3rd Y/ TBL/ Infectious

Module
Fever of Unknown Origin
 objectives
At the end of this session students should be able to:
• Define fever and discuss its pathogenesis.
• Define criteria of fever of unknown origin (FUO).
• Classify FUO.
• Recognize the main causes of FUO.
• discuss the important points in history and physical
examination useful in diagnosis of FUO
• List types of infections you should look for.
• Outline the necessary investigations.
• State when empirical treatment may be started.
 Fever; Hyperthermia
Fever >37.5 °C
Elevated body temperature mediated by
an increase in the hypothalamic heat-
regulating set point
Hyperthermia
Increase in body temp. (>41°) that
overrides or bypasses the normal
homeostatic mechanisms
PATHOGENESIS OF FEVER
 Case
• A 25 year old male presented with fever for the
last 24 days. Fever was mainly at night and
occurred daily. It was associated with profuse
sweating, anorexia and weight loss. He received
oral amoxycillin for 5 days without benefit. He is
in hospital for the last 7 days but till now there is
no definite diagnosis and he is labeled as a case
of Fever of Unknown Origin (FUO)
 Questions
1-What is the definition and causes of FUO?

2-What are the factors that affect the etiology?

3-What are the important points in history and

physical examination to consider?

4-What are the investigations needed for the

diagnosis of the cause?
Answer of Q1
Not every fever with unclear
cause or source = FUO
 FUO
Definition changed 1961 Petersdorf RB et al.
1991 Durack DT et al.
More than 200 diseases
Major diagnostic challenge

• “Most patients with FUO are not suffering from

unusual diseases; instead they exhibit atypical
manifestations of common illnesses.”

Petersdorf RT, Beeson PB. Fever of unexplained origin:

Report on 100 cases.
Medicine 1961;40:1-30
 • (1) a temperatures of
>38.3°C on several
Fever of unknown occasions
origin (FUO) was • (2) a duration of fever of
defined by
Petersdorf and
>3 weeks
Beeson in 1961 as • (3) failure to reach a
diagnosis despite 1 week
of inpatient investigations
 New Definition
Change of FUO definition by Durack and Street
• Classical FUO
Duration >3 weeks + Fever ≥38.3° C +
Diagnosis uncertain despite appropriate
investigations, after ≥3 outpatient visits or ≥3
days in hospital
• Nosocomial FUO
• Neutropenic FUO
• HIV-associated FUO
 Definition Of Neutropenic FUO

• Less than 500 neutrophils/ mm-3

• Fever ≥ 38.3°C (>101°F) on several
occasions.
• Diagnosis uncertain after 3 days
despite appropriate investigations.
(including at least 48-h incubation of
microbiological cultures)
Examples: Perianal infection, aspergillosis, candidemia
 Definition Of Nosocomial FUO
• Hospitalized patient.
• Fever ≥ 38.3°C (>101°F) on several occasions.
• Infection does not present or incubating on
admission
• Diagnosis uncertain after 3 days despite
appropriate investigations.
(including at least 48-h incubation of microbiological cultures)

