The syndrome of pyrexia of unknown origin (PUO) was first defined in 1961 but remains a clinical challenge for many physicians. Different subgroups with PUO have been suggested, each requiring different investigative strategies: classical, nosocomial, neutropenic, and HIV-related. This could be expanded to include the elderly as a fifth group. The causes are broadly divided into four groups: infective, inflammatory, neoplastic, and miscellaneous. Increasing early use of positron emission tomography–computed tomography (PET-CT) and the development of new molecular and serological tests for infection have improved diagnostic capability, but up to 50% of patients still have no cause found despite adequate investigations. Reassuringly, the cohort of undiagnosed patients has a good prognosis. In this article we review the possible aetiologies of The definition of pyrexia of unknown origin (PUO) dates back to 1961; it was described as a persistent fever above 38.3°C (100°F) that evades diagnosis for at least 3 weeks, including 1 week of investigation in hospital. PUO and present a systematic clinical approach to the investigation and management of patients, recommending potential second-line investigations when the etiology is unclear

1. Fever of Unknown Origin
DR ABU SHURAIH SAKHRI

2. Objectives
• Definition and pathophysiology of fever
• FUO: classifications and etiology
• Diagnostic workup of FUO
• Prognosis

3. Fever versus Hyperthermia
• Fever: resetting of the thermostatic set-point
in the anterior hypothalamus and the
resultant initiation of heat-conserving
mechanisms until the internal temperature
reaches the new level.
• Hyperthermia: an elevation in body
temperature that occurs in the absence of
resetting of the hypothalamic
thermoregulatory center

4. Mechanisms of Hyperthermia and
Associated Conditions
1. Excessive heat production: exertional
hyperthermia, thyrotoxicosis,
pheochromocytoma, cocaine, delerium
tremens, malignant hyperthermia
2. Disorders of heat dissipation: heat stroke,
autonomic dysfunction
3. Disorders of hypothalamic function:
neuroleptic malignant syndrome, CVA,
trauma

5. Wunderlich’s Maxim
• After analyzing >1 million axillary
temperatures from ~25,000 patients,
Wunderlich identified 37.0° C (36.2-37.5) as
the mean temperature in healthy adults.
• Temperature readings >38.0° C were deemed
as “suspicious/probably febrile.”

6. Normal Body Temperature
• For healthy individuals 18 to 40 years of age, the
mean oral temperature is 36.8° ± 0.4°C (98.2° ±
0.7°F)
• Low levels occur at 6 A.M. and higher levels at 4
to 6 P.M.
• The maximum normal oral temperature is 37.2°C
(98.9°F) at 6 A.M. and 37.7°C (99.9°F) at 4 P.M.
• These values define the 99th percentile for
healthy individuals.
Mackowiak, et al., JAMA 1992;268:1578

7. Normal Body Temperature Caveats
• Rectal temperatures are generally 0.4°C
(0.7°F) higher than oral readings.
• Tympanic membrane (TM) values are 0.8°C
(1.6°F) lower than rectal temperatures when
thermometer is in the unadjusted-mode.

8. Mackowiak, P. A. Arch Intern Med 1998;158:1870-1881.
Hypothetical Model for the Febrile Response
Interleukin-1 β and TNF-α play prominent roles
in fever production by stimulating the release of
cyclic AMP from the glial cells and activating
neuronal endings from the thermoregulatory
center that extend into the area.

9. Bacterial Pyrogens
• Lipopolysaccharide (LPS) endotoxin
Endotoxin binds to LPS-binding protein and is transferred to CD14 on
macrophages, which stimulates the release of TNFα.
• Staphylococcus aureus enterotoxins
• Staphylococcus aureus toxic shock syndrome toxin
(TSST)
Both Staphylococcus toxins are superantigens and activate T cells leading
to the release of interleukin (IL)-1, IL-2, TNFα and TNFβ, and interferon
(IFN)-gamma in large amounts
• Group A and B streptococcal toxins
Exotoxins induce human mononuclear cells to synthesize not only TNFα
but also IL1 and IL-6

10. Fever of Unknown Origin
(Historical Definition)
• Fever of at least 3 weeks’ duration
• Temperature of 101° F (38.3° C) on
several occasions
• No diagnosis after a 1 week evaluation in
the hospital
Petersdorf and Beeson Medicine 1961;40:1

