162 Fever Without a Focus

Keith R. Powell

Fever is a common manifestation of infectious diseases but is not predictive of severity. Many common viral (e.g., rhinitis, pharyngitis, pneumonia) and bacterial (e.g., otitis media, pharyngitis, impetigo) infections are usually benign in normal hosts and respond well to appropriate antimicrobial or supportive therapy. Other infections (e.g., sepsis, meningitis, pneumonia, osteoarticular infections, pyelonephritis), if untreated, may have significant morbidity or mortality. Most febrile episodes in a normal host can be diagnosed by a careful history and physical examination and require few if any laboratory tests. However, there are well-defined high-risk groups that, on the basis of age, associated diseases, or immunodeficiency status, require a more extensive evaluation and, in certain situations, prompt antimicrobial therapy before a pathogen is identified (Table 162-1).

FEVER WITHOUT LOCALIZING SIGNS

Fever without localizing signs or symptoms, usually of acute onset and present for less than 1 wk, is a common diagnostic dilemma for pediatricians caring for children younger than 36 mo of age. Infants younger than 4 wk of age may acquire community pathogens but are also at risk for late-onset neonatal bacterial diseases and perinatally acquired herpes simplex virus infection. Young infants demonstrate limited signs of infection, often making it difficult to distinguish clinically between serious bacterial infections and self-limited viral illnesses.

Infants Younger than 3 mo of Age.

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Table 162-1. Febrile Patients at Increased Risk for Serious Bacterial Infections

Risk GroupDiagnostic Considerations

Immunocompetent Patients

Neonates (<28 days)Sepsis and meningitis caused by group B Streptococcus, Escherichia coli, Listeria monocytogenes, and herpes simplex virus

Infants <3 moSerious bacterial disease in 10-15%, including bacteremia in 5%, of febrile infants <3 mo

Infants and children 3-36 moOccult bacteremia in 1.5%; increased risk with temperature >39°C and white blood cell count >15,000/μL

Hyperpyrexia (>40°C)Meningitis, bacteremia, pneumonia, heatstroke, hemorrhagic shock-encephalopathy syndrome

Fever with petechiaeBacteremia and meningitis caused by Neisseria meningitidis, Haemophilus influenzae type b, and Streptococcus pneumoniae

Immunocompromised Patients

Sickle cell diseaseSepsis, pneumonia, and meningitis caused by S. pneumoniae, osteomyelitis caused by Salmonella (as well as Staphylococcus)

AspleniaBacteremia and meningitis caused by N. meningitidis, H. influenzae type b, and S. pneumoniae

Complement/properdin deficiencySepsis caused by N. meningitidis

AgammaglobulinemiaBacteremia, sinopulmonary infection

AIDSS. pneumoniae, H. influenzae type b, and Salmonella infections

Congenital heart diseaseInfective endocarditis; brain abscess with right-to-left shunting

Central venous lineStaphylococcus aureus, coagulase-negative staphylococci, Candida

MalignancyBacteremia with gram-negative enteric bacteria, S. aureus, and coagulase-negative staphylococci; fungemia with Candida and Aspergillus

An infectious agent, usually viral, is identified in 70% of infants younger than 3 mo of age with fever; the remainder are presumed to have self-limited but undiagnosed viral infections. However, fever in an infant younger than 3 mo of age should always suggest the possibility of serious bacterial disease. Serious bacterial infections are present in 10-15% of previously healthy term infants presenting with rectal temperatures of 38°C or greater. These infections include sepsis, meningitis, urinary tract infections, enteritis, osteomyelitis, and suppurative arthritis. Bacteremia is present in 5% of febrile infants younger than 3 mo of age; organisms responsible for bacteremia include group B Streptococcus and Listeria monocytogenes (late-onset neonatal sepsis and meningitis) and community-acquired pathogens including Salmonella (enteritis), Escherichia coli (urinary tract infection), Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae type b (sepsis and meningitis), and Staphylococcus aureus (osteoarticular infection). Pyelonephritis is more common in uncircumcised infant boys, neonates and infants with urinary tract anomalies, and young girls. Other potential bacterial diseases in this age group include otitis media, pneumonia, omphalitis, mastitis, and other skin and soft tissue infections.

