Prolonged Pyrexia:
Dr Raju C Shah, MD, Dped, FIAP
Prolonged Pyrexia (Fever) of unknown origin (PUO/FUO) has been described using several
definitions. In 1961 Petersdorf and Beeson defined FUO in adults as fever, documented
temperature above 101° F on several occasions, persisting for more than 3 weeks and an uncertain
diagnosis after extensive evaluation in the hospital for 1 week.[1] These definitions, although still
employed, may not be very useful for pediatric patients in today's clinical environment. Many
diagnostic tests were not available when the FUO definitions were made .This increased
armamentarium of diagnostic tests has changed the approach to patients with prolonged fevers.
Indeed, many cases defined as FUO in the past are now diagnosed early in the course of illness.
Fever of more than 2 weeks duration is considered prolonged pyrexia undiagnosed after extensive
investigations.
The biggest concern in evaluating FUO is identifying patients whose fever has a serious or lifethreatening cause in which diagnostic delay could lead to a poor outcome. In a comprehensive
overview of fever in pediatric patients Kathryn Edwards[2] pointed out that the initial approach to
any patient with history of prolonged fever is to document its presence and the pattern(s) of
presentation. Most research conducted with children has identified infectious diseases as the most
common cause of FUO, with anywhere between 30% and 70% of cases explained by infection. [3, 4]
Obtaining a comprehensive exposure and travel history is essential for establishing a working
differential diagnosis. Many diseases are endemic to certain regions of the world (i.e., typhoid
fever, tuberculosis, malaria) or to certain countries (i.e., ehrlichiosis, Lyme disease, blastomycosis,
tularemia, and histoplasmosis).[3, 4] Exposure to pets or wild animals may also give a clue to the
diagnosis (i.e., cat-scratch disease, brucellosis, leptospirosis, salmonellosis, tularemia, visceral larva
migrans, and toxoplasmosis) [3] In addition attention to localized infection as the cause of FUO is
also helpful. Urinary tract infections, sinusitis, mastoiditis, or central nervous system infections are
some common diseases presenting as FUO.[3, 4]
Clinicians must remember that PUO is more likely to be uncommon presentation of common disease
rather than an uncommon disease. In most of cases diagnostic difficulties posed by inappropriately
treated pyrexias and most errors in diagnosis can be due to cursory incomplete examination than
due to lack of knowledge & skills.
When one examines any child with prolonged pyrexia it is very important to look for red flag if any
like
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Fever lasting over 4 wks
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Bone pains, adenopathy, patechie and ecchymoses
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Persistent thrombocytosis, elevated PMC, leucopenia, pancytopenia, dropping HB
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Mouth ulcers, hair fall, extreme weakness
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Features of Kawasaki Disease
If yes – hospitalize at a higher center for investigations and management.
History is very useful in any case of prolonged pyrexia. The following questions might be helpful:
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What is the timing of the current illness?
When did the fever start?
How long has the fever been present? Are there any related symptoms?
What is the patient's medical history? The history may not be applicable in all cases,
but it must be explored to reveal potential high risk or complicating factors.
Has the child's activity significantly changed during the illness?
Is the child tolerating fluids at home? Has the child been less interested in eating?
Have the stool patterns changed in consistency or frequency?
Has there been recent antibiotic use?
Has there been exposure to illness through babysitters, day care contacts, or other
caregivers? Are others at home sick?
Have the sleep patterns changed? Has the patient been snoring more at night than
usual?
Has there been any recent travel that might have exposed the child to illnesses?
Clinical Pearl:
The clinician should be aware that even the most thorough evaluation
can fail to reveal the underlying cause of FUO. If no cause can be
determined, repeated physical examinations and patience are then the
best approach.
