This document discusses the approach to pyrexia of unknown origin (FUO) in children. It defines FUO and classifies it into four categories: classic FUO, healthcare-associated FUO, immune deficient FUO, and HIV-related FUO. For each category, it provides the definition, leading causes, aspects of history and examination to focus on, appropriate investigations, management considerations, and typical time course. It also discusses the various etiologies that can cause FUO and provides guidance on taking a thorough history, performing a physical examination, and selecting initial investigations. The key takeaway is that FUO may represent an uncommon manifestation of a common disease and the workup should be tailored thoughtfully to each case.

1. APPRAOCH TO PYREXIA OF
UNKNOWN ORIGIN
BY
M.MADHURI REDDY
PG PAEDIATRICS

2. DEFINITION
 Children with fever, documented by a health care provider, for
which cause could not be identified even after 3 weeks of
evaluation as an outpatient or after 1 week of evaluation in the
hospital

3. CLASSIFICATION
 4 categories :
1.Classic FUO
2. Health care associated FUO
3. Immune deficient FUO
4. HIV – related FUO

4. CLASSIC FUO
 Definition: fever of > 380 C ,lasted for > 3 wks, >2 visits or
1 wk in hospital
Patient location : community , clinic or hospital
 Leading causes : cancer , infections , inflammatory
conditions, undiagnosed , habitual hyperthermia
History emphasis : H/O travel , contacts , animal & insect
exposure , medications , immunization , family history ,
cardiac valve disorder

5. Examination emphasis :fundi, oropharynx , temporal artery ,
abdomen , lymph nodes , spleen , joints , skin , nails , genitalia
, lower limb deep veins .
Investigation emphasis : Imaging , biopsies , erythrocyte
sedimentation rate , skin test
Management : Observation , outpatient temperature chart ,
investigations , avoidance of empirical drug treatment
Time course of disease : For months

6. HEALTH CARE ASSOCIATED FUO
 Definition : Fever of > 380 C ,lasted for > 1 week , not
present or incubating on admission
 Patient location : Acute care hospital
Leading causes : Hospital acquired infections , post-
operative complications , drug fever
History emphasis : Operation & procedures , devices
used , anatomic considerations , drug treatment

7. Examination emphasis :Wounds , drains , devices
, sinuses , urine
Investigation emphasis : Imaging , bacterial
cultures & other microbiological investigations
Management : Depends upon situation
Time course of disease : Lasts for weeks .

8. IMMUNE DEFICIENT FUO
Definition : Fever of > 380 C , lasted for > 1 wk & negative
culture after 48 hrs
Patient location : Hospital or clinic
 Leading causes : Majority are due to infections but cause
has been documented in only 40-60%
 History emphasis : Stage of chemotherapy , drugs
administered , underlying immunosuppressive disorders

9. Examination emphasis : Skin folds , IV sites , lungs,
perianal area
Investigation emphasis : Chest radiograph , bacterial
cultures
Management : Antimicrobial treatment
Time course of disease : Lasts for days .

10. HIV – RELATED FUO
 Definition : Fever of >38 C , >3 wks for outpatients ,
>1 wk for inpatients & HIV infection confirmed
Patient location : Community , clinic or hospital
Leading causes : HIV (primary infection) , typical &
atypical mycobacteria , CMV , toxoplasmosis ,
cryptococcosis , lymphomas , immune reconstitution
inflammatory syndrome (IRIS)
History emphasis : drugs,exposures,risk
factors,travel,contacts,stage of hiv infection

11.  Examination emphasis : Mouth , sinuses , skin , lymph
nodes , eyes , lungs,perianal area.
 Investigation emphasis : Blood & lymphocyte count ,
serologic tests , chest X-ray , stool examination, biopsies of
lung , bone marrow & liver for cultures and cytologic tests ,
brain imaging
 Management : Antiviral & antimicrobial protocols , vaccines
, revision of treatment regimen , good nutrition
 Time course of disease : Lasts for weeks to months

12. ETIOLOGY
ABSCESSES
Abdominal , Brain ,
Dental ,Hepatic
Pelvic
Perinephric
Rectal
Subphrenic
Psoas
 LOCALIZED INFECTIONS
 Cholangitis
 Infective endocarditis
 Mastoiditis
 Osteomyelitis
 Pneumonia
 Pyelonephritis
 Sinusitis

13.  BACTERIAL
 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)

14.  SPIROCHETES
 Borrelia burgdorferi (Lyme disease)
 Relapsing fever (Borrelia recurrentis)
 Leptospirosis
 Rat bite fever (Spirillum minus; spirillary form
of rat bite fever)
 Syphilis
 FUNGAL DISEASES
 Blastomycosis (extrapulmonary)
 Coccidioidomycosis (disseminated)
 Histoplasmosis (disseminated)
 Chlamydia
 Lymphogranuloma venereum
 Psittacosis
 RICKETTSIA
 Ehrlichia canis
 Q fever
 Rocky Mountain spotted fever
 Tick-borne typhus
 VIRUSES
 Cytomegalovirus
 Hepatitis viruses
 HIV
 Epstein-Barr virus