Viral pathogens can be identified in 40-60% of febrile infants younger than 3 mo of age. In contrast to bacterial infections, which have no seasonal pattern, viral diseases have a distinct pattern: respiratory syncytial virus and influenza A virus infections are more common during the winter, whereas enterovirus infections usually occur in the summer and fall.

The approach to febrile patients younger than 3 mo of age includes a careful history and physical examination. Ill-appearing (toxic) febrile infants younger than 3 mo of age require prompt hospitalization and immediate parenteral antimicrobial therapy after cultures of

blood, urine, and cerebrospinal fluid (CSF) are obtained. Ceftriaxone (50 mg/kg/dose every 24 hr with normal CSF findings, or 80 mg/kg/dose every 24 hr with CSF pleocytosis) or cefotaxime (50 mg/kg/dose every 6 hr), plus ampicillin (50 mg/kg/dose every 6 hr) to cover for L. monocytogenes and Enterococcus, is an effective initial antimicrobial regimen for ill-appearing infants without focal findings. This regimen is effective against the usual bacterial pathogens causing sepsis, urinary tract infection, and enteritis in young infants. However, if meningitis is suspected because of CSF abnormalities, vancomycin (15 mg/kg/dose every 6 hr) should be given to cover for possible penicillin-resistant S. pneumoniae, in addition to the ceftriaxone/cefotaxime and ampicillin, until the results of culture and susceptibility tests are known.

Infants younger than 3 mo of age with fever who appear generally well; who have been previously healthy; who have no evidence of skin, soft tissue, bone, joint, or ear infection; and who have a total white blood cell (WBC) count of 5,000-15,000 cells/μL, an absolute band count of less than 1,500 cells/μL, and normal urinalysis results are unlikely to have a serious bacterial infection. The negative predictive value with 95% confidence of these criteria for any serious bacterial infection is greater than 98%, and greater than 99% for bacteremia.

Occult Bacteremia in Children 3 Mo-3 Yr of Age.

Approximately 30% of febrile children 3 mo-3 yr of age have no localizing signs of infection. Occult bacteremia (bacteremia without an apparent focus of infection) due to S. pneumoniae, N. meningitidis, and Salmonella occurs in approximately 1.5% of relatively well-appearing children between 3-36 mo of age with fever (rectal temperature ≥38.0°C). The increased incidence of bacteremia among young children may be due in part to a maturational immune deficiency in the production of opsonic IgG antibodies to the polysaccharide antigens present on encapsulated bacteria. S. pneumoniae accounts for 90% of cases of occult bacteremia, with N. meningitidis and Salmonella accounting for most of the remaining positive cultures. H. influenzae type b was an important cause of occult bacteremia in young children before the universal use of conjugate H. influenzae type b vaccines. Common bacterial infections among children 3-36 mo of age who have localizing signs include otitis media, upper respiratory tract infection, pneumonia, enteritis, urinary tract infection, osteomyelitis, and meningitis. In this age group, bacteremia is present in 11% of febrile children with pneumonia and 1.5% of febrile children with otitis media or pharyngitis.

Risk factors indicating increased probability of occult bacteremia include temperature 39°C or greater, WBC count 15,000/ μL or greater, or an elevated absolute neutrophil count, band count, erythrocyte sedimentation rate, or C-reactive protein. The incidence of bacteremia among infants 3-36 mo of age increases as the temperature and WBC count increase. However, no combination of laboratory tests or clinical assessment is completely accurate in predicting the presence of occult bacteremia. Socioeconomic status, race, gender, and age (within the range of 3-36 mo) do not appear to affect the risk for occult bacteremia.