The three most common etiological categories of FUO in children in order of frequency are
infectious diseases, connective tissue diseases, and neoplasm. In addition, there are causes of FUO,
such as drug fever, factitious fever, central nervous system dysfunction, and others, that do not fit
into the above categories. In a few cases, there may be a very slow progression to obvious clinical
manifestations of rheumatic disease or chronic inflammatory disorder. Commonest causes of fever
are – Typhoid, Respiratory infections, Tuberculosis, UTI, Deep seated abscesses, Extended viral
infections, Osteomyelitis, Brucellosis, endocarditis, Connective tissue inflammation and
malignancies esp. related to blood and lymphnodes. However, in the majority of patients, fever will
eventually resolve without any specific cause ever being delineated [5, 6]. Some of the periodic fever
may also need to be ruled out. The most important periodic fever syndromes identified are PFAPA
(periodic fever, aphthous stomatitis, pharyngitis, and adenitis) syndrome, familial Mediterranean
fever, hyper-IgD syndrome (HIDS), and tumor necrosis factor receptor-associated periodic
syndrome (familial Hibernian syndrome). In many cases, a definitive diagnosis is never established
and fever resolves.
Clinical Pearl:
Assiduous examination of ears, nose, throat, sinuses & chest very important as more than 50% cases are having Respiratory
cause.
Clues to FUO Cause
To help narrow down what is causing fever in the child, following questions can help:
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Has he been around anyone else that has been sick?
Has he traveled out of the country recently? (Malaria)
Has he been around any farm animals or wild animals? (Brucellosis, Tularemia)
Do you have any pets? (reptiles - Salmonella infections, Birds - Psittacosis)
Has he been bitten by a tick? (Lyme Disease, Q Fever, Rocky Mountain Spotted
Fever)
Has he been scratched by a kitten? (cat-scratch disease)
Has he eaten any raw or undercooked foods or drink unpasteurized milk or juice?
Does he have a heart murmur? (bacterial endocarditis)
Has he been taking any medications? (drug fever)
Does anything like this run in the family? (familial Mediterranean fever)
In addition to the fever, has he had other symptoms, like night sweats and weight
loss? (lymphoma)
Clinical Pearls:
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In most of cases diagnostic difficulties posed by inappropriately
treated pyrexias
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Most errors in diagnosis due to cursory, incomplete examination
than due to lack of knowledge & skills
In all cases of prolonged pyrexia following algorithmic approach can make the task easier.
Algorithm for Prolonged Pyrexia
Fever of more than 15 days
Proven Etiology or
Site of Infection identified
No diagnosis /
No response to empirical therapy
Review basis of Diagnosis
Definitive
Presumptive
Consider Resistant Infection
Attempt definitive diagnosis with appropriate
serology, histology, microbiology
Change / Add Antibiotic
Change / add antibiotic
Consider complications of disease
Or Immunodeficiency
Search for associated complications
Drain pus, hematoma, if identified
Remove shunts, prostheses, etc.
Consider resistance only if microbial diagnosis
available or only as a last option
Rule out immunodeficiency
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Review Symptoms, Physical signs and Investigations at every stage &
Reconsider Diagnosis
Consider second pathology only as last option
- Review symptoms, signs and investigations
- Perform additional relevant investigations
Definitive/
Presumptive
Institute appropriate treatment
Continue to observe/investigate
No definitive
diagnosis
Next page..
Algorithm for Prolonged Pyrexia (page 2)
No definitive diagnosis
Child toxic, sick, unstable,
High risk group
Yes
Specific therapy,
If not possible – use broad-spectrum
antibiotic combination
Continue to observe/investigate
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No
Stop antibiotics
Observe
Reinvestigate
Review Symptoms, Physical signs and Investigations at every
stage & Reconsider Diagnosis
Consider second pathology only as last option
References:
1.
Miller L, Sisson B, Tucker L, Schaller J. Prolonged fevers of unknown origin in children: Patterns of presentation
and outcome. J Pediatr. 1996; 12:419-423.
2.
Edwards K. Fever: From FUO to PFAPA to recurrent or persistent. Program and abstracts from the American
Academy of Pediatrics National Conference and Exhibition; October 9-13, 2004; San Francisco, California. Session
S375.
3.
Campbell J. Fever of unknown origin in a previously healthy child. Semin Pediatr Infect Dis. 2002;13:64-66.
4.
Miller M, Szer I, Yogev R, Bernstein B. Fever of unknown origin. Pediatr Clin North Am. 1995;42:999-1015.
5.
Steele R. Fever of unknown origin. A time for patience with your patients. Clin Pediatr. 2000;39:719-720.
6.
Alpern ER, Henretig FM. Fever. Fleisher GR, Ludwg S, Henretig FM, eds. Textbook of Pediatric Emergency
Medicine. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:295-306.