Fever of unknown origin (FUO) is a very common term used by clinicians to refer to any febrile illness without an initial obvious etiology.
- Most febrile illnesses either resolve before a diagnosis can be made or eventually show typical clinical features or positive for specific investigations that lead to arrive at a correct diagnosis. These group of febrile illnesses are not called as FUO
- The term FUO is reserved only for prolonged febrile illnesses without an established etiology despite of intensive evaluation and diagnostic testing.
Definitions
With the advent of modern diagnostic tools, the definition of FUO has changed over time.
Petersdorf and Beeson had defined fever of unknown origin (FUO) in 1961 as patients having:
- Temperatures of more than 38.3°C (more than 101°F) at least on two occasions
- For a duration of more than 3 weeks
- Failure to reach a diagnosis despite 1 week of inpatient investigation.
This traditional definition has been modified from time to time.
- In recent days, patients with FUO undergo various investigations in outpatient department and are hospitalized only if their clinical condition warrants. Thus the in-patient evaluation requirement has been eliminated from the definition
- As in immunocompromised patients, the diagnostic workup requires an entirely different and extensive list of investigations, they were excluded from the FUO definition
- The diagnostic workup (investigation) criteria has been changed from quantitative criterion (diagnosis uncertain after 1 week of evaluation) to a qualitative criterion which requires the performance of a specific list of investigations before labeling a case as FUO. This will help in optimal comparison of patients with FUO from different geographic areas.
The Current Definition of FUO
Accordingly, FUO is now defined as follows:
1. Fever ≥38.3°C (≥101°F) on at least two occasions
2. Duration of illness of ≥3 weeks
3. No known immunocompromised state
4. Diagnosis that remains uncertain after a thorough history-taking, physical examination, and the following obligatory investigations:
- ESR and CRP (C-reactive protein) level
- Platelet count, leukocyte count (total and differential), and hemoglobin
- Electrolytes, creatinine, total protein, ferritin and protein electrophoresis
- Enzymes such as alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, creatine kinase
- Antinuclear antibodies, and rheumatoid factor
- Urinalysis Culture: blood cultures (3 negative cultures) and urine culture
- Radiology: Chest X-ray, abdominal USG
- Tuberculin skin test or interferon γ release assay.
Etiology of FUO
FUO has both infectious and non-infectious etiology.
- Infections (36%): This accounts for majority of FUO cases. All groups of microbial infections (both localized and systemic) can cause FUO (Table 1)
- Neoplasms (19%): For example, lymphoma, leukemia, myeloma, renal, colon and liver cancers, etc. Non-infectious
- Inflammatory Diseases (19%): For example, connective tissue disorders like rheumatoid arthritis, SLE (systemic lupus erythematosus), etc.
- Miscellaneous Causes (19%): Granulomatous diseases Inherited and metabolic diseases Thermoregulatory disorders.
- Undiagnosed cases (7%).
Table1. Infectious causes of fever of unknown origin.
laboratory Diagnosis
Specimen Collection
Prior to specimen collection, a complete clinical history (including details of travel, immunization, exposure to any other patients) and physical examination should be carried out that may be helpful in choosing the appropriate specimen such as blood, urine, bone marrow aspirate, pus from abscesses, etc.
Microscopy
Blood microscopy: Useful for detection of malaria parasites (ring forms and gametocytes), filarial nematodes (microfilariae), Leishmania donovani (LD bodies or amastigote forms), Toxoplasma (tachyzoites) and trypanosomes (trypomastigote forms)
- Stool wet mount: For the detection of cyst, trophozoite or ova of a parasitic agent causing FUO (e.g. Entamoeba histolytica)
- Gram stain of pus, sputum and other specimens can be carried out for detection of the causative agent
- Ziehl-Neelsen stain for M. tuberculosis.
- Periodic acid-schiff (PAS) or Gomori methenamine silver (GMS) stain for the detection of fungal morphology.
Culture
- Blood culture is done for typhoid fever, brucellosis
- Culture on Lowenstein Jensen medium is done for M. tuberculosis
- Culture of pus and exudate specimen from the abscesses: for the detection of the causative agent
- Sabouraud dextrose agar (SDA) culture: For fungal isolation
- Cell line culture: Culture in appropriate cell lines is useful for the isolation of virus, e.g. human diploid cell line for cytomegalovirus (CMV).
Serological Tests
- ELISA and rapid tests for viral diseases such as hepatitis B and C, HIV, CMV, EBV infections, etc.
- Standard agglutination test: For brucellosis
- Microscopic agglutination test: For leptospirosis
- Cold agglutination test: For Mycoplasma
- Weil Felix test: For rickettsial diseases
- Paul-Bunnell test: For infectious mononucleosis
- Widal test: For typhoid fever
- Microimmunofluorescence test for chlamydial infections
- Rheumatoid arthritis (RA) factor: For rheumatoid arthritis
- Antinuclear antibody detection by immunofluorescence or ELISA for diagnosis of SLE.
Molecular Tests
If the infective organism load is very low, PCR can be very useful as it amplifies the specific gene. Multiplex PCR can be carried out which can simultaneously detect the common etiological agents of bloodstream infections.
Other Tests
- Complete blood count: Increased neutrophil count indicates pyogenic infections
- Raised ESR (erythrocyte sedimentation rate) Histopathological examinations of the biopsies obtained from tumors may suggest the underlying etiology
- Imaging methods: Chest X-ray (for diagnosis of tuberculosis) and CT or MRI scan to identify the malignant tumors and their extension
- ECG and echocardiography for rheumatic fever and infective endocarditis.
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