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Without therapy, occult bacteremia may resolve spontaneously without sequelae, may persist, or may lead to localized infections, such as meningitis, pneumonia, cellulitis, or suppurative

arthritis. The pattern of sequelae may be related to both host factors and the offending organism. In some children, the occult bacteremic illness may represent the early signs of serious localized infection rather than merely a transient disease state. H. influenzae type b bacteremia is characteristically of higher grade, as determined by quantitative blood culture techniques, and is associated with a higher risk of localized serious infection than is bacteremia due to S. pneumoniae. Hospitalized children with H. influenzae type b bacteremia often develop focal infections, such as meningitis, epiglottitis, cellulitis, or osteoarticular infection, whereas fewer than 5% of these bacteremias can be considered transient or occult. In contrast, among all patients with pneumococcal bacteremia (occult, symptomatic, or focal), spontaneous resolution occurs in 30-40%, with a higher rate of spontaneous resolution among well-appearing children with occult pneumococcal bacteremia.

Treatment of toxic-appearing febrile children 3-36 mo of age who do not have focal signs of infection includes hospitalization and prompt institution of antimicrobial therapy after specimens of blood, urine, and CSF are obtained for culture. Meningitis in patients with occult bacteremia that develops after a lumbar puncture does not represent inoculation of bacteria by the puncture but is coincidental and represents meningeal infection that was developing before the lumbar puncture.

A retrospective review of more than 500 well-appearing febrile children discharged from an emergency department since 1987 and subsequently confirmed to be bacteremic with S. pneumoniae found 28% of untreated children to have persistent bacteremia or a focal infection (4% had meningitis) compared with only 5% of children who had received oral or parenteral antimicrobials when first seen (1% had meningitis). In addition, children who received antimicrobial therapy were less likely to be febrile upon return. A retrospective study of children with bacterial meningitis showed that children who received antimicrobial therapy before the diagnosis of S. pneumoniae meningitis was confirmed had fewer complications attributable to meningitis. These findings argue for empirical antimicrobial therapy for well-appearing children younger than 36 mo of age who have not received H. influenzae type b and S. pneumoniae conjugate vaccines who have a rectal temperature of 39°C or greater and a WBC count of 15,000/μL or greater.

Consensus practice guidelines published in 1993 recommended that infants 3-36 mo of age who have a temperature less than 39°C and who do not appear toxic can be observed as outpatients without performing diagnostic tests or administering antimicrobial agents. For nontoxic-appearing infants with a rectal temperature of 39°C or greater, two options were suggested: (1) obtain a blood culture and give empirical antimicrobial therapy (ceftriaxone, a single dose of 50 mg/kg, not to exceed 1 g) or (2) if the WBC count is 15,000/μL or greater, obtain a blood culture and give empirical antimicrobial therapy. A third option, not offered in these guidelines, for selected infants is to obtain a blood culture and observe as outpatients without empirical antimicrobial therapy with return for re-evaluation within 24 hr. Regardless of the management option, the family should be instructed to return immediately if the child's condition deteriorates or new symptoms, such as rash, develop.

Studies of febrile infants age 3-36 mo conducted in the United States since the introduction of universal immunization of infants with H. influenzae type b conjugate vaccines have demonstrated that this pathogen has been virtually eliminated as a cause of occult bacteremia. In 2000, a heptavalent S. pneumoniae conjugate vaccine was introduced and recommended for universal administration during infancy. Based on efficacy trials, it is anticipated that there will be a significant (≥90%) decrease in occult bacteremia caused by S. pneumoniae in

vaccinated infants. Guidelines for the management of febrile children 3-36 mo of age who have received both H. influenzae type b and S. pneumoniae conjugate vaccines have yet to be established, but a stronger case for careful observation without the empirical administration of antimicrobial agents can now be made.

If S. pneumoniae is isolated from the blood, the child should return to the physician as soon as possible after the culture results are known. If the child appears well, is afebrile, and the physical findings remain normal, a second blood culture should be obtained if the child did not receive antimicrobial treatment at the first visit; all children should receive a total of 7-10 days of oral antimicrobial therapy. If the child appears ill and continues to have fever with no identifiable focus of infection, or if H. influenzae or N. meningitidis is present in the initial blood culture, the child should have a repeat blood culture, be evaluated for meningitis (including lumbar puncture), and either receive treatment in the hospital with appropriate antimicrobial agents or be given ceftriaxone and be managed as an outpatient. If the child develops a localized infection, therapy is directed toward the specific pathogen and the particular site.

