1. Fever of Unknown Origin
Bryan Youree
Vanderbilt University Medical Center

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
For DTs, GABA (inhibitory neurotransmitter) receptors are down regulated and its neuronal activity decreased in alcohol withdrawal. In addition, norepinephrine is increased do to decreased alpha-2 inhibition of its release. Both contribute to hyperarousal.
NMS is believed to result from central nervous system dopamine receptor blockade. Hyperthermia results from increased myocyte metabolic activity and altered hypothalamic thermoregulation.

5. What is the normal human body temperature?
A. 37.5° C
B. 98.6° F
C K
D. Each human being is a unique individual, and therefore, normal temperature cannot be defined.

6. What is the normal human body temperature?
A. 37.6° C
B. 98.6° F
C K
D. Each human being is a unique individual, and therefore, normal temperature cannot be defined.

7. Wunderlich’s Maxim
After analyzing >1 million axillary temperatures from ~25,000 patients, Wunderlich identified 37.0° C ( ) as the mean temperature in healthy adults.
Temperature readings >38.0° C were deemed as “suspicious/probably febrile.”
1Wunderlich C. Das Verhalten der Eiaenwarme in Krankenheiten.
Leipzig, Germany: Otto Wigard;1868.
2Mackowiak, et al., JAMA 1992;268:1578

8. 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

9. 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.

10. How does fever occur? A. Build up of evil humors B. IL-1 and IL-6
C. TNF
D. Disruption of the medulla oblongata
E. A and D
F. B and C

11. How does fever occur? A. Build up of evil humors B. IL-1 and IL-6
C. TNF
D. Disruption of the medulla oblongata
E. A and D
F. B and C

12. Hypothetical Model for the Febrile Response
Sagittal view of the brain and upper spinal cord showing the multisynaptic pathway of skin and spinal thermoreceptors through the spinothalamic tract (STt) and reticular formation (RF) to the anterior hypothalamus, preoptic region, and the septum
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.
Mackowiak, P. A. Arch Intern Med 1998;158:

13. 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

14. 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

15. 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

16. Categories of FUO Patient’s situation
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 (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.

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

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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
Felty's syndrome (FS) is an uncommon but severe subset of seropositive rheumatoid arthritis (RA) complicated by granulocytopenia and splenomegaly (90%).

24. Malignancies
Lymphoma
Renal cell carcinoma
Hepatocellular carcinoma

25. 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?
However, Engeron76 studied 100 postoperative cardiac surgery patients and was unable to demonstrate a relationship between atelectasis and fever. Furthermore, when atelectasis is induced in experimental animals by ligation of a mainstem bronchus, fever does not occur However, Kisala and coworkers79 demonstrated that IL-1 and TNF- levels of macrophage cultures from atelectatic lungs were significantly increased compared with the control lungs. The role of atelectasis as a cause of fever is unclear; however, atelectasis probably does not cause fever in the absence of pulmonary infection.
76. Engoren, M (1995) Lack of association between atelectasis and fever. Chest 107,81-84[Abstract]
77. Shields, RT (1949) Pathogenesis of postoperative pulmonary atelectasis an experimental study. Arch Surg 48,
78. Lansing, AM (1963) Mechanism of fever in pulmonary atelectasis. Arch Surg 87, [ISI]
79. Kisala, JM, Ayala, A, Stephan, RN, et al (1993) A model of pulmonary atelectasis in rats: activation of alveolar macrophage and cytokine release. Am J Physiol 264(3 Pt 2),R610-R614[Abstract/Free Full Text]

26. Episodes in Dallas (n=51)
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 %
Gender (male/female)
27/18
53/44
56/44
Hx of atopic disease 3 2
Previous hx of drug allergy 4 12 11
Fever patterns reported
Continuous
Remittent
Intermittent
Hectic 51 19 6 26 41 9 7 13 62 10 28 21
Rigors 52 53
Relative bradycardia 5
Hypotension 18
Rash
Pruritus 20
Leukocytosis (>10K)
Eosinophilia (>300/mm3) 22
Hematologic 1
Deaths
Mackowiak and LeMaistre Ann Intern Med 1987;106:728

27. 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

28. 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
1Volk et al. J Clin Pathol 1998;110:150
2Riley et al. J Clin Pathol 1995:48:706
Mourand et al. Arch Intern Med 2003;163:545

29. 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

30. Proposed Approach to FUO
Mourad, O. et al. Arch Intern Med 2003;163:
Mourad, et al. Arch Intern Med. 2003;163:545
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31. Approach to Fever in the ICU
Marik, P. E. Chest 2000;117:

32. 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.
Larson et al. Medicine 1982;61:269

33. 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