This document discusses pyrexia of unknown origin (PUO), defined as a fever over 38°C for at least 3 weeks without an identifiable cause despite investigations. It lists common causes of fever including infections, tissue injury, malignancy, drugs, and immune or inflammatory disorders. For PUO, a diagnostic strategy is outlined including comprehensive history, exam, routine tests, cultures, imaging like chest x-ray, ultrasound or gallium scan, and biopsy if needed to identify systemic infections, occult abscesses, tumors, or non-infectious inflammatory diseases as potential causes. The diagnostic challenge of PUO is to systematically evaluate and rule out common causes through appropriate testing and imaging studies.

1. INFECTIOUS DISEASES
PYREXIA OF UNKNOWN ORIGIN
(PUO)
PROF FARHAT BASHIR

2. FEVER
 FEVER: >37.8C
 Elevated body temperature mediated by an increase in
the hypothalamic heat regulating set point

3. PATHOGENESIS OF FEVER

4. CAUSES OF FEVER
 Infection
 Tissue injury - infarction, trauma
 Malignancy
 Drugs
 Immune-mediated disorders
 Other inflammatory disorders
 Endocrine disorders
 Factitious of self-induced fever

5.  VIRAL---rhinovirus, adenovirus, enterovirus, influenza
 BACTERIAL---Staph aureus, Salmonella typhi, S.
paratyphi
 PROTOZOAL----malaria
 POST ANIMAL EXPOSURE--- Coxiella, Leptospira,
Brucella
 GRANULOMATOUS INFECTION--- tuberculosis,
histoplasmosis
Infections presenting as fever
without localizing signs or symptoms

6. DEFINITION
1. Fever ≥ 38.0°C (>101°F) on several
occasions

7. DEFINITION
1. Fever ≥ 38.3°C (>101°F) on several
occasions
2. Duration ≥ 3 weeks

8. DEFINITION
1. Fever ≥ 38.3°C (>101°F) on several
occasions
2. Duration ≥ 3 weeks
3. Failure to reach a diagnosis despite 3days
appropriate in-hospital investigation or 2
outpatient visits

9. TYPES OF FUO
 CLASSICAL
 NOSOCOMIAL
 NEUTROPENIC
 HIV-associated

10. NOSOCOMIAL FUO
 Hospitalized patient
 Fever ≥ 38.3°C (>101°F) on several occasions
 Infection 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

11. 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

12. 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

13. Major disease categories
Infections
Neoplastic diseases
Non-infectious inflammatory diseases (NIID)
Minor categories
Factitious fever
Drug-related fever
Habitual hyperthermia
(should always be considered before starting FUO
work-up)
Classification of causative diseases

14. • INFECTIONS Systemic or Localized
CAUSES OF FUO

15. INFECTIONS
Systemic infections
Most common:
Tuberculosis and endocarditis
Less common:
- Epstein-Barr virus and cytomegalovirus
- toxoplasmosis, brucellosis
- Q fever, cat-scratch disease, malaria
- HIV or opportunistic infections associated
with AIDS

16. INFECTIONS
Localized infections
Most common:
Occult abscess (liver, spleen, kidney, brain,
bone)
Less common:
- Cholangitis
- Osteomyelitis
- Urinary tract infection
- Paranasal sinusitis

17. • INFECTIONS Systemic or Localized
• NEOPLASTIC DISEASES
Haematological neoplasms
Non-Hodgkin lymphoma
Leukemia
Hodgkin’s disease
Other
CAUSES OF FUO

18. • INFECTIONS Systemic or Localized
• NEOPLASTIC DISEASES
Haematological neoplasms Solid tumors
Non-Hodgkin lymphoma Renal carcinoma
Leukemia Colon
Hodgkin’s disease Liver
Other Other
CAUSES OF FUO

19. • INFECTIONS Systemic or Localized
• NEOPLASTIC DISEASES
Haematological neoplasms Solid tumors
Non-Hodgkin lymphoma Renal carcinoma
Leukemia Colon
Hodgkin’s disease Liver
Other Other
• NON-INFECTIOUS INFLAMMATORY DISEASES
(NIID)
Collagen diseases, autoimmune dis., vasculitides, Crohn
CAUSES OF FUO

20. NIID - AUTOIMMUNE DISORDERS
Most common:
- systemic lupus erythematosus
- cryoglobulinemia
- polyarteritis nodosa
Less common:
- Giant cell arteritis
- Polymyalgia rheumatica

21. • INFECTIONS Systemic or Localized
• NEOPLASTIC DISEASES
Haematological neoplasms Solid tumors
Non-Hodgkin lymphoma Renal carcinoma
Leukemia Colon
Hodgkin’s disease Liver
Other Other
• NON-INFECTIOUS INFLAMMATORY DISEASES
(NIID)
Collagen diseases, autoimmune dis., vasculitides, Crohn
d.
• MISCELLANOUS
Granulomatous, Whipple d.,Cardiac myxoma,
Castleman dis.,etc.
CAUSES OF FUO

22. • INFECTIONS Systemic or Localized
• NEOPLASTIC DISEASES
Haematological neoplasms Solid tumors
Non-Hodgkin lymphoma Renal carcinoma
Leukemia Colon
Hodgkin’s disease Liver
Other Other
• NON-INFECTIOUS INFLAMMATORY DISEASES
(NIID)Collagen diseases, autoimmune dis., vasculitides, Crohn
• MISCELLANOUS
Granulomatous, Whipple d.,Cardiac myxoma, etc.
• UNDIAGNOSED
CAUSES OF FUO

23. DIAGNOSTIC STRATEGY

24. 1. Comprehensive history
including travel history, risk for venereal diseases,
hobbies, contact with pet animals and birds, etc.
2. Comprehensive physical examination
3. Routine blood tests
complete blood count including differential, ESR or
CRP, electrolytes, renal and hepatic tests, creatine
phosphokinase, lactate dehydrogenase
4. Microscopic urinalysis
MINIMUM DIAGNOSTIC EVALUATION 1.

25. 5. Cultures of blood, urine
and other normally sterile compartments if clinically
indicated, e.g. joints, pleura, cerebrospinal fluid
6. Chest radiograph
7. Abdominal (including pelvic)
ultrasonography
8. Autoantibodies
ANA, ANCA, Rheumatoid factor, etc.
9. Tuberculin skin test
10. Serological tests directed by local
epidemiological data
MINIMUM DIAGNOSTIC EVALUATION 2.

26. Imaging Possible diagnoses
Chest radiograph Tuberculosis, malignancy,
Pneumocystis carinii pneumonia
CT of abdomen or pelvis/contrast Abscess, malignancy
Gallium 67 scan Infection, malignancy
Indium-labeled leukocytes Occult septicemia
Technetium Tc 99m Acute infection and inflammation
of bones and soft tissue
MRI of brain
PET scan
Malignancy, autoimmune
conditions
Malignancy, inflammation
Transthoracic or transesophageal
echocardiography
Bacterial endocarditis
Venous Doppler study Venous thrombosis
Biopsy
DIAGNOSTIC IMAGING IN PATIENTS WITH FUO

27. Complete history and physical assessment
Positive findings Order appropriate and
specific diagnostic testing
No
CBC, electrolytes, LFT, blood culture, urine analysis,
urine culture, ESR, PPD skin test, chest radigraph
Positive results Order appropriate follow-up
diagnostic testing
No
CT of abdomen / pelvis with contrast
Assign most likely category
Infection Malignancies Autoimmune (NIID) Miscellaneous
Algorithm for the Diagnosis of FUO