Fever of unknown origin

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Chapter 18 FEVER OF UNKNOWN ORIGIN

Kevin Haggerty and Theodore X. O’Connell

General Discussion

Petersdorf and Beeson10 defined fever of unknown origin (FUO) as fever persisting for longer than 3 weeks, a documented temperature of greater than 101° F (38.3° C) on several occasions, and an uncertain diagnosis after intensive study for at least 1 week. Subsequently, in 1968 Dechovitz and Moffet2 defined FUO in children as fever lasting longer than 2 weeks for which no diagnosis could be made. With the advent of more advanced diagnostic modalities, a more contemporary definition in children is a minimum of 14 days of daily documented temperature of 38.3° C or greater without apparent cause, after performance of repeated physical examinations and screening laboratory tests.

The list of possible causes of FUO is extensive and is outlined below. Although the incidence of the causes of FUO in children may change, most investigators have found that infections predominate. New infectious disease etiologies continue to be added to the list of causes of FUO in children: Epstein-Barr virus (EBV), Lyme disease, hepatitis viruses, and human immunodeficiency virus (HIV). Reported cases demonstrate an increase in cases of osteomyelitis of the axial skeleton and infections resulting from different presentations of Bartonella henselae infections.

The approach to a patient with unexplained fever begins with a detailed history and physical examination. The history should review general complaints, not discounting seemingly benign symptoms. Additionally, careful attention must be given to an inventory of recent travel history, living environment, diet, pet and animal exposure, and recent medications. Organ involvement may not always be apparent by history or physical examination when a child first presents with prolonged fever. Physical findings may take weeks to develop, and repeated questioning and physical examinations are critical in the management of any child with prolonged fever.

No algorithms for the evaluation of FUO have been established because the differential diagnosis is so extensive. We have listed tests that can be considered in the evaluation of FUO. The tests should be used based on findings from the history and physical examination. As time passes and the fever persists, the evaluation should become more extensive because common causes of fever become less likely. The child with fever of more than 2 weeks’ duration often needs to be admitted to the hospital after the initial outpatient evaluation. The pattern of fever can be assessed, the work-up can be expedited, and the possibility of factitious fever can be eliminated.

Medications Associated with Fever of Unknown Origin

Medications commonly cause febrile episodes in children. Drug fever usually develops 7 to 10 days after the initiation of therapy and may be the sole or most prominent reaction to a medication. Theoretically, any new medication may cause drug fever; the following are the most commonly reported medications:

• Carbamazepine

• Cephalosporins

• Cimetidine

• Hydralizine

• Penicillins

• Phenobarbitol

• Quinidine

• Sulfonamides

Causes of FUO

Infectious Causes

• Bacterial infections
image Brucellosis
image Cat-scratch disease (Bartonella henselae)
image Diskitis
image Dysentery (Yersinia enterocolitica, Salmonella spp., Campylobacter jejuni)
image Intraspinal abscess
image Leptospirosis
image Lyme disease
image Mastoiditis
image Osteomyelitis
image Otitis media
image Pelvic abscess
image Peritonsillar abscess
image Pneumocystis carinii pneumonia
image Pneumonia
image Pyelonephritis
image Pyogenic hepatic abscess
image Q fever (Coxiella burnetii)
image Retroperitoneal abscess
image Rocky mountain spotted fever
image Salmonella (disseminated infection or focal osteomyelitis)
image Septic bursitis
image Sinusitis
image Subacute bacterial endocarditis
image Syphilis
image Tonsillitis
image Tracheobronchitis
image Tuberculosis
image Tularemia
image Typhoid fever
image Urinary tract infection (UTI)

Viral infections

image Cytomegalovirus (CMV)
image EBV (most commonly isolated virus)
image Enterovirus
image Hepatitis A, B, C
image HIV
image Influenza A and B
• Other infectious agents
image Aspergillosis
image Blastomycosis
image Coccidioides immitis
image Cryptococcal infections
image Ehrlichiosis
image Entamoeba histolytica
image Histoplasmosis
image Malaria
image Toxoplasmosis

Immunodeficiency Diseases

Primary immunodeficiency diseases usually present with repeated infections; however, prolonged fever can be the presenting manifestation before a definite infection has been identified.

• Common variable immunodeficiency
• Leukocyte adhesion deficiency
• Terminal complement component deficiency
• Wiskott-Aldrich syndrome
• X-linked agammaglobulinemia

Neoplastic Causes

• Acute lymphocytic leukemia

• Hodgkin lymphoma

• Neuroblastoma

Rheumatologic Causes

• Behcet’s syndrome

• Idiopathic thrombocytopenic purpura

• Infantile-onset multisystem inflammatory disease

• Juvenile dermatomyositis

• Juvenile rheumatoid arthritis

• Mixed connective tissue disease

• Polymyositis

• Prelupus syndromes

• Scleroderma

• Systemic lupus erythematosus

• Systemic sclerosis

• Vasculitis

Miscellaneous Causes

• Central nervous system (CNS) dysfunction

• Diabetes insipidus

• Ectodermal dysplasia

• Factitious fever

• Familial dysautonomia (Riely-Day syndrome)