Fever with Petechiae.

Independent of age, fever with petechiae with or without localizing signs indicates high risk for life-threatening bacterial infections such as bacteremia, sepsis, and meningitis. From 8-20% of patients with fever and petechiae have a serious bacterial infection, and 7-10% have meningococcal sepsis or meningitis (see Chapter 176). H. influenzae type b disease can also present with fever and petechiae (see Chapter 178). Management includes prompt hospitalization, culture of blood and CSF, and administration of appropriate parenteral antimicrobial agents.

Fever in Patients with Sickle Cell Disease.

Infection is the most common cause of death among children with sickle cell disease (see Chapter 454.1). The incidence of infection is greatest among children younger than 5 yr of age. The increased risk of infection in these children is due in part to functional asplenia and a defect in the properdin (alternate complement) pathway. Fever without localizing signs in patients with sickle cell disease is a common presentation of infection due to S. pneumoniae (sepsis, pneumonia, meningitis), H. influenzae type b (meningitis), Staphylococcus aureus (osteomyelitis), Salmonella (osteomyelitis), and E. coli (pyelonephritis).

The management of patients with sickle cell hemoglobinopathies requires culture of blood and, if indicated, CSF, stool, and bone, and administration of antimicrobial agents. Children who appear seriously ill, have temperatures of 40°C or greater, have WBC less than 5,000/μL or greater than 30,000/μL, or who have pulmonary infiltrates or complications of sickle cell disease or severe pain should be hospitalized. Other febrile infants with sickle cell disease can be given intramuscular ceftriaxone and cared for as outpatients after appropriate specimens have been obtained for culture. These children should be re-evaluated within 24 hr, or earlier if their condition deteriorates or new symptoms develop.

Prevention of pneumococcal sepsis is possible by instituting long-term penicillin therapy continued until adolescence (oral penicillin V, 125 mg twice daily for children younger than 5 yr of age and 250 mg orally twice daily for children 5 yr of age and older). Pneumococcal and H. influenzae vaccines provide some protection but do not supplant long-term

antimicrobial therapy.

Hyperpyrexia.

Hyperpyrexia (temperature greater than 41°C) is uncommon and is not associated with higher rates of serious bacterial infections than temperatures of 40.0°C. Infants and children with hyperpyrexia should be carefully evaluated as for all children with fever.

FEVER OF UNKNOWN ORIGIN

The term fever of unknown origin (FUO) is best reserved for children with a fever documented by a health care provider and for which the cause could not be identified after 3 wk of evaluation as an outpatient or after 1 wk of evaluation in hospital. Patients with fever not meeting these criteria, and specifically those admitted to the hospital with neither an apparent site of infection nor a noninfectious diagnosis, may be considered to have fever without localizing signs. In most of these children, the development of additional clinical manifestations over a relatively short period confirms the infectious nature of the illness.

Etiology.

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BOX 162-1. Diagnostic Considerations of Fever of Unknown Origin in Children

Actinomycosis Bartonella henselae (cat-scratch disease) Brucellosis Campylobacter Francisella tularensis (Tularemia) Listeria monocytogenes (Listeriosis) Meningococcemia (chronic) Mycoplasma pneumoniae Rat-bite fever (Streptobacillus moniliformis; streptobacillary form

of rat-bite fever) Salmonella Tuberculosis Yersiniosis

Abscesses: abdominal, brain, dental, hepatic, pelvic, perinephric, rectal, subphrenic

Cholangitis Infective endocarditis Mastoiditis Osteomyelitis Pneumonia Pyelonephritis

Sinusitis

Caused by specific organism Localized infections

Borrelia burgdorferi (Lyme disease) Relapsing fever (Borrelia recurrentis) Leptospirosis Rat-bite fever (Spirillum minus; spirillary form of rat-bite fever) Syphilis

