FEVER OF UNKNOWN ORIGIN

DR. JUAN CARLOS BECERRA MARTÍNEZ

CÁTEDRA DE MEDICINA INTERNA-MC3087

TECNOLÓGICO DE MONTERREY, CAMPUS GUADALAJARA

Definition and Classification Fever of unknown origin (FUO):

Was defined by Petersdorf and Beeson in 1961 as:○ 1.- Temperatures of >38.3°C○ 2.- A duration of fever of >3 weeks○ 3.- Failure to reach a diagnosis despite 1 week of inpatient

investigation.

Durack and Street have proposed a revised classification: 1.- Classic FUO 2.- Nosocomial FUO 3.- Neutropenic FUO 4.- FUO associated with HIV infection.

Harrison’s 18th Ed.

Definition and Classification Classic FUO:

This newer definition is broader, stipulating three outpatient visits or 3 days in the hospital without elucidation of a cause or 1 week of "intelligent and invasive" ambulatory investigation.

Harrison’s 18th Ed.

Definition and Classification Nosocomial FUO:

Fever >38.3°C develops on several occasions in a hospitalized patient who is receiving acute care and in whom infection was not manifest on admission.

3 days of investigation and including at least 2 days’ incubation of cultures.

Harrison’s 18th Ed.

Definition and Classification Neutropenic FUO:

Temperature >38.3°CNeutrophil count <500/ml3 days of investigation2 days’ incubation of cultures

Harrison’s 18th Ed.

Definition and Classification HIV-associated FUO:

Fever >38.3°C>4 weeks for outpatients or >3 days for

hospitalized patientsHIV infectionAppropriate investigation over 3 days, including 2

days’ incubation of cultures.

Harrison’s 18th Ed.

Classic FUO in Adults

Harrison’s 18th Ed.

Classic FUO in Adults Infections:

Is the #1 cause of Classic FUO Tuberculosis, typhoid fever and malaria remain a leading diagnosable cause of

FUO. Others:

○ CMV, EBV, HIV○ Intraabdominal abscesses ○ Osteomyelitis○ Endocarditis○ Prostatitis, dental abscesses, sinusitis, and cholangitis ○ Fungal diseases: histoplasmosis, paracoccidioidomycosis and coccidioidomycosis○ Chikungunya virus○ Cryptococcus neoformans○ Plasmodium○ Babesiosis

Harrison’s 18th Ed.

Classic FUO in Adults Neoplasms:

Are the next most common cause of FUO after infections

Noninfectious inflammatory diseases:Systemic rheumatologic or vasculitic diseases:

○ Polymyalgia rheumatica, lupus, and adult Still's disease Granulomatous diseases:

○ Sarcoidosis, Crohn's disease, and granulomatous hepatitis.

Harrison’s 18th Ed.

Classic FUO in Adults

Harrison’s 18th Ed.

Classic FUO in Adults

Harrison’s 18th Ed.

Classic FUO in Adults Classic FUO in the elderly (>50 years):

Giant-cell arteritis is the leading etiologic entity in this category (15–20% of FUO cases)

Tuberculosis is the most common infection causing FUO in the elderly

Colon cancer is an important cause of FUO with malignancy in this age group.

Harrison’s 18th Ed.

Classic FUO in Adults Miscellaneous causes:

Drug feverPulmonary embolismFactitious feverThe hereditary periodic fever síndromes:

○ Familial Mediterranean fever○ Hyper-IgD syndrome, ○ TNF receptor–associated periodic syndrome (also known as TRAPS or

familial Hibernian fever)○ Familial cold urticaria○ Muckle-Wells síndrome

Congenital lysosomal storage diseases:○ Gaucher's and Fabry's disease.

Harrison’s 18th Ed.

Classic FUO in Adults

Harrison’s 18th Ed.

Classic FUO in Adults

Harrison’s 18th Ed.

Classic FUO in Adults

Harrison’s 18th Ed.

Classic FUO in Adults Drug-related etiology:

Virtually all classes of drugs can cause fever:○ Antimicrobial agents (b-lactam antibiotics)○ Cardiovascular drugs (quinidine)○ Antineoplastic drugs ○ Drugs acting on the central nervous system: phenytoin

Harrison’s 18th Ed.

Classic FUO in Adults It is axiomatic that, as the duration of fever

increases, the likelihood of an infectious cause decreases.

Harrison’s 18th Ed.

Approach to the patient with classic FUO

Abbreviations: ANA, antinuclear antibody; CBC, complete blood count; CMV, cytomegalovirus; CRP, C-reactive protein; CT, computed tomography; Diff, differential; EBV, Epstein-Barr virus; ESR, erythrocyte sedimentation rate; FDG, fluorodeoxyglucose F18; NSAIDs, nonsteroidal anti-inflammatory drugs; PET, positron emission tomography; PMN, polymorphonuclear leukocyte; PPD, purified protein derivative; RF, rheumatoid factor; SPEP, serum protein electrophoresis; TB, tuberculosis; TIBC, total iron-binding capacity; VDRL, Venereal Disease Research Laboratory test.

Harrison’s 18th Ed.

Nosocomial FUO More than 50% of patients with nosocomial FUO are infected:

Intravascular lines, septic phlebitis, and prostheses.

The best approach is to focus on sites where occult infections may be sequestered:

The sinuses of intubated patients or a prostatic abscess in a man with a urinary catheter.

Clostridium difficile colitis.

In <25% of patients the fever has a noninfectious cause: Acalculous cholecystitis, deep-vein thrombophlebitis, and pulmonary embolism.

Others: Drug fever, transfusion reactions, alcohol/drug withdrawal, adrenal insufficiency, thyroiditis, pancreatitis, gout.

Harrison’s 18th Ed.

Nosocomial FUO Multiple blood, wound, and fluid cultures are

mandatory.

20% of cases of nosocomial FUO may go undiagnosed.

In many hospital settings, empirical antibiotic therapy for nosocomial FUO now includes vancomycin for coverage of S. Aureus as well as broad-spectrum gram-negative coverage with piperacillin/tazobactam, ticarcillin/clavulanate, imipenem, or meropenem.

Harrison’s 18th Ed.

Neutropenic FUO Neutropenic patients are susceptible to focal bacterial and fungal infections:

Bacteremic infections, Infections involving catheters Perianal infections.

Candida and Aspergillus infections are common. Others: Herpes simplex virus or CMV

50–60% of febrile neutropenic patients are infected, and 20% are bacteremic.

The IDSA dictates the use of vancomycin plus ceftazidime, cefepime, or a carbapenem with or without an aminoglycoside to provide empirical coverage for bacterial sepsis

Harrison’s 18th Ed.

HIV-Associated FUO HIV infection alone may be a cause of fever.

Mycobacterium avium or M. intracellulare, tuberculosis, toxoplasmosis, CMV infection, Pneumocystis infection, salmonellosis, cryptococcosis, histoplasmosis, strongyloidiasis

Non-Hodgkin's lymphoma

Of particular importance drug fever are all possible causes of FUO.

Blood cultures and by liver, bone marrow, and lymph node biopsies. Chest CT should be performed to identify enlarged mediastinal nodes.

FUO has an infectious etiology in >80% of HIV-infected patients.

Harrison’s 18th Ed.