Approach to

prolonged fever
.
 Prolonged fever

• Undiagnosed fever
• Prolonged fever
• Prolonged fever of unknown origin
• Fever of unknown origin (FUO)
 Fever without source
(Fever with localizing signs; FWS)

“ fever < 1 week without obvious source from Hx, PE & Ix ”

Self limited S&S Prolonged fever

(FUO)
Diagnosis
Studies of FUO in children: Causes
. .
( )

3 -2 P 2004 1,137 38.7 0 0 0 61.3

>5 R 1965 165 55.2 5.5 1.8 10.9 26.6
>7 P 2004 117 65.8 0.9 3.4 10.3 19.7
>7 R 2011 1,638 51 9 6 11 23
>2 R 1975 100 52 20 6 10 12
>2 R 1990 221 78 5 2 0 15
>2 R 2003 80 58.7 6.3 2.5 20 12.5
>2 R 2006 91 41.7 13.2 2.2 15.4 27.5
>3 R 1972 99 29.3 11.1 8.1 19.2 32.3
>3 R 1977 54 33 20 13 15 19
>3 R 1991 109 22 6 2 3 67
>3 R 1994 113 36.3 13.3 9.7 21.2 19.5
>3 P 2006 185 37.8 12.9 6.5 13.7 29.1
 FUO

S&S <7 (FWS) >7 >2 >3

4 (

( 3 ) connective tiss dis,

lab CBC, U/A, U/C, ESR, <7 + T.T, ± ANA
CRP, H/C, ±CXR (
lab S&S
)* T.T
- FUO - Hx, PE, Ix
- empirical Hx, PE S&S Ix
ATBs - empirical ATBs
 Definition of FUO

Fever >38.3 0C for >7 days with no

diagnosis from history, physical
examination & preliminary lab test
in the hospital or as an outpatient

Lorin MI. Textbook of pediatric infectious diseases 1992.

Palazzi DL Textbook of pediatric infectious diseases 2009.
 Causes of FUO
common diseases are much
more than uncommon diseases

1. incomplete presentation of
common disorders
2. uncommon presentation of
common disorders
 Meta-analysis: Causes of FUO

• 1,638 patients, age 0-18 years

• 18 Studies from 1950- 2009 in English (13), French
(2), Spanish (2) and Polish (1)
• Criteria: Fever > 7 days with no definite cause

• Causes:
- Infectious diseases 51 %
- Collagen vascular disease 9 %
- Malignancy 6 %
- Miscellaneous disorders 11 %
- No diagnosis 23 %
Chow A. World J Pediatr 2011;7:5-10.
 Causes of FUO : Infectious diseases
System Percent (%)
Infectious
Respiratory tract 50
Urinary tract
Diseases
6-8
CNS 6-8
TB 6
Bloodstream, GI 4, 4
Bone & joint, CVS 4, 4
Mononucleosis 4
Occult abscess 2

Chow A. World J Pediatr 2011;7:5-10.

 Causes of FUO: BMA (n=117)
-Prospective descriptive study , January-December 2003
-BMA Medical College and Vajira Hospital, Bangkok
- Age <15 yrs , Fever >7 days

Undiagnosis 19.7%
Infectious
diseases 65.8%

Neoplasms
3.4% Collagen vas dis
0.9%

. 2547.
 Cause: Infectious disease No.
1. Infection 77
Pneumonia 14

Acute pyelonephritis 7

Otitis media, Bronchitis, Pulmonary TB, 5

Gastroenteritis, Abscess, Septicemia

Sinusitis 4

Meningitis, Pharyngitis, Infectious mononucleosis 3

Lymphadenitis, Osteomyelitis, Septic arthritis, 2

Enteric fever

Empyema thoracis, Peritonitis, Infective 1

endocarditis, Scrub typhus

Not found: malaria, leptospirosis, melioidosis, dengue

. 2547.
Causes of FUO: endemic infections (n 1,137)

-Prospective study, in 10 community based hospitals in 1991-1993

-Age >2 yrs , Fever 3-14 days

Endemic infections Percent

Scrub typhus 7.5
Murine typhus 5.3
Enteric fever 1.9
Leptospirosis 1.1
Chikungunya 1.1
Melioidosis 0.9
Leelarasamee A. J Med Assoc Thai 2004;87:464-72.
 FUO: Endemic infection
in Thailand
• Malaria
• Melioidosis
• Rickettsia: scrub typhus, murine
typhus
• Leptospirosis
 Respiratory tract infections

