FEVER OF UNKNOWN ORIGIN

1
FEVER OF UNKNOWN ORIGIN (FUO,
PUO) Various definitions e.g. unexplained
fever lasting gt 4 weeks or lasting gt 10 days
and still unexplained despite preliminary
investigations
2

• Temperature regulation
• Mainly in anterior hypothalamus
• Temperature reflects balance between heat
  production (central)
• heat loss (peripheral)
• Normal circadian rhythm (lowest c 0400-0600)

3
Pyrogens

• Most fevers are caused by release of endogenous
  pyrogens
• (polypeptide) in response to injury, infection,
  inflammation,
• Antigenic challenge. Most are cytokines.
• Endogenous pyrogens may be triggered by exogenous
  pyrogens
• Mainly microbes /- their toxins
• exotoxins polypeptides, mainly from Gram
  positives
• endotoxins mainly LPS from cell wall (Gram
  negatives)
• - also induce other pathological changes
• e.g. septic shock
• Also drugs, other chemicals

4

• Temperature control
• Hypothalamus responds to
• Input from peripheral warm/cold receptors
• Temp of blood supplying hypothalamus
• Central temp gt peripheral
• Normally heat production gt energy requirements
• to preserve core temp i.e. nett heat loss
• Control is peripheral vasoconstriction/dilation,
  sweating, shivering
• central behaviour modification
  (via thalamus to cortex)

5

• Various hyperthermic states
• Environmental e.g. heavy exercise on a hot day
• excessive warm
  clothing
• Drugs may interfere with vasodilatation
• Malignant hyperthermia e.g. after anaesthesia
  in
• predisposed individuals
• Hypothalamic fever from cerebral trauma,
  haemorrhage
• etc

6

• Temperature measurement
• invasive probes
• peripheral measurement oral, axillary,
  rectal,( urine)
• Remember intra- and inter-personal variation

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Fever good or bad? Treatment of disease with
fever e.g. historic treatment of syphilis
with malaria e.g. (experimentally) malignant
tumours with heat Should fever be
treated? some immunological functions improve
with raised temp suppression of microbial
growth with raised temp NB excessive fevers
must be treated
8

• Acute phase reactants
• Certain proteins, other substances appear in
  blood, tissues
• in response to inflammation
• Leucocytes
• C-reactive protein
• Erythrocyte sedimentation rate (ESR)
• Various alpha-2 globulins
• Haptoglobin
• Cytokines
• May be used in the diagnosis or monitoring of
  infections

9

• PUO
• Most febrile illnesses declare their origins
• within 1-2 weeks or resolve spontaneously.
• Occasionally they continue unabated for 2-3 weeks
  or more.
• If they defy simple investigation, they may be
  called PUO.
• Four categories
• Classic PUO
• Nosocomial PUO
• Neutropenic PUO
• Immunosuppressed PUO
• Systematic evaluation needed
• Resist temptation to give empiric treatment
  without
• careful consideration

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• Classic PUO
• May be divided into age groups, e.g.
• lt 6 years
• 6-14 years
• gt14 years
• Main causes are
• Infectious
• Inflammatory (collagen/vascular/autoimmune)
• Neoplastic
• Other
• Probability that cause will lie within one of
  these categories
• depends on variable such as age, geographic
  location, type
• of institution/practice.
• Duration also important.

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• Work-up
• Observe temperature chart
• ? True fever
• Consider diurnal variation
• ?Pattern
• 2. History
• Localising features e.g. rash, arthralgia
• Drugs, injections
• Travel
• Occupation/hobbies/domestic exposure/pets
• 3. Physical Examination
• must be exhaustive
• must be repeated
• look especially for rashes, lymph nodes,
• eye signs

