Fever of unknown origin (FUO)
Definition
FUO was defined by Petersdorf and Beeson in 1961
1. Temperatures>38.3oConseveraloccasions
2. Adurationoffeverof>3weeks
3. Failuretoreachadiagnosisdespite1weekof inpatient investigation
Classification
1. Classic FUO
Definition
1) Temperaturesof>38.3°Conseveraloccasions;
2) Adurationoffeverof>3weeks;
3) Failuretoreachadiagnosisdespite:3outpatient visits or 3 days in the hospital
without elucidation of a cause or 1 week of ‘intelligent and invasive’ ambulatory investigation
Causes
1) Infections (localized pyogenic infections, systemic bacterial infections, intravascular infections...)
2) Neoplasms (malignant, benign)
3) Collagen vascular/Hypersensitivity Diseases
4) Miscellaneous Conditions
5) Others
Granulomatous Diseases
Habitual Hyperthermia
Inherited and Metabolic Diseases
Thermoregulatory Disorders
Factitous Fevers
• Common infectious causes of FUO
- Unrecognized abscess (ex:abdominal,perinephric)
- Endocarditis– less common than in past! (ex: HACEK, Bartonella, Aspergillus, Coxiella...)
- Tuberculosis
- Histoplasmosis
- Osteomyelitis
• Common connective tissue causes of FUO
- Adult Still’s disease (Fever, rash, arthritis)
- Rheumatoid Arthritis (RA)
- Systemic Lupus Erythematosus (SLE)
- Temporal Arteritis (>50 years old, headache, symptoms of PMR, high ESR)
- Polymyalgia Rheumatica (PMR)
• Common malignacies causes of FUO
- Lymphoma (most common cause)
- Leukemia
- Tumors metastatic to the liver
- Renal cell carcinoma
• Miscellaneous causes of FUO
- Factitious Fever (ex: Fraudulent vs. Self-induced)
- Drug fever (ex: Antibiotics, Antihistamines, NSAIDS)
- Familial fever syndromes
- Hemophagocytic syndrome
- Inflammatory Bowel Disease (IBD)
- Pheochromocytoma
- Pulmonary embolism (PE)
- Thrombotic Thrombocytopenic Purpura (TTP)
- Thyroiditis
As the duration of fever increases, the likelihood of an infectious cause decreases.
2. Nosocomial FUO
1) A temperature of >= 38.3℃ develops on several occasions in a hospitalized patient
who is receiving acute care and in whom infection was not manifest or incubating on admission
2) Three days of investigation, including at least 2 days’ incubation of cultures,
is the minimum requirement for this diagnosis
3) Patients who have a fever start after at least 24 hours of hospitalization
Etiologies include
- Drug fever
- Nosocomial infections
- Post operative complications
- Central fever (stroke)
Nosocomial FUO Diagnosis
- Consider underlying individual susceptibility of the patient with the potential complications of hospitalization
- More than 50% of patients with nosocomial FUO are infected
- Look for infected foreign bodies, abscesses and hematomas
- Check sites where occult infections may be sequestrated, such as paranasal sinuses of intubated patients
or a prostatitis in a man with a urinary catheter
- C.difficile colitis may be associated with fever and leukocytosis before the onset of diarrhea.
- In 25% of patients with nosocomial FUO, the fever has a noninfectious cause (eg. acalculous cholecystitis, deep-vein thrombophlebitis, pulmonary embolism etc.).
- Consider : drug fever, transfusion reactions, alcohol/drug withdrawal, adrenal insufficiency
- Multiple blood, wound, fluid cultures are mandatory
- Advanced radiological imaging
- IV lines must be changed and cultured, suspected drugs stopped for 72 hours
- 20% of nosocomial FUO may go undiagnosed
Nosocomial FUO Treatment
- empirical therapy started if bacteriemia, fungemia, persistently high virus load are a threat
- empirical antibiotic therapy includes vancomycin (MRSA) + broad spectrum gram negative coverage with piperacyllin/tazobactam, imipenem or meropenem
3. Neutropenic FUO
1) A temperature of ≥ 38.3 °C on several occasions;
2) In a patient whose neutrophil count is <500/uL or is expected to fall to that level in 1-2 days;
3) A diagnosis is invoked if a specific cause is not identified after 3 days of investigation, including at least 2 days’ incubation of cultures.
Febrile neutropenic patients receive empiric courses of broad spectrum antibiotics and often antifungal agents. ex. vancomycin + ceftazidime/cefepime or carbapenem +/- aminogycoside
- Neutropenic patients are susceptible to focal bacterial and fungal infections, bacteriemic infections, infections involving catheters
- Candida and Aspergillus infections are common
- 50-60% of febrile, neutropenic patients are infected and 20% are bacteriemic
4. HIV-associated FUO
1) A temperature of >=38,3 ° on several occasions over a period of > 4 weeks for outpatients or> 3 days for hospitalized patients with HIV infection
2) This diagnosis is invoked if appropriate investigation over 3 days,
including 2 days’ incubation of cultures, reveals no source
• HIV infection alone may be a cause of fever (e.g. acute retroviral disease)
• FUO in HIV patients has an infectious etiology in > 80% of cases
• drug fever and lymphoma remain important considerations
Under such circumstances, debilitating symptoms are treated with NSAIDs and glucocorticoids are the LAST resort
Common causes of HIV-Related FUO
- Mycobacterial disease
- Pneumocystosis (PCP)
- Cytomegalovirus (CMV)
- Histoplasmosis
- Lymphoma
- Drug fever
Evaluation of FUO
1. Comprehensive history
Localizing symptoms? Workplace? Pets? Recent travel? History of connective tissue disease (CTD)? History of cancer/immunosuppression? Medications? Drug use? Familial fever syndromes?
2. Comprehensive physical examination
including: temporal arteries, rectal digital examination, sinus tenderness, listen for murmur, look for stigmata of endocarditis, splenomegaly, hepatomegaly, etc.
3. Routine blood tests
complete blood count including differential, CRP, PCT, ESR (erythrocyte sedimentation rate)
electrolytes, renal and hepatic tests, creatine phosphokinase, lactate dehydrogenase
4. Microscopic urinalysis (luekocyturia, dysmorphic erytrocytes, protein)
5. Cultures of blood, urine and other normally sterile compartments
if clinically indicated, e.g. joints, pleura, cerebrospinal fluid
6. Chest radiograph
7. Abdominal (including pelvic) ultrasonography
8. Autoantibodies
ANA, ANCA, Reuma factor, etc.
9. Serological tests
HIV, HBV, HCV, CMV, EBV serology, and others directed by local epidemiological data
10. Advanced radiological imaging
CT, MRI, positron emission tomography (PET) to detect localised infections and occult neoplasms
11. Bone marrow biopsy
12. Thick blood smears should be examined for Plasmodium – if malaria suspected
13. Thin blood smears to identify Babesia, Trypanosoma, Leishmania, Leptospira in patients with specific history
14. Lymphnode or liver biopsy
15. Peritoneal lavage
16. Laparoscopic biopsy
17. Exploratory laparotomy
References
Harrison Internal medicion
Uptodate
PubMed
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