Fever of unknown origin

(F U O)
:Prepared by
Prof. Yasser M Foad
Presented By
Ass. prof. Ehab M
Abdelraheem
.Endemic Med. Dep
A temperature higher than 38.3°C
that lasts for more than three
weeks with no obvious source
despite appropriate investigation

Petersdorf RG, Beeson P. Medicine 1961

 Bacterial Diseases
:Tuberculosis
Chest radiographs can be normal
Negative tubeculin (PPD) tests
Cultures may not become positive for 4-6
weeks
TB of the kidney or mesenteric lymph
nodes tends to manifest as a FUO by
lacking characteristic localized
manifestations
 Bacterial Diseases
Endocarditis

Absence of a murmur-
Failure of blood cultures to yield the-
organism
Prior antibiotic therapy-
 Bacterial Diseases
Brucellosis: Considered in patients with
persistent fever and a history of contact with
cattle, swine, goats, and sheep

Salmonellosis: chronic type

or Neisseria gonorrhoeae,
Spirochetal diseases
 Viral Diseases
Herpes viruses
:CMV and EBV
Prolonged fever with constitutional symptoms-
with no prominent organ manifestations
lymph nodes are not very enlarged-
lymphocytosis with atypical lymphocytes-
Serologic testing can confirm the correct-
diagnosis (repeated after 3 weeks)
 Fungal Diseases

Suspected with Immunosuppression-

Candida albicans and histoplasmosis-

are the main organisms

blood cultures :negative in 50% of the cases -

 Parasitic Diseases

.Toxoplasmosis -

.Malaria -

.Trypanosoma, Leishmania, and Amoebiasis -

. Fasciola and schistosoma-

 Neoplasms
• Lymphomas: when the disease is confined to the retroperitoneal lymph
nodes

• Leukemias: preleukemic states, the peripheral blood smear and bone

marrow aspirate may not reveal the correct diagnosis.

• Solid tumors: renal cell carcinoma most commonly is associated with

FUO, with fever being the only presenting symptom in 10% of cases

• Malignant histiocytosis: rare rapidly progressive malignant

disease that manifests with high fevers, weight loss, enlarged lymph
nodes, and hepatosplenomegaly.
Collagen and autoimmune diseases
• Systemic-onset JRA:High-spiking fevers, nonpruritic rashes, arthralgias and
myalgias, pharyngitis, and lymphadenopathy. leukocytosis, elevated ESR, anemia, and
abnormal liver function tests

• polyarteritis nodosa (PAN), RA, and mixed connective

t d: should be considered because of their potential for nonspecific presentations.

• GCA: temporal headache, jaw claudication, fever, visual disturbances, temporal artery
tenderness or decreased pulsation elevated ESR, mild-to-moderate anemia, elevated platelets,
and abnormal liver function tests (25% of cases)
• PMR:

• PMR: symmetrical pain and stiffness involving the lumbar spine and large proximal
muscles
 Granulomatous diseases
• Sarcoidosis: lymph node and pulmonary involvement.
Erythema nodosum occasionally present

• Regional enteritis:Crohn`s disease is the most common

gastrointestinal cause of FUO

• Granulomatous hepatitis: TB, syphilis, brucellosis,

sarcoidosis, Crohn`s disease, Hodgkin`s disease).
 Endocrine

• Hyperthyroidism and subacute thyroiditis are

the 2 most common endocrinologic causes of FUO

• Adrenal insufficiency is a rare, potentially fatal, very

treatable endocrine cause of FUO. Considered in patients with nausea,
vomiting, weight loss, skin hyperpigmentation, hypotension,
hyponatremia, and hyperkalemia.
 Miscellaneous causes

• Drug fever A history of allergy, skin rashes, or peripheral eosinophilia often

is absent in cases of drug fever.

• Familial Mediterranean fever : Recurrent febrile episodes at

varying intervals are associated with pleural, abdominal, or joint pain due to
polyserositis

• Peripheral pulmonary emboli and occult

thrombophlebitis.

• self-limiting necrotizing lymphadenitis (Kikuchi

disease).
 Factitious fever
• 10% of FUO cases in some series and is most commonly encountered
among young adults with health care experience or knowledge

• evidence of psychiatric problems or a history of multiple

hospitalizations exists at different institutions

• Rapid changes of body temperature without associated shivering or

sweating, large differences between rectal and oral temperature, and
discrepancies between fever, pulse rate, or general appearance
• observed in patients who manipulate or exchange their thermometers.

• Alternatively, fever may be caused by injection of nonsterile material

(eg, feces, milk)
Algorithm for diagnosis

American Family Physicians 2003

Archieves of internal medicine 2003
Step 1: Thorough history
Age-

-Current symptoms

- Medications and herbal remedies

-Occupational exposures

-Pets; hobbies; travel

-Sexual activities.

