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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

MRCPCH PhD

Consultant Paediatric

Immunologist


Pre test
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

  • ATYPICALLY


What is a puo
What is a PUO?

Reid

Petersdorf

& Beeson

Dechovitz

& Moffet




Malignancies
Malignancies

  • 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


Endocarditis
Endocarditis

  • 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.



History
History

  • 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?

PubMed

Google

Consultation

CXR

Tea

Biopsy

US Abdomen

Blood culture

ECHO

CT

Other Tests

Bloods

ASOT

TB tests

PCRs

Throat swab

BMA

HIV test

Urinalysis





Serology
Serology

  • 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

  • ASOT is negative.


Biopsy
Biopsy

  • 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.


Consultation
Consultation

  • 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


Urinalysis
Urinalysis

  • 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


PCRs

  • EBV, CMV, HHV6, HHV7, HHV8 are negative

  • Adeno is negative

  • Hep A and B are negative


Additional tests
Additional tests

Immunology

Serology


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


Tea

  • You cannot have tea until you are finished the exercise.


ECHO

  • Normal structure.

  • Normal flows.

  • No shunts or leaks.

  • Satisfactory function.

  • Pressures could not be determined because of anatomical integrity.


Biopsy1
Biopsy

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


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