• Otitis media, sinusitis, mastoiditis

: mild symptoms, neglect

• Pneumonia
: incomplete or uncommon
presentations
 Tuberculosis
• Extrapulmonary TB:
: liver, abdominal lymph node, pericardium
: no specific signs & symptoms
: no infiltration

• Disseminated TB:
: esp. without characteristic miliary CXR
tuberculin test, AFB positive <50%
 Infective endocarditis
• Subacute, esp. right sided IE
• No skin lesions, no murmur
• Echocardiography: no vegetations
• H/C: no growth because of previous
ATBs, HACEK, Coxiella burnetii,
anaerobes
Infective endocarditis
 Bone & Joint infections

• Young children
• Plain radiographs: not sensitive
in early phase
• Radioisotopic bone scan
 Concealed abscess
• Abdominal abscess
• Some have only persistent fever with negative
H/C
• Previous intra-abdominal disease or surgery
• Liver abscess: hepatomegaly and RUQ
tenderness and normal liver enzymes
• Bacterial hepatitis and cholangitis: can occur
in the absence of jaundice and signs of liver
dysfunction
 Collagen vascular disease

Diseases Percent
JRA 60-65
SLE 15-20
Vasculitis 6.7
Others 10-15
Chantada G. Pediatr Infect Dis J 1994;13:206-3
Chow A. World J Pediatr 2010;7:5-10.
 Systemic JRA

•Fever, adenopathy, anemia,

hepatosplenomegaly, later arthritis,
irridocyclitis, leukocytosis and elevated ESR
• Some have fever for many monthes before
other manifestations occur and negative lab
result
•evanescent erythematous rash
Systemic JRA
 Systemic lupus erythematosus

• 4 of 11 criteria
• fever, mouth ulcer, butterfly rash, hair
loss, joint complaints, adenopathy,
pleuritis, hematologic, nephrologic and
neurologic manifestations, ANA, etc.
• fever alone and later developed other
manifestations
Systemic lupus erythematosus
 Rheumatic Fever
• Jones criteria (major & minor signs)
• fever, arthralgia, migratory arthritis, chorea,
carditis, subcutaneous nodules, erythema
marginatum, elevated ESR, CRP, prolonged
PR interval and evidence of GAS infection
( throat C/S, ASO )
• fever alone and other signs develop later
• Chorea may be alone
 Malignancy
• Prolonged fever with some non-specific
S&S e.g. anemia, bleeding, adenopathy,
hepatosplenomegaly, bone pain
• Most common: leukemia, lymphoma
• Others: neuroblstoma, Wilm tumor,
hepatoma, sarcoma, etc
 Kawasaki disease
• Infants may have partially S&S or
present only a brief period (Atypical
Kawasaki)
• may have only coronary aneurysm
+ little S&S
Kawasaki disease
 Drug fever
• On ATB > 7-10 days
• Look well
• No definite source of fever
• No leukocytosis
• Afebrile after discontinue ATB
for 2 days
 Hemophagocytic syndrome

• Prolonged fever, hepatosplenomegaly,

cytopenia at least 2 cell lines,
hypertriglyceridemia, hypofibrinogenemia,
elevated serum ferritin, hemophagocytosis
in the BM, liver, spleen and LN

• Initial FUO and progress to clinical S&S as

overwhelming sepsis
 Other causes of FUO

• Thermoregulatory dysfunction
: severe CNS injuries
• Ectodermal dysplasia
: inability to sweat
• Diabetes inspidus
• Periodic fever
• Inflammatory bowel disease
 Undiagnosis
• Viral infection
• Rare diseases:
-long term F/U 3-5 years: good prognosis
-86% fever abates spontaneously
-14% rare diseases: e.g. Crohn’s disease,
periodic fever, JRA, etc.

Miller LC. J Pediatr 1996;12:419-23.