Blastomycosis (extrapulmonary) Coccidioidomycosis (disseminated) Histoplasmosis (disseminated)

Lymphogranuloma venereum Psittacosis

Ehrlichia canis Q fever Rocky Mountain spotted fever Tick-borne typhus

Infectious mononucleosis (Epstein-Barr virus)

Cytomegalovirus Hepatitis viruses HIV

Amebiasis Babesiosis Giardiasis Malaria Toxoplasmosis Trichinosis Trypanosomiasis Visceral larva migrans (Toxocara)

Behçet's disease Juvenile dermatomyositis Juvenile rheumatoid arthritis

Rheumatic fever Systemic lupus erythematosus

Drug fever Hypersensitivity pneumonitis Pancreatitis Serum sickness Weber-Christian disease

Atrial myxoma Cholesterol granuloma Hodgkin's disease Inflammatory pseudotumor Leukemia Lymphoma Neuroblastoma Wilms' tumor

Crohn's disease Granulomatous hepatitis Sarcoidosis

Anhidrotic ectodermal dysplasia Fabry's disease Familial dysautonomia Familial Mediterranean fever Hypertriglyceridemia Ichthyosis Sickle cell crisis

Chronic active hepatitis Diabetes insipidus (non-nephrogenic and nephrogenic) Factitious fever Hypothalamic-central fever Infantile cortical hyperostosis Inflammatory bowel disease Kawasaki disease Kikuchi-Fujimoto disease Pancreatitis Periodic fever Poisoning Pulmonary embolism Thrombophlebitis Thyrotoxicosis

See Box 161-1

Persistent Recurrent Resolved

Bacteria Spirochetes Fungal diseases Chlamydia Rickettsia Viruses Parasitic diseases Rheumatologic diseases Hypersensitivity diseases Neoplasms Granulomatous diseases Familial-hereditary diseases Miscellaneous Recurrent or relapsing fever Undiagnosed fever

Abscesses: abdominal, brain, dental, hepatic, pelvic, perinephric, rectal, subphrenic

Diabetes insipidus (non-nephrogenic and nephrogenic) Infections

The principal causes of FUO in children, using these rigorous criteria, are infections and rheumatologic (connective tissue or autoimmune) diseases (Box 162-1). Neoplastic disorders should also be seriously considered, although most children with malignancies do not have fever alone. The possibility of drug fever should be considered if the patient is receiving any drug. Drug fever is usually sustained and not associated with other symptoms. Discontinuation of the drug is associated with resolution of the fever, generally within 72 hr, although certain drugs, such as iodides, are excreted for a prolonged period with fever that may persist for as long as 1 mo after drug withdrawal.

Most fevers of unknown or unrecognized origin result from atypical presentations of common diseases. In some cases, the presentation as an FUO is characteristic of the disease, such as juvenile rheumatoid arthritis (JRA), but the definitive diagnosis can be established only after prolonged observation because initially there are no associated or specific findings on physical examination and all laboratory results are negative or normal.

In the United States, the systemic infectious diseases most commonly implicated in children with FUO (by the rigorous criteria) are salmonellosis, tuberculosis, rickettsial diseases,

syphilis, Lyme disease, cat-scratch disease, atypical prolonged presentations of common viral diseases, infectious mononucleosis, cytomegalovirus (CMV) infection, viral hepatitis, coccidioidomycosis, histoplasmosis, malaria, and toxoplasmosis. Less common infectious causes of FUO include tularemia, brucellosis, leptospirosis, and rat-bite fever. AIDS alone is not usually responsible for FUO, although febrile illnesses frequently occur in patients with AIDS as a result of opportunistic infections.

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JRA and systemic lupus erythematosus are the connective tissue diseases associated most frequently with FUO. Inflammatory bowel disease, rheumatic fever, and Kawasaki disease are also commonly reported as causes of FUO. If factitious fever (inoculation of pyogenic material or manipulation of the thermometer by the patient or parent) is suspected, the presence and pattern of fever should be documented in the hospital. Prolonged and continuous observation, which may include electronic surveillance, of patients is imperative. FUO lasting more than 6 mo is uncommon in children and suggests granulomatosis or autoimmune disease. Repeat interval evaluation, including history , physical examination, and roentgenographic studies, is required.

