This document discusses pyrexia of unknown origin (PUO). It defines PUO as a fever over 38°C lasting more than 3 weeks without an obvious cause despite evaluations. Common causes include infections (40%), malignancies (25%), and autoimmune diseases (15%). The document outlines the pathogenesis of fever and classifications of PUO. It describes the approach to evaluating a PUO patient through history, exam, and staged laboratory/imaging investigations. Empirical treatment trials are generally not recommended until a cause is found due to risks of misleading outcomes. The prognosis is determined by the underlying disease, with neoplasms having the worst outcomes.

1. PYREXIA OF UNKNOWN
ORIGIN
PREPARED BY : BESTOON S. ISMAEL
SUPERVISED BY: Dr.
SASAN

2. Introduction
 Body teperature is normally maintained within
1-1.5°c in arange of 37-38° c ,normal body
temperature is generally cosidered to be 37°c
.
 Low levels occur at 6 A.M and higher levels
at 4 - 6 P.M

3. • Normal body
temperature is
maintained by a complex
regulatory system in the
anteroir
hypothalamus,preoptic
area,temperature
sensitive area,thermal
set point .

4. Pathogenesis of fever
 Pyrogens
 Substances mediate the elevation of core body temperature.
 Exogenous and endogenous pyrogens.
Exogenous pyrogens:
 Derived from outside the host ,like Microorganisms, toxins and
microbial products,large molecule ,can not pass blood brain barrier
 It induce release of endogenouse pyrogens from macrophages.

5. Endogenous pyrogens
derived from the
macrophages ,small
molecule ,can pass blood
brain barrier.
•Pyrogen cytokines trigger
hypothalamus to release
PGE2 resulting in resetting
of thermostatic
temperature,activation of
vasomotor center
,vasodilatation and heat
production.

6. Pyrexia of Unknown Origin
• Original Definition (by Petersdorf and Beeson, 1961)
• Temperatures ≥ 38.3ºC (101ºF) on several
occasions
• Fever ≥ 3 weeks
• Failure to reach a diagnosis despite 1 week of
inpatient investigations or 3 outpatient visits .

7. Pyrexxia of Unknown Origin
 New definition;
temperature > 38 ° c,
lasting for more than 14 days
without an obvious cause despite a comlete
history, physical examination and routine
screening laboratory evaluation.”

8. Factors that may make it difficult to find a
cause include:

A common illness that does not have the usual
symptoms,sinusitis may be a symptomatic.

Illness, whose other symptoms appear later

Illnesses who may have a delayed positive
test

Person is unable to communicate about other
symptoms .

Genetic condition that causes periodic fevers.

9. common causes of PUO
Infection
(40%)
Malignancy
(25%)
Autoimmun
e Disease
(15%)
Others/
Miscellaneo
us (10%)
Undiagnose
d (10%)

10. Classification Durack and Street’s classification
 Classical
 Nosocomial
 Neutropenic
 PUO associated with HIV infection

11. Classic PUO
 Temperature >38.3°C (100.9°F)
 Duration of >3 weeks
 Evaluation of at least 3 outpatient visits or 3 days in
hospital
 Etiologies
I. Infections
II. Malignancies
III. Collagen Vascular Disease
Others/Miscellaneous which includes drug-induced fever.

12. 1. Infections
 Bacterial: abscesses, TB,
complicated UTI,
endocarditis, osteomyelitis,
sinusitis, prostatitis,
cholecystitis, empyema,
biliary tract infection,
brucellosis, typhoid,,,, etc.
 Viral: CMV, infectious
mononucleosis, HIV, etc.
 Parasite: Malaria,
toxoplamosis,
leishmaniasis, etc.
 Fungal: histoplasmosis, etc.
 As duration of fever
increases, infectious etiology
decreases
Malignancy and factitious
fevers are more common in
patients with prolonged FUO.

13. 2 . Malignancies
 Haematological
 Lymphoma
 Chronic leukemia
 Non-haematological
 Renal cell cancer
 Pancreatic cancer
 Colon cancer
 Hepatoma

14. 3. Collagen vascular disease / Autoimmune disease
 Temporal arteritis
 Rheumatoid arthritis
 Rheumatoid fever
 Inflammatory bowel disease
 Reiter's syndrome
 Systemic lupus
erythematosus
 Polyarteritis nodosa
 Giant cell arteritis
 Kawasaki disease

15. miscellaneous
 Hyperthyroidism
 Alcoholic hepatitis
 Inflammatory bowel
disease
 Deep Venous Thrombosis
 Drugs;

16.  Factitious fever
Munchausen syndrome
munchausen by proxy
 Thermoregulatory disorders
 Central
• Brain tumor
• Hypothalamic dysfunction
 Peripheral
• Hyperthyroidism
• Pheochromocytoma

17. Fever pattern
Continuous fever: e.g. lobar
pneumonia, typhoid, urinary
tract infection,brucellosis.
Intermittent fever:
e.g. malaria, pyaemia,
or septicemia..
Remittent
fever: e.g, infective
endocarditis.
Pel-Ebstein fever
; Hodgkin's lymphoma

18. Nosocomial PUO
 Temperature >38.3°C
 Patient hospitalized ≥ 24 hours but no fever or incubating on admission
 Evaluation of at least 3 days
 More than 50% of patients with nosocomial PUO
are due to infection.
 Focus on sites where occult infections may be
sequestered, such as:
- Sinusitis of patients with NG or oro-tracheal tubes.
- Prostatic abscess in a man with a urinary catheter.
 25% of non-infectious cause includes:
- Acalculous cholecystitis,
- Deep vein thrombophlebitis
- Pulmonary embolism.

