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1. AIMS OF THE PUO LECTURE
1. Define the pyrexia of unknown
origin and the mechanism of
fever.
2. Identify the causes of puo
3. Discuss how to approach to puo
from clinical and investigation
point of views

2. ‘Fever’ : temperature of more than 38.0°C
• Fever is a response to cytokines and acute phase
proteins
• occurs in infections and in non-infectious condition

3.  Fever > 38.3 on several occasions
 Fever lasting more than 3 weeks
 No diagnosis despite 1 week of
inpatient workup

4. Aetiology of pyrexia of unknown origin
(PUO)
1.Infections (~30)
A. Specific locations
 Abscesses: as liver , Renal, pulmonary, CNS
 Infections of oral cavity (including dental and sinuses)
 Bone and joint infections
 Infective endocarditis
B. Specific organisms
 Tuberculosis (particularly extrapulmonary)*
 HIV-1 infection
 cytomegalovirus (CMV), Epstein–Barr virus (EBV)
 Fungal infections (e.g. Aspergillus spp., Candida spp.)

5. C. Specific patient groups
1) Imported infections:
Malaria, dengue, influenza ,HIV, Brucella spp., amoebic
liver abscess, enteric fevers, Leishmania spp.
2) Nosocomial infections
Infections related to prosthetic materials and surgical
procedures
3) HIV-positive individuals
AIDS-defining infections as Pneumocystis jirovecii

6. 2. Malignancy (~20%)
1. Haematological malignancy :
Lymphoma, leukaemia and myeloma
2. Solid tumours
Renal, liver, colon, stomach, pancreas,
kidney

7. 3. Connective tissue disorders (~15%)
1. Older adults
- Temporal arteritis/polymyalgia rheumatica
2. Younger adults
- Still’s disease (juvenile rheumatoid arthritis)
- Systemic lupus erythematosus (SLE)
- Vasculitic disorders as polyarteritis nodosa
- - Polymyositis
- Behçet’s disease
3. Geographically restricted
- Rheumatic fever

8. 4. Miscellaneous (~20%)
A. Cardiovascular
Atrial myxoma, aortitis, aortic dissection
B. Respiratory
pulmonary embolism and extrinsic allergic alveolitis
C. Gastrointestinal
Inflammatory bowel disease,hepatitis and pancreatitis
D. Endocrine/metabolic
Thyrotoxicosis, phaeochromocytoma, adrenal insufficiency,
hypertriglyceridaemia
E. Haematological
Haemolytic anaemia, thrombotic thrombocytopenic purpura,
myeloproliferative disorders, graft-versus-host disease
F. Inherited
Familial Mediterranean fever and periodic fever syndromes
G. Drug reactions
Antibiotic fever, drug hypersensitivity reactions etc.

9. H. Factitious fever
1. A patient who looks well
2. Bizarre temperature chart with absence of diurnal
variation
3. Temperature > 41°C
4. Absence of sweating
5. Normal ESR and CRP despite high fever
6. Evidence of self-injection
7. Normal temperature during supervised (observed)
measurement
5. Idiopathic (~15%)

10. Diagnosis:
History
 Recent travel
 Exposure to pets and other animals
 Sexual history
 Work environment
 Contact with other people with similar
symptoms
 Family history
 Past medical history list of medications
 Include OTC

11. Physical Exam
 Complete General and systemic examination
 Skin
 Mucus membranes
 Lymphadenopathy
 Organomegaly

12. Fever as a pathognomonic sign of diseases
Fever and skin rash
 Chicken pox  day one
 Rubella  day two
 Measles  ….. Three
 Typhus  …… four
 Typhoid  ….. five

13. Fever and lymphadenopathy
 Brucellosis
 CMV, EBV, Aids
 Toxoplasmosis, Syphilis
Fever and Jaundice
 Cholangitis , hepatitis , malaria , yellow
fever

14. Fever and pulmonary involvement
Influenza
Pneumonia
Sever Acute Respiratory syndrome SARS

15. Fever in old age
1. Fever :oral temperatures are unreliable. Rectal
measurement or eardrum
2. Acute confusion:
3. Prominent causes include :
 Infection: tuberculosis ,intra-abdominal abscesses,
urinary tract infection and infective endocarditis.
 Non-infective causes include polymyalgia
rheumatica/temporal arteritis and tumours.
 undiagnosed PUO less than in young people.

16. Microbiological investigation of PUO
A- Microscopy
1. Blood for atypical lymphocytes (EBV, CMV, HIV-1, hepatitis
viruses or Toxoplasma gondii), trypanosomiasis, malaria.
2. Sputum for mycobacteria, fungi
3. Stool for ova, cysts and parasites
4. Biopsy : light microscopy (mycobacteria, fungi, Leishmania)
electron microscopy (viruses, protozoa )
5. Urine for RBC, WBC , schistosome ova

17. B. Culture
1. Aspirates and biopsies (e.g. joint, deep abscess)
2. Blood, including prolonged culture and special media
3. Sputum for mycobacteria
4. Cerebrospinal fluid (CSF)
5. Stool and Urine

18. C. Antigen detection
1. Blood e.g. HIV p24 antigen,
2. CSF for cryptococcal antigen
3. Bronchoalveolar lavage fluid for Aspergillus
4. throat swab for respiratory viruses
5. Urine, e.g. for Legionella antigen

19. D. Nucleic acid detection(PCR)
1. Blood for Bartonella spp. and viruses
2. CSF for viruses and bacteria
3. throat swab for viruses
4. Bronchoalveolar lavage for resp. Viruses
5. Tissue specimens, e.g. for Tropheryma whipplei
6. Urine e.g. for Chlamydia trachomatis, Neisseria g.
7. Stool e.g. for norovirus, rotavirus

20. E. Immunological tests
1. Serology (antibody detection) for viruses, fungi and
bacteria and protozoa
2. Interferon-γ release assay for diagnosis of TB
Note :
• This list does not apply to every patient with a PUO.
• selected according to:
* predisposing factors,
* exposures and local availability,

21. F- Additional investigations in PUO
 Serological tests
• Autoantibody screen, Complement levels
 Echocardiography
 Ultrasound of abdomen
 CT/MRI of thorax, abdomen and/or brain
 Imaging of the skeletal system
• Plain X-rays, CT/MRI spine, Isotope bone scan
 Labelled white cell scan
 Positron emission tomography (PET)
 Biopsy
 Bronchoscopy and lavage ,
 Lymph node aspirate or biopsy
 Biopsy of liver
 Bone marrow aspirate and biopsy
 Temporal artery biopsy

22. Fever must be treated in some groups of
patients :
1. Preexisting disease like IHD, Stroke , pulmonary dis.
2. Elderly
3. Pregnant
4. Temp. > 39 ْc
5. Children with fit

23. Prognosis
• mortality of PUO is 30–40%,
• mainly attributable to malignancy in older
patients.
• If no cause is found, the long-term mortality
is low and fever often settles spontaneously.