This document provides information on fever of unknown origin (FUO). It defines FUO as a fever over 38.3°C for at least 3 weeks without a confirmed diagnosis after tests and visits. Common causes include infections, cancers, and autoimmune disorders. The evaluation involves medical history, exam, lab tests, imaging and biopsies to identify infectious, inflammatory or malignant sources. Treatment focuses on the underlying cause rather than empiric antibiotics or steroids. Some cases remain undiagnosed, but most adult patients have a good prognosis in these situations.

1. Fever of unknown origin
Prepared by: Dr Yousef Biuk

2. Definition:
 ▶ Illness of at least 3 weeks duration.
 ▶ Fever over 38.3°C on several occasions.
 ▶ Diagnosis has not been made after 3 outpatient
visits or 3 days of hospitalization.

3. Epidemiology
 Fever of unknown origin (FUO) was first defined in 1961 by
Petersdorf and Beeson, then has been modified lately
 More than 30% of FUO cases in persons older than 50 years
are related to connective-tissue disorders and vasculitic
diseases
 Male-to-female incidence ratio is 2:1
 Among patients with HIV infection, approximately 75% of cases
of FUO are infectious in nature
 The fraction of undiagnosed FUOs dropped from over 75
percent in the 1930s to fewer than 10 percent in the 1950s.
 Since then the fraction of FUOs that go undiagnosed has
steadily increased.

4. Additional categories of FUO
 Hospital-associated FUO: refers to the hospitalized
patient with fever of 38.3°C or higher on several occasions,
due to a process not present or incubating at the time of
admission, in whom initial cultures are negative and the
diagnosis remains unknown after 3 days of investigation
 Neutropenic FUO: includes patients with fever of 38.3°C or
higher on several occasions with < 500 neutrophils per
microliter in whom initial cultures are negative and the
diagnosis remains uncertain after 3 days
 HIV-associated FUO: HIV-positive patients with fever of
38.3°C or higher who have been febrile for 4 weeks or more
as an outpatient or 3 days as an inpatient in whom the
diagnosis remains uncertain after 3 days of investigation

5. A. Common Causes
 Most cases represent unusual manifestations of
common diseases and not rare or exotic diseases—
eg, tuberculosis, endocarditis, gallbladder disease,
and HIV (primary infection or opportunistic infection)
are more common causes of FUO than Whipple
disease or familial Mediterranean fever.

6. B. Age of Patient
 In adults, infections (25–40% of cases) and cancer (25–
40% of cases) account for the majority of FUOs. In
children, infections are the most common cause of FUO
(30–50% of cases) and cancer a rare cause (5–10% of
cases).
 Autoimmune disorders occur with equal frequency in
adults and children (10–20% of cases), but the diseases
differ.
 Juvenile rheumatoid arthritis is particularly common in
children, whereas SLE, Wegener granulomatosis, and
polyarteritis nodosa are more common in adults.

7. C. Duration of Fever
 Patients who have been febrile for 6 months or longer,
Infection, cancer, and autoimmune disorders combined
account for only 20-25% of FUOs in these patients.
 Other entities such as granulomatous diseases
(granulomatous hepatitis, Crohn disease, ulcerative
colitis, familial Mediterranean fever, allergic alveolitis)
become important causes and account for another 25%.
 Approximately 50% (>6 months of FUO) of cases remain
undiagnosed
 One-fourth of patients who say they have been febrile for
6 months or longer actually have no true fever or
underlying disease.

8. D. Immunologic Status
 In the neutropenic patient, fungal infections and occult
bacterial infection are important causes of FUO.
 In the patient taking immunosuppressive medications
(particularly organ transplant patients),
cytomegalovirus (CMV) infections are a frequent
cause of fever, as are fungal infettions, Pneumocystis
jirovecii (carini) pneumonia, and mycobacterial
infections.