Diagnosis.

The evaluation of FUO requires a thorough history and physical examination supplemented by a few screening laboratory tests, and additional laboratory and radiographic tests as indicated by the history or abnormalities found on examination or initial screening.

HISTORY.

The age of the patient is helpful in evaluating FUO. Children younger than 6 yr of age often have a respiratory or genitourinary tract infection, localized infection (abscess, osteomyelitis), JRA, or, rarely, leukemia. Adolescent patients are more likely to have tuberculosis, inflammatory bowel disease, autoimmune processes, and lymphoma, in addition to the causes of FUO found in younger children.

A history of exposure to wild or domestic animals should be solicited. Zoonotic infections in the United States are increasing in frequency and are often acquired from pets that are not overtly ill. Immunization of dogs against specific disorders such as leptospirosis may prevent canine disease but does not always prevent the animal from carrying and shedding leptospires, which may be transmitted to household contacts. A history of ingestion of rabbit or squirrel meat may provide a clue to the diagnosis of oropharyngeal, glandular, or typhoidal tularemia. A history of tick bite or travel to tick- or parasite-infested areas should be obtained.

Any history of pica should be elicited. Ingestion of dirt is a particularly important clue to infection with Toxocara (visceral larva migrans) or Toxoplasma gondii (toxoplasmosis).

A history of unusual dietary habits or travel as early as the birth of the child should be sought. Malaria, histoplasmosis, and coccidioidomycosis may re-emerge years after visiting or living in an endemic area. It is important to identify prophylactic immunizations and precautions

taken by the individual against ingestion of contaminated water or food during foreign travel. Rocks, dirt, and artifacts from geographically distant regions that have been collected and brought into the home as souvenirs may serve as vectors of disease.

A medication history should be pursued rigorously. This should include over-the-counter preparations and topical agents, including eye drops, which may be associated with atropine-induced fever.

The genetic background of a patient also is important. Descendants of the Ulster Scots may have FUO because they are afflicted with nephrogenic diabetes insipidus. Familial dysautonomia (Riley-Day syndrome), a disorder in which hyperthermia is recurrent, is more frequent among Jews than other population groups. Ancestry from the Mediterranean should suggest the possibility of familial Mediterranean fever.

PHYSICAL EXAMINATION.

Sweating in a febrile child should be noted. The continuing absence of sweat in the presence of an elevated or changing body temperature suggests dehydration due to vomiting, diarrhea, or central or nephrogenic diabetes insipidus. It also should suggest anhidrotic ectodermal dysplasia, familial dysautonomia, or exposure to atropine.

A careful ophthalmic examination is important. Red, weeping eyes may be a sign of connective tissue disease, particularly polyarteritis nodosa. Palpebral conjunctivitis in a febrile patient may be a clue to measles, coxsackievirus infection, tuberculosis, infectious mononucleosis, lymphogranuloma venereum, and cat-scratch disease. In contrast, bulbar conjunctivitis in a child with FUO suggests Kawasaki disease or leptospirosis. Petechial conjunctival hemorrhages suggest infective endocarditis. Uveitis suggests sarcoidosis, JRA, systemic lupus erythematosus, Kawasaki disease, Behçet's disease, and vasculitis. Chorioretinitis suggests CMV, toxoplasmosis, and syphilis. Proptosis suggests orbital tumor, thyrotoxicosis, metastasis (neuroblastoma), orbital infection, Wegener's granulomatosis, or pseudotumor.

The ophthalmoscope should also be used to examine nailfold capillary abnormalities that are associated with connective tissue diseases such as juvenile dermatomyositis and systemic scleroderma (see Fig. 149-3). Immersion oil or lubricating jelly is placed on the skin adjacent to the nailbed, and the capillary pattern is observed with the ophthalmoscope set on +40.