• Hemophagocytic syndrome

• Infantile cortical hyperostosis (Caffey disease)

• Inflammatory bowel disease

• Kawasaki disease

• Medications

• Mucha-Habermann disease

• Munchausen syndrome by proxy

• Periodic fever syndromes

image Blau syndrome
image Familial cold autoinflammatory syndrome
image Familial cold urticaria syndrome
image Familial Mediterranean fever
image Hyperimmunoglobulin D and periodic fever syndrome
image Muckle-Wells syndrome
image Neonatal-onset multisystem inflammatory disease
image PAPA syndrome (pyogenic sterile arthritis, Pyoderma gangrenosum, and acne syndrome)
image Tumor necrosis factor receptor–associated periodic syndrome

• Rhabdomyolysis

• Thyrotoxicosis

Key Historical Features

Onset and pattern of fever

Severity and duration of fever

Review of systems and complaints

• Abdominal pain
• Adenopathy
• Anorexia
• Bowel symptoms or change in bowel frequency
• Chills
• Diarrhea
• Dizziness
• Focal areas of pain
• Genitourinary symptoms
• Headache
• Irritability
• Joint pain
• Joint stiffness
• Joint swelling
• Listlessness
• Myalgias
• Nausea
• Night sweats
• Oral ulcers
• Pallor
• Pharyngitis
• Rash
• Sleep disturbances or changes in sleep patterns
• Weight loss
• Visual change
• Vomiting
• Weakness

Medical history

Surgical history

Medications

Social history

• Place of birth
• Foreign Travel
• Play and living environment (rural areas, camping trips)
• Pet and animal exposure
• Drug use
• Sexual history, including possible sexual abuse
• Family structure and caretaker relationships

Family medical history

• Leukemia
• Paroxysmal febrile syndromes

Key Physical Findings

Vital signs

Nutritional status

Growth curve plots of height and weight

General assessment of overall health

Ocular and funduscopic examination: pupillary response to light can be impaired in CNS dysfunction; vasculitic lesions may be seen on fundoscopic exam. Disseminated tuberculosis (TB) or toxoplasmosis can produce funduscopic abnormalities. Conjunctivitis is present in a number of illnesses: bulbar conjunctivitis may be seen in infectious mononucleosis, lupus erythematosus may present with palpebral conjunctivitis, and Kawasaki disease can have a predominantly bulbar conjunctivitis.

Oropharyngeal examination: pharyngeal hyperemia without exudates may be associated with EBV, CMV, toxoplasmosis, tularemia, or leptospirosis infections. Loss of teeth and gingival hypertrophy can be a sign of leukemia or Langerhans histocytosis. The presence of aphthous stomatitis may indicate lupus, mixed connective tissue disease, or vasculitis.

Neck examination for cervical lymphadenopathy

Cardiovascular examination for friction rubs or prominent or new murmurs

Pulmonary examination for rales or consolidation

Abdominal examination for masses, hepatomegaly, splenomegaly, or focal tenderness

Genitourinary examination

Pelvic examination in adolescent females for cervical discharge, cervical motion tenderness, or adnexal tenderness

Musculoskeletal examination for gait, assessment of strength, point tenderness over the bones, joint tenderness, joint effusion, or limited range of motion in the joints. Each joint should be evaluated for swelling, warmth, redness, and range of motion. Long bones must be palpated carefully for bony tenderness. The spine should be palpated and assessed for range of motion.

Skin examination for rash, petechiae, jaundice (hepatitis, malaria), seborrhea (histoplasmosis), erythrema nodosum (Coccidioides immitis), changes in dermal thickness, tightening or contractures, pigmentation changes, nail changes, or alopecia.

Rectal examination for bloody stool or lesions

Neurologic examination for focal deficits, changes in mental status, ataxia, or seizure activity

Initial Work-Up

During the first week, common causes of fever should be excluded through screening tests and cultures. After the first week of fever, the work-up typically becomes more extensive and no longer is focused on the common infections. The history and physical examination should help guide the tests that are ordered. Tests from each of the following lists may be included or excluded at any time during the evaluation of FUO, as suggested by the clinical findings.