Talano JAM. Clin Pediatr 2000;39:715-7.
 Diagnosis
• 86.2% diagnosed by repeated
thorough history, PE and basic
laboratory tests

• Investigations:
69.2% non-invasive
30.8% invasive: mostly by biopsy
Gaeta GB. Nucl Med Commun 2006;27:205-11.
 Clues
• Fever: duration
• High spiking fever : transient bacteremia with
pyogenic infection, JRA
• Recurrent infection & immune defect e.g. cyclic
neutropenia, Ig G subclass deficiency,
anatomical defect
• Recent surgery: nidus of occult infection
• Blood transfusion: hepatitis, HIV, malaria, CMV,
EBV
• Rash : collagen vas, neoplasm, infection
 Clues
• jaundice : hepatitis, leptospirosis, cholecystitis
• Murmur : BE, RF, myocarditis, Kawasaki
disease Abdominal pain, bloody stool,
diarrhea, weight loss: inflammatory bowel dis
• Conjunctivitis : Kawasaki, lepto, scrub, SLE
• Roth spots : IE
• Uveitis ( slit lamp ) : JRA, Crohn,
toxoplasmosis
 Clues
• Generalized adenopathy with hepatosplenomegaly :
virus ( IM, HIV , mononucleosis like e.g. CMV, toxo ),
collagen ( JRA ), leukemia
• Localized adenopathy : staph, strep, TB, cat scratch,
malignancy
• Arthralgia, arthritis, myalgia, localized limp pain:
collagen vascular dis, osteomyelitis, septic arthritis,
reactive arthritis (enteric bacilli e.g. salmonella,
shigella )
• Bony tenderness : osteomyelitis, neoplasmic
marrow invasion
• Muscular soreness : underlying abscess
 Clues
• Papilledema : brain tumor,
meningoencephalitis, subdural hematoma
• Meningeal, focal neurosigns : meningitis,
meningoencephalitis, neoplasm
• Rectal exam: abdominal & pelvic abscess or
tumor
• Pancytopenia, neutropenia,
thrombocytopenia, lymphoblasts : perform
bone marrow aspiration
• Lymphocytosis : virus ( IM, )
 Causes of delayed diagnosis

• Atypical or incomplete manifestations

• Incomplete Hx & PE
• Incorrect or misinterpreted laboratory
investigation
• Premedication
• Rare disease
McClung HJ. Am J Dis Child 1972;124:544-50.
Pizzo PA. Pediatrics 1975;55:468-73.
Lohr JA. Clin Pediatr 1977;16:768-73.
 Management
• Careful Hx & PE
• Initial laboratory investigation
-CBC with peripheral smear
-Hemoculture
-ESR, CRP
-Urine examination, U/C (wbc>5)
-CXR
-Tuberculin test
 Management
• Consider ANA
• Specific treatment depends on causes
• Symptomatic treatment: paracetamol,
tepid sponge, redehydration, etc.
• Stable patients who initial evaluation
failed to make diagnosis : Follow up and
re- evaluation (repeat Hx, PE, Lab).
 Management
• Inappropriate empirical antibiotics may
alter typical signs of occult infections
(e.g. meningitis, osteomyelitis,
abdominal abscess)
• Empirical treatment: NSAIDs for JRA,
antiTB drugs for disseminated TB
• Prognosis better than adults
• Mortality rate 2.5-17%
Serious diseases or need specific treatment

Clinical manifestations Laboratory test

Joint WBC >15,000

ANC >10,000
Skin
ESR > 20
Cardiovascular

Pizzo PA, Pediatrics 1975;55:468-73.

Chantada G. Pediatr Infect Dis J 1994;13:260-3.
. 2547;43:108-115.
 Conclusion: FUO
• Fever >7 days with no diagnosis by Hx, PE,
initial lab.
• Initial lab: CBC with peripheral smear, H/C,
ESR, CRP, U/A (U/C if wbc >5/HPF), CXR, T.T
• Consider ANA for connective tissue diseases
• Incomplete manifestations of common diseases
> rare dis.
• Key for diagnosis: repeat Hx, PE, and selected
laboratory tests
• Explain to the parents what are you doing and
planning for management for relief anxiety
 Conclusion: FUO
• Cause: infection (51%), collagen vascular
diseases (9%), malignancy (6%), miscellaneous
(11%), undiagnosis (23%)
• Undiagnosis: majority are self limited despite a
prolonged course of fever
• Joint, skin, cardiovascular manifestations, WBC
>15,000/mm3, absolute PMN> 10,000/mm3, and
ESR >20 mm/hr may indicate the patient who
has serious disease or need specific treatment
• Consider empirical treatment in JRA,
disseminated TB
Thank You