2. PYREXIA OF UNKNOWN ORIGIN Dr. Alaa Jumaa

3. PUO is A Common disease presenting ATYPICALLY

6. Terminology Old Definition: Petersdorf and Beeson (1961) 1. Fever higher than 38.3 o C on several occasions. 2. Duration of fever – 3 weeks 3. Uncertain diagnosis after one week of study in hospital New Definition:  Eliminated the in-hospital evaluation requirements → 3 outpatient visits, or 3 days in hospital. … Ambulatory as well as in hospital

7. Categories of Illness Causing PUO Infections30 - 40 % Malignancies20 – 25 % Collagen Vascular Disease10 – 20 % Miscellaneous15 – 20 % Undiagnosed10 – 15 %

8. Epidemiology and Etiology 1970 → up to date: Infection is the most frequent. 1930 → 70% undiagnosed PUO 2000 → 5-10% undiagnosed PUO  Diagnostic Advances: Modify the spectrum of PUO causing diseases: 1. Serology: HIV / Brucella / SLE 2. Imaging Tech: Abscesses/Solid Tumor

9. Geography MalariaSaudi (malaria area)/Africa/India BrucellaSaudi/Gulf Area Kala-AzarYemen/Sudan/India LeprosyYemen/Najran… TyphoidIndia/Pakistan/Egypt/Indonesia HistoplasmosisUSA … (West Coast) Tuberculosis All over the world. Liver Abscess AIDS

10. 9 J Postgrad Med 2001; 47(2):104-107 Geography

11. DIAGNOSIS AND TREATMENT DIAGNOSIS AND TREATMENT

12. Diagnostic Approach Careful History Physical Examination (repeated) Diagnostic Testing

13. History Verify the presence of fever:  Series of 347 patients → for prolonged fever → 35% were ultimately: a. No fever b. Factitious Fever Duration of Fever:  The longer the duration → the less likely to have infection and malignancy.

14. History A history of exposure to wild or domestic animals should be solicited (zoonotic disease ) Ingestion of dirt is a particularly important clue to infection with Toxoplasma gondii (toxoplasmosis). Ancestry from the Mediterranean should suggest the possibility of familial Mediterranean fever (FMF).

15. History Travel:  Travel to an area known to be endemic for certain disease: Name of the area, duration of stay Onset of illness … (incubation period) 1 – 10 Days10 – 21 DaysWeeks - Months Malaria Kala Azar PlagueTyphoidAmoebiasis DengueBrucellaHIV SalmonellaHepatitis AHepatitis

16. History Drug and Toxin History:  almost all drug can cause drug fever …  Antihistamine  beta lactam  anti-TB …  Salicylates and other NSAID …  eye drops, which may be associated with atropine-induced fever.

17. History Localizing Symptoms:  May Indicate the source of fever: Bone achosteomylitis Bone Metastasis HeadacheChronic Meningitis RUQ PainLiver Abscess LUQ PainSplenic Abscess Subtle changes in behaviorGranulomatous Meningitis

18. History Family History:  search for possible infectious or hereditary disorders Tuberculosis FMF Past Medical Condition: Lymphoma→may recur Rheumatic Fever→may recur

19. Physical Examination Document the Fever:  Significant and persistent for more than ONE occasion. Analyzing the Pattern:  Neither specific Nor sensitive enough to be considered diagnostic … EXCEPT Tertian & Quarter Pattern→Malaria Pel-Ebstein Pattern →Lymphoma/Tuberculosis Pulse-Temp Dissociation → Typhoid/Brucellosis

20. Pattern of Fever

21. Physical Examination Sweating in a febrile child should be noted  familial dysautonomia, or exposure to atropine. A careful ophthalmic examination is important Hyperemia of the pharynx, with or without exudate, suggests  infectious mononucleosis, CMV infection, toxoplasmosis, salmonellosis,Kawasaki disease. The muscles and bones should be palpated carefully.

22. Physical Examination Examine for Lymphadenopathy Cervical Area 1. Lymphoma (Localized)2. Tuberculosis 3. Infectious Mononucleosis 4. Lymphadenitis (bacterial)

23. Diagnostic Testing 1. CBC with a differential WBC count and a urinalysis should be part of the initial laboratory evaluation. 2. An erythrocyte sedimentation rate (ESR). 3. C-reactive protein is another acute-phase reactant that becomes elevated and returns to normal more rapidly than the ESR.

24. Diagnostic Testing serology 1. Anti-nuclear Antibodies 2. Rheumatoid Factor 3. CMV Antibody … IgM 4. Heterophile Antibody Test in children and young adult 5. Tuberculin Skin Test … 5 unit ID 6. Thyroid Function Test 7. HIV Screening

25. Diagnostic Testing Cultures  Blood Obtain more than 3 blood cultures from separate venipunctures over 24 hr period if you are suspecting inf. Endocarditis prior antimicrobial use. Incubate the blood for 4 weeks, to detect the presence of SBE & Brucellosis  Sputum: For Tuberculosis  Any normal sterile: CSF/urine/pleural or peritoneal fluid Bone marrow aspirate → Tuberculosis/Brucellosis Lymph node Bx → TB

26. Diagnostic Testing Imaging Studies: … to localize abnormalities for definite tests or treatment  Chest x-ray: Atelectasis}1. Liver ↑ Hemi diaphragm} Abscess2. Spleen Pleural Effusion}3. Pancreatic 4. Subphrenic Mediastinal mass → Lymphoma/Tuberculosis/ Sarcoid If CXR is (N) → Repeat on weekly basis

27. Diagnostic Testing  CT-Scan → CT scan chest Mediastinal mass → Tuberculosis/Lymphoma/ Sarcoidosis CT-Scan Abdomen → very effective to visualize  All types of abscesses  Retroperitoneal tumor, lymph node or haematoma  MRI: spleen, lymph node and the brain  Radionuclide scans

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

29. 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 diagnosis.  Side effect of the drugs can be misleading.

30. Therapeutic Trials  To hold therapeutic trials in the early stage… except in: Patient who is very sick to wait. All tests have failed to uncover the etiology. Tuberculosis Culture-negative endocarditis.

31. THANK YOU