FEVER OF UNKNOWN ORIGIN

Question 1

FUO is now defined as

Answer 1

1. Fever ≥38.3C (≥101 F) on at least two occasions
   
   2. Illness duration of ≥3 weeks
   3. No known immunocompromised state
   4. Diagnosis that remains uncertain after a thorough history-taking, physical examination, and the obligatory investigations
      • ESR and CRP
      • CBC
      • electrolytes, creatinine
      • total protein
      • AST, ALT, Alk phos
      • lactate dehydrogenase
      • creatine kinase
      • ferritin
      • ANA and RF
      • protein electrophoresis
      • urinalysis
      • blood cultures (n = 3)
      • urine culture
      • chest x-ray
      • abdominal ultrasonography
      • TST or IGRA

Question 2

Up to half of all infections in patients with FUO outside Western nations are caused by ____________

Answer 2

M. tuberculosis

Question 3

The most common diagnosis of FUO among the neoplasms

Answer 3

Malignant lymphoma

Question 4

Fever artificially induced by the patient—for example, by IV injection of contaminated water

Answer 4

Factitious fever

Question 5

Is the term when the patient is normothermic but manipulates the thermometer

Answer 5

Fraudulent fever

Question 6

TRUE OR FALSE: FUO in the elderly results from an atypical manifestation of a common disease

Answer 6

TRUE

• FUO in the elderly results from an atypical manifestation of a common disease, among which giant cell arteritis and polymyalgia rheumatica are most frequently involved

Question 7

The most common infectious disease associated with FUO in elderly patients

Answer 7

Tuberculosis

Question 8

TRUE OR FALSE: Performing more than three blood cultures or more than one urine culture is useless in patients with FUO in the absence of PDCs

Answer 8

TRUE

• Repeating blood or urine cultures is useful only when previously cultured samples were collected during antibiotic treatment or within 1 week after its discontinuation

Question 9

TRUE OR FALSE: Patients should be asked to return during a febrile episode so that the history, physical examination, and laboratory tests can be repeated during a symptomatic phase

Answer 9

TRUE

• In patients with recurrent fever lasting >2 years, it is very unlikely that the fever is caused by infection or malignancy.

Question 10

TRUE OR FALSE: Empirical therapeutic trials with antibiotics, glucocorticoids, or antituberculous agents should be avoided in FUO except when a patient’s condition is rapidly deteriorating

Answer 10

TRUE

• Antibiotic or antituberculous therapy may irrevocably diminish the ability to culture fastidious bacteria or mycobacteria

Question 11

When to initiate empiric antibiotic treatment in patients with FUO?

Answer 11

Hemodynamic instability or neutropenia is a good indication for empirical antibiotic therapy

Question 12

When to start a trial of therapy for tuberculosis?

Answer 12

If TST or IGRA is positive or if granulomatous disease is present with anergy and sarcoidosis seems unlikely

• If the fever does not respond after 6 weeks of empirical antituberculous treatment, another diagnosis should be considered.

Question 13

TRUE OR FALSE: In patients in whom FUO remains unexplained, prognosis is favorable

Answer 13

TRUE

• FUO-related mortality rates have continuously declined over recent decades
• the risk of death related to FUO is dependent on the underlying disease

Question 14

A trial of what drug can be considered in patients whose FUO has not been diagnosed after later-stage diagnostic tests

Answer 14

Therapeutic trials with ANAKINRA can be considered in patients whose FUO has not been diagnosed after later-stage diagnostic tests

• Anakinra, a recombinant form of the naturally occurring IL-1 receptor antagonist (IL-1Ra), blocks the activity of both IL-1α and IL-1β.

Question 15

Characterized by urticaria, bone pain, and monoclonal gammopathy

Answer 15

Schnitzler syndrome

Question 16

The most important step in the diagnostic workup in patients with FUO?

Answer 16

The search for potentially diagnostic clues (PDCs) through complete and repeated history-taking and physical examination and the obligatory investigations

Question 17

Which of the following criteria is NOT part of the current definition of Fever of Unknown Origin (FUO)?
A) Fever ≥38.3°C (≥101°F) on at least two occasions
B) Illness duration of ≥3 weeks
C) Presence of immunosuppression
D) Diagnosis remains uncertain after obligatory investigations

Answer 17

Correct Answer: C) Presence of immunosuppression
Rationale: FUO is defined in patients without a known immunocompromised state. Immunocompromised patients have a different classification of FUO (e.g., neutropenic FUO).

Question 18

In non-Western nations, which infectious disease is the most common cause of FUO?
A) Malaria
B) Dengue fever
C) Mycobacterium tuberculosis
D) Brucellosis

Answer 18

Correct Answer: C) Mycobacterium tuberculosis
Rationale: Up to half of FUO cases in non-Western nations are caused by Mycobacterium tuberculosis, making it the leading infectious etiology in these regions.