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Laboratory Tests Dictated partly by information
obtained by history/exam. Baseline test should
be discriminative, but typically include
urinalysis blood count simple
biochemistry various cultures (incl
blood) direct examination of blood
fluid CXR some serology More directed
testing proceeds depending on clinical course and
results of above. ? Tuberculin testing
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5. Non-invasive procedures include plain
Xrays CT, MRI ultrasonography/echocardiography
radionuclide scans 6. Invasive
procedures Marrow) aspiration Liver
) specimens to microbiology anatomical
pathology/cytopath Biopsy of other sites where
abnormalities are detected. Bronchoscopy,
other endoscopy, laparoscopy
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Causes of classic PUO Bacterial infections -
abscesses osteomyelitis infective
endocarditis biliary infections urinary
tract infections tuberculosis miscellaneous
e.g. Whipples disease Salmonella
infections Acute rheumatic fever
Cat scratch disease
Brucellosis Q fever
spirochaetal, rickettsial, chlamydial
infections
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Classic PUO Fungal, viral, parasitic
infections (N.B. malaria)
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Neoplastic diseases Tumours may cause fever in
their own right or solid tumours may cause
luminal obstruction secondary infection e.g.
bronchus, bile duct Hodgkins disease Non-Hodgkin
s lymphoma Leukaemias Renal cell
carcinoma Hepatoma Atrial myxoma Disseminated
carcinomatosis
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Hypersensitivity autoimmune diseases Predominan
tly Systemic lupus erythematosus Stills
disease Polyarteritis nodosa Polymyalgia
rheumatica Erythema multiforme Mixed connective
tissue disease Drug fever Hypersensitivity
vasculitis Idiopathic vasculitis Serum
sickness Rheumatic fever
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Other causes Long list of individually uncommon
causes Inherited disorders (e.g. familial
Mediterranean fever) Hypertriglyceridaemia CNS
causes Fevers after neurosurgery Factitious
fevers Pulmonary embolism Postpericardiotomy
syndrome Septic thrombophlebitis After
radiotherapy Cirrhosis Cyclical
neutropenia Exaggerated circadian
rhythms Undiagnosed
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• Special considerations in management
• How far to take investigations?
• When to stop
• Empirical treatment?

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NOSOCOMIAL (hospital-acquired) FEVERS ?
Infection or something else Assess 1. for
source urinary tract respiratory surgical
sites vascular access primary
bacteremia non-bacterial infections etc 2.
for severity immediate empiric therapy
needed? supportive treatment? 3. for likely
organism/s
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• Organisms
• Previous culture results
• (infection or colonisation)
• Identification may be guessed from nature of
  infection?
• Antibiotic sensitivities known or predictable?
• Evidence from quick preliminary tests
• e.g. urine microscopy, Gram stain of pus

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• Treat straight away or wait?
• Should depend on severity of infection and/or
• risk of rapid progression
• Remove ( culture) IV lines?
• If severe, generally give wide cover then
  narrow
• when organism is known or clinical situation
  is better understood
• One or more antibiotics?
• one is more convenient but use of some
  broad-spectrum agents
• is restricted by the hospitals drug policy to
  prevent overuse

23

• Fever in neutropenic patients
• (total neutrophil count lt0.5 x 106/L)
• Risk severity depend on
• Degree of neutropenia
• Duration
• More problematic in haematology than oncology
  patients

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• Neutropenia
• Special risk sites
• Ulcerated or damaged (by chemo/radio therapy)
• mucosal surfaces (mouth, whole GI tract)
• Vascular lines, especially semipermanent
• (Hickman catheters, Port-a-Caths, central lines)
• Empiric therapy must be started straight away
• (after collection of cultures)

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• Neutropenic patients
• Antibiotic combinations (2) are usual
• in case of resistance
• better outcome with Pseudomonas aeruginosa
• Combination should cover all likely organisms
• therefore important to know
• if patient is colonised with any problem
• ( antibiotic-resistant) organism
• prevalence of problem organisms in the unit
• (if patient has been in hospital for an
  extended period)

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e.g. if MRSA is endemic, include vancomycin e.g.
if multiresistant Gram negatives are prevalent,
choose antibiotics on basis of known
sensitivities Most bacterial cultures will be
positive within 48 hours (often less) It often
takes 48 hours to know whether a treatment is
working Therefore review _at_ 48 hours and adjust
drugs in light of clinical progress and culture
results Simplify treatment wherever
possible N.B. Blood cultures are important but
usually negative
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• If no improvement _at_ 48 hours
• ? development of evidence of local infection
• ? Resistant or unusual organism/s
• ? non-bacterial infection (? fungal)
• Consider an antifungal (amphotericin,
  fluconazole)
• _at_ 72-96 hours

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• Systemic fungal infections (neutropenia)
• usually only after profound prolonged
  neutropenia
• mainly in respiratory tract or IV lines
• may be yeasts (mainly Candida spp) or moulds
• (e.g. Aspergillus spp)
• diagnosis may be difficult (negative blood
  cultures)
• patients often tolerate amphotericin poorly
• duration is problematic