FUO is sometimes due to hypothalamic dysfunction. A clue to this disorder is failure of pupillary constriction due to absence of the sphincter constrictor muscle of the eye. This muscle develops embryologically when hypothalamic structure and function also are undergoing differentiation.

Fever resulting from familial dysautonomia may be suggested by lack of tears, an absent corneal reflex, or by a smooth tongue with absence of fungiform papillae. Tenderness to tapping over the sinuses or the upper teeth suggests sinusitis. Recurrent oral candidiasis may be a clue to various disorders of the immune system.

Fever blisters are common findings in patients with pneumococcal, streptococcal, malarial, and rickettsial infection. They also are common in children with meningococcal meningitis (which usually does not present as FUO) but rarely are seen in children with

meningococcemia. Fever blisters also are rarely seen with Salmonella or staphylococcal infections.

Hyperemia of the pharynx, with or without exudate, suggests infectious mononucleosis, CMV infection, toxoplasmosis, salmonellosis, tularemia, Kawasaki disease, or leptospirosis.

The muscles and bones should be palpated carefully. Point tenderness over a bone may suggest occult osteomyelitis or bone marrow invasion from neoplastic disease. Tenderness over the trapezius muscle may be a clue to subdiaphragmatic abscess. Generalized muscle tenderness suggests dermatomyositis, trichinosis, polyarteritis, Kawasaki disease, or mycoplasmal or arboviral infection.

Rectal examination may reveal perirectal lymphadenopathy or tenderness, which suggests a deep pelvic abscess, iliac adenitis, or pelvic osteomyelitis. A guaiac test should be obtained; occult blood loss may suggest granulomatous colitis or ulcerative colitis as the cause of FUO.

Repetitive chills and temperature spikes are common in children with septicemia (regardless of cause), particularly when associated with renal disease, liver or biliary disease, infective endocarditis, malaria, brucellosis, rat-bite fever, or a loculated collection of pus. The general activity of the patient and the presence or absence of rashes should be noted. Hyperactive deep tendon reflexes may suggest thyrotoxicosis as the cause of FUO.

LABORATORY FINDINGS.

Ordering a large number of diagnostic tests in every child with FUO according to a predetermined list may waste time and money. Alternatively, prolonged hospitalization for sequential tests may be more costly. The tempo of diagnostic evaluation should be adjusted to the tempo of the illness; haste may be imperative in a critically ill patient, but if the illness is more chronic, the evaluation can proceed more slowly and deliberately and, usually, in an outpatient setting. If there are no clues in the patient's history or on physical examination that suggest a specific infection or area of suspicion, it is unlikely that diagnostic studies will be helpful.

A complete blood cell count with a differential WBC count and a urinalysis should be part of the initial laboratory evaluation. An absolute neutrophil count less than 5,000/μL is evidence against indolent bacterial infection other than typhoid fever. Conversely, patients with polymorphonuclear leukocytes greater than 10,000/mL or nonsegmented polymorphonuclear leukocytes greater than 500/mL have a high likelihood of having a severe bacterial infection. Direct examination of the blood smear with Giemsa or Wright stain may reveal organisms of malaria, trypanosomiasis, babesiosis, or relapsing fever.

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An erythrocyte sedimentation rate (ESR) greater than 30 mm/hr indicates inflammation and the need for further evaluation for infectious, autoimmune, or malignant diseases. An ESR greater than 100 mm/hr suggests tuberculosis, Kawasaki disease, malignancy, or autoimmune disease. A low ESR does not eliminate the possibility of infection or JRA. C-reactive protein is another acute phase reactant that becomes elevated and returns to normal more rapidly than

the ESR. Although experts may prefer use of one over the other, there is no evidence that there is value in measuring both the ESR and C-reactive protein in the same patient.

Blood cultures should be obtained aerobically. Anaerobic blood cultures have an extremely low yield and should be obtained only if there are specific reasons to suspect anaerobic infection. Multiple or repeated blood cultures may be required to detect bacteremia associated with infective endocarditis, osteomyelitis, or deep-seated abscesses. Polymicrobial bacteremia suggests factitious self-induced infection or gastrointestinal (GI) pathology. The isolation of leptospires, Francisella, or Yersinia may require selective media or specific conditions not routinely used. Urine culture should be obtained routinely.

