Pyrexia of Unknown Origin
Stephen Hughes
MRCPCH PhD
Consultant Paediatric
Immunologist
PRE-TEST
•
The commonest cause of PUO is:
a) A common disease presenting in an atypical
way.
b) A rare disease presenting in atypical way.
c) A common disease presenting typically.
d) A rare disease presenting typically.
• The answer is ..A
• ..The commonest cause of PUO IS
• …Common disease presenting
•
ATYPICALLY
What is a PUO?
1956
Reid
1961
Petersdorf
& Beeson
1968
Dechovitz
& Moffet
Age > 14
T > 37.4°C x3 or 38°C x1
Fever - predominant symptom
Insufficient symptoms / signs to localise
Days > 21, T > 38.3°C
1/52 hospital investigation
Days > 14
No clear diagnosis
What is a PUO now?
Now
+
2 hospital visits, or
Hospital investigations for 3 days
Neutropeni
c PUO
Neutrophils < 1.0
Diagnosis not clear at 3 days
Nosocomial Admission infection screen negative
PUO
Diagnosis not clear at 3 days
HIV PUO
HIV infected, fever for 4 weeks
Diagnosis not clear after 3 days
Series
Author
Brewis
Dechovitz
McClung
Pizzo
Feigin
Lohr
Jacobs
Year
65
68
72
75
76
77
98
N
165
5
8
14
99
21
100
14
20
14
54
35
146
14
Days
Infection
77%
25%
29%
52%
35%
33%
44%
CVD
5%
0%
2%
11%
75%
0%
0%
0%
11%
3%
8%
16%
20%
0%
6%
10%
15%
5%
5%
10%
15%
6%
13%
15%
6%
1%
3%
3%
5%
0%
11%
12%
30%
19%
42%
IBD
Malign
Misc
No Δ
Malignancies
• Are much more common in adults
– (40 vs. 10%).
• Either because of infection or cytokines
• Most commonly:
– Lymphoma
} 80% of malignancies with PUO
– Leukaemia
– Neuroblastoma
– Sarcomas and Hepatomas
Who should have a BMA?
1. Patients with suggestive blood film /
count or other evidence pointing to
Leukaemia / Lymphoma
2. Culture for TB, Salmonella, Leishmania
Infection frequencies
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Infectious mononucleosis (EBV or CMV)
Other viruses (NB. measles, hepatitis, HIV
UTI
Pneumonia
Various URTIs
Endocarditis (Staph. Strep. HACEK, Bruce, Cox, Rick)
Tuberculosis
Streptococcosis
Bartonella (cat scratch disease)
Meningitis / para meningeal abscess
Enteric infection (Salmonella, Yersinia)
Malaria
Brucella
HSV (generalised but occult)
(up to 20%)
(up to 15%)
(up to 15%)
(up to 10%)
(up to 10%)
(up to 5%)
(up to 5%)
(up to 5%)
(up to 5%)
(up to 5%)
(up to 5%)
(up to 1%)
(up to 1%)
(up to 1%)
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
• 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?
1. Is there a risk factor?
2. Is there a new murmur?
3. Is there a BC positive for Staph or
viridans Strep?
4. 5-10% of IE have negative BCs
1. Because of antibiotics or
2. Fastidious organisms (HACEK) or
3. Aspergillus, Bart, Bruce, Cox, Rick,
Mycobacteria, Noca, Chlamydia, viruses…
How do I get the ECHO?
5. Is there splenomegaly, emboli,
petechiae, splinters, clubbing, Osler
nodes, Roth spots, Janeway lesions or
haematuria
6. What is the ESR and the RF?
7. 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
• 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.
Could it be TB?
• Yes
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)
• 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)
•
•
•
•
•
•
•
•
•
•
•
•
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)
• By days 10-14, if no diagnosis is reached and not
already done:
• ANA, dsDNA, C3, C4, ENA, Cardiolipin, RF
• Lupus anticoagulant (if clotting abnormal)
20% risk
• 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)
•
•
•
•
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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
• 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
• 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
• 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 …
Most likely culprits…
1.
2.
3.
You want a what?
PubMed
CXR
Google
Tea
Consultation
Biopsy
Blood culture
US Abdomen
CT
ECHO
Other Tests
TB tests
ASOT
PCRs
Throat swab
HIV test
BMA
Bloods
Urinalysis
CXR
Throat swab culture
CT
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
• 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
• 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
• 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?
• Tests of immunity aren’t going to help you.
• The serologies are all negative.
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
• Good idea.
• With whom shall we consult?
• Respiratory, ENT, Endocrinology, Bone,
Rheumatology, Infection, Immunology,
Gastroenterology, Haematology,
Cardiology, Intensive care?
Abdominal ultrasound
• Normal
Blood cultures
• Negative at 5 days
Urinalysis
• Normal urine on dipstick, no cells on
microscopy and no growth
Haem & Biochemistry
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•
•
•
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
PCRs
• EBV, CMV, HHV6, HHV7, HHV8 are
negative
• Adeno is negative
• Hep A and B are negative
Additional tests
Immunology
Serology
HIV test
• Negative
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
• 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.
Biopsy
Necrotising
histiocytic
lymphadenitis
Absent
neutrophils
Normal
histiocytes
and
lymphocytes
Diagnosis made
1. Kikuchi Fujimoto syndrome
2. A disease most commonly of young
Asian women.
3. Usually lymphadenitis of cervical chain
4. Can cause PUO
5. Mimics TB / lymphoma
6. Diagnosis made by pathologist
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