Examples: Septic thrombophlebitis, sinusitis,

Clostridium difficile colitis, drug fever
 HIV-associated FUO
• Confirmed HIV infection
• Fever ≥ 38.3°C (>101°F) on several
occasions
• Duration of ≥4 weeks (outpatients) or
≥4 days in hospitalized patient
• Diagnosis uncertain after 3 days
despite appropriate investigations
(including at least 48-h incubation of
microbiological cultures)
Examples: M. avium/M. intracellulare infection, tuberculosis, non-
Hodgkin's lymphoma, drug fever
Answer of Q2
 Factors affecting Etiology
1-Age and Gender.
2-Residence and Travel.
3-Immune status of the patient.
4-Nosocomial or hospital acquired.
5-Concomitant diseases.
 History
• Fever: Pattern, periodicity, how was it measured
• Associated symptoms such as sweating, vomiting,
headaches etc.
• Target specific organ systems if patient has problems
in that system
• Past med and surg hx. NB prostheses in situ
• Medications/ vaccines
• Family hx of hereditary diseases, connective tissue
disorders or recent illnesses (TB/ AIDS)
• Sexual history
• Occupation, pets, travel
 Examination
• Full physical examination is needed. Should be very
detailed and review all systems.
• For exams make sure to examine:
– Hands for stigmata of infective endocarditis
– Retinal exam for candidiasis or toxoplasmosis
– Teeth (infective endo or abscess)
– Lymphadenopathy (AIDS or chronic infections)
– Hepatosplenomegaly (Lymphoma/leukaemia)
– Breast/testicular exams
– Any sore joints
Answer of Q3
 CAUSES OF FUO
• INFECTIONS Systemic or Localized Typhoid, Brucella, UTI,
TB, Malaria, SBE, Hidden abscess, viral infections, others
• NEOPLASTIC DISEASES
- Haematological neoplasms (Leukemia, Hodgkin’s disease, Non-
Hodgkin lymphoma)
- Solid tumors (Colon, Liver)
- Renal cell carcinoma

• NON-INFECTIOUS INFLAMMATORY DISEASES (NIID)

a) Connective tissue diseases: SLE, Behjet Dis, Adult Stills Dis. others.
b) Vasculitides: Polyarteritis Nodosa, others.
c) Granulomatous disorders: Crohn’s Dis.,Wegner Gran., others
• MISCELLANOUS: Drug fever, DVT, etc.
• UNDIAGNOSED
 Causes of FUO: big & little 3
• Big three:
• Infections
• Malignancies
• Inflammatory
• Little three
• Drug fever
• Factitious fever
• Habitual hyperthermia
Answer of Q4

Investigations
Minimal Initial Diagnostic Workup For
FUO
• Comprehensive history
• Physical examination
• CBC + differential
• Blood film reviewed by hematopathologist
• Routine blood chemistry
• UA and microscopy
• Blood (x 3) and urine cultures
• Chest radiography and abdominal ultrasound.

Mourad, et al. Arch Intern Med. 2003;163:545

• Hepatitis serology (if abnormal LFTs)
• Antinuclear antibodies, rheumatoid factor
• HIV antibody
• CMV IgM antibodies; heterophile antibody test
(if c/w mono-like syndrome), serological tests
for typhoid fever, Brucellosis and Kala azar.
• Q-fever serology (if risk factors)
 Evaluation of Adult patient with classical FUO
• Comprehensive history (including travel
history, risk for venereal diseases, hobbies,
pet animals and birds, etc.)
• Comprehensive physical examination
(including temporal arteries, rectal digital
examination, etc.)
• Routine blood tests (CBC including
differential, ESR or CRP, electrolytes, renal
and hepatic tests, CK and LDH)
• Microscopic urinalysis
• Cultures of blood, urine other normally
 Evaluation of Adult patient with classical FUO
• Antinuclear and antineutrophilic
cytoplasmic antibodies, rheumatoid factor
• Tuberculin skin test
• Serological tests directed by local
epidemiological data
• Further evaluation directed by
abnormalities detected by above test; e.g.

- HIV antibodies depending on detailed history

- CMV-IgM and EBV serology in case of
abnormal
 Therapeutic trials in classic FUO
- Therapeutic trail to be considered in case of deterioration

Therapeutic trails are seldom diagnostically rewarding and

tend to obscure rather than to illuminate.

* Symptomatic: NSAID
* Antibiotics:
• Broad spectrum antibiotics: stop if no
defervescence after 3 days.
• Consider tetracyclines (or macrolides)
* Antituberculosis therapy: strongly consider in
 Conclusions
• 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
malignant
•Keep in mind
– The diagnostic spectrum
– Local epidemiology
– ‘Big three’ – ‘Little three’
– Common causes are frequent.

‘When ‘potentially diagnostic clues’ are absent or misleading,

‘return to basics’, ‘wait and see’ and/or