PYREXIA OF UNKNOWN ORIGIN

Dr. Alaa Jumaa

PUO is

A Common disease presenting ATYPICALLY

Terminology

Old Definition: Petersdorf and Beeson (1961)

1. Fever higher than 38.3oC 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

Categories of Illness Causing PUO

Infections 30 - 40 %

Malignancies 20 – 25 %

Collagen Vascular Disease 10 – 20 %

Miscellaneous 15 – 20 %

Undiagnosed 10 – 15 %

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

Geography

Malaria Saudi (malaria area)/Africa/India

Brucella Saudi/Gulf Area

Kala-Azar Yemen/Sudan/India

Leprosy Yemen/Najran…

Typhoid India/Pakistan/Egypt/Indonesia

Histoplasmosis USA … (West Coast)

Tuberculosis

All over the world.Liver Abscess

AIDS

9

0

10

20

30

40

50

60

Infect Neopl CVD Other Unknown

India UK

J Postgrad Med 2001; 47(2):104-107

Geography

DIAGNOSIS AND TREATMENT

Diagnostic Approach

Careful History Physical Examination (repeated) Diagnostic Testing

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.

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).

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 Days 10 – 21 Days Weeks - Months

Malaria Malaria Kala Azar

Plague Typhoid Amoebiasis

Dengue Brucella HIV

Salmonella Hepatitis A Hepatitis

History

Drug and Toxin History:almost all drug can cause drug fever … Antihistaminebeta lactamanti-TB … Salicylates and other NSAID …eye drops, which may be associated with

atropine-induced fever.

History

Localizing Symptoms: May Indicate the source of fever:

Bone ach osteomylitis

Bone Metastasis

Headache Chronic Meningitis

RUQ Pain Liver Abscess

LUQ Pain Splenic Abscess

Subtle changes in behavior Granulomatous Meningitis

History

Family History:search for possible infectious or hereditary

disorders Tuberculosis FMF

Past Medical Condition:Lymphoma → may recurRheumatic Fever → may recur

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 → MalariaPel-Ebstein Pattern → Lymphoma/TuberculosisPulse-Temp Dissociation → Typhoid/Brucellosis

Pattern of Fever

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.

Physical Examination

Examine for Lymphadenopathy

Cervical Area 1. Lymphoma(Localized) 2. Tuberculosis

3. Infectious Mononucleosis

4. Lymphadenitis (bacterial)

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.

Diagnostic Testing

serology1. 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

Diagnostic Testing

CulturesBlood

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 TuberculosisAny normal sterile:

CSF/urine/pleural or peritoneal fluid Bone marrow aspirate → Tuberculosis/Brucellosis Lymph node Bx → TB

Diagnostic Testing

Imaging Studies: … to localize abnormalities for definite tests or treatmentChest x-ray:

Atelectasis } 1. Liver

↑ Hemi diaphragm } Abscess 2. Spleen

Pleural Effusion } 3. Pancreatic

4. Subphrenic Mediastinal mass → Lymphoma/Tuberculosis/

Sarcoid If CXR is (N) → Repeat on weekly basis

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

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

Therapeutic Trials

Limitation and risk of empirical therapeutic trials:Rarely specificUnderlying 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.

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.

THANK YOU