Fevers of unknown origin (FUO)

With increasing duration of fever of unknown origin, decreases the probability that it is caused by an infection
Non-fever
1. Most frequently found in young women
2. It does not exceed 37.5° (axillary measurement)
3. No pathological significance, with physiological accentuation of the physiological circadian rhythm
Triggered fever
1. Frequently observed in children or adolescents of both sexes
2. Found in individuals with special behavioral characteristics such as hypersensitivity, fragility, but also cunning and temerity
3. Motivating factor is usually a difficult moment in school or family
Fever of unknown origin (FUO)
1. Definition
  1. Temperature > 38.3°C
  2. Fever lasting > 3 weeks
  3. Failure of any attempt to justify the diagnosis of febrile symptoms after a week research hospital
2. Causes
  1. Infectious
    1. Extrapulmonary tuberculosis
    2. Malaria
    3. Mononucleosic syndromes
    4. Endocarditis
    5. Fungal infections
  2. Non infectious
    1. Hematologic malignancies
    2. Solid tumors
    3. Immunological diseases
    4. Granulomatous diseases
    5. Extensive tissue necrosis with resorption of pyrogenic substances (heart attacks, pulmonary thromboembolism)
    6. Hemorrhage
    7. Hemolysis
    8. Replacement diseases and metabolic diseases
    9. Endocrinopathies
    10. Hypersensitivity to drugs
    11. Direct, local stimulation, of the thermoregulatory centers (eg. tumor or cerebral hemorrhage)
3. The most useful and fast criterion is the anamnesis, with the search and evaluation of the symptomatology, followed by the 1st level examinations
4. Classification
  1. Classical
    1. T > 38.3°
    2. Duration of > 3 wk
    3. Evaluation of ≥ 3 visits or 3 d in hospital
    4. Leading causes
      1. Cancer
      2. Infections
      3. Inflammatory conditions
      4. Undiagnosed
  2. Nosocomial
    1. Leading causes
      1. Nosocomial infections (e.g. from C. difficile)
      2. Postoperative complications
      3. Drug-induced fever
      4. Deep vein thrombosis (DVT)
    2. Characteristics
      1. T > 38.3°
      2. Patient hospitalized ≥ 24h, fever not present or incubating on admission
      3. Evaluation of at least 3 d
  3. Neutropenic (immune deficient)
    1. Common agents involved
      1. Bacteria
      2. Fungi (Candida and Aspergillus)
    2. Characteristics
      1. T > 38.3°
      2. Absolute neutrophil count ≤ 500 per mm3
      3. Evaluation of at least 3 d
  4. HIV associated
    1. Causes
      1. Majority due to opportunistic infections
        Mycobacteria, CMV, toxoplasma, Pneumocystis jirovecii, Cryptococcus
      2. Tumors
      3. IRIS
      4. HIV infection itself
        Characterized by fever, rash and lymphadenopathy in 40-70% of patients
    2. Fever is either continuous or recurrent
    3. The use of HAART has reduced the incidence of HIV-associated FUO
    4. Characteristics
      1. T > 38.3°
      2. Duration of > 4 wk for outpatients, > 3 d for inpatients
      3. HIV infection confirmed
5. Opportunistic infections
  1. The relative frequency of each cause of FUO is influenced by many factors, such as:
    1. Counts of CD4+
    2. Viral load
    3. Geographical context and local prevalence of certain infectious agents
6. Diagnosis
  1. Anamnesis
    1. At first you should exclude the 3 minor causes of FUO
      1. Factitious fever: assess the fever personally
      2. Usual hypertermia: establish an appropriate thermal curve
      3. Drug-induced fever
  2. Physical evaluation
    1. Associated symptoms
      1. Fever + rash: Rickettsial, borreliosis
      2. Fever + jaundice: hepatitis, colangitis
      3. Fever + lymphadenopathy: HIV, EBV, CMV, lymphoma
      4. Fever + diarrhea: HIV, intestinal parasites
      5. Fever + urinary frequency/dysuria/stranguria: UTI
      6. Fever + pain: localized abscess
      7. Fever + pathological pulmonary examination: TB
      8. Fever + localized or diffuse myoarthralgias: borreliosis
    2. Fundoscopical evaluation
      1. Infectious endocarditis
      2. HIV (HIV retinopathy)
      3. CMV (CMV retinitis is the most common retinal infection in patients with advanced HIV infection)
      4. Toxoplasmosis
      5. Cryptococcosis
    3. Skin lesions or mucous membrane lesions
    4. Abnormal masses
    5. Enlarged masses
    6. Painful points
  3. Lab and instrumental examinations
    1. First-level exams
      1. Blood count with formula
      2. Study of lymphocyte subsets (CD4+, CD8+)
      3. Standard urinalysis (with evaluation of the sediment)
      4. Inflammatory indices
      5. Markers of organ function
      6. Indicators of immunologic disorders
      7. Multi-test Merieux
      8. QuantiFERON, Mantoux test with tuberculin PPD
      9. Cultures and serological tests
      10. Full serology for hepatitis virus infection
    2. Second-level exams
    3. Third-level exams (invasive)
      1. Biopsies
      2. Endoscopy (gastroscopy, colonoscopy, broncos copy with BAL)
      3. Exploratory laparoscopy
  4. Ex adiuvantibus diagnosis
Evaluation of the type of fever
1. Malaria: rarely typical with prophylaxis
2. Cyclic neutropenia
  1. Fever and neutropenia every 21 days
3. Horgkin's disease
4. Familial Mediterranean fever (FMF)
  1. Familiarity, association with sierositis

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Fevers of unknown origin (FUO)

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