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Pyrexia of Unknown Origin. Stephen Hughes MRCPCH PhD Consultant Paediatric Immunologist. PRE-TEST. The commonest cause of PUO is: A common disease presenting in an atypical way. A rare disease presenting in atypical way. A common disease presenting typically.

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pyrexia of unknown origin

Pyrexia of Unknown Origin

Stephen Hughes


Consultant Paediatric


pre test
  • The commonest cause of PUO is:
    • A common disease presenting in an atypical way.
    • A rare disease presenting in atypical way.
    • A common disease presenting typically.
    • A rare disease presenting typically.
The answer is ..A
  • ..The commonest cause of PUO IS
  • …Common disease presenting
what is a puo
What is a PUO?



& Beeson


& Moffet

  • Are much more common in adults
    • (40 vs. 10%).
  • Either because of infection or cytokines
  • Most commonly:
    • Lymphoma
    • Leukaemia
    • Neuroblastoma
    • Sarcomas and Hepatomas

} 80% of malignancies with PUO

who should have a bma
Who should have a BMA?
  • Patients with suggestive blood film / count or other evidence pointing to Leukaemia / Lymphoma
  • Culture for TB, Salmonella, Leishmania
infection frequencies
Infection frequencies
  • Infectious mononucleosis (EBV or CMV) (up to 20%)
  • Other viruses (NB. measles, hepatitis, HIV (up to 15%)
  • UTI (up to 15%)
  • Pneumonia (up to 10%)
  • Various URTIs (up to 10%)
  • Endocarditis (Staph. Strep. HACEK, Bruce, Cox, Rick) (up to 5%)
  • Tuberculosis (up to 5%)
  • Streptococcosis (up to 5%)
  • Bartonella (cat scratch disease) (up to 5%)
  • Meningitis / para meningeal abscess (up to 5%)
  • Enteric infection (Salmonella, Yersinia) (up to 5%)
  • Malaria (up to 1%)
  • Brucella (up to 1%)
  • HSV (generalised but occult) (up to 1%)
infectious mononucleosis
Infectious mononucleosis
  • Diagnosis is made by EBV PCR on blood (EDTA)
  • Support is offered by
    • Atypical lymphocytes (a late finding, in some)
    • Heterophile antibodies (IgM binding sRBCs)
    • IgM antibodies to EBV
  • Other causes include
    • CMV, Toxoplasma, HIV, Rubella, HepAB, HHV678
  • If the child has congenital or acquired cardiac disease, endocarditis must be excluded.
  • If there is no pre-morbid cardiac disease, is endocarditis possible? Y
  • In which patients: those with lines
  • What chance of endocarditis if there are no risk factors and no signs? <5%
  • What are the critical tests? BC, BC, BC
how do i get the echo
How do I get the ECHO?
  • Is there a risk factor?
  • Is there a new murmur?
  • Is there a BC positive for Staph or viridans Strep?
  • 5-10% of IE have negative BCs
    • Because of antibiotics or
    • Fastidious organisms (HACEK) or
    • Aspergillus, Bart, Bruce, Cox, Rick, Mycobacteria, Noca, Chlamydia, viruses…
how do i get the echo1
How do I get the ECHO?
  • Is there splenomegaly, emboli, petechiae, splinters, clubbing, Osler nodes, Roth spots, Janeway lesions or haematuria
  • What is the ESR and the RF?
  • Remember, the sensitivity of TTE is 80%. TOE can be considered if the Duke criteria require it later in the period of assessment
bart bruce rick cox
Bart, Bruce, Rick & Cox
  • Bartonella (5) - the cat scratch illness, usually regional adenopathy, sometimes PUO. Sometimes HSM, sometimes Haem abnormalities. Diagnosis by serology.
  • Brucella (1) - must have exposure (farm animal contact or unpasteurised milk). LFTs rise. Diagnosis by serology.
  • Rickettsia (0) - imported.
  • Coxiella (0) - Q fever, cats and unpasteurised milk. Diagnosis by serology.
  • Full history and examination (repeatedly)
  • Travel
  • Pets
  • Contact with ticks
  • Contact with animals
  • Drinking unpasteurised milk
  • Cardiac disease
  • Dental history
  • Growth
  • Drugs
investigations step 1
Investigations (step 1)
  • Decision to investigate fever (arrival): verify fever
  • Urinalysis and culture unless it is on the list,
  • Blood culture it won’t get done
  • Throat swab
  • FBC (and film)
  • CRP (and ESR) (if the blood flows, take it)
  • NPS for viruses Could it be ‘flu?
  • Stool culture with OCP if travelled Salmonella?
  • For consideration at 5 days - is this Kawasaki?
  • If it is, store serum now
investigations step 2
Investigations (step 2)
  • By days 5-7, if any focal signs or symptoms appeared, follow them.
  • Carefully record antimicrobial prescriptions
  • Do anything missed from step 1 and organise:
  • CXR occult pneumonia
  • LP occult meningitis
  • More BC yield rises
  • ASOT Streptococcosis is common
  • Coagulation abnormalities will direct inv
  • Ferritin massive elevation helpful
  • Serum to be saved acute serology
  • Request BMA If haem abnormal
  • US Abdomen harmless / helpful
investigations step 3
Investigations (step 3)
  • By days 10-14, if no diagnosis is reached and not already done:
  • ANA, dsDNA, C3, C4, ENA, Cardiolipin, RF 20% risk
  • Lupus anticoagulant (if clotting abnormal)
  • ECG, ECHO, converse with cardiology 1-5% risk
  • Mantoux, QFG, ESR, Gastric lavage / sputum 1-5% risk
  • LP (if not already done) 1-5% risk
  • CT of any suspect region
    • Brain, Chest, Abdo, ENT
  • Bone scan for pelvic, skeletal osteomyelitis
  • Serology for Bartonella 5% risk
  • Serology for HIV, other microbes and save serum
investigations step 4
Investigations (step 4)
  • By day 21,
  • Review everything again…
  • TFTs
  • CT abdomen (regardless of signs)
  • Biopsy of abnormal tissue, inc:
    • LNs
    • Gut
    • Skin
    • (Liver)
  • Define immune status of child (call the immunologist)
  • Stop drugs, if started
  • Wait for clues.
endocrine causes for puo
Endocrine causes for PUO
  • Hyperthyroidism
    • Occasionally cause PUO → most frequently diagnosed clinically.
    • Often accompanied by weight loss.
    • No local neck pain and typically enlarged non-tender thyroid.
  • Adrenal
    • Rare, potentially fatal, but eminently treatable cause of PUO.
    • Consider if: nausea/vomit, ↓weight, ↓BP, ↓Na & ↑K.
rheumatology and puo
Rheumatology and PUO
  • 10-20% of cases in most series
  • In the earlier series, Rheumatic fever was key
  • More recently, SoJIA > SLE > vasculitis (PAN, Behcet, WG) & HLH > Sarcoidosis
a case
A case
  • 14 year old girl with one month history of fever and malaise …
  • She received 10 days amoxicillin from GP but no response …
  • On exam, T = 38.4°C … several lymph nodes in the neck … non-tender and rubbery …
you want a what
You want a what?