15.  PARASITIC DISEASES
 Amebiasis ,Babesiosis ,Giardiasis
 ,MalariaToxoplasmosis,Trichinosis
 Trypanosomiasis
 Visceral larva migrans (Toxocara)
 NEOPLASMS
 Atrial myxoma
 Cholesterol granuloma
 Hodgkin disease
 Inflammatory pseudotumor
 Leukemia
 Lymphoma
 Pheochromocytoma
 Neuroblastoma
 Wilms tumor
 RHEUMATOLOGIC DISEASES
 Behçet disease
 Juvenile dermatomyositis
 Juvenile idiopathic arthritis
 Rheumatic fever
 Systemic lupus erythematosus
 HYPERSENSITIVITY DISEASES
 Drug fever
 Hypersensitivity pneumonitis
 Serum sickness
 Weber-Christian disease

16.  GRANULOMATOUS DISEASES
 Crohn disease
 Granulomatous hepatitis
 Sarcoidosis
 Angiitis
 FAMILIAL AND HEREDITARY
DISEASES
 Anhidrotic ectodermal dysplasia
 Autonomic neuropathies
 Fabry disease
 Familial dysautonomia
 Familial Hibernian fever
 Familial Mediterranean fever and the
many other autoinflammatorydiseases
 hypertriglyceridemia
 Ichthyosis
 Sickle cell crisis
 Spinal cord/brain injury

17.  MISCELLANEOUS
 Addison disease
 ,Castleman disease
 Chronic active hepatitis
 Cyclic neutropenia
 Diabetes insipidus (nonnephrogenic and
nephrogenic)
 Factitious fever
 Hemophagocytic syndromes
 Hypothalamic-central fever
 Infantile cortical hyperostosis
 Inflammatory bowel disease
 Kawasaki disease
 Kikuchi-Fujimoto disease
 Metal fume fever
 Pancreatitis
 Periodic fever syndromes
 Poisoning
 Pulmonary embolism
 Thrombophlebitis
 Thyrotoxicosis, thyroiditis

18. HISTORY
History should be taken from the child or reliable informant
 AGE
-> 1-5 yrs - common causes are RTI,UTI,diarrhoea and
osteomyelitis
->5-10 yrs-measles,mumps,chicken pox,typhoid
->10yrs-TB, typhoid ,rheumatic fever
 GENDER -> Females-urinary tract infections,pelvic infections
-> Males-allergic fever(hay fever), typhoid ,
tuberculosis,malaria

19.  ADDRESS -> endemic regions for malaria and japanese
encephalitis,epidemics,out breaks in that area
 CHIEF COMPLAINTS -> History of fever and other symptoms
should be taken in chronological order,give clue towards
system involved
eg:-
fever,dysuria ,loin pain –UTI
fever ,drowsiness ,convulsions - meningitis, encephalitis

20. ONSET
ACUTE INSIDIUOUS
Tuberculosis
Malignancies
Typhoid
Measles
Mumps
Acute sinusitis
Malaria
UTI
Pneumonia

21. GRADE
TB
HIV
Sinusitis
Diptheria
Dengue
Malaria
Typhoid
LOW GRADE  HIGH GRADE

22. DURATION
SHORT DURATION
 Malaria
 Dengue
 Measles
 varicella
LONG DURATION
Brucellosis
Malignancies
Rheumatic fever
Tuberculosis
Granulomatous diseases

23. PROGRESSION ->Viral fever peaks in 2 days and declines
-> Bacterial fever worsens day by day without treatment
-> Parasite fever like malaria shows cyclical cold,hot and
sweating stages.
TYPE -> Continuous-viral
- Remittent-enteric fever , collagen vascular diseases
-Intermittent - Malaria , Brucellosis, filarial fever
 Step ladder fever-Typhoid
Saddle back fever – dengue
Pelebstein fever – Hodgkin lymphoma
Undulant fever - brucellosis

24.  Associated with ->
Chills and rigors- Malaria,brucellosis ,otitis media , UTI ,
follicular tonsillitis, filaria
Myalgia- brucellosis,dengue,bartonellosis
Sweating-Meningitis ,TB ,Bacteraemia ,Malaria
Remission
Abrupt – malaria
Remission like a wave - brucellosis

25.  History of travel to endemic areas,how long,any
precautions.
 Epidemics in resident area
 Pets - toxoplasmosis,visceral larva migrans
 Contact with animals – leptospirosis,brucellosis
 Tick bites-relapsing fever, Q fever
 Blood transfusion - malaria,hepatitis-B
 Migrating joint pains - Rheumatic fever
 Loss of weight-malignancies
 History of recurrent fever,oral thrush -
immunocompromised
 Joint pains,rash,photosensitivity - autoimmune

26. Past history - of surgeries(occult infection)
 Family history - similar complaints suggest
infectious disease,genetic background-familial
dysautonomia(recurrent hyperpyrexia)
Personal history - diet -> unpasteurized
milk(brucellosis,TB),raw egg (salmonella)
Loss of appetite - malignancies ,TB
Immunization history - vaccination induced fever.
e.g,DPT,measles
Treatment history - drug induced fever

