Pyrexia of unknown origin {PUO) and Fever without focus:

Dr. Dave Fuller

Pyrexia of unknown origin (PUO) was originally described as presence of significant fever without any clear
focus for a period of 3 weeks
1
. More recent definitions have adjusted this to significant fever without a clear
focus after 3 outpatient consultations
2
. Even by the adjusted definition, PUO is uncommon in children. A much
more common scenario is the febrile child without any clear focus at the first or second consultation. This article
will focus mainly on the febrile child without a clear focus, while also touching on PUO in children.

Fever without any clear focus
It is not uncommon in a primary care setting to see children who are febrile without any clear focus. This is
partly because young children are not able to clearly describe (or sometimes even localise) their symptoms,
partly because clinical signs can be harder to find in children compared with adults and also because a number
of the illnesses that cause significant fever in children do not show a clear focus in the initial phase and
sometimes for the duration of the illness.

The approach to a febrile child is firstly dictated by the age of the child:

Children under 3 months of age
Any child under 3 months of age with a significant fever (> 38 degrees core temperature
3
, > 37.5 degrees PA)
requires referral and septic workup including lumbar puncture
4
. Although many of these may ultimately have a
viral infection, it is very difficult to distinguish between viral and serious bacterial infection in this age group. In
addition, this age group are at increased risk of serious bacterial infection and have the potential to deteriorate
quickly if they do have serious bacterial infection. Most of these children are also treated empirically with
broad-spectrum intravenous antibiotics to cover the major likely pathogens, which include Gram negative
infections, Group B Streptococcus and Listeria.

Children 3 months to 3 years
Children in this age group are not at as high a risk as children under 3 months, but are still at greater risk of
serious bacterial infection compared with older children, particularly with encapsulated organisms
(Pneumococcus, Meningococcus and Haemophilus influenzae). A careful history and examination should be
performed looking for an underlying focus. In this age group, symptoms are often non-specific, although
sometimes subtle features suggesting a focus of infection may be found. For example, young children with
pneumonia will often not have focal signs of pneumonia, although will usually have some clinical features
pointing to a respiratory focus, such as cough or mild tachypnoea. If these features are found in a young child,
there should be a low threshold for performing a CXR, even in the absence of focal respiratory signs.













In this age group, the next appropriate step depends on whether the child looks well, miserable or unwell. A
good approach to ascertaining whether a child is well or unwell is looking at ABC:
Level of Alertness and Activity
Assessing Breathing, looking for evidence of fast or laboured breathing (including respiratory rate, recession
and added noises)
Assessing Circulation, looking for tachycardia and delayed capillary return

Pediatric Lumbar puncture
A febrile child who appears well (alert and interactive with normal respiratory rate and effort, normal capillary
return (< 2 seconds) needs to have a urine check, but is otherwise safe to review within 24 hours, or sooner if
they deteriorate (table 1). A child who is unwell (lethargic, poorly interactive, difficult to rouse, inconsolable,
tachycardic, tachypnoeic, poor peripheral perfusion) requires urgent referral for further workup, with a full
septic workup likely to be indicated. In between these 2 extremes is the child who is miserable, but still
interactive. These can be the most difficult group in which to determine the best management. They at least
warrant a urine culture and for many a full blood count and CRP can also be useful guides as to the likelihood
of underlying serious bacterial infection (with a high neutrophil count and left shift on FBE and high CRP
being more suggestive of bacterial infection). If there is any degree of concern, referral for further urgent
assessment is warranted.

In the child who is observed without treatment and reviewed, it is common that the fever will resolve or a clear
focus becomes evident. There is no role for oral antibiotics just in case these are unlikely to be effective
against serious systemic bacterial infection and lead to diagnostic confusion by partially treating serious
illnesses such as meningitis. If a child with fever and no focus is unwell enough to make you want to start
antibiotics, further workup up and/or referral are appropriate. In the event of a bacterial focus becoming
evident, some of these will be effectively treated with oral antibiotics.

Children over 3 years
Over 3 years of age, serious bacterial infection is less likely, and they are better at localising symptoms, but a
similar approach to that outlined above is appropriate.

Table 1: Assessment and management of fever with no focus in children 3 months to 3 years (from
RCH Clinical Practice Guidelines)
4

Description Management
Child looks well SPA urine if < 6 mths
Discharge home on symptomatic
treatment
Arrange medical review within
24 hr, or sooner if deteriorates
Child looks miserable but is still
relatively alert, interactive and
responsive
Discuss with registrar or
consultant prior to any
investigations
(at least SPA urine if < 6 mths)
Child looks unwell
(i.e. lethargic, poorly
interactive, difficult to rouse, incon-
solable, tachycardia, tachypnoea,
poor peripheral perfusion)
Full sepsis workup: FBE, blood
culture, SPA or catheter urine,
CXR (if respiratory symptoms or
signs), lumbar puncture. Note:
LP should not be performed in
a child with impaired conscious
state or focal neurological signs
(see Lumbar puncture
guidelines)
Admit to hospital for observation
+/- i.v. antibiotics
Temperature >38.9
o
C
and no clear focus
of infection
PUO:
One of the commonest causes of apparent PUO in children is a string of several viral infections
one after the other. A careful history will reveal that the initial febrile illness (sometimes with
accompanying viral symptoms) had been settling before the onset of another febrile illness.

In children with a true PUO, 30-50% of cases are due to infections, 5-10% to cancer, and
autoimmune disorders 10-20%
5
. Potential causes are listed in table 2. In a child with a true PUO,
a thorough history is needed, focusing particularly on potential exposures or risk factors.
Examination may provide a clue for further investigation, such as abdominal pain with an
abdominal abscess, a heart murmur for endocarditis, lymphadenopathy pointing to EBV / CMV /
Toxoplasmosis or Bartonella infection or a salmon-coloured rash in systemic juvenile idiopathic
arthritis.

Investigations should be directed by the history and examination in consultation with a
Paediatrician.

Table 2: Important causes of true PUO in children



























References-
1
Fever of unknown origin, emedicine article accessed at http://emedicine.medscape.com/article/217675-
clinical
2
Durack TC, Street AC; Fever of unknown origin--reexamined and
redefined. Curr Clin Top Infect Dis. 1991;11:35-51
3
Measured rectally or by tympanic or arterial thermometer, noting that tympanic and arterial thermometers
are not reliable in young children)
4
RCH Clinical Practice Guidelines, Fever in a child under 3, accessed at http://www.rch.org.au/
clinicalguide/cpg.cfm?doc_id=5181
5
Pyrexia of unknown origin, accessed at http://www.patient.co.uk/doctor/Pyrexia-of-Unknown-Origin-
(PUO).htm
Infective Abscess
Tuberculosis
Endocarditis
Osteomyelitis
CMV / EBV
Other viral infections
Malaria
Toxoplasmosis
Cat scratch disease
Malignancies Lymphoma
Leukemia
Autoimmune Systemic juvenile idiopathic
arthritis (JIA)
SLE
Familial Mediterranean fever