, pneumonia, pyelonephritis, meningitis, and/or sepsis; also, Salmonella species and Staphylococcus aureus [eg, in nursery outbreaks], which in addition to bacteremia and sepsis, can cause soft-tissue, bone, and joint infections)

1–3 months: Streptococcus pneumoniae, group B streptococci, Neisseria meningitidis, L. monocytogenes (these organisms can cause bacteremia, pneumonia, meningitis, and/or sepsis; other common infections include otitis media [S. pneumoniae, Haemophilus influenzae, Moraxella catarrhalis], urinary tract infection [E. coli and other enteric pathogens], enteritis [Salmonella species, Shigella and others], skin and soft-tissue infections [S. aureus, group A and B streptococci], bone and joint infections [S. aureus, Salmonella species])

3–24 months: S. pneumoniae, N. meningitidis (these organisms can cause bacteremia, meningitis, and/or sepsis; other common infections include otitis media and pneumonia [S. pneumoniae, H. influenzae, M. catarrhalis], urinary tract infection [E. coli and other enteric pathogens], enteritis [Salmonella species, Shigella and others], skin and soft-tissue infections [S. aureus, group A streptococci], bone and joint infections [S. aureus, Salmonella species, Kingella kingae])

> 24 months: S. pneumoniae, N. meningitidis (these organisms can cause bacteremia, meningitis, and/or sepsis; other common infections include otitis media, sinusitis, and pneumonia [S. pneumoniae, H. influenzae, M. catarrhalis, mycoplasma], pharyngitis or scarlet fever [group A streptococci], urinary tract infection [E. coli and other enteric pathogens], enteritis [Salmonella species, Shigella and others], skin and soft-tissue infections [S. aureus, group A streptococci], bone and joint infections [S. aureus, Salmonella species, K. kingae])

Mycobacterium tuberculosis in exposed or at-risk populations

Rickettsial infections in appropriate geographic locations

Other vector-transmitted infection (eg, Lyme disease)

Noninfectious

Thermoregulatory disorders (eg, dysautonomia, diabetes insipidus, anhidrosis)

Toxic ingestions (eg, anticholinergics)

Drugs

Fungal infections

Neonates or immunocompromised hosts: Candida species most common (urinary tract infection, meningitis, and/or sepsis)

Acute recurrent/periodic

Viral infections

Frequent or back-to-back minor viral illnesses in a young child

Periodic fever syndromes

Periodic fever with aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome

Hyperimmunoglobulinemia D syndrome (HIDS)

Chronic (fever of unknown origin)

Infectious*

Viral infections (eg, Epstein-Barr virus, cytomegalovirus, hepatitis viruses, arboviruses)

Enteric infections (eg, Salmonella)

Abscesses (intra-abdominal, hepatic, nephric)

Bone and joint infections (eg, osteomyelitis, septic arthritis)

HIV infection (uncommon)

Tuberculosis (uncommon)

Parasitic infections (eg, malaria—uncommon)

Lyme disease (rarely causes chronic fever)

Noninfectious

Connective tissue disorders (eg, juvenile idiopathic arthritis, systemic lupus erythematosus, acute rheumatic fever)

Cancer (most commonly lymphoreticular malignancies such as lymphoma or leukemia but also neuroblastoma or sarcomas)

Drugs

Thermoregulatory disorders (eg, dysautonomia, diabetes insipidus, anhidrosis)

Pseudo FUO

* There are many infectious causes of chronic fever. This list is not exhaustive.

Evaluation

History

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 upper respiratory infection), 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, urinary tract infection, 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 (tuberculosis, 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.

Physical examination

Vital signs are reviewed, noting abnormalities in temperature and respiratory rate. In ill-appearing children, blood pressure 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 Table: Examination of the Febrile Child).