11. Historical Causes of FUO
• Hippocrates: excess of yellow bile
• Middle Ages: demonic possession
(encephalitis?)
• 18th Century: Friction associated with the flow
of blood through the vascular system and
from fermentation and putrefaction occurring
in the blood and intestines

12. Categories of FUO
Feature Nosocomial Neutropenic HIV-associated Classic
Patient’s
situation
Hospitalized,
acute care, no
infection when
admitted
Neutrophil count
either <500/µL or
expected to
reach that level in
1-2 days
Confirmed HIV-
positive
All others with
fevers for ≥3
weeks
Duration of
illness while
investigated
3 daysb 3 daysb 3 daysb (or 4
weeks as
outpatient)
3 daysb or 3+
outpatient
visits
Examples Septic
thrombophlebitis,
sinusitis, C.
difficile colitis,
drug fever
Perianal infection,
aspergillosis,
candidemia
MAIc infection,
TB, non-
Hodgkin’s
lymphoma, drug
fever
Infections,
malignancy,
inflammatory
diseases, drug
fever
aAll require temperatures of ≥38.3°C (101°F) on several occasions.
bIncludes at least 2 days’ incubation of microbiology cultures.
cM. avium/M. intracellulare.
Modified from DT Durack, AC Street, in JS Remington, MN Swartz (eds):
Current Clinical Topics in Infectious Diseases. Cambridge, MA, Blackwell, 1991.

13. Etiology of FUO Over a 40 Year Period
Mourad, et al. Arch Intern Med. 2003;163:545

14. Infectious Causes of FUO
• Intraabdominal abscess (liver, splenic, psoas, etc)
• Appendicitis, cholecystitis, tubo-ovarian abscess,
pyometra
• Intracranial abscess, sinusitis, dental abscess
• Chronic pharyngitis, tracheobronchitis, lung abscess
• Septic jugular phlebitis, mycotic aneurysm,
endocarditis, intravenous catheter infection, vascular
graft infection
• Wound infection, osteomyelitis, infected joint
prosthesis, pyelonephritis, prostatitis

15. Infectious Causes of FUO
• Intraabdominal abscess (liver, splenic, psoas, etc)
• Appendicitis, cholecystitis, tubo-ovarian abscess,
pyometra
• Intracranial abscess, sinusitis, dental abscess
• Chronic pharyngitis, tracheobronchitis, lung abscess
• Septic jugular phlebitis, mycotic aneurysm,
endocarditis, intravenous catheter infection, vascular
graft infection
• Wound infection, osteomyelitis, infected joint
prosthesis, pyelonephritis, prostatitis

16. Infectious Causes of FUO
• Intraabdominal abscess (liver, splenic, psoas, etc)
• Appendicitis, cholecystitis, tubo-ovarian abscess,
pyometra
• Intracranial abscess, sinusitis, dental abscess
• Chronic pharyngitis, tracheobronchitis, lung abscess
• Septic jugular phlebitis, mycotic aneurysm,
endocarditis, intravenous catheter infection, vascular
graft infection
• Wound infection, osteomyelitis, infected joint
prosthesis, pyelonephritis, prostatitis

17. Infectious Causes of FUO
• Intraabdominal abscess (liver, splenic, psoas, etc)
• Appendicitis, cholecystitis, tubo-ovarian abscess,
pyometra
• Intracranial abscess, sinusitis, dental abscess
• Chronic pharyngitis, tracheobronchitis, lung abscess
• Septic jugular phlebitis, mycotic aneurysm,
endocarditis, intravenous catheter infection, vascular
graft infection
• Wound infection, osteomyelitis, infected joint
prosthesis, pyelonephritis, prostatitis

18. Infectious Causes of FUO
• Tuberculosis, Mycobacterium avium complex, syphilis, Q
fever, legionellosis
• Salmonellosis (including typhoid fever), listeriosis,
ehrlichiosis,
• Actinomycosis, nocardiosis, Whipple’s disease
• Fungal (candidaemia, cryptococcosis, sporotrichosis,
aspergillosis, mucormycosis, Malassezia furfur)
• Malaria, babesiosis, toxoplasmosis, schistosomiasis,
fascioliasis, toxocariasis, amoebiasis, infected hydatid
cyst, trichinosis, trypanosomiasis
• Cytomegalovirus, HIV, Herpes simplex, Epstein-Barr virus,
parvovirus B19

