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.Variability in Defining PUO
An FUO in children has been defined as a daily rectal temperature greater than 38.3°C (101°F),lasting for at least 2 weeks, the cause of which has not been determined by simple diagnostic tests, including a complete history and thorough physical examination. Some experts would add that 1 of the 2 weeks of fever should be documented in the hospital. (Feigin RD, Shearer WT. Fever of unknown origin in children.Curr Probl Pediatr.1976;6:1ospital.) Fever of 38.3 or greater of at least eight days duration, with no apparent diagnosis after initial outpatient or hospital evaluation that includes a careful history and physical exam and initial laboratory assessment. Tolan, R.W. Fever of Unknown Origin: A Diagnostic Approach to This Vexing Problem. Clinical Pediatrics. 2010 49:207) Etiology-Origin of Fever
Collagen vascular diseases (10-15%), and
Numerous miscellaneous diseases (15-20%).
The literature also reveals that, as previously mentioned, between 5 and 15% of FUO cases defy diagnosis, despite exhaustive studies. (Pyrexia of Unknown Origin: Approach to management , Singapore Medical Journal 2005 Vol36: 204-208)
Abdominal, brain, dental, hepatic, pelvic, perinephric, rectal, subphrenic,psoas
- Bartonella henselae (cat-scratch disease)
- Francisella tularensis,Listeria monocytogenes
- Rat-bite fever (Streptobacillus moniliformis; streptobacillary form)
- Others -Mycoplasma pneumoniae ,Yersiniosis, Actinomycosis , Campylobacter , Meningococcemia (chronic) -rarely
- Localized infections- Cholangitis ,Infective endocarditis ,Mastoiditis , Osteomyelitis,Pneumonia ,Pyelonephritis ,Sinusitis
- Borrelia burgdorferi(Lyme disease),Relapsing fever (Borrelia recurrentis)
- Rat-bite fever (Spirillum minus; spirillary form of rat-bite fever)
Blastomycosis (extrapulmonary) ,Coccidiodomycosis (disseminated) ,Histoplasmosis (disseminated)
Chlamydia (Lymphogranuloma venereum,Psittacosis)
Rickettsia (Ehrlichia canis ,Q fever,Rocky Mountain spotted fever ,Tick-borne typhus)
CMV, Hepatitis viruses ,HIV, IM (Epstein-Barr virus)
Amebiasis , Giardiasis ,Babesiosis ,Malaria ,Toxoplasmosis
Trichinosis ,Trypanosomiasis ,Visceral larva migrans (Toxocara)
- Behçet disease
- Juvenile dermatomyositis
- Rheumatic fever
- Hypersensitivity diseases-Drug fever,Hypersensitivity pneumonitis ,Pancreatitis ,Serum sickness ,Weber-Christian disease
- Atrial myxoma
- Cholesterol granuloma
- Hodgkin disease
- Inflammatory pseudotumor
- Wilms tumor
- Crohn disease
- Granulomatous hepatitis
- Anhidrotic ectodermal dysplasia
- Fabry disease
- Familial dysautonomia
- Familial Mediterranean fever
- Sickle cell crisis
- Chronic active hepatitis
- Diabetes insipidus (non-nephrogenic and nephrogenic)
- Factitious fever
- Hemophagocytic syndromes
- Hypothalamic-central fever
- Infantile cortical hyperostosis
- Inflammatory bowel disease
- Kawasaki disease
- Periodic fevers
- Pulmonary embolism , Thrombophlebitis ,
Persistent, Recurrent, Resolved
A careful history and physical examination is the first step in evaluating a patient with fever of unknown origin.
o Duration, height and pattern, measurement technique
o Appearance of the child during the febrile episode
o Whether or not the fever responds to antipyretic drugs
Lack of response to NSAIDs may indicate a non-inflammatory condition as the cause of the fever
o Associated sweating
Fever, sweating and heat intolerance may indicate hyperthyroidism
Fever, heat intolerance and absence of sweating is suggestive of ectodermal dysplasia
o Intermittent:high spike and rapid defervescence-Pyogenic infection ,Can also occur in tuberculosis, lymphoma , JRA
o Remittent:fluctuating peaks and baseline that does not return to normal-Viral infections ,Can occur with bacterial infections, especially endocarditis, sarcoid, lymphoma and atrial myxoma
o Sustained: persist with little or no fluctuation-Typhoid fever, typhus and brucellosis
o Relapsing: afebrile for one or more days in between febrile episodes-Malaria, rat bite fever, Borrelia infection and lymphoma
o Recurrent: episodes of fever of more than six month’s duration-Metabolic defects,CNS dysregulation of temperature control,Periodic disorders such as cyclic neutropenia, hyperimmunoglobulin D syndrome and deficiencies of selected
Examination of the characteristics and distribution of the rash will help in the diagnosis of the cause.