9. E. Classification of Causes of FUO
 1. Infections
 2. Neoplasms
 3. Autoimmune disorders
 4. Miscellaneous causes
 5. Undiagnosed FUO

10. 1. Infection
 Both systemic and localized infections can cause FUO.
Tuberculosis and endocarditis are the most common systemic
infections
 Mycoses, viral diseases (particularly infection with Epstein-Barr
virus and CMV), toxoplasmosis, brucellosis, Q fever,
salmonellosis, malaria, and many other less common infections
have been implicated
 Primary infection with HIV or opportunistic infections associated
with AIDS—particularly mycobacterial infections—can also cause
FUO
 The most common form of localized infection causing FUO is an
occult abscess. Liver, spleen, kidney, brain, and bone abscesses
may be difficult to detect
 Cholangitis, osteomyelitis, urinary tract infection, dental abscess,
or paranasal sinusitis may cause prolonged fever

11. 2. Neoplasms
 Many cancers can present as FUO. The most common
are lymphoma (both Hodgkin and non- Hodgkin) and
leukemia. Post transplant lymphoproliferative
disorders may also present with fever.
 Other diseases of lymph nodes, such as
angioimmunoblastic lymphoma and Castleman
disease, can also cause FUO
 Primary and metastatic tumors of the liver are
frequently associated with fever, as are renal cell
carcinomas. Atrial myxoma is an often forgotten
neoplasm that can result in fever.

12. 3. Autoimmune disorders
 Still disease, systemic lupus erythematosus, and
polyarteritis nodosa are the most common causes of
autoimmune-associated FUO.
 Giant cell arteritis and polymyalgia rheumatica are
seen almost exclusively in patients over 50 years of
age and are nearly always associated with an
elevated erythrocyte sedimentation rate (> 40 mm/h).

13. 4. Miscellaneous causes
 Many other conditions have been associated with
FUO but less commonly than the foregoing types of
illness.
 Examples include thyroiditis, sarcoidosis, Whipple
disease, familial Mediterranean fever, recurrent
pulmonary emboli, alcoholic hepatitis, drug fever, and
factitious fever.

14. 5. Undiagnosed FUO
 Despite extensive evaluation, the diagnosis remains
unknown in 15% or more of patients.
 Of these patients, the fever abates spontaneously in
about 75% with no diagnosis; in the remainder, more
classic manifestations of the underlying disease
appear over time.

15. 0
10
20
30
40
50
60
Infection Malignancy Inflammatory Other No Diagnosis
The percentage of patients with fever of unknown origin
categorised by causes during decades
1950s 1970s 1980s 1990s 2000s

16. Approach to the patient with FUO
 Medical history
 Physical examination
 Investigations
 Treatment

17. Medical history
 Fever (Pattern, periodicity, how was it measured, associated
symptoms such as sweating, vomiting, headaches etc.)
 Past medical and surgical history (prosthesis, cardiac illness,
diabetes, transplant)
 Occupational and Travel history
 Pets
 Contact with ticks, animals
 Diet (Drinking unpasteurised milk)
 History of addiction
 Sexual behaviour (any other high risk behaviour)
 Drug and toxin history
 Immunisation and Immunocompromise

18. History (continued)
 Subtle findings may be elicited through a careful
history. Examples include:
 Subtle changes in behavior consistent with
granulomatous meningitis
 Jaw claudicating consistent with giant cell arteritis.
 Nocturia consistent with prostatitis.
 Revising the history on several occasions may provide
new clues in difficult cases.

19. Physical examination
 The general appearance
 The skin: rash, cutaneous findings of endocarditis
 Perineum and feet
 Spine, bones, joints
 Abdomen
 Thyroid
 Rectal and pelvic examination
 Lymphadenopathy
 Cardiac examination
 Repeated examination may be needed

20. Common signs and symptoms
and associated causes of fever
 Altered mentation—tuberculous meningitis, cryptococcal
meningitis, carcinomatous meningitis, brucellosis, typhoid fever,
sarcoid meningitis
 Arthritis or arthralgia—systemic lupus erythematosus, infective
endocarditis, Lyme disease, Whipple’s disease, brucellosis,
inflammatory bowel disease
 Animal contact—brucellosis, toxoplasmosis, leptospirosis,
Q fever, rat bite fever
 Cough—tuberculosis, Q fever, typhoid fever, sarcoidosis,
Legionnaires’ disease
 Conjunctival suffusion—leptospirosis, relapsing fever, Rocky
Mountain spotted fever
 Epistaxis—Wegener’s granulomatosis, relapsing fever