Question 19

Which of the following is the most common neoplastic cause of FUO?
A) Pancreatic cancer
B) Malignant lymphoma
C) Hepatocellular carcinoma
D) Lung cancer

Answer 19

Correct Answer: B) Malignant lymphoma
Rationale: Malignant lymphoma is the most frequent neoplastic cause of FUO due to its ability to produce cytokines that contribute to prolonged fever.

Question 20

Which condition is characterized by urticaria, bone pain, and monoclonal gammopathy in patients with FUO?
A) Adult-onset Still’s disease
B) Schnitzler syndrome
C) Polymyalgia rheumatica
D) Familial Mediterranean fever

Answer 20

Correct Answer: B) Schnitzler syndrome
Rationale: Schnitzler syndrome is associated with urticaria, bone pain, and monoclonal gammopathy and should be considered in FUO cases with these features.

Question 21

Which of the following drugs is NOT commonly associated with drug-induced fever?
A) Vancomycin
B) Phenytoin
C) Ibuprofen
D) Allopurinol

Answer 21

Correct Answer: C) Ibuprofen
Rationale: While NSAIDs can cause hypersensitivity reactions, ibuprofen is not a common cause of drug-induced fever compared to medications like vancomycin, phenytoin, and allopurinol.

Question 22

Which of the following is TRUE regarding factitious and fraudulent fever?
A) Factitious fever is caused by external infections
B) Fraudulent fever involves artificially inducing fever using an infectious agent
C) Factitious fever is more common in young women in healthcare professions
D) Fraudulent fever is more common in elderly men

Answer 22

Correct Answer: C) Factitious fever is more common in young women in healthcare professions
Rationale: Factitious fever is artificially induced by the patient, often seen in young women in healthcare settings. Fraudulent fever involves thermometer manipulation rather than actual fever.

Question 23

What is the first-line imaging modality for FUO workup?
A) Chest X-ray
B) Abdominal ultrasound
C) MRI
D) PET/CT

Answer 23

Correct Answer: B) Abdominal ultrasound
Rationale: Abdominal ultrasound is preferred over CT in the initial FUO workup due to its lower cost, lack of radiation, and absence of side effects.

Question 24

Which test is included in the obligatory FUO workup to screen for tuberculosis?
A) Sputum culture
B) Tuberculin skin test (TST) or interferon-gamma release assay (IGRA)
C) Chest CT
D) Bronchoscopy

Answer 24

Correct Answer: B) Tuberculin skin test (TST) or interferon-gamma release assay (IGRA)
Rationale: TST or IGRA is part of the standard FUO workup to detect latent or active tuberculosis, though false negatives can occur in immunosuppressed patients.

Question 25

What is the role of 18F-FDG PET/CT in the FUO diagnostic approach?
A) Differentiates between infection and malignancy
B) Useful in detecting low-grade infections and vasculitis
C) Replaces the need for lymph node biopsy
D) Detects viral infections

Answer 25

Correct Answer: B) Useful in detecting low-grade infections and vasculitis
Rationale: FDG-PET/CT is effective in identifying chronic infections, vasculitis, and malignancies, but it cannot differentiate between infection, sterile inflammation, and malignancy.

Question 26

When should empirical antibiotic or antituberculous therapy be considered in FUO?
A) As soon as FUO is diagnosed
B) Only if the patient has neutropenia or hemodynamic instability
C) If fever persists for more than 2 weeks
D) Empirical treatment should always be started before investigations

Answer 26

Correct Answer: B) Only if the patient has neutropenia or hemodynamic instability
Rationale: Empirical therapy should be avoided unless the patient is neutropenic or hemodynamically unstable, as it can obscure diagnostic clues.

Question 27

Studies of FUO have shown that a definitive cause is more likely to be found in which age group?
A) Infants
B) Young adults
C) Elderly patients
D) Adolescents

Answer 27

Correct Answer: C) Elderly patients
Rationale: Studies indicate that a cause for FUO is more frequently identified in elderly patients than in younger individuals. This is due to the atypical presentation of common diseases in older adults.

Question 28

Among elderly patients with FUO, which infectious disease is most commonly responsible?
A) Brucellosis
B) Tuberculosis
C) Infective endocarditis
D) Lyme disease

Answer 28

Correct Answer: B) Tuberculosis
Rationale: Tuberculosis is the most common infectious disease causing FUO in elderly individuals, often presenting with atypical or extrapulmonary manifestations.

Question 29

What is the first step in evaluating a patient with fever of unknown origin (FUO)?
A) Start empirical antibiotic treatment
B) Conduct PET/CT imaging
C) Perform history and physical examination
D) Order a temporal artery biopsy

Answer 29

Correct Answer: C) Perform history and physical examination
Rationale: A thorough history and physical examination is the most important first step in evaluating FUO to identify potentially diagnostic clues (PDCs).