Definitions of fever of unknown origin

Fever is a common complaint of patients presenting to a doctor. The cause is usually immediately apparent or is discovered within a few days, or the temperature settles spontaneously. However, if the patient’s fever is > 38.3°C (101°F) on several occasions and continues for more than 3 weeks despite 1 week of intensive evaluation, a provisional diagnosis of ‘fever of unknown origin’ (FUO) is made based on the classic definition of FUO. However, an increasing number of patients with serious underlying diseases are successfully kept alive by modern medicine necessitating a revision in FUO terminology, especially with regard to particular patient risk groups (Table 29.1).

Table 29.1 Definitions of fever of unknown origin (FUO)

Definition	Symptoms	Diagnosis
Classical FUO	Fever (> 38.3°C) on several occasions and more than 3 weeks’ duration	Uncertain despite appropriate investigations after at least three outpatient visits or 3 days in hospital, including at least 2 days’ incubation of microbiologic cultures
Nosocomial (hospital-acquired) FUO	Fever (> 38.3°C) on several occasions in a hospitalized patient receiving acute care; infection not present or incubating on admission	Uncertain after 3 days despite appropriate investigations, including at least 2 days’ incubation of microbiologic cultures
Neutropenic FUO	Fever (> 38.3°C) on several occasions; neutrophil count < 500/mm³ in peripheral blood, or expected to fall below that number within 1–2 days	Uncertain after 3 days despite appropriate investigations, including at least 2 days’ incubation of microbiologic cultures
HIV-associated FUO	Fever (> 38.3°C) on several occasions; fever of more than 4 weeks’ duration as an outpatient or more than 3 days’ duration in hospital; confirmed positive HIV serology	Uncertain after 3 days despite appropriate investigations, including at least 2 days’ incubation of microbiologic cultures

The classic definition of FUO requires that the fever is of 3 or more weeks’ duration, but in compromised patients infections frequently progress rapidly because of inadequate host defences. Consequently, the pace of the investigations needs to be rapid if appropriate therapy is to be initiated.

Causes of FUO

Infection is the most common cause of FUO

For centuries, fever has been recognized as a characteristic sign of infection and, historically, infection has been the most common cause of FUO, especially in children. However, there are important non-infectious causes of fever, most notably:

• malignancies

• collagen-vascular diseases.

These non-infectious causes need to be differentiated from infections during the investigation of a patient with a FUO. Despite intense and prolonged investigations, the cause of fever remains undiagnosed in a significant number of patients. However, in the absence of significant weight loss or indication of severe underlying disease, the outcome, though potentially long term, is generally positive. The reported incidence of different FUO aetiologies has varied over time (Fig. 29.2) due in part to patient demographics and advances in medical diagnostics. One must also consider that patients may have a factitious fever (produced artificially by the patient, e.g. in Munchausen syndrome).

Figure 29.2 Causes of fever of unknown origin over time. Historically, infection has been the single most common cause but a significant number of fevers remained undiagnosed.

(Data from Mourand, O., Palda, V., Detsky, A.S. 2003. Arch. Intern. Med. 163: 545–555; Bleeker-Rovrs, C.P., Vos, F.J., de Kleijn E.M, Mudde, A.H., Dofferhoff, T.S., Richter, C., Smilde, T.J., Krabbe, P.F., Oyen, W.J., van der Meer, J.W. 2007. Medicine 86:26–38.)

Infective causes of classical FUO

The most common infective causes of classic FUO are shown in Table 29.2. These can be divided into two main groups:

• infections such as tuberculosis and typhoid fever caused by specific pathogens

• infections such as urinary tract infections, biliary tract infections and abscesses, which can be caused by a variety of different pathogens.

Table 29.2 Representative infective causes of fever of unknown origin (FUO)

Infection	Usual cause
Bacterial
Tuberculosis	Mycobacterium tuberculosis
Enteric fevers	Salmonella typhi
Osteomyelitic	Staphylococcus aureus (also Haemophilus influenzae in young children, Salmonella in patients with sickle-cell disease)
Endocarditis	Oral streptococci, Staph. aureus, coagulase-negative staphylococci
Brucellosis	Brucella abortus, B. melitensis and B. suis
Abscesses (esp. intra-abdominal)	Mixed anaerobes and facultative anaerobes from gut flora
Biliary system infections	Gram-negative facultative anaerobes, e.g. E. coli
Urinary tract infections	Gram-negative facultative anaerobes, e.g. E. coli
Lyme disease	Borrelia burgdorferi
Relapsing fever	Borrelia recurrentis
Leptospirosis	Leptospira interrogans serovar icterohaemorrhagiae
Rat bite fever	Spirillum minus (Spirillum minor)
Typhus	Rickettsia prowazekii
Spotted fever	Rickettsia rickettsii, Rickettsia conori
Psittacosis	Chlamydophila psittaci
Q fever	Coxiella burnetii
Parasitic
Malaria	Plasmodium species
Trypanosomiasis	Trypanosoma brucei
Amoebic abscesses	Entamoeba histolytica
Toxoplasmosis	Toxoplasma gondii
Fungal
Candidiasis	Candida albicans
Cryptococcosis	Cryptococcus neoformans
Histoplasmosis	Histoplasma capsulatum
Viral
AIDS	HIV
Infectious mononucleosis	Epstein–Barr virus, cytomegalovirus
Hepatitis	hepatitis viruses

A wide range of infections can present as FUO. Some, such as brucellosis, are zoonoses, and many are vector-borne. Therefore the patient must have had appropriate exposure to contract these infections. For example, there are about 2000 cases of malaria annually in the UK (ca.1300 in the USA), the overwhelming majority of which are contracted outside the country. A travel history is therefore very important.

Most of these infections are described in detail elsewhere in this book. Bacterial endocarditis is discussed below.

Significant infection may be present in the absence of fever in some groups of patients, notably: