FEVER OF UNKNOWN ORIGIN (PUO)- APPROACH
- 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
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