Tuberculin skin testing should be performed with intradermal placement of 5 units of purified protein derivative (PPD) that has been kept appropriately refrigerated.

Radiographic examination of the chest, sinuses, mastoids, or GI tract may be indicated by specific historical or physical findings. Radiographic evaluation of the GI tract for inflammatory bowel disease may be helpful in evaluating selected children with FUO and no other localizing signs or symptoms.

Examination of the bone marrow may reveal leukemia; metastatic neoplasm; mycobacterial, fungal, or parasitic diseases; and histiocytosis, hemophagocytosis, or storage diseases. If a bone marrow aspirate is performed, cultures for bacteria, mycobacteria, and fungi should be obtained.

Serologic tests may aid in the diagnosis of infectious mononucleosis, CMV infection, toxoplasmosis, salmonellosis, tularemia, brucellosis, leptospirosis, cat-scratch disease, Lyme disease, rickettsial disease, and, on some occasions, JRA. As serologic tests for more diseases become available through commercial laboratories, it is important to ascertain the sensitivity and specificity of each test before relying on these results to make a diagnosis. For example, serologic tests for Lyme disease outside of reference laboratories have been generally unreliable.

Radionuclide scans may be helpful in detecting abdominal abscesses as well as osteomyelitis, especially if the focus cannot be localized to a specific limb or multifocal disease is suspected. Gallium citrate (67Ga) localizes in inflammatory tissues (leukocytes) associated with tumors or abscesses. 99mTc phosphate is useful for detecting osteomyelitis before plain roentgenograms demonstrate bone lesions. Granulocytes tagged with indium (111In) or iodinated IgG may be useful in detecting localized pyogenic processes. Echocardiograms may demonstrate the presence of vegetation on the leaflets of heart valves, suggesting infective endocarditis. Ultrasonography may identify intra-abdominal abscesses of the liver, subphrenic space, pelvis, or spleen.

Total body CT or MRI permits detection of neoplasms and collections of purulent material without the use of surgical exploration or radioisotopes. CT and MRI are helpful in identifying lesions of the head, neck, chest, retroperitoneal spaces, liver, spleen, intra-abdominal and intrathoracic lymph nodes, kidneys, pelvis, and mediastinum. CT or ultrasound-guided aspiration or biopsy of suspicious lesions has reduced the need for exploratory laparotomy or thoracotomy. MRI is particularly useful for detecting osteomyelitis if there is concern about a specific limb. Diagnostic imaging can be very helpful in confirming or evaluating a suspected diagnosis but rarely leads to an unsuspected cause.

Biopsy is occasionally helpful in establishing a diagnosis of FUO. Bronchoscopy, laparoscopy, mediastinoscopy, and GI endoscopy may provide direct visualization and biopsy material when organ-specific manifestations are present.

Treatment.

Fever and infection in children are not synonymous; antimicrobial agents should not be used as antipyretics, and empirical trials of medication should generally be avoided. An exception may be the use of antituberculous treatment in critically ill children with suspected disseminated tuberculosis. Empirical trials of other antimicrobial agents may be dangerous and can obscure the diagnosis of infective endocarditis, meningitis, parameningeal infection, or osteomyelitis. Hospitalization may be required for laboratory or radiographic studies that are unavailable or impractical in an ambulatory setting, for more careful observation, or for temporary relief of parental anxiety. After a complete evaluation, antipyretics may be indicated to control fever and for symptomatic relief (see Chapter 161).

Prognosis.

Children with FUO have a better prognosis than do adults. The outcome in a child is dependent on the primary disease process, which is usually an atypical presentation of a common childhood illness. In many cases, no diagnosis can be established and fever abates spontaneously. In as many as 25% of cases in which fever persists, the cause of the fever remains unclear, even after thorough evaluation.

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