27. PHYSICAL EXAMINATION
 Careful and complete examination
 Repetitive examination to pick up subtle or new signs
 Look for the child’s general appearance, built and nourishment,
for temperature pattern ,
pulse rate –relative bradycardia in typhoid, meningitis ,dengue,
Skin – look for rashes , petechiae, splinter hemorrhages,
subcutaneous nodules

28. Eye
-> Anemia- malaria, kala azar ,ALL , SABE
-> Icterus – infectious hepatitis, malaria, weil’s disease,liver
abscess
Red weeping eyes – connective tissue disease - PAN
 Palpebral conjunctivitis
 measles, coxsackievirus infection, tuberculosis, infectious
mononucleosis,
 lymphogranuloma venereum, or cat-scratch disease
 Bulbar conjunctivitis – Kawasaki disease , leptospirosis

29. Proptosis – orbital tumor , thyrotoxicosis, orbital infection , wegener
granulomatosis , metastases(neuroblastoma)
-> Roth’s spots – infective endocarditis
-> Uveitis – sarcoidosis, SLE, kawasaki disease,vasculitis
-> Chorioretinitis – CMV, toxoplasmosis , syphilis

30. Tenderness to tapping over sinus – sinusitis
Oral cavity - Hyperemia of pharynx
Tender tooth –> periapical abscess
Recurrent oral candidiasis –> disorder of immune system
Neck - Enlargment or tenderness of thyroid gland –> thyroiditis
Heart- Murmur –> infective endocarditis
Abdomen –
Splenomegaly –> malaria, kala azar , CML
Abdominal tenderness -> pelvic abccess
Loin tenderness -> pyelonephritis
Hepatomegaly- > liver abscess , primary or metastatic malignancy

31. Muscle and bone –
Point tenderness- occult osteomyelitis or bone marrow invasion
from neoplasms
Painful and swollen joints – arthritis –> rheumatic fever
Rectal examination – pelvic abscess,adenitis

33. INVESTIGATIONS
 On IP or OP basis,
determined on a case by case
basis,
OP if chronic
 CBC,DC
 Urine analysis
 Blood smear
 ESR
 Serologic tests
 Tuberculin test
 Blood and urine culture
 Bone marrow examination(
aspiration and biopsy)
 Xray ,2D ECHO,USG,CT , MRI ,
Radionuclide scans

34. BLOOD SMEAR ->WITH GIEMSA ORWRIGHT STAIN
MALARIA
TRYPANOSOMIASIS
RELAPSING FEVER
BABESIOSIS

35. ESR >30 mm -
inflammation -> further evaluation
ESR >100 mm -TB/malignancy/autoimmune/
kawasaki disease

36.  BLOOD CULTURES –
- Normally aerobic culture is done as anaerobic culture gives low
yield
- Repeated culture done in case of infective endocarditis and
osteomyelitis
- Poly microbial infection suggests GI infection.
 RADIOLOGICAL EXAMINATION – sinuses,mastoid,GIT,chest
 SEROLOGICTESTS – widal test,ANA,RF, for infectious
mononucleosis,cmv,brucellosis,toxoplasmosis

37.  RADIONUCLEIDE SCANS - These are mainly helpful in detecting abdominal
abscess & osteomyelitis and in multifocal disease.

 ECHOCARDIOGRAPHY - detects vegetations on valve leaflets in infective
endocarditis
 ULTRASONOGRAPHY detects intra- abdominal abscesses of liver and spleen
 CT SCAN AND MRI - detection of neoplasms,CT scan guided aspiration and
biopsy,MRI for detecting osteomyelitis

40. TREATMENT
 Emphasis in patients with classic FUO is on continuous observation
and examination with avoidance of empiricaltherapy
 Indication of empirical therapy is vital signs instability and
neutropenia
 The ultimate treatment of FUO is tailored to the underlying diagnosis.
 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.

41. An exception may be the use ofantituberculous
treatment in critically ill children with suspected
disseminatedtuberculosis.
 Empirical trials of other antimicrobial agents may be
dangerous and can obscure the diagnosis of infective
endocarditis,meningitis, parameningeal infection, or
osteomyelitis

42. TAKE HOME MESSAGE
 FUO may represent uncommon manifestation of common disease.
 work-up should be cost effective and thoughtful and clinically appropriate.
 Empirical treatment sometimes may be justified, however one should
remember that treatment should not be worse than disease.
 In India infections notably extra pulmonary tuberculosis is the most common
cause of FUO.
 Noninfectious causes like collagen vascular disease and neoplasms are
becoming important differential diagnosis.
 Patience, compassion, equanimity, vigilance and intellectual flexibility are
indispensable attributes for the clinician in dealing successfully with FUO.

43. REFERENCES
 NELSONTEXTBOOK OF PAEDIATRICS SOUTH ASIAN 1ST EDITION
 IAPTEXTBOOK OF PEDIATRIC INFECTIOUS DISEASES 1ST EDITION
 IAPTEXTBOOK OF PEDIATRICS 6TH EDITION