Table
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Examination of the Febrile Child

Area

Finding

Possible Cause

Skin

Nonblanching rash (ie, petechiae or purpura)

Variety of infections including enterovirus, meningococcemia, and Rocky Mountain spotted fever

Vesicular lesions

Lacelike maculopapular rash on trunk and extremities with slapped-cheek appearance

Focal erythema with swelling, induration, and tenderness

Evanescent erythematous morbilliform rash on trunk and proximal extremities

Bull’s-eye erythematous rash, single or multiple lesions

Erythematous, sandpaper-like rash

Scarlet fever (group A streptococcal infection)

Erythroderma

Toxic shock syndrome, toxin-mediated disease

Fontanelle (infants)

Bulging

Ears

Red, bulging tympanic membrane, loss of landmarks and mobility

Nose

Congestion, discharge

Nostril flaring with inspiration

Lower respiratory infection

Throat

Redness

Sometimes exudate or swelling

Sometimes drooling

Pharyngitis (upper respiratory infection or strep infection)

Neck

Focal adenopathy with overlying redness, warmth, and tenderness; possible torticollis

Lymphadenitis secondary to Staphylococcus aureus or group A streptococcal infection

Focal adenopathy with limited or no redness, warmth, or tenderness

Generalized cervical adenopathy

Viral infection (particularly Epstein-Barr virus)

Pain or resistance to flexion (meningismus*)

Meningitis

Lungs

Coughing, tachypnea, crackles, rhonchi, decreased breath sounds, wheezing

Lower respiratory infection (eg, pneumonia, bronchiolitis, chronic foreign body aspiration)

Heart

New murmur, particularly mitral or aortic regurgitant

Abdomen

Tenderness, distention

Absent bowel sounds

Mass

Tumor

Hepatomegaly

Splenomegaly

In neonate, Epstein-Barr virus infection, TORCH infections (toxoplasmosis, other pathogens [syphilis, varicella-zoster, parvovirus B19], rubella, cytomegalovirus, herpes simplex virus), coxsackievirus, HIV

Leukemia, lymphoma

Genitourinary

Costovertebral tenderness (less reliable in younger children)

Pyelonephritis

Testicular tenderness

Extremities

Joint swelling, erythema, warmth, tenderness, decreased range of motion

Septic arthritis (very tender)

Lyme arthritis

Rheumatoid or inflammatory disorder

Focal bone tenderness

Swelling of the hands or feet

* Meningismus is not consistently present in children < 2 years with meningitis.

Red flags

The following findings are of particular concern:

  • Age < 1 month

  • Lethargy, listlessness, or toxic appearance

  • Respiratory distress

  • Petechiae or purpura

  • Inconsolability

Interpretation of findings

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 < 36 months indicates higher risk of serious bacterial infection.

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/minute 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 > 36 months who are otherwise well and not toxic-appearing. Typically, they have a viral respiratory illness (recent ill contact, runny nose, wheeze, or cough) or gastrointestinal illness (ill contact, diarrhea, and vomiting). Other findings also suggest specific causes (see Table: Examination of the Febrile Child).

However, in infants and children < 36 months, 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 months), and older infants and children (3 to 36 months). 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 syndrome); intermittent headaches with runny nose or congestion (sinusitis); weight loss, high-risk exposure, and night sweats (tuberculosis); weight loss or difficulty gaining weight, heart palpitations, and sweating (hyperthyroidism); and weight loss, anorexia, and night sweats (cancer).

Testing for acute fever

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 months, 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 month of age require a white blood cell (WBC) count with a manual differential, blood cultures, urinalysis and urine culture (obtained by catheterization, not an external bag) and cerebrospinal fluid (CSF) evaluation with culture and appropriate polymerase chain reaction (PCR) testing (eg, for herpes simplex, enterovirus) as indicated by historical risk factors. Chest x-ray is done in neonates with respiratory manifestations. Stool is sent for culture or enteric PCR stool test in neonates with diarrhea. Neonates are hospitalized and given empiric IV antibiotic coverage for the most common neonatal pathogens (eg, using ampicillin and gentamicin or ampicillin and cefotaxime); antibiotics are continued until blood, urine, and CSF cultures have been negative for 48 hours. Acyclovir also should be given if neonates are ill-appearing, have mucocutaneous vesicles, have onset of illness at about 2 weeks of age, have a maternal history of genital herpes simplex virus (HSV) infection, or have seizures; acyclovir is stopped if results of CSF HSV PCR testing are negative.