19. Immune deficient/ Neutropenic PUO
 Temperature >38.3°C
 Neutrophil count ≤ 500 per mm3
 Evaluation of at least 3 days
 Patients on chemotherapy or immune deficiencies are
susceptible to:
- Opportunistic bacterial infection
- Fungal infections such as candidiasis
- Infections involving catheters
- Perianal infections.
 Examples of aetiological agent:
- aspergillus
- Candida
- CMV
- Herpes simplex

20. HIV-associated PUO
 Temperature >38.3°C
 Duration of >4 weeks for outpatients, >3 days for inpatients
 HIV infection confirmed
 HIV infection alone may be a cause of fever.
 Common secondary causes include:
- Tuberculosis
- CMV infection
• Non-Hodgkin's lymphoma
- Drug-induced fever

21. A Clinical Approach
Pyrexia of Unknown Origin

22. History Taking
(HOPI)
1。Onset
 - acute:
 - gradual:
2。Character;
3。Antecedents
 dental extraction:
 Urinary catheterization;

23. 4。Associated symptoms
 Chills & rigors
 Night sweats
 Loss of weight
 Cough and Dyspnoea
 Headache
 Joint pain

24.  Abd. Pain
 Bone pain
 Sorethroat
 Dysuria, rectal pain
 Altered bowel habit
 Skin rash

25.  PMH
 PSH
 DRUGHx
 FHx

26.  Travel
 Residental area
 Occupation
 Contact with domestic / wild animal / birds :
 Diet history
 Sexual orientation
 Close contact with TB patients

27. Physical Examination
Pyrexia of Unknown Origin

28. 
 GENERAL
 HANDS
 ARMS
 AXILLA
 HEAD,
 EYE
 FACE
 MOUTH

29. Abdomen
 T.FEVER
 HMG
 SMG
 RCC
 Testis
 DRE
 PV

30.  CHEST;CVS, RS
 Signs of meningism
 FNS

31. Investigation
Pyrexia of Unknown Origin

32. Stage 1: Laboratory investigations
Stage 1: (screening
tests)
1. Full blood count
2. ESR & CRP
3. BUSE
4. LFTs
5. Blood culture
6. Serum virology
7. Urinalysis and
culture
8. Sputum culture and
sensitivity
9. Stool occult blood
10. CXR
11. Tuberculin test

33. Microscopy:
Direct examination of b.smears

34. Stage 2:
1. Repeat history and
examination
2. Protein
electrophoresis
3. CT (chest,
abdomen, pelvis)
4. Autoantibody
screen (ANA, RF,
ANCA, anti-
dsDNA)
5. ECG
Stage 2: Laboratory investigations
6. Bone marrow
examination
7. LP
8. Temporal artery
biopsy
9. HIV test
counselling

35. Stage 3:
1. Echocardiography
2. (Indium-labelled
WC scan – IBD,
abscesses, local
sepsis)
3. Barium studies
4. IVU
5. Liver biopsy
Stage 3: Laboratory investigations
6. Exploratory
laparotomy
7. Bronchoscopy

36. STAGE 3 [CONT] ; Imaging
Studies
Chest radiograph
CT of abdomen or pelvis with
contrast agent
Gallium 67 scan
MRI of brain
PET scan
Transthoracic or transesophageal
echocardiography
Venous Doppler study

37. Diagnosis …. CONT….
 LP,LIVER , LN or BMbx
 CONSULTATION.

38. Pyrexia of Unknown Origin
The majority of disease remaining after an
initial NEGATIVE work-up are:
1. Neoplasm
2. Seronegative Collagen Vascular Disease
3. TB
4. Drug
5. Elderly with Endocarditis
6. HIV with or without infection or malignancy
7. Implanted prosthetic devices
8. Travel … New Exposure
38

39. Stage 4
Therapeutic trials:
 Empirical treatment with corticosteroids or NSAIDS or
antimicrobials
 Antimycobacterial agents in AIDS & neutropenic
 Blind therapy;

40. Therapeutic Trials
 Limitation and risk of empirical therapeutic
trials:
 Rarely specific
 Underlying disease may remit spontaneously false
impression of success.
 Disease may respond partially and this may lead
to delay in specific dx
 SE drugs can be misleading.
40

41.  Therapy withheld until cause is found
 Empirical corticosteroids or anti inflammatories in
temporal arteritis.
 Vital sign instability & neutropenia –
Fluoroquinolones + piperacillin,
vancomycin + ceftazidime/cefepime/
carbapenem with or without aminoglycoside,

42. Therapeutic Trials
 What is the best
therapy for PUO
patient?
 To hold therapeutic
trials in the early
stage … demolish…
except in:
 Patient who is very
sick to wait.
 All tests have failed
to uncover the
etiology.
42

43. Prognosis
 Prognosis is determined primarily by
the underlying disease.
 Outcome is worst for neoplasms.
 FUO patients who remain
undiagnosed after extensive
evaluation generally have a
favorable outcome and the fever
usually resolves after 4-5 weeks.
43

44. Summary
 FUO is often a diagnostic
dilemma,quandary.
 Infections comprise ~30% of cases
 Bone marrow biopsies are of low
diagnostic yield
 Diagnostic approach should occur in a
step-wise fashion based on the H&P
 Patient’s that remain undiagnosed
generally have a good prognosis
44

45. References
 NELSON ESSENSSIALS OF PEDIATRICS 6th
ED.
 Harrison’s principles of internal medicine
18th edition.
 Mandell, Bennet & Dolin’s, principle of infectious
disease 6th edition.

46. …….Thank you