19. Collagen Vascular Diseases
• Adult Still’s disease, SLE
• Giant cell arteritis/polymyalgia rheumatica,
ankylosing spondylitis
• Wegener’s granulomatosis
• Rheumatic fever
• Polymyositis, rheumatoid arthritis
• Felty’s syndrome, eosinophilic fasciitis

20. Malignancies
• Lymphoma
• Lymphoma
• Lymphoma
• Renal cell carcinoma
• Hepatocellular carcinoma

21. Miscellaneous Causes of FUO
• Complex partial status epilepticus, cerebrovascular
accident, brain tumour, encephalitis
• Drug fever, Sweet’s syndrome, familial
Mediterranean fever
• Gout, pseudogout
• Kawasaki’s syndrome, Kikuchi’s syndrome
• Crohn’s disease, ulcerative colitis, sarcoidosis,
granulomatous hepatitis
• Deep vein thrombosis
• Atelectasis?

22. Drug Fever
• No characteristic fever pattern
was observed.
• Maximum temperatures ranged
from 38°C to 43°C
• The mean lag time between
initiation of a drug and the
onset of fever was 21 days, but
lag times varied considerably.
• Alpha methyldopa and
quinidine were the two drugs
most commonly implicated, but
antimicrobials (as a group) were
responsible for the largest
number of episodes.
Episodes
in Dallas
(n=51)
Episodes
in Lit.
(n=97)
Total
Episodes
(n=148)
n n %
Gender (male/female) 27/18 53/44 56/44
Hx of atopic disease 0 3 2
Previous hx of drug allergy 4 12 11
Fever patterns reported
Continuous
Remittent
Intermittent
Hectic
51
0
19
6
26
41
9
7
13
12
62
10
28
21
41
Rigors 26 52 53
Relative bradycardia 5 4 11
Hypotension 6 21 18
Rash
Pruritus
20
11
6
0
18
7
Leukocytosis (>10K) 11 0 7
Eosinophilia (>300/mm3) 21 12 22
Hematologic 1 12 9
Deaths 2 4 4
Mackowiak and LeMaistre Ann Intern Med 1987;106:728

23. Minimal Initial Diagnostic Workup For FUO
Comprehensive history
• Physical examination
• CBC + differential
• Blood film reviewed by hematopathologist
• Routine blood chemistry
• UA and microscopy
• Blood (x 3) and urine cultures
• Antinuclear antibodies, rheumatoid factor
• HIV antibody
• CMV IgM antibodies; heterophile antibody test (if c/w mono-like
syndrome)
• Q-fever serology (if risk factors)
• Chest radiography
• Hepatitis serology (if abnormal LFTs)
Mourad, et al. Arch Intern Med. 2003;163:545

24. Liver Biopsy and Bone Marrow Biopsy
• Diagnostic yield of liver
biopsy has ranged from 14%
to 17%.
• Physical exam finding of
hepatomegaly or abnormal
liver profile are not helpful
in predicting abnormal
biopsy result.
• Complication rate is 0.06%
to 0.32%
• The diagnostic yield of bone
marrow cultures in
immunocompetent
individuals has been found
to be 0% to 2%1,2
Mourand et al. Arch Intern Med 2003;163:545
1Volk et al. J Clin Pathol 1998;110:150
2Riley et al. J Clin Pathol 1995:48:706

25. Diagnostic Value of Naproxen
• 77 patients presenting
with FUO were treated
with naproxen.
• Overall temperature
decreased from 39.1°C
to 37.4°C.
• The sensitivity of the
naproxen test for
neoplastive fever was
55% and the specificity
was 62%.
Vanderschueren, et al. Am J Med 2003;115:572

26. Copyright restrictions may apply.
Mourad, O. et al. Arch Intern Med 2003;163:545-551.
Proposed Approach to FUO
Mourad, et al. Arch Intern Med. 2003;163:545

27. Approach to Fever in the ICU

28. 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.

29. Summary
• FUO is often a diagnostic dilemma
• 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

30. THANK YOU