US Abdomen

Blood culture



Other Tests



TB tests


Throat swab


HIV test


  • Complement fixation tests for Mycoplasma, Chlamydia, Adenovirus, Legionella, Coxiella were all available. Convalescent specimens are awaited.
  • Samples were sent for Toxoplasma, Bartonella, Brucella, EBV, CMV…
  • We have a brief (two week) wait…
  • ASOT is negative.
  • Seriously, no.
  • Sorry, not today.
  • There are 5 children about to breach their 20 week wait for routine surgery.
  • Your request is noted and will be processed through the usual channels, but please don’t hesitate to make another choice.
tests of immunity
Tests of immunity
  • What on earth are we looking for?

Q. is she immune suppressed?

Q. What is the diagnosis?

Q. Evidence for recent immune dysregulation (Igs, B and T cells)

immune function
Immune Function
  • History tells you about immune suppression.
  • Immune function is harder.
  • T cell numbers are normal.
  • There are no abnormalities on routine testing
what is the diagnosis
What is the diagnosis?
  • Tests of immunity aren’t going to help you.
  • The serologies are all negative.
immune dysregulation
Immune Dysregulation
  • She does make immunoglobulin: lots of it -
    • IgG 18.2, IgA 1.2, IgM 4.8
  • She has all the right cells.
  • Good idea.
  • With whom shall we consult?
  • Respiratory, ENT, Endocrinology, Bone, Rheumatology, Infection, Immunology, Gastroenterology, Haematology, Cardiology, Intensive care?
blood cultures
Blood cultures
  • Negative at 5 days
  • Normal urine on dipstick, no cells on microscopy and no growth
haem biochemistry
Hb 13.2

MCV 95

Plt 252

WBC 3.2

N 1.8

L 1.0

M 0.3

E 0.1

ESR 42

U&E normal

Alb 32

ALT 50

LDH 378

CRP 24

Haem & Biochemistry
  • EBV, CMV, HHV6, HHV7, HHV8 are negative
  • Adeno is negative
  • Hep A and B are negative
additional tests
Additional tests



hiv test
HIV test
  • Negative
tb tests
TB tests
  • Mantoux negative
  • Quantiferon Gold negative
  • No contact history
  • No AAFB seen on any sample.
  • Cultures still awaited many weeks later.
bone marrow aspirate
Bone marrow aspirate
  • Haematologists will do it, but reluctantly.
  • Suggests you arrange imaging and then a biopsy of a node
  • You cannot have tea until you are finished the exercise.
  • Normal structure.
  • Normal flows.
  • No shunts or leaks.
  • Satisfactory function.
  • Pressures could not be determined because of anatomical integrity.

Necrotising histiocytic lymphadenitis

Absent neutrophils

Normal histiocytes and lymphocytes

diagnosis made
Diagnosis made
  • Kikuchi Fujimoto syndrome
  • A disease most commonly of young Asian women.
  • Usually lymphadenitis of cervical chain
  • Can cause PUO
  • Mimics TB / lymphoma
  • Diagnosis made by pathologist
thanks for participating
Thanks for participating
  • Assessment of a fever is dominated by history and examination
  • Repeated assessment probably has more value than blind screening
  • Uncommon presentation of common illness is the norm
  • Involvement of colleagues is critical
  • With longer fever the cause is either more benign or more malign