Fever of Unknown Origin

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

5. What is the normal human body temperature? A. 37.5° C B. 98.6° F C. 340.15 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. 340.15 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 (36.2-37.5) 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 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;158:1870-1881.

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. 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

24. Malignancies • Lymphoma • Lymphoma • 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?

26. 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. 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. 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 Liver Biopsy and Bone Marrow Biopsy 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. 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%. Diagnostic Value of Naproxen Vanderschueren, et al. Am J Med 2003;115:572

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

31. Approach to Fever in the ICU Marik, P. E. Chest 2000;117:855-869

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