PYREXIA OF UNKNOWN ORIGIN PREPARED BY : BESTOON S. ISMAEL

SUPERVISED BY: Dr. SASAN

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

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

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.

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.

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 .

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.”

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.

common causes of PUO

Infection (40%)

Malignancy (25%)

Autoimmune Disease (15%)

Others/ Miscellaneo

us (10%)

Undiagnosed (10%)

Classification Durack and Street’s classification

Classical Nosocomial Neutropenic PUO associated with HIV infection

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.

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.

2 . Malignancies

Haematological Lymphoma Chronic leukemia

Non-haematological Renal cell cancer Pancreatic cancer Colon cancer Hepatoma

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

miscellaneous

Hyperthyroidism Alcoholic hepatitis Inflammatory bowel

disease Deep Venous Thrombosis

Drugs;

Factitious fever Munchausen syndrome munchausen by proxy

Thermoregulatory disorders

Central

•    Brain tumor

•  Hypothalamic dysfunction

Peripheral

•    Hyperthyroidism

•    Pheochromocytoma

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

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.

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

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

A Clinical Approach

Pyrexia of Unknown Origin

History Taking

(HOPI)

1。Onset - acute: - gradual:

2。 Character;

3。 Antecedents

dental extraction: Urinary catheterization;

4。 Associated symptoms Chills & rigors

Night sweats

Loss of weight Cough and Dyspnoea

Headache

Joint pain

Abd. Pain

Bone pain

Sorethroat

Dysuria, rectal pain

Altered bowel habit Skin rash

PMH

PSH

DRUGHx

FHx

Travel

Residental area

Occupation

Contact with domestic / wild animal / birds : Diet history

Sexual orientation Close contact with TB patients

Physical Examination

Pyrexia of Unknown Origin

GENERAL HANDS ARMS AXILLA HEAD, EYE FACE MOUTH

Abdomen

T.FEVER HMG SMG RCC Testis DRE PV

CHEST;CVS, RS Signs of meningism FNS

Investigation

Pyrexia of Unknown Origin

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

CMV MALARIAL PARASITE

TRYPANASOMNIASIS

Microscopy:

Direct examination of b.smears

Stage 2:1. Repeat history and

examination2. Protein

electrophoresis3. CT (chest,

abdomen, pelvis)4. Autoantibody

screen (ANA, RF, ANCA, anti-dsDNA)

5. ECG

Stage 2: Laboratory investigations

6. Bone marrow examination

7. LP8. Temporal artery

biopsy9. HIV test

counselling

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

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

Diagnosis …. CONT….

LP,LIVER , LN or BMbx CONSULTATION.

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Pyrexia of Unknown Origin

The majority of disease remaining after an

initial NEGATIVE work-up are:1. Neoplasm2. Seronegative Collagen Vascular

Disease3. TB4. Drug5. Elderly with Endocarditis6. HIV with or without infection or

malignancy7. Implanted prosthetic devices8. Travel … New Exposure

Stage 4

Therapeutic trials:

Empirical treatment with corticosteroids or NSAIDS

or antimicrobials

Antimycobacterial agents in AIDS & neutropenic

Blind therapy;

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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.

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,

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.

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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.

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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

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.

…….Thank you