Complete blood cell count (CBC) with differential and platelet count To evaluate for leukocytosis (infection or rheumatologic disease), leukemia, or thrombocytopenia
Erythrocyte sedimentation rate (ESR) To evaluate for inflammatory processes
Electrolytes To evaluate for metabolic derangements such as acidosis
Urinalysis and urine culture To evaluate for cystitis, pyelonephritis, or inflammatory nephritis
Liver function tests To screen for hepatitis
Hepatitis screening tests To evaluate for viral hepatitis
Blood cultures To evaluate for bacteremia and subacute bacterial endocarditis
Streptococcal enzyme titers To evaluate for exposure to Streptococcus spp.
Lyme titers To evaluate for Lyme disease, especially in endemic areas or if there is a history of travel to an endemic area
Antinuclear antibody To evaluate for rheumatologic processes
Purified protein derivative (PPD) To evaluate for exposure to TB
Chest radiograph To evaluate for cardiac and pulmonary disease

Additional Work-Up

C-reactive protein If an inflammatory process is suspected, as an alternative test to the ESR
Thyroid-stimulating hormone (TSH) and thyroxine (T4) If thyrotoxicosis is suspected
Stool cultures If enteritis or typhoid fever is suggested by history
Total protein and albumin To evaluate nutritional status and hepatic synthetic function
IgG, IgM, and IgA If immunodeficiency is suspected
IgD To evaluate for hyperimmunoglobulin D syndrome
Rheumatoid factor If juvenile rheumatoid arthritis is suspected
HIV test If HIV infection is suspected
EBV titers If EBV infection is suspected
CMV screening If CMV infection is suspected
Urine vanillylmandelic acid (VMA) and metanephrines If pheochromocytoma is suspected
Stool guaiac testing If enteritis is suspected
Sweat chloride test If cystic fibrosis is suspected
Venereal Disease Research Laboratory (VDRL) To evaluate for syphilis
Lumbar puncture with Gram stain, cell counts, cultures, and viral studies If CNS infection or inflammation is suspected.
Bartonella titer If cat-scratch disease is suspected
Toxoplasmosis titer If toxoplasmosis is suspected
Rickettsia titer If Rickettsial infection is suspected
Francisella titer If tularemia is suspected
Coxiella titer If Q fever is suspected
Candida skin test To test cellular immunity if primary immunodeficiency is suspected
Synovial fluid analysis evaluation If a single joint is swollen
Synovial biopsy If a single joint is swollen and the tuberculin test is positive to evaluate for tuberculous arthritis
Lymph node biopsy If persistent lymphadenopathy is present and a diagnosis has not been determined
Bone marrow biopsy If an oncologic process or bone marrow infiltrative process is suspected
Bone biopsy If a bony lesion is found on imaging study
B-lymphocyte quantification and antibody titers against protein antigens such as tetanus To test humoral immunity if primary immunodeficiency is suspected
Total hemolytic complement levels If congenital complement deficiency is suspected
Thick and thin smears for malaria If malaria is suspected

Imaging Studies

Electrocardiogram (ECG) and echocardiogram If endocarditis, myocarditis, or pleural effusion is suspected
Radiographs of specific bones If osteomyelitis or tumor is suspected
Sinus x-rays or computed tomography (CT) If sinusitis is suspected
Bone scan To evaluate for osteomyelitis or juvenile arthritis
CT scan of the abdomen To evaluate for intra abdominal abscess or tumor
Abdominal ultrasound To evaluate for intra abdominal abscess or tumor
Gallium scan To evaluate for intra abdominal abscess or tumor
CT scan of the chest If thoracic pathology is suspected
CT scan or magnetic resonance imaging (MRI) of the brain If CNS tumor or abscess is suspected
Electroencephalography If encephalitis is suspected
MRI of the spine To evaluate for tumor, abscess, or diskitis
MRI of the abdomen To evaluate for abscess
Vesicoureterogram or intravenous pyelogram If urinary tract pathology is suspected
Barium enema If colonic pathology is suspected
Colonoscopy with biopsy If inflammatory bowel disease is suspected

References

1. Baraff L.J. Management of fever without source in infants and children. Ann Emerg Med. 2000;36:602–614.

2. Dechovitz A.B., Moffet H.L. Classification of acute febrile illnesses in childhood. Clin Pediatr. 1968;7:649–653.

3. Finkelstein J.C., Christiansen C.L., Platt R. Fever in pediatric primary care: occurrence, management, and outcomes. Pediatrics. 2000;105:260–265.

4. Ishimine P. Fever without source in children 0 to 36 months of age. Pediatr Clin North Am. 2006;53:167–194.

5. Jacobs R.F., Schutze G.E. Bartonella henselae as a cause of prolonged fever and fever of unknown origin in children. Clin Infect Dis. 1998;26:80–84.

6. Miller L., Sisson B.A., Tucker L.B., Schaller J.G. Prolonged fevers of unknown origin in children: patterns of presentation and outcome. J Pediatr. 1996;12:419–421.

7. Miller M.L., Szer I., Yogev R., Bernstein B. Fever of unknown origin. Pediatr Clin North Am. 1995;42:999–1015.

8. Padeh S. Periodic fever syndromes. Pediatr Clin North Am. 2005;52:577–609.

9. Palazzi D.L., McClain K.L., Kaplan S.L. Hemophagocytic syndrome in children: an important diagnostic consideration in fever of unknown origin. Clin Infect Dis. 2003;36:306–312.

10. Petersdorf R.G., Beeson P.B. Fever of unexplained origin: report on 100 cases. Medicine (Baltimore). 1961;40:1–30.

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