-Known familial disorders

. -Previous surgical procedures

: Step 1
Repeated physical
examination
.The rash associated with Still's disease is evanescent and easily missed
Thickening or tenderness of the temporal artery-
Osler's nodes, Janeway lesions, and conjunctival petechiae may not be present
initially in a patient with endocarditis
Thyroid swelling

Periodontal abscess
Sinusitis
Step 2

Repeate minimal
investigations
 CBC count and microscopic examination

• Anemia is an important finding

• Ensure that leukemias are not missed in aleukemic or

preleukemic cases.

• Suspect herpesvirus infection if the patient has lymphocytosis

with atypical cells.

• A leukocytosis with an increase in bands suggests an occult

bacterial infection.

• Diagnose malaria and spirochetal diseases with peripheral blood

smear; however, repeated examinations often are necessary.
 Serum chemistry

• At least one liver function test is usually abnormal, with an

underlying disease originating in the liver or a disease that
causes nonspecific alterations of the liver (eg,
granulomatous hepatitis)

• Most other chemistry tests rarely contribute to the

diagnosis, though they are frequently ordered.

• Blood cultures for aerobic and anaerobic pathogens are

essential in the evaluation; however, no more than 6 sets
of blood cultures are required.
 Serologies
• usually 4-fold, increase of antibodies specific to an
infectious microorganism

• Brucellosis, CMV, infectious mononucleosis, HIV,

amebiasis, toxoplasmosis, and chlamydial
diseases

• These diagnostic tests are of limited value in most

patients with FUO, but they are appropriate for
evaluation of the above illnesses in the correct
clinical and epidemiological setting
 Serologies

• Frequently check antinuclear antibody (ANA) titers,

rheumatologic factor, thyroxine level, and ESR because
they are helpful in diagnosing a selected condition (lupus,
RA, thyroiditis, hyperthyroidism, GCA, PMR). Their
diagnostic accuracy is limited in other autoimmune and
collagen vascular diseases.
 Imaging
• Do not exclude intraabdominal process with a
negative ultrasound in presence of suggestive
symptoms

• Intravenous pyelography may be more sensitive

than the CT scan in detecting processes involving
the descending urinary tract

• Magnetic resonance imaging (MRI) can be very

useful in cases where osteomyelitis and
vasculitides is suspected
Step 3

Discontinue all non essential

medications
Antimicrobial
agents
Carbapenems
Cephalosporins
Minocycline HCl
Nitrofurantoin
Penicillins
Rifampin
Sulfonamides
Anticonvulsants
Barbiturates
Carbamazepine
Phenytoin
Cardiovascular
Hydralazine HCl
Procainamide HCl
Quinidine
Histamine2 (H2) blockers
Cimetidine
Ranitidine HCl
Herbal remedies
NSAIDs
Ibuprofen
Sulindac
Phenothiazines
Salicylates
 Discontinue all non essential medications

Fever persists: step 4 Fever resolved

Step 4

Abdominal CT
Tc based nuclear medicine
PET tomography
•A technetium bone scan may be a more sensitive
method for documenting skeletal involvement
when suspecting osteomyelitis
Positron emission tomography (PET) scanning has enhanced
the detection of occult neoplasms, lymphomas, and vasculitides
 Abdominal CT
Tc based and PET imaging

:Focus identifed
obtain : No focus
Tissue biopsy go to step 5
Step 5

Infective endocarditis
suspected ?
 Duke criteria

Clinical criteria for infective

:endocarditis requires
Two major criteria, or •
One major and three minor criteria, •
or
Five minor criteria •
Positive blood culture for Infective Endocarditis -
- Evidence of endocardial involvement

1Predisposing factor presence

2.Fever >38 degree
3.Immunological problems like
Glomerulonephritis, Osler's Nodes
4.Positive Blood Culture
5.Evidence of embolism
6. Positive Echocardiogram
Duke criteria , transesophageal echocardiography

: No
Yes go to step 6
Step 6

Leg doppler for DVT

 Leg doppler

Positive for
DVT: LMWH: : No
Yes go to step 7
Or No
Step 7

:Fever persists
Look at age
Age >50 Age < 50

T A biopsy Yes : No
Or No Liver biopsy
laparoscopy

No: go to step 8
 Biopsies
• The final diagnosis is obtained during direct
biopsy examination of involved tissue.

• Liver biopsy rarely results in helpful data for

patients without abnormal liver function
tests or abnormal imaging.
Step 8

:Fever persists
Follow up clinically
The prognosis of FUO is dependent on
the etiological category. Undiagnosed
FUO has a very favorable outcome.
Patients in whom the above diagnostic
investigations fail to identify a cause
should be followed clinically with serial
history reviews and physical
examinations until the fever resolves
or new diagnostic clues are found.
Thank you