A maculopapular, petechial, or urticarial rash -bacterial infections or with medication-related fever.
Viral infections -non-specific maculopapular or a petechial rash.
Many inflammatory/vasculitic disorders present with a rash.
septic arthritis and osteomyelitis;
viral infections such as infectious mononucleosis, CMV, toxoplasmosis, and tick-borne illnesses (Lyme disease or Rocky Mountain spotted fever);
medication-related reactions; or malignancies
Poor growth, poor appetite, and weight loss are observed with any chronic illness as opposed to a history that is of relatively short duration (e.g., bacterial infections).
Absent tears are observed in autonomic disease.
There may be a history of recent tick or mosquito bite with Lyme disease, Rocky Mountain spotted fever, and malaria infection.
Bone pains are present in osteomyelitis, leukemia, juvenile idiopathic arthritis (JIA), and SLE.
CNS symptoms -encephalitis, bacterial endocarditis, myocarditis, cerebral abscesses, tuberculous meningitis, secondary spread from a malignancy, severe inflammatory disorders (e.g., SLE), and cerebral malaria. Chorea is present with advanced rheumatic fever.
Urinary symptoms of dysuria, frequency, and haematuria accompany UTIs such as cystitis and pyelonephritis.
o Include past or current complaints
o Sick contacts
o Animal exposures
Household pets, domestic animals in the community and wild animals
o Travel history starting at birth
Site of travel
Prophylactic medications and immunizations for travel
Exposure to contaminated food and water while traveling
Exposure to other persons with recent travel
o Tick or mosquito bites
o Consumption of raw or undercooked meat or raw shellfish
o Consumption of dirt (pica)
o Ulster Scots: nephrogenic diabetes insipidus
o Sephardic Jewish, Armenian, Turkish or Arab descent: familial Mediterranean fever , Ashkenazi Jewish descent: familial dysautonomias
Careful physical exam which should be performed while the patient is febrile
Special attention to the following areas:
General appearance and vital signs
Skin and scalp
Heart rate-Tachycardia -common with fever, but persistent tachycardia may suggest thyroid storm or endocarditis/myopericarditis.
Respiration-Tachypnoea may be present in pneumonia, or multisystem disorders with lung involvement.
Hypertension-inflammatory/vasculitic disorders, chr pyelonephritis, SLE, and thyroid storm.
Postural hypotension -toxic shock syndromes, medication-related, and autonomic disorders.
Pallor-leukemia, lymphoma, most chronic bacterial infections and inflammatory/vasculitic illnesses, malaria, and tuberculosis.
Jaundice-Present in patients with hepatic abscess and infectious mononucleosis.
Clubbing-Present in patients with endocarditis, inflammatory bowel disease, and tuberculosis.
Isolated cervical lymphadenopathy -Kawasaki disease and cat-scratch disease.
Disseminated lymphadenopathy -Infectious mononucleosis, CMV, toxoplasmosis, leukemia, lymphomas, tick-borne illnesses, and some inflammatory/vasculitic illnesses.
Most bacterial infections give rise to regional lymphadenopathy.
The ulceroglandular form of tularaemia typically presents with lymphadenopathy.
Directed toward likely cause of fever based on information gained from the history and physical
Timing of labs and studies is based on severity of illness
For Serious cases no diagnostic test should be delayed.
o Anemia: malaria, IE, IBD, SLE or tuberculosis
o Thrombocytosis: Kawaskai disease
o WBC: atypical lymphocytes -viral infection, immature forms -leukemia , Eosinophilia-parasitic, fungal, neoplastic, allergic or immunodeficiency disorders
ESR and CRP: non-specific acute phase reactants and general indicators of inflammation Initial Tests:
Urinalysis and urine culture: UTI is a common source of FUO, sterile pyuria is suggestive of Kawaski disease or genitourinary tuberculosis
Chest X Ray: evaluate for infiltrates or lymphadenopathy
Serum electrolytes, BUN, creatinine and hepatic enzymes
HIV: significant variability in manifestations of primary HIV infection
1.CBC ,PS,ESR, CRP
2.Aerobic blood C/S, UA, urine C/S,
3.CXR, tuberculin skin test,
4.Electrolytes, BUN, creatinine,
5.hepatic enzymes, HIV serology
Blood cultures: obtain several sets if infective endocarditis is a consideration
Additional Tests are Guided by information obtained with history, physical exam and results of initial testing
Stool studies: culture, ova and parasites in patients with loose stools or recent travel
Bone marrow: most useful in diagnosing malignancy, histiocytic disorders and hemophagocytic disease, not helpful in diagnosing infection
Serologies: targeted approach is indicated
HIV serology for all children with FUO
Syphilis is recommended for neonates, young infants and adolescents
Consider evaluation for EBV, CMV, toxoplasmosis, bartonellosis, brucellosis, tularemia as well as parasitic infections such as strongyloidiasis
Serum ANA: obtain in children over age 5 with family history of rheumatologic disease
Immunoglobulins:serum IgG, IgA and IgM in children with evidence of recurrent or persistent infections and in those with persistent fever and a negative initial evaluation
Molecular testing: (ie PCR) may be useful in specific cases
Ophthalmologic exam can be helpful to evaluate uveitis or leukemic infiltration
Imaging and other evaluations
o Indicated if inflammatory bowel disease is suspected
o Consider if fever may be due to intrabdominal abscess -psoas abscess or cat scratch disease .
