Pyrexia of Unknown Origin

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Pyrexia of Unknown Origin

• Stephen Hughes
• MRCPCH PhD
• Consultant Paediatric
• Immunologist

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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.

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• The answer is ..A
• ..The commonest cause of PUO IS
• Common disease presenting
• ATYPICALLY

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What is a PUO?
Reid
Petersdorf Beeson
Dechovitz Moffet
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What is a PUO now?
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Series
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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
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Who should have a BMA?

• Patients with suggestive blood film / count or
  other evidence pointing to Leukaemia / Lymphoma
• Culture for TB, Salmonella, Leishmania

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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)

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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

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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? lt5
• What are the critical tests? BC, BC, BC

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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

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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

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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.

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Could it be TB?

• Yes

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History

• Full history and examination (repeatedly)
• Travel
• Pets
• Contact with ticks
• Contact with animals
• Drinking unpasteurised milk
• Cardiac disease
• Dental history
• Growth
• Drugs

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Investigations (step 1)

• Decision to investigate fever (arrival) verify
  fever
• Urinalysis and culture unless it is on the list,
• Blood culture it wont 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

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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

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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

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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.

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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.

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Rheumatology and PUO

• 10-20 of cases in most series
• In the earlier series, Rheumatic fever was key
• More recently, SoJIA gt SLE gt vasculitis (PAN,
  Behcet, WG) HLH gt Sarcoidosis

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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 38.4C several lymph nodes in the
  neck non-tender and rubbery

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Most likely culprits

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You want a what?
PubMed
Google
Consultation
CXR
Biopsy
Tea
US Abdomen
Blood culture
ECHO
CT
Other Tests
Bloods
ASOT
TB tests
Throat swab
PCRs
BMA
HIV test
Urinalysis
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CXR
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Throat swab culture
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CT
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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

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ASOT

• ASOT is negative.

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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 dont
  hesitate to make another choice.

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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)
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Immune Function

• History tells you about immune suppression.
• Immune function is harder.
• T cell numbers are normal.
• There are no abnormalities on routine testing

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What is the diagnosis?

• Tests of immunity arent going to help you.
• The serologies are all negative.

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Immune Dysregulation

• She does make immunoglobulin lots of it -
• IgG 18.2, IgA 1.2, IgM 4.8
• She has all the right cells.

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Consultation

• Good idea.
• With whom shall we consult?
• Respiratory, ENT, Endocrinology, Bone,
  Rheumatology, Infection, Immunology,
  Gastroenterology, Haematology, Cardiology,
  Intensive care?

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Abdominal ultrasound

• Normal

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Blood cultures

• Negative at 5 days

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Urinalysis

• Normal urine on dipstick, no cells on microscopy
  and no growth

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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

• UE normal
• Alb 32
• ALT 50
• LDH 378
• CRP 24

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PCRs

• EBV, CMV, HHV6, HHV7, HHV8 are negative
• Adeno is negative
• Hep A and B are negative

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Additional tests
Immunology
Serology
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HIV test

• Negative

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TB tests

• Mantoux negative
• Quantiferon Gold negative
• No contact history
• No AAFB seen on any sample.
• Cultures still awaited many weeks later.

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Bone marrow aspirate

• Haematologists will do it, but reluctantly.
• Suggests you arrange imaging and then a biopsy of
  a node

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Tea

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

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ECHO

• Normal structure.
• Normal flows.
• No shunts or leaks.
• Satisfactory function.
• Pressures could not be determined because of
  anatomical integrity.

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Biopsy

• Necrotising histiocytic lymphadenitis
• Absent neutrophils
• Normal histiocytes and lymphocytes

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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

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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