21.  Epididymo-orchitis—tuberculosis, lymphoma, polyarteritis nodosa,
brucellosis, leptospirosis, infectious mononucleosis
 Hepatomegaly—lymphoma, disseminated tuberculosis, metastatic
carcinoma of liver, alcoholic liver disease, hepatoma, relapsing fever,
granulomatous hepatitis, Q fever, typhoid fever, malaria, visceral
leishmaniasis
 Lymphadenopathy—lymphoma, tuberculosis, infectious
mononucleosis, cytomegalovirus infection, toxoplasmosis, HIV
infection, brucellosis, Whipple’s disease
 Renal angle tenderness—perinephric abscess, chronic pyelonephritis
 Splenomegaly—leukaemia, lymphoma, tuberculosis, brucellosis, sub
acute bacterial endocarditis, cytomegalovirus infection, Epstein-Barr
virus mononucleosis, rheumatoid arthritis, sarcoidosis, relapsing
fever, alcoholic liver disease, typhoid fever,
 Subconjunctival hemorrhage—infective endocarditis, leptospirosis
 Uveitis—tuberculosis, sarcoidosis, adult Still’s disease, systemic lupus
erythematosus, Behcet’s disease

22. A. Laboratory Tests
 CBC, ESR,CRP
 Routine chemistry RFT,LFT,LDH,CPK
 Urinalysis and microscopy
Stool for ova, cyst, parasite
Blood culture (+fungal culture) – three biopsies from different
sites over a period of at least several hours (before A.Bs)
 Study of fluid from joint aspiration, pleural fluid, Ascitic fluid,
CSF (Lumbar puncture), gastric aspirate
 Tuberculin skin test and sputum examination
 Serology for Hepatitis, HIV antibody assay and HIV viral
load for patients at high risk
 Test for CMV, EBV, Q fever
 ANA, ANCA, Rheumatoid factor

23. B. Imaging
 Chest X-Ray
 Sinus X-Ray
 USS abdomen and pelvis
 Abdominal CT
 Useful for looking at the liver, spleen, and retroperitoneum
 Useful to look for abdominal lymphoma and abscess
 Chest CT
 MRI Brain
 Echocardiography

24. C. Biopsy
 Liver Biopsy:
• For possible granulomatous hepatitis or other
granulomatous diseases such as sarcoidosis
• in the work-up for miliary tuberculosis
 Lymph node biopsy: for malignancy, especially
lymphoma, or infections
 Temporal artery biopsy:
• Giant cell arteritis cause of FUO ~16% of patients
• Safe, recommended in elderly with FUO
 Other tissue diagnosis: Bone marrow (miliary TB), skin,
pericardial, pleural (extra-pulmonary TB)

25. Treatment
 Although it is tempting to begin an empiric course of
anti- microbials for FUO, it is rarely helpful and may
delay diagnosis if the etiology is infectious (eg, by
reducing the sensitivity of blood cultures).
 Empiric administration of corticosteroids should be
discouraged because they can suppress fever and
exacerbate many infections.
 Corticosteroids should not replace relevant biopsies
for steroid-responsive disease such as sarcoidosis,
other granulomatous diseases, or vasculitis.
 The appropriate duration of a therapeutic trial is also
unclear since a number of infections such as
endocarditis or pelvic inflammatory disease can take
as much as one week for fever to abate, even with
appropriate therapy.

26. When to Refer
 Any patient with FUO and progressive weight loss
and other constitutional signs.
 Any immunocompromised patient (eg, transplant
recipients and HIV-infected patients).
 Infectious diseases specialists may also be able to
coordinate and interpret specialized testing (eg, Q
fever serologies) with outside agencies, such as the
US Centers for Disease Control and Prevention.

27. When to Admit
 Any patient who is rapidly declining with weight loss
where hospital admission may expedite work-up.
 If FUO is present in immunocompromised patients, such
as those who are neutropenic from recent chemotherapy
or those who have undergone transplantation
(particularly in the previous 6 months).

28. Summary
 Fever of unknown origin (FUO) is defined as fever
higher than 38.3ºC on several occasions lasting for at
least three weeks without an established etiology
despite intensive evaluation and diagnostic testing.
 Three general categories of illness account for the
majority of "classic" FUO cases and have been
consistent through the decades.
 These categories are infections, malignancies, and
collagen vascular diseases.

29. Summary
 The most important aspects of the evaluation of a
patient with FUO are to take a careful history, perform
a detailed physical examination, and to reassess the
patient frequently.
 Diagnostic workup may fail to identify an etiology in
as many as 30 to 50 percent of patients.
 Most adults who remain undiagnosed have a good
prognosis.

30. Thank you