Imaging of the nasal sinuses or mastoid is recommended if sinusitis is a possible etiology for FUO
ECG/Echocardiography should be performed if there is concern for infective endocarditis
Biopsy is recommended only when there is evidence of specific organ involvement
Computed Tomography Scanning- If USG fails to help reveal the diagnosis, obtain CT scans of the abdomen in all patients with symptoms suggesting an intra-abdominal process, Intravenous pyelographymay be more sensitive than CT scanning in detecting processes involving the descending urinary tract, but CT scanning is preferred for most other processes of the retroperitoneal space.
Magnetic Resonance Imaging-osteomyelitis, vasculitides.
Upper and lower gastrointestinal tract, including retrograde cholangiography when indicated or when searching for Crohn disease,Whipple disease, biliary tract disease, and gastrointestinal tumors..
Ventilation and perfusion radionucleotide studies to document pulmonary emboli.
A technetium bone scan may be a more sensitive method for documenting skeletal involvement when osteomyelitis is suspected in a patient in whom conventional radiography has shown no compatible changes.
Consider radionucleotide studies using gallium citrate or granulocytes labeled with indium In 111 (111In) for diagnosis of occult abscesses, neoplasms, or soft-tissue lymphomas.
Generally avoid empiric treatment with anti-inflammatory medications or antibiotics as an effort to diagnose the patient’s condition.
Empiric antibiotics can mask or delay diagnosis of infections such as meningitis, infectious endocarditis or osteomyelitis
O Nonsteroidal agents in presumed JIA
O Antituberculosis drugs in critically ill children with possible disseminated TB
O Clinically deteriorating with suspicion of bacteremia or sepsis.
Antibiotics if used should be at targeted disease rather than blancket therapy with 4-5 antibiotics.
In general, empiric therapy has little or no role in cases of classic fever of unknown origin (FUO).Treatment should be directed toward the underlying cause, as needed, once a diagnosis is made.Some studies suggest a few exceptions to this general approach, including the following:
1.Cases that meet criteria for culture-negative endocarditis
2.Cases in which findings or the clinical setting suggests cryptic disseminated TB (or, occasionally, other granulomatous infections)
3.Cases in which temporal arteritis with vision loss is suspected.
Inpatient Treatment-No evidence supports prolonged hospitalization in patients who are clinically stable and whose workup findings are unrevealing.
Outpatient Care-Conduct close follow-up procedures and systematic reevaluation studies to prevent clinical worsening. Guide further workup studies on an outpatient basis.
Patient Transfer-The need for transfer is indicated if (1) the current facility is unable to establish a diagnosis, (2) diagnostic tests are unavailable at the existing facility, or (3) the patient deteriorates clinically.
Several studies have found that prolonged, undiagnosed FUO generally carries a favorable prognosis.
The Best Approach
“ there is no substitute for observing the patient , talking to him and thinking about him”
1.Nelson Text Book of Pediatrics 18thEdition
2.Ergönül O, Willke A, Azap A, et al. Revised definition of ‘fever of unknown origin’: limitations and opportunities.J Infect. Jan 2005;50(1)
3.Cunha BA.Fever of Unknown Origin. New York, NY: Informa Healthcare; 2007
4.Pyrexia of Unknown Origin: Approach to management ,Singapore Medical Journal 2005 Vol 36: 204-208)
5.Feigin RD, Shearer WT. Fever of unknown origin in children.Curr Probl Pediatr.1976;6:1ospital.
6.Tolan, R.W. Fever of Unknown Origin: A Diagnostic Approach to This Vexing Problem. Clinical Pediatrics. 2010 49:207