Febrile children between 1 month and 3 months of age require a different approach, which has evolved over the last few decades because the number of children in this age group who turn out to have a potentially serious bacterial infection has been markedly reduced by routine immunization against H. influenzae type b and S. pneumoniae. Clinicians must nonetheless maintain vigilance because, although serious bacterial infections have been reduced, they have not been eliminated. Therefore, clinicians who choose to observe without treatment or send home under parental observation need to have a greater certainty regarding that child's low-risk status than that of a child who is tested, admitted, and treated.

Infants in this 29- to 90-day age group are differentiated based on

  • Temperature

  • Clinical appearance

  • Laboratory results

Typically, all infants 29 to 60 days of age and infants 61 to 90 days of age who are ill-appearing or with risk factors for serious bacterial infection (eg, significant congenital anomalies, prematurity, technology dependence, unvaccinated) should have a WBC count with a manual differential, blood cultures, urinalysis and urine culture (obtained by catheterization, not an external bag), and lumbar puncture with CSF evaluation, including culture. Chest x-ray is done in those with respiratory manifestations, and stool is sent for stool culture or enteric PCR stool test in those with diarrhea. Some experts may defer WBC count and blood culture in well-appearing febrile infants 61 to 90 days of age without risk factors for serious bacterial infection pending urinalysis results. Lumbar puncture can be deferred 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/mcL [5 to 15 × 109/L]) if done, 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.

Infants between 1 month and 3 months of age with a documented respiratory syncytial virus (RSV) or influenza infection appear to have a markedly reduced risk of serious bacterial infection, which some experts believe permits modifications to the above recommendations. Well-appearing febrile infants in this age group with RSV bronchiolitis, or with influenza documented by PCR testing during a period of high seasonal prevalence and who have normal urinalysis results, do not necessarily require blood or CSF studies or empiric antibiotics. Children with abnormal urinalysis results, especially those between 29 days and 60 days of age, warrant additional laboratory evaluation and management as described below.

Febrile infants between 1 month and 3 months who are ill-appearing, have an abnormal cry, or have rectal temperature ≥ 38.5° C have a high risk of serious bacterial infection regardless of initial laboratory results. Such infants should be hospitalized and given empiric antibiotic therapy using ceftriaxone or cefotaxime pending the results of blood, urine, and CSF cultures.

Well-appearing infants between 1 month and 3 months with CSF pleocytosis, an abnormal urinalysis or chest x-ray, or a peripheral WBC count ≤ 5,000/mcL (≤ 5 × 109/L) or ≥ 15,000/mcL (≥ 15 × 109/L) 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 strongly considered (if not already done) especially in infants 29 to 60 days of age.

Well-appearing febrile infants between 1 month and 3 months 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 serious bacterial infections. Such infants can be managed as outpatients if reliable follow-up is arranged within 24 hours 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 hours 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 months and 36 months of age 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 serious bacterial infection with WBC count, cultures of blood, urine, and, when meningitis is suspected, CSF. Those with tachypnea or a WBC count > 20,000/mcL (> 20 × 109/L) 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) 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/mcL (> 20 × 109/L) . Children who have a WBC count ≥ 15,000/mcL (≥ 15 × 109/L) 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 hours by telephone or by return visit, at which time preliminary culture results are reviewed. If the social situation suggests that follow-up within 24 hours 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 hours or earlier if they become sicker or if new symptoms or signs develop.

For well-appearing children who have a temperature > 39° C and fever without source and who are completely immunized, risk of bacteremia is < 0.5%. At this low-risk level, most laboratory testing and empiric antibiotic therapy are neither indicated nor cost-effective. However, because urinary tract infection (UTI) can be an occult source of infection in fully immunized children in this age group, girls < 24 months, circumcised boys < 6 months, and uncircumcised boys < 12 months 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 hours. 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 months, 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 syndrome should be considered in young children who have periodic high fever at intervals of about 3 to 5 weeks with aphthous ulcers, pharyngitis, and/or adenitis. Between episodes and even during the episodes, the children appear healthy. Diagnosis requires 6 months 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 erythrocyte sedimentation rate (ESR) and markedly elevated IgD (and often IgA). Genetic testing is available for familial Mediterranean fever (FMF), TNF receptor–associated periodic syndrome (TRAPS), and HIDS.

Testing for chronic fever

For chronic fever (fever of unknown origin [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

  • Complete blood count (CBC) with manual differential

  • Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)

  • Blood cultures

  • Urinalysis and urine culture

  • Chest x-ray

  • Serum electrolytes, blood urea nitrogen (BUN), creatinine, albumin, and hepatic enzymes

  • HIV serology

  • Tuberculin skin test (PPD)

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, systemic lupus erythematosus, or tuberculosis (TB). Thrombocytosis is a nonspecific acute-phase reactant. The total WBC count and the differential generally are less helpful, although children with an absolute neutrophil count > 10,000/mcL (> 10 × 109/L) have a higher risk of serious bacterial infection. If atypical lymphocytes are present, a viral infection is likely. Immature WBCs 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 Fever of Unknown Origin (FUO)).

Blood cultures should be done in all patients with FUO at least once and more often if suspicion of serious bacterial infection is high. Three blood cultures should be done over 24 hours 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 a tuberculin skin test (PPD) are done because primary HIV infection or TB can manifest as FUO.

Other tests are done selectively based on findings:

  • Stool testing

  • Bone marrow examination

  • Serologic testing for specific infections

  • Testing for connective tissue and immunodeficiency disorders

  • Imaging

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, includes but is 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 years with a strong family history of rheumatologic disease. A positive ANA test suggests an underlying connective tissue disorder, particularly systemic lupus erythematosus. 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 gastrointestinal 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 gastrointestinal 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 central nervous system is generally not helpful in the evaluation of children with FUO. However, 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) 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 a diagnostic measure except when juvenile idiopathic arthritis is suspected; in such cases, a trial of nonsteroidal anti-inflammatory drug (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

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

  • Ibuprofen

Acetaminophen tends to be preferred because ibuprofen decreases the protective effect of prostaglandins in the stomach and, if used chronically, can lead to gastritis. Epidemiologic studies have suggested a possible association between the development of asthma and maternal and infant use of acetaminophen and ibuprofen. A randomized drug trial comparing the two showed that these drugs in usual doses do not lead to worsening of existing asthma (1). However, the question remains whether the use of these drugs during pregnancy or early childhood increases the risk of developing asthma. If used, the dosage of acetaminophen is 10 to 15 mg/kg orally, IV, or rectally every 4 to 6 hours. The dosage of ibuprofen is 10 mg/kg orally every 6 hours. 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), but 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 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.

Things to avoid

Wiping the body down with isopropyl alcohol should be strongly discouraged because alcohol can be absorbed through the skin and cause toxicity. Numerous folk remedies exist, ranging from the harmless (eg, putting onions or potatoes in socks) to the uncomfortable (eg, coining, cupping).

Treatment reference

  • 1. Sheehan WJ, Mauger DT, Paul IM, et al: Acetaminophen versus ibuprofen in young children with mild persistent asthma. N Engl J Med 375(7):619–630, 2016. doi: 10.1056/NEJMoa1515990.

Key Points

  • Most acute fever is caused by viral infections.

  • Causes and evaluation of acute fever differ depending on the age of the child.

  • A small